FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bodmer, D Eleveld, M Kater-Baats, E Janssen, I Janssen, B Weterman, M Schoenmakers, E Nickerson, M Linehan, M Zbar, B van Kessel, AG AF Bodmer, D Eleveld, M Kater-Baats, E Janssen, I Janssen, B Weterman, M Schoenmakers, E Nickerson, M Linehan, M Zbar, B van Kessel, AG TI Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21) SO HUMAN MOLECULAR GENETICS LA English DT Article ID LUNG-CANCER; TUMOR-SUPPRESSOR; FHIT GENE; CHROMOSOME-TRANSLOCATION; HUMAN SEMAPHORIN; EXPRESSION; IDENTIFICATION; TRANSCRIPTS; REGION; SUPERFAMILY AB Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth. C1 Univ Med Ctr, Dept Human Genet, Nijmegen, Netherlands. NCI, Frederick Canc & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NIH, Urol Oncol Sect, Bethesda, MD 20892 USA. RP Bodmer, D (reprint author), Univ Med Ctr, Dept Human Genet, Nijmegen, Netherlands. RI Geurts van Kessel, Ad/A-2810-2010; Bodmer, D./L-4207-2015; Eleveld, Marc/J-9146-2016 NR 55 TC 28 Z9 29 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 MAR 15 PY 2002 VL 11 IS 6 BP 641 EP 649 DI 10.1093/hmg/11.6.641 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 535QC UT WOS:000174654300004 PM 11912179 ER PT J AU Kondrashov, AS Shabalina, SA AF Kondrashov, AS Shabalina, SA TI Classification of common conserved sequences in mammalian intergenic regions SO HUMAN MOLECULAR GENETICS LA English DT Article ID ZINC-FINGER PROTEIN; REGULATORY ELEMENTS; NONCODING SEQUENCES; BINDING-SITES; MOUSE GENOME; C-ELEGANS; GENE; DNA; ALIGNMENTS; TRANSCRIPTION AB Comparisons between orthologous intergenic regions of related genomes reveal numerous hits, i.e. pairs of relatively short highly similar sequences that evolved slowly, perhaps due to selective constraint. We analyzed and classified 2638 hits found within 100 pairs of complete, orthologous intergenic regions of human and murine genomes. We identified all common fragments of hits that align well with many other hits and constructed their classification. Our analysis revealed 20 abundant classes each containing 10 or more fragments. Fragments of the same class may perform the same function, e.g. bind a particular protein. Ten of the abundant classes apparently correspond to known functional consensuses, whereas others may represent novel conserved sites. Thus, large-scale comparative analysis of slowly evolving intergenic sequences can provide valuable insights into their function. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Shabalina, SA (reprint author), NIH, Natl Ctr Biotechnol Informat, 45 Ctr Dr, Bethesda, MD 20892 USA. RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 NR 33 TC 38 Z9 38 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 MAR 15 PY 2002 VL 11 IS 6 BP 669 EP 674 DI 10.1093/hmg/11.6.669 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 535QC UT WOS:000174654300007 PM 11912182 ER PT J AU Marchand, C Pourquier, P Laco, GS Jing, NJ Pommier, Y AF Marchand, C Pourquier, P Laco, GS Jing, NJ Pommier, Y TI Interaction of human nuclear topoisomerase I with guanosine quartet-forming and guanosine-rich single-stranded DNA and RNA oligonucleotides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TELOMERE-BINDING-PROTEIN; DIOL EPOXIDE ADDUCTS; NUCLEOTIDE-SEQUENCE; CLEAVAGE COMPLEXES; RAT HEPATOCYTES; ANTICANCER DRUG; TERMINAL DOMAIN; SPLICING FACTOR; QUADRUPLEX DNA; G4 DNA AB Human nuclear DNA topoisomerase I (top1) plays a crucial role in DNA replication, transcription, and chromosome condensation. In this study, we show that intra- and intermolecular guanosine quartets (G-quartets) can inhibit top1-mediated DNA cleavage at a high affinity site. Top1-mediated DNA cleavage was also inhibited by a 16-mer single-stranded oligodeoxynucleotide (ODN) containing a G-rich sequence (G(2)T(2)G(5)TG(2)TG(3)) and by its RNA equivalent, neither of which form G-quartet structures. A comparison of various single-stranded ODN for their ability to inhibit top1-mediated DNA cleavage indicated that G-rich sequences containing repeats of 2 or 3 consecutive guanines interspaced with thymines specifically inhibited top1. We also found that both single-stranded and G-quartet-forming ODNs bind to top1 without being cleaved by the enzyme. These results demonstrate that either DNA or RNA G-rich single-stranded and G-quartet-forming oligonucleotides can bind to top1 and prevent cleavage of duplex DNA. C1 NIH, Mol Pharmacol Lab, Canc Res Ctr, NCI, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Med, Infect Dis Sect, Houston, TX 77030 USA. RP Pommier, Y (reprint author), NIH, Mol Pharmacol Lab, Canc Res Ctr, NCI, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. RI Marchand, Christophe/D-8559-2016 NR 65 TC 32 Z9 34 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 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2002 VL 277 IS 11 BP 8906 EP 8911 DI 10.1074/jbc.M106372200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531DK UT WOS:000174400600024 PM 11756434 ER PT J AU Le Stunff, H Peterson, C Thornton, R Milstien, S Mandala, SM Spiegel, S AF Le Stunff, H Peterson, C Thornton, R Milstien, S Mandala, SM Spiegel, S TI Characterization of murine sphingosine-1-phosphate phosphohydrolase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; SPHINGOLIPID METABOLISM; CELL-GROWTH; SPHINGOSINE; PHOSPHATASE; IDENTIFICATION; APOPTOSIS; RECEPTOR; ACTIVATION; REGULATOR AB In the present study we have characterized mammalian sphingosine-1-phosphate phosphohydrolase (SPP1), an enzyme that specifically dephosphorylates sphingosine 1-phosphate (SIP) and which differs from previously described lipid phosphate phosphohydrolases. Based on sequence homology to murine SPP1, we cloned the human homolog. Transfection of human embryonic kidney 293 and Chinese hamster ovary cells with murine or human SPP1 resulted in marked increases in SPP1 activity in membrane fractions that were used to examine its enzymological properties. Unlike other known type 2 lipid phosphate phosphohydrolases (LPPs), but similar to the yeast orthologs, mammalian SPP1s are highly specific toward long chain sphingoid base phosphates and degrade SIP, dihydro-SIP, and phyto-S1P. SPP1 exhibited apparent Michaelis-Menten kinetics with SIP as substrate with an apparent K-m of 38.5 mum and optimum activity at pH 7.5. Similar to other LPPs, SPP1 activity was also independent of any cation requirements, including Mg2+, and was not inhibited by EDTA but was markedly inhibited by NaF and Zn2+. However, SPP1 has some significantly different enzymological properties than the LPPs: the aliphatic cation propanolol, which is an effective inhibitor of type 1 phosphatidate phosphohydrolase activities and is only modestly effective as an inhibitor of LPPs, is a potent inhibitor of SPP1; the activity was partially sensitive to N-ethylmaleimide but not to the thioreactive compound iodoacetamide; and importantly, low concentrations of Triton X-100 and other non-ionic detergents were strongly inhibitory. Thus, in agreement with Cluster analysis which shows that outside of the consensus motif there is very little homology between SPP1s and the other type 2 lipid phosphohydrolases, SPP1s are significantly different and divergent from the mammalian LPPs. C1 Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Merck Res Labs, Rahway, NJ 07065 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem, Med Coll Virginia Campus,1101 E Marshall St,Rm 2-0, Richmond, VA 23298 USA. FU NIGMS NIH HHS [GM43880] NR 39 TC 57 Z9 58 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2002 VL 277 IS 11 BP 8920 EP 8927 DI 10.1074/jbc.M109968200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531DK UT WOS:000174400600026 PM 11756451 ER PT J AU Bies, J Markus, J Wolff, L AF Bies, J Markus, J Wolff, L TI Covalent attachment of the SUMO-1 protein to the negative regulatory domain of the c-Myb transcription factor modifies its stability and transactivation capacity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN-LIKE PROTEIN; NUCLEAR-PORE COMPLEX; GTPASE-ACTIVATING PROTEIN; DNA-BINDING; PHOSPHORYLATION SITE; V-MYB; ONCOGENIC ACTIVATION; NF-M; TRANSFORMATION; RANGAP1 AB The transcription factor c-Myb is subject to several types of post-translational modifications, including phosphorylation, acetylation, and ubiquitination. These modifications regulate the transcription and transforming activity as well as the proteolytic stability of c-Myb. Here we report the covalent modification of c-Myb with the small ubiquitin-related protein SUMO-1. Mutational analysis identified two major sumolation sites (Lys(499) and Lys(523)) in the negative regulatory domain. Interestingly, the single mutation K523R completely abolished modification of c-Myb with SUMO-1, suggesting that sumolation of Lys(523) is required for modification of other lysines in c-Myb. In accordance with this observation, we found that the SUMO-1-conjugating enzyme Ubc9 interacted only with a region surrounding Lys(523) (also called the PEST/EVES motif). Experiments aimed at determining the proteolytic stability of sumolated and unmodified forms of c-Myb, revealed that at least two covalently attached SUMO-1 molecules dramatically increased the stability of c-Myb. However, mutations of the SUMO-1 modification sites did not alter its stability, suggesting that a mechanism(s) other than competition of ubiquitin and SUMO-1 for the same lysine is involved in the stabilization of sumolated c-Myb protein. Finally, the K523R mutant of c-Myb, entirely deficient in sumolation, was shown to have an increased transactivation capacity on a Myb-responsive promoter, suggesting that SUMO-1 negatively regulates the transactivation function of c-Myb. Thus, modification of c-Myb with SUMO-1 represents a novel mechanism through which the negative regulatory domain can exert its suppressing activity on c-Myb transactivation capacity. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. Slovak Acad Sci, Canc Res Inst, Dept Mol Virol, Bratislava 83391, Slovakia. RP Bies, J (reprint author), NCI, Cellular Oncol Lab, NIH, 37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. NR 59 TC 134 Z9 136 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2002 VL 277 IS 11 BP 8999 EP 9009 DI 10.1074/jbc.M110453200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531DK UT WOS:000174400600036 PM 11779867 ER PT J AU Maurady, A Zdanov, A de Moissac, D Beaudry, D Sygusch, J AF Maurady, A Zdanov, A de Moissac, D Beaudry, D Sygusch, J TI A conserved glutamate residue exhibits multifunctional catalytic roles in D-fructose-1,6-bisphosphate aldolases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RABBIT MUSCLE ALDOLASE; FRUCTOSE BISPHOSPHATE ALDOLASE; ELECTRON-DENSITY MAPS; CRYSTAL-STRUCTURE; FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE; ACTIVE-SITE; ACETOACETATE DECARBOXYLASE; TERMINAL REGION; REFINEMENT; RESOLUTION AB The aldolase catalytic cycle consists of a number of proton transfers that interconvert covalent enzyme intermediates. Glu-1137 is a conserved amino acid that is located in the mammalian fructose-1,6-bisphosphate aldolase active site. Its central location, within hydrogen bonding distance of three other conserved active site residues: Lys-146, Glu-189, and Schiff base-forming Lys-229, makes it an ideal candidate for mediating proton transfers. Point mutations, Glu-187 --> Gln, Ala, which would inhibit proton transfers significantly, compromise activity. Trapping of enzymatic intermediates in Glu-187 mutants defines a proton transfer role for Glu-187 in substrate cleavage and Schiff base formation. Structural data show that loss of Glu-187 negative charge results in hydrogen bond formation between Lys-146 and Lys-229 consistent with a basic pK(a) for Lys229 in native enzyme and supporting nucleophilic activation of Lys-229 by Glu-187 during Schiff base formation. The crystal structures also substantiate Glu-187 and Glu-189 as present in ionized form in native enzyme, compatible with their role of catalyzing proton exchange with solvent as indicated from solvent isotope effects. The proton exchange mechanism ensures Glu-187 basicity throughout the catalytic cycle requisite for mediating proton transfer and electrostatic stabilization of ketamine intermediates. Glutamate general base catalysis is a recurrent evolutionary feature of Schiff base-forming aldolases. C1 Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Univ Sherbrooke, Dept Biochem, Fleurimont, PQ J1H 5N4, Canada. RP Sygusch, J (reprint author), Univ Montreal, Dept Biochem, CP 6128,Stn Ctr Ville, Montreal, PQ H3C 3J7, Canada. NR 53 TC 32 Z9 33 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2002 VL 277 IS 11 BP 9474 EP 9483 DI 10.1074/jbc.M107600200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531DK UT WOS:000174400600099 PM 11779856 ER PT J AU Lai, WS Kennington, EA Blackshear, PJ AF Lai, WS Kennington, EA Blackshear, PJ TI Interactions of CCCH zinc finger proteins with mRNA - Non-binding tristetraprolin mutants exert an inhibitory effect on degradation of Au-rich element-containing mRNAs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA; NUCLEOTIDE-SEQUENCE; C-ELEGANS; GENE; DEADENYLATION; EXPRESSION; FAMILY; ALPHA; TIS11; DESTABILIZATION AB Tristetraprolin (TTP), the prototype of a small family of CCCH tandem zinc finger (TZF) domain proteins, is a physiological stimulator of instability of the mRNAs encoding tumor necrosis factor-a and granulocyte/macrophage colony-stimulating factor in certain cell types. TTP stimulates mRNA turnover after binding to class II AU-rich elements (AREs) within the X-untranslated regions of both mRNAs. In turn, this binding is dependent upon the key CCCH residues in the TZF domain. To evaluate other primary sequence requirements for ARE binding in this novel mRNA-binding domain, we mutated many of the conserved residues within the TZF domain of human TTP and evaluated the effects of these mutations on RNA binding in a cell-free system and TTP-induced mRNA instability in cell transfection experiments. These mutations revealed a number of conserved amino acids that were required for binding and begin to define the primary protein sequence requirements for this novel mRNA-binding motif. Unexpectedly, all of the point mutations that prevented TTP binding to RNA also caused an increase in steady-state levels of ARE-containing mRNAs in cell transfection experiments. Actinomycin D experiments suggested that this effect was due to inhibition of mRNA turnover. Although expression of the mutant form of TTP could also inhibit the destruction of tumor necrosis factor-a mRNA by wild-type TTP, the primary mechanism did not involve heterodimerization with wild-type TTP because the 293 cells used in these studies express no detectable endogenous TTP. These data suggest that TTP may act, at least in part, by physically interacting with an enzyme activity or protein complex and functionally stimulating its ability to deadenylate class II ARE-containing mRNAs. C1 NIEHS, NIH, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, NIH, Off Clin Res, POB 12233,A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 26 TC 102 Z9 103 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2002 VL 277 IS 11 BP 9606 EP 9613 DI 10.1074/jvc.M110395200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531DK UT WOS:000174400600114 PM 11782475 ER PT J AU Urba, WJ Alvord, WG AF Urba, WJ Alvord, WG TI Are all hypotheses generated before data analysis prospective? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID METASTATIC MELANOMA; THERAPY; CANCER C1 Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR 97213 USA. NCI, Data Management Serv Inc, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Urba, WJ (reprint author), Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR 97213 USA. NR 6 TC 4 Z9 4 U1 0 U2 0 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 2002 VL 20 IS 6 BP 1431 EP 1433 PG 3 WC Oncology SC Oncology GA 534QF UT WOS:000174597100001 PM 11896085 ER PT J AU Mason, N Aliberti, J Caamano, JC Liou, HC Hunter, CA AF Mason, N Aliberti, J Caamano, JC Liou, HC Hunter, CA TI Cutting edge: Identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; TOLL-LIKE RECEPTORS; TOXOPLASMA-GONDII; IFN-GAMMA; INTRACELLULAR PARASITE; ADAPTIVE IMMUNITY; DENDRITIC CELLS; P40 EXPRESSION; INTERLEUKIN-12; INDUCTION AB The production of IL-12 is required for immunity to many intracellular pathogens. Recent studies have shown that c-Rel, a member of the NF-kB family of transcription factors, is essential for LPS-induced IL-12p40 production by macrophages. In this study, we demonstrate that c-Rel is also required for IL-12p40 production by macrophages in response to Cotyne-bacterium parvum, CpG oligodeoxynucleotides, anti-CD40 and low molecular weight hyaluronic acid. However, c-Rel(-/-) mice infected with Toxoplasma gondii produce comparable amounts of IL-12p40 to infected wild-type mice and have an IL-12-dependent mechanism of resistance to this infection. Furthermore, c-Rel was not required for IL-12p40 production by macrophages or dendritic cells in response to soluble Toxoplasma Ag, and neutrophils from c-Rel(-/-) mice contain normal amounts of preformed IL-12p40. Together these studies reveal the presence of c-Rel-dependent pathways critical for IL12p40 production in response to inflammatory stimuli and demonstrate a novel c-Rel-independent pathway of IL-12p40 production during toxoplasmosis. C1 Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Birmingham, Sch Med, MRC, Ctr Immune Regulat, Birmingham, W Midlands, England. Cornell Univ, Coll Med, Cornell Div Immunol, Dept Med, New York, NY 10021 USA. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, 3800 Spruce St, Philadelphia, PA 19104 USA. RI Hunter, Christopher/H-1970-2011; Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013; Caamano, Jorge/I-6778-2012 OI Aliberti, Julio/0000-0003-3420-8478; Caamano, Jorge/0000-0003-3530-7056 FU NIAID NIH HHS [AI 46288] NR 36 TC 77 Z9 78 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2002 VL 168 IS 6 BP 2590 EP 2594 PG 5 WC Immunology SC Immunology GA 529BP UT WOS:000174280400002 PM 11884420 ER PT J AU Zaitseva, M Kawamura, T Loomis, R Goldstein, H Blauvelt, A Golding, H AF Zaitseva, M Kawamura, T Loomis, R Goldstein, H Blauvelt, A Golding, H TI Stromal-derived factor 1 expression in the human thymus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; MEDULLARY EPITHELIAL-CELLS; SCID-HU MOUSE; DENDRITIC CELLS; NEGATIVE SELECTION; HUMAN THYMOCYTES; APOPTOTIC CELLS; HIV-1 INFECTION; BONE-MARROW; EBI1-LIGAND CHEMOKINE AB Stromal-derived factor-1 (SDF-1), the only known ligand for the chemokine receptor CXCR4, is broadly expressed in cells of both the immune and central nervous systems, and it can induce the migration of resting leukocytes and hemopoletic progenitors. SDF-1 mRNA was previously detected in human thymus-derived stromal cells, but its role in thymopoiesis was unknown. Here we show that SDF-1 is expressed in medullar epithelial cells forming Hassall's corpuscles (HQ). In search of the cell type that may be attracted by SDF-1(+) cells in the medulla, we determined that dendritic cells (DC) could be found in situ in close proximity to SDF-1(+) epithelial cells in HC. In HIV-1-infected SCID-hu thymuses, DC contained apoptotic cells and were located within enlarged HC. It was further demonstrated that uptake of apoptotic thymocytes by immature DC induced an increase in CXCR4 expression and SDF-1-mediated chemotaxis. Our data suggest a role for SDF-1 in the elimination of apoptotic thymocytes. C1 US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Zaitseva, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bldg 29B,Room 3G21,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 45 TC 35 Z9 36 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 MAR 15 PY 2002 VL 168 IS 6 BP 2609 EP 2617 PG 9 WC Immunology SC Immunology GA 529BP UT WOS:000174280400006 PM 11884424 ER PT J AU Williams, JA Sharrow, SO Adams, AJ Hodes, RJ AF Williams, JA Sharrow, SO Adams, AJ Hodes, RJ TI CD40 ligand functions non-cell autonomously to promote deletion of self-reactive thymocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NEGATIVE SELECTION; DENDRITIC CELLS; THYMIC SELECTION; EPITHELIAL-CELLS; IN-VIVO; B-CELLS; ACTIVATION; EXPRESSION; RESPONSES; RECEPTOR AB CD40 ligand (CD40L) -deficient mice have been shown to have a defect in negative selection of self-reactive T cells during thymic development. However, the mechanism by which CD40L promotes deletion of autoreactive thymocytes has not yet been elucidated. We have studied negative selection in response to endogenous superantigens in CD40L-deficient mice and, consistent with previous reports, have found a defect in negative selection in these mice. To test the requirement for expression of CD40L on T cells undergoing negative selection, we have generated chimeric mice in which CD40L wild-type and CD40L-deficient thymocytes coexist. We find I hat both CD40L wild-type and CD40L-deficient thymocytes undergo equivalent and efficient negative selection when these populations coexist in chimeric mice. These results indicate that CD40L can function in a non-cell-autonomous manner during negative selection. Deletion of superantigen-reactive thymocytes was normal in B7-1/B7-2 double-knockout mice, indicating that CD40-CD40L-dependent negative selection is not solely mediated by B7 up-regulation and facilitation of B7-dependent T cell signaling. Finally, although the absence of CD40-CD40L interactions impairs negative selection of autoreactive CD4(+) and CD8(+) cells during thymic development, we find that self-reactive T cells are deleted in the mature CD4(+) population through a CD40L-independent pathway. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Williams, JA (reprint author), NCI, Expt Immunol Branch, NIH, 10 Ctr Dr,Room 4B-10, Bethesda, MD 20892 USA. NR 28 TC 24 Z9 24 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 2002 VL 168 IS 6 BP 2759 EP 2765 PG 7 WC Immunology SC Immunology GA 529BP UT WOS:000174280400025 PM 11884443 ER PT J AU Uehara, S Grinberg, A Farber, JM Love, PE AF Uehara, S Grinberg, A Farber, JM Love, PE TI A role for CCR9 in T lymphocyte development and migration SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMUS-EXPRESSED CHEMOKINE; RECEPTOR TRANSGENIC MICE; MUCOSAL IMMUNE-SYSTEM; MURINE BONE-MARROW; INTRAEPITHELIAL LYMPHOCYTES; CELL DEVELOPMENT; REGIONAL SPECIALIZATION; CUTTING EDGE; TECK; DIFFERENTIATION AB CCR9 mediates chemotaxis in response to CCL25/thymus-expressed chemokine and is selectively expressed on T cells in the thymus and small intestine. To investigate the role of CCR9 in T cell development, the CCR9 gene was disrupted by homologous recombination. B cell development, thymic alphabeta-T cell development, and thymocyte selection appeared unimpaired in adult CCR9-deficient (CCR9(-/-)) mice. However, competitive transplantation experiments revealed that bone marrow from CCR9(-/-) mice was less efficient at repopulating the thymus of lethally irradiated Rag-1(-/-) mice than bone marrow from littermate CCR9(+/+) mice. CCR9(-/-) mice had increased numbers of peripheral gammadelta-T cells but reduced numbers of gammadeltaTCR(+) and CD8alphabeta(+)alphabetaTCR(+) intraepithelial lymphocytes in the small intestine. Thus, CCR9 plays an important, although not indispensable, role in regulating the development and/or migration of both alphabeta(-) and gammadelta(-) T lymphocytes. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 48 TC 178 Z9 186 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 2002 VL 168 IS 6 BP 2811 EP 2819 PG 9 WC Immunology SC Immunology GA 529BP UT WOS:000174280400032 PM 11884450 ER PT J AU Durbin, JE Johnson, TR Durbin, RK Mertz, SE Morotti, RA Peebles, RS Graham, BS AF Durbin, JE Johnson, TR Durbin, RK Mertz, SE Morotti, RA Peebles, RS Graham, BS TI The role of IFN in respiratory syncytial virus pathogenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERLEUKIN-8 GENE-EXPRESSION; INTERFERON-GAMMA; T-CELLS; TARGETED DISRUPTION; RSV CHALLENGE; BALB/C MICE; TRANSCRIPTIONAL INHIBITION; TISSUE EOSINOPHILIA; EPITHELIAL-CELLS; HUMAN MONOCYTES AB Formalin-inactivated respiratory syncytial virus (RSV) vaccine preparations have been shown to cause enhanced disease in naive hosts following natural infection. In this study we demonstrate a similar pattern of enhanced disease severity following primary RSV infection of IFN-nonresponsive STAT1(-/-) mice. STAT1(-/-) mice showed markedly increased illness compared with wildtype BALB/c animals following RSV inoculation despite similar lung virus titers and rates of virus clearance. Histologically, STAT1(-/-) animals had eosinophilic and neutrophilic pulmonary infiltrates not present in wild-type or IFN-gamma(-/-)-infected mice. In cytokine analyses of infected lung tissue, IFN-gamma was induced in both STAT1(-/-) and wild-type mice, with preferential IL-4, IL-5, and IL-13 induction only in the STAT1(-/-) animals. Eotaxin was detected in the lungs of both wild-type and STAT1(-/-) mice following infection, with a 1.7-fold increase over wild-type in the STAT1(-/-) mice. Using a peptide epitope newly identified in the RSV fusion protein, we were able to demonstrate that wild-type memory CD4(+) T cells stimulated by this peptide produce primarily IFN-gamma, while STAT1(-/-)CD4(+) cells produce primarily IL-13. These findings suggest that STAT1 activation by both type I (alphabeta) and type II (gamma) IFNs plays an important role in establishing a protective, Th1 Ag-specific immune response to RSV infection. C1 Childrens Hosp, Childrens Res Inst, Wexner Inst Pediat Res, Columbus, OH 43205 USA. Ohio State Univ, Div Pediat Pathol, Dept Pediat, Coll Med & Publ Hlth, Columbus, OH 43210 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Durbin, JE (reprint author), Childrens Hosp, Childrens Res Inst, Wexner Inst Pediat Res, Room 411,700 Childrens Dr, Columbus, OH 43205 USA. FU NIAID NIH HHS [R01-AI-33933, R01-AI-47226]; NICHD NIH HHS [P30-HD-34615] NR 70 TC 127 Z9 128 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 2002 VL 168 IS 6 BP 2944 EP 2952 PG 9 WC Immunology SC Immunology GA 529BP UT WOS:000174280400048 PM 11884466 ER PT J AU Douek, DC Betts, MR Brenchley, JM Hill, BJ Ambrozak, DR Ngai, KL Karandikar, NJ Casazza, JP Koup, RA AF Douek, DC Betts, MR Brenchley, JM Hill, BJ Ambrozak, DR Ngai, KL Karandikar, NJ Casazza, JP Koup, RA TI A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T cell responses reveals a potential mechanism for control of viral escape SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE CLONES; IN-VIVO; FINE SPECIFICITY; INFECTION; VARIANTS; USAGE; IMMUNODOMINANCE; EXPANSIONS; REPERTOIRE; SELECTION AB Escape from the CD8(+) T cell response through epitope mutations can lead to loss of immune control of HIV replication. Theoretically, escape from CD8(+) T cell recognition is less likely when multiple TCRs target individual MHC/peptide complexes, thereby increasing the chance that amino acid changes in the epitope could be tolerated. We studied the CD8(+) T cell response to six immunodominant epitopes in five HIV-infected subjects using a novel approach combining peptide stimulation, cell surface cytokine capture, flow cytometric sorting, anchored RT-PCR, and real-time quantitative clonotypic TCR tracking. We found marked variability in the number of clonotypes targeting individual epitopes. One subject recognized a single epitope with six clonotypes, most of which were able to recognize and lyse cells expressing a major epitope variant that arose. Additionally, multiple clonotypes remained expanded during the course of infection, irrespective of epitope variant frequency. Thus, CD8(+) T cells comprising multiple TCR clonotypes may expand in vivo in response to individual epitopes, and may increase the ability of the response to recognize virus escape mutants. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, Dept Expt Transplantat & Immunol, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Mega Bases Inc, Evanston, IL 60201 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. RP Douek, DC (reprint author), NIAID, Vaccine Res Ctr, NIH, Room 3509,40 Convent Dr, Bethesda, MD 20892 USA. NR 33 TC 159 Z9 163 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 2002 VL 168 IS 6 BP 3099 EP 3104 PG 6 WC Immunology SC Immunology GA 529BP UT WOS:000174280400066 PM 11884484 ER PT J AU Keiser, PB Reynolds, SM Awadzi, K Ottesen, EA Taylor, MJ Nutman, TB AF Keiser, PB Reynolds, SM Awadzi, K Ottesen, EA Taylor, MJ Nutman, TB TI Bacterial endosymbionts of Onchocerca volvulus in the pathogenesis of posttreatment reactions SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ADVERSE REACTIONS; LYMPHATIC FILARIASIS; MAZZOTTI REACTION; IVERMECTIN; DIETHYLCARBAMAZINE; CALPROTECTIN; PROTEIN; SEVERITY; INTERLEUKIN-6; CHEMOTHERAPY AB Treatment of onchocerciasis with diethylcarbamazine (DEC) or ivermectin is associated with a posttreatment reaction characterized by fever, tachycardia, hypotension, lymphadenopathy, and pruritus. To investigate the role of the Wolbachia bacterial endosymbiont of Onchocerca volvulus in these reactions, serum samples collected before and after treatment with either anthelmintic were assessed for evidence of Wolbachia DNA. By use of real-time quantitative polymerase chain reaction, Wolbachia DNA was detected in both groups-with significantly higher levels in those who received DEC(P<.0001). In the ivermectin group, there was a significant correlation between levels of bacterial DNA and serum tumor necrosis factor-α (P=.013). Peak DNA levels correlated with reaction scores (P=.048). Significant correlations were also seen between Wolbachia DNA and the antibacterial peptides calprotectin (P=.021) and calgranulin B (P<.0001). These findings support a role for Wolbachia products in mediating the inflammatory responses seen following treatment of onchocerciasis and suggest new targets for modulating these reactions. C1 NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Onchocerciasis Chemotherapy Res Ctr, Hohoe, Ghana. Emory Univ, Dept Int Hlth, Atlanta, GA 30322 USA. Univ Liverpool, Liverpool Sch Trop Med, Div Mol Biol & Immunol, Cellular Immunol Lab, Liverpool L3 5QA, Merseyside, England. RP Keiser, PB (reprint author), NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. OI Taylor, Mark/0000-0003-3396-9275 NR 30 TC 72 Z9 74 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2002 VL 185 IS 6 BP 805 EP 811 DI 10.1086/339344 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 527WD UT WOS:000174210200011 PM 11920298 ER PT J AU Leipe, DD Wolf, YI Koonin, EV Aravind, L AF Leipe, DD Wolf, YI Koonin, EV Aravind, L TI Classification and evolution of P-loop GTPases and related ATPases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE molecular evolution; LUCA; GTPase; TRAFAC; SIMIBI ID GTP-BINDING PROTEIN; CHROMOSOME PARTITIONING PROTEINS; SIGNAL RECOGNITION PARTICLE; ELONGATION-FACTOR SELB; CELL-CYCLE CONTROL; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; NUCLEOTIDE-BINDING; SACCHAROMYCES-CEREVISIAE; BACILLUS-SUBTILIS AB Sequences and available structures were compared for all the widely distributed representatives of the P-loop GTPases and GTPase-related proteins with the aim of constructing an evolutionary classification for this superclass of proteins and, reconstructing the principal events in their evolution. The GTPase superclass can be divided into two large classes, each of which has a unique set of sequence and structural signatures (synapomorphies). The first class, designated TRAFAC (after translation factors) includes enzymes involved in translation (initiation, elongation, and release factors), signal transduction (in particular, the extended Ras- like family), cell motility, and intracellular transport. The second class, designated SIMIBI (after signal recognition particle, MinD, and BioD), consists of signal recognition particle (SRP) GTPases, the assemblage of MinD-like ATPases, which are involved in protein localization, chromosome partitioning, and membrane transport, and a group of metabolic enzymes with kinase or related phosphate transferase activity. These two classes together contain over 20 distinct families that are further subdivided into 57 subfamilies (ancient lineages) on the basis of conserved sequence motifs, shared structural features, and domain architectures. Ten subfamilies show a universal phyletic distribution compatible with presence in the last universal common ancestor of the extant life forms (LUCA). These include four translation factors, two OBG-like GTPases, the YawG/YlqF-like GTPases (these two subfamilies also:consist of predicted translation factors), the two signal-recognition-associated GTPases, and the DARP subfamily of MinD-like ATPases. The distribution of nucleotide specificity among the proteins of the GTPase superclass indicates that the common ancestor of the entire superclass was a GTPase and that a secondary switch to ATPase activity has occurred on several independent occasions during evolution. The functions of most GTPases that are traceable to LUCA are associated with translation. However, in contrast to other superclasses of P-loop NTPases (RecA-F1/F0, AAA +, helicases, ABC), GTPases do not participate in NTP-dependent nucleic acid unwinding and reorganizing activities. Hence, we hypothesize that the ancestral GTPase was an enzyme with a generic regulatory role in translation, with subsequent diversification resulting in acquisition of diverse functions in transport, protein trafficking, and. signaling. In addition to the classification of previously known families of GTPases and related ATPases, we introduce several previously undetected families and describe new functional predictions. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 191 TC 593 Z9 602 U1 2 U2 43 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 15 PY 2002 VL 317 IS 1 BP 41 EP 72 DI 10.1006/jmbi.2001.5378 PG 32 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 534WT UT WOS:000174613300003 PM 11916378 ER PT J AU Chang, CS Newton, DL Rybak, SM Wlodawer, A AF Chang, CS Newton, DL Rybak, SM Wlodawer, A TI Crystallographic and functional studies of a modified form of eosinophil-derive neurotoxin (EDN) with novel biological activities SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE crystal structure; atomic resolution; cytotoxic ribonuclease; Kaposi sarcoma; active site ID RESOLUTION CRYSTAL-STRUCTURE; RIBONUCLEASE-A; KAPOSIS-SARCOMA; NONSECRETORY RIBONUCLEASE; CYTOTOXIC RIBONUCLEASES; PREGNANT-WOMEN; CELL-LINE; MOLSCRIPT; COMPLEX; PROGRAM AB The crystal structure of a post-translationally modified form of eosinophil-derived neurotoxin (EDN) with four extra residues on its N terminus ((-4)EDN) has been solved and refined at atomic resolution (1 A). Two of the extra residues can be placed unambiguously, while the density corresponding to two others is poor. The modified N terminus appears to influence the position of the catalytically important His129, possibly explaining the diminished catalytic activity of this variant. However, (-4)EDN has been shown to be cytotoxic to a Kaposi's sarcoma tumor cell line and other endothelial cell lines. Analysis of the structure and function suggests that the reason for cytotoxicity is most likely due to cellular recognition by the N-terminal extension, since the intrinsic activity of the enzyme is not sufficient for cytotoxicity and the N-terminal extension does not affect the conformation of EDN. C1 NCI, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. NCI, SAIC Frederick, Frederick, MD USA. NCI, Dev Therapeut Program, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01 CO 56000] NR 42 TC 9 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 15 PY 2002 VL 317 IS 1 BP 119 EP 130 DI 10.1006/jmbi.2001.5406 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 534WT UT WOS:000174613300008 PM 11916383 ER PT J AU Chen, S Diamond, JS AF Chen, S Diamond, JS TI Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina SO JOURNAL OF NEUROSCIENCE LA English DT Article DE rat; retina; ganglion cell; low-affinity antagonist; glutamate transporter; spillover ID AMINO-ACID RECEPTORS; TIME-COURSE; MULTIVESICULAR RELEASE; EXCITATORY SYNAPSES; HIPPOCAMPAL SLICES; SILENT SYNAPSES; BIPOLAR CELLS; NEURONS; CURRENTS; TRANSPORTERS AB NMDA and AMPA receptors (NMDARs and AMPARs) are colocalized at most excitatory synapses in the CNS. Consequently, both receptor types are activated by a single quantum of transmitter and contribute to miniature and evoked EPSCs. However, in amphibian retina, miniature EPSCs in ganglion cell layer neurons are mediated solely by AMPARs, although both NMDARs and AMPARs are activated during evoked EPSCs. One explanation for this discrepancy is that NMDARs are located outside of the synaptic cleft and are activated only when extrasynaptic glutamate levels increase during coincident release from multiple synapses. Alternatively, NMDARs may be segregated at synapses that either are not spontaneously active or yield miniature EPSCs that are too small to detect. In this study, we examined excitatory, glutamatergic synaptic inputs to neurons in the ganglion cell layer of acute slices of rat retina. EPSCs, elicited by electrically stimulating presynaptic bipolar cells, exhibited both NMDAR- and AMPAR-mediated components. However, spontaneous EPSCs exhibited only an AMPAR-mediated component. The effects of low-affinity, competitive receptor antagonists indicated that NMDARs encounter less glutamate than AMPARs during an evoked synaptic response. Reducing glutamate uptake or changing the probability of release preferentially affected the NMDAR component in evoked EPSCs; reducing uptake revealed an NMDAR component in spontaneous EPSCs. These results indicate that NMDARs are located extrasynaptically and that glutamate transporters prevent NMDAR activation by a transmitter released from a single vesicle and limit their activation during evoked responses. C1 NINCDS, Synapt Physiol Unit, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), NINCDS, Synapt Physiol Unit, NIH, Bldg 36,Room 2C09,36 Convent Dr, Bethesda, MD 20892 USA. RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 NR 50 TC 121 Z9 129 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 15 PY 2002 VL 22 IS 6 BP 2165 EP 2173 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 530VP UT WOS:000174379900016 PM 11896156 ER PT J AU Sato, M Hikosaka, O AF Sato, M Hikosaka, O TI Role of primate substantia nigra pars reticulata in reward-oriented saccadic eye movement SO JOURNAL OF NEUROSCIENCE LA English DT Article DE basal ganglia; monkey; single-unit recording; memory-guided saccade; motivation; reward expectation ID MONKEY CAUDATE NEURONS; BASAL GANGLIA; FUNCTIONAL-PROPERTIES; OCULOMOTOR FUNCTIONS; AUDITORY RESPONSES; NUCLEUS; RAT; STIMULATION; MODULATION; EXPECTATION AB To test the hypothesis that the basal ganglia are related to reward-oriented saccades, we examined activity of substantia nigra pars reticulata (SNr) neurons by using a one-direction-rewarded version of the memory-guided saccade task (1DR). Many SNr neurons changed (decreased or increased) their activity after and before a visual cue (post-cue and pre-cue activity). Post-cue decreases or increases tended to be larger to a contralateral cue. They were often modulated prospectively by the presence or absence of reward, either positively (enhanced in the rewarded condition) or negatively (enhanced in the nonrewarded condition). The positive reward modulation was more common among decreasing type neurons, whereas no such preference was observed among increasing type neurons. The reward-contingent decrease in SNr neuronal activity would facilitate rewarded saccades by inducing disinhibition in superior colliculus (SC) neurons. In contrast, the increase in SNr activity would suppress a saccade less selectively (rewarded or nonrewarded) by augmenting inhibition of SC neurons. The post-cue activity was often preceded by anticipatory pre-cue activity. Most typically, post-cue decrease was preceded by pre-cue decrease, selectively when the contralateral side was rewarded. This would reinforce the reward-oriented nature of SNr neuronal activity. The decreases and increases in SNr activity may be derived directly and indirectly, respectively, from the caudate (CD), where neurons show reward-contingent pre-cue and post-cue activity. These results suggest that the CDSNr-SC mechanism would promote saccades oriented to reward. C1 Juntendo Univ, Sch Med, Dept Physiol, Tokyo 1138421, Japan. Juntendo Univ, Sch Med, Dept Neurosurg, Tokyo 1138421, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50, Bethesda, MD 20892 USA. EM oh@lsr.nei.nih.gov NR 39 TC 104 Z9 106 U1 2 U2 8 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 MAR 15 PY 2002 VL 22 IS 6 BP 2363 EP 2373 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 530VP UT WOS:000174379900035 PM 11896175 ER PT J AU Clay, JR Kuzirian, A AF Clay, JR Kuzirian, A TI Trafficking of axonal K+ channels: Potential role of Hsc70 SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE squid axons; ion channels; kinesin; nerve ID SQUID GIANT-AXON; EXTRUDED AXOPLASM; LOLIGO-PEALEI; TRANSPORT; LOCALIZATION; VESICLES; KINESIN; ORGANELLES; PROTEINS; NEURONS AB Voltage-gated potassium ion channels in axons underlie the repolarization phase of the membrane action potential and help to set the resting potential. In addition to being present in the axolemma, they are also found in axoplasm in small vesicles, 30-50 nm in diameter, which may serve as a reserve pool of K+ channel protein (Clay and Kuzirian [2000] J Neurobiol 45:172-184). We have developed a novel technique for extracting these vesicles from axoplasm, which relies on the ability of Texas red to bind to them, thereby reducing their buoyancy so that they are amenable to pelleting by ultracentrifugation (Clay and Kuzirian [2000] J Neurobiol 45:172-184). The mechanism underlying this process may be binding of Texas red to Hsc70, which is primarily a cytosolic protein. However, a small portion of it is located on the surface of vesicles. Kinesin is also on the vesicle surface. This protein is membrane bound in our in vitro vesicle preparation when solutions that do not contain MgATP are added to extruded axoplasm. The addition of MgATP to the solution appears to release a significant amount of kinesin from the vesicles, possibly by the Hsc70-MgATP catalysis mechanism recently proposed by Tsai et al. Published 2002 Wiley-Liss, lnc. C1 NINCDS, Ion Channel Biophys Unit, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP Clay, JR (reprint author), NINCDS, Ion Channel Biophys Unit, NIH, Bldg 36,Room 4A21,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 11 Z9 11 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR 15 PY 2002 VL 67 IS 6 BP 745 EP 752 DI 10.1002/jnr.10182 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 526ZC UT WOS:000174158700006 PM 11891788 ER PT J AU Polesskaya, OO Sokolov, BP AF Polesskaya, OO Sokolov, BP TI Differential expression of the "C" and "T" alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE allele ratio; postmortem brain; 5-HT2A mRNA; 5-HT2A protein; imprinting ID T102C POLYMORPHISM; FRONTAL-CORTEX; SEROTONIN RECEPTORS; MESSENGER-RNAS; ASSOCIATION; BINDING; POSTMORTEM; SYSTEM; BRAIN; IDENTIFICATION AB A genetic association between schizophrenia and a silent C/T(102) polymorphism in the 5-HT2A receptor gene (5-HT2AR) has been previously reported; however, the mechanisms underlying this association remain unknown. Here we developed an improved quantitative assay for measurements of allele ratios, which revealed that the expression of allele "C" in the temporal cortex of normal heterozygous individuals was significantly lower than the expression of allele "T" (allele "C" to allele "T" ratio of similar to0.8, P < 0.0001). Confirming decreased expression of allele "C," total levels of 5-HT2AR mRNA and protein in normal individuals with the C/C genotype were lower than in individuals with the T/T genotype. Similarly to normal individuals, allele "C" to allele "T" ratio in heterozygous schizophrenics was reduced (similar to0.8, P < 0001). This ratio was independent of neuroleptic treatment history. By contrast, total levels of 5-HT2AR mRNA correlated inversely with neuroleptic free interval prior to death (r = -0.67, P < 0.001) suggesting a reversible neuroleptic effect. Total levels 5-HT2AP mRNA in neuroleptic free (> 26 weeks) schizophrenics (n = 11) were significantly lower than in controls (P = 0.03). The data suggest that increased prevalence of allele "C" among schizophrenics may be due to intrinsically low expression of this allele, which may contribute to a deficit in 5-HT2AR expression in some schizophrenics. Published 2002 Wiley-Liss, Inc. C1 NIDA, Mol Neuropsychiat Sect, NIH, Baltimore, MD 21224 USA. NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD 21224 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Sokolov, BP (reprint author), NIDA, Mol Neuropsychiat Sect, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 43 TC 184 Z9 190 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR 15 PY 2002 VL 67 IS 6 BP 812 EP 822 DI 10.1002/jnr.10173 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 526ZC UT WOS:000174158700014 PM 11891796 ER PT J AU Wagnerova, J Cervenakova, L Balabanov, R Zitron, I Dore-Duffy, P AF Wagnerova, J Cervenakova, L Balabanov, R Zitron, I Dore-Duffy, P TI Cytokine regulation of E-selectin in rat CNS microvascular endothelial cells: differential response of CNS and non-CNS vessels SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE endothelial cells; central nervous system; microvessels; E-selectin; gene regulation; cytokines; interleukin-1; tumor necrosis factor (TNF) ID LEUKOCYTE ADHESION MOLECULE-1; TUMOR-NECROSIS-FACTOR; IN-VIVO; MEDIATED ACTIVATION; MULTIPLE-SCLEROSIS; GENE-EXPRESSION; PRIMARY CULTURE; MESSENGER-RNA; BRAIN; MONOCYTES AB We have compared the induced expression of E-selectin in primary cultures of rat brain microvascular endothelial cells (EC), pericytes and in non-CNS microvascular endothelium stimulated with the cytokines, IL-1beta (20 ng/ml), and tumor necrosis factor (TNF)-alpha (75 ng/ml). Expression was studied at both the protein and mRNA levels. Fluorescence in-situ hybridization (FISH) was used to examine de novo synthesis of E-selectin mRNA. Laser cytometric analysis was used as a novel approach to the quantitaion of FISH. In-situ hybridization was performed using two PCR-generated probes. The first probe (517 bp) spanned the lectin and epidermal growth factor (EGF)-like domain. The second probe (562 bp) spanned the CR3, 4, and 6 domains. E-selectin-specific mRNA was localized to the perinuclear regions of the EC. Both cytokines, IL-1beta and TN-alpha significantly increased E-selectin gene expression in CNS EC but not pericytes. IL-1beta induced higher E-selectin mRNA levels than TNF-alpha. The maximum number of mRNA-positive cells was observed after stimulation for 4-6 h. Surface protein expression was sustained for up to 48 h following addition of cytokine. This was in contrast to the transient expression in non-CNS EC indicating that pure primary CNS EC display slightly different kinetics of E-selectin expression than non-CNS EC. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Wayne State Univ, Detroit Med Ctr, Sch Med, Dept Neurol,Div Neuroimmunol, Detroit, MI 48201 USA. NIH, Lab CNS Studies, Bethesda, MD USA. Beaumont Hosp, Dept Gastroenterol, Southfield, MI USA. RP Dore-Duffy, P (reprint author), Wayne State Univ, Detroit Med Ctr, Sch Med, Dept Neurol,Div Neuroimmunol, 421 E Canfield Ave, Detroit, MI 48201 USA. NR 39 TC 8 Z9 8 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD MAR 15 PY 2002 VL 195 IS 1 BP 51 EP 62 AR PII S0022-510X(01)00685-2 DI 10.1016/S0022-510X(01)00685-2 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 539AU UT WOS:000174847900007 PM 11867074 ER PT J AU Stahl, CE Redei, E Wang, Y Borlongan, CV AF Stahl, CE Redei, E Wang, Y Borlongan, CV TI Behavioral, hormonal and histological stress markers of anxiety-separation in postnatal rats are reduced by prepro-thyrotropin-releasing hormone 178-199 SO NEUROSCIENCE LETTERS LA English DT Article DE corticotropin release-inhibiting factor; exploratory activity; vocalizations; corticosterone; adrenocorticotropic hormone; stress; paraventricular nucleus ID RHESUS-MONKEYS; ADULT RATS; BRAIN; ADOLESCENTS; FLUOXETINE; DISORDERS; RESPONSES; CHILDREN; DISTRESS; DIAZEPAM AB We investigated in the present study whether systemic injections of prepro-thyrotropin-releasing-hormone 178-199 (PPTRH 178-199) in postnatal 3-days old rat pups can provide ameliorative effects in a model of anxiety-separation disorder. The pups were individually separated from their mother and placed in a novel environment. PPTRH 178-199-treated animals started exploring the novel environment in a significantly shorter time and elicited significantly less distress vocalizations than control animals. PPTRH 178-199-treated animals also had markedly lower serum adrenocorticotropic hormone and corticosterone compared to control animals. Furthermore, we observed a significant increase in PPTRH 178-199 immunoreactive cell bodies in the hypothalamus of PPTRH 178-199-treated animals compared to controls, suggesting that the peptide crossed the blood-brain barrier. PPTRH 178-199 treatment can help to reduce behavioral and hormonal disturbances associated with anxiety-separation situations. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Walter Reed Army Med Ctr, Dept Internal Med, Washington, DC 20307 USA. Northwestern Univ, Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. Natl Def Med Ctr, Taipei 100, Taiwan. RP Borlongan, CV (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Borlongan, Cesar/0000-0002-2966-9782 NR 22 TC 8 Z9 9 U1 3 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 15 PY 2002 VL 321 IS 1-2 BP 85 EP 89 AR PII S0304-3940(01)02349-7 DI 10.1016/S0304-3940(01)02349-7 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 537EX UT WOS:000174746700022 PM 11872263 ER PT J AU Rothman, RB Dersch, CM Carroll, FI Ananthan, S AF Rothman, RB Dersch, CM Carroll, FI Ananthan, S TI Studies of the biogenic amine transporters. VIII: Identification of a novel partial inhibitor of dopamine uptake and dopamine transporter binding SO SYNAPSE LA English DT Article DE cocaine; dopamine; dopamine transporter ID RAT CAUDATE MEMBRANES; I-125 RTI-55; 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; COCAINE BINDING; REUPTAKE; 1-<2-(DIPHENYLMETHOXY)ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES; BLOCKERS; MAZINDOL; DOMAINS; ANALOGS AB Using [I-125]RTI-55 to label the dopamine transporter (DAT), our laboratory has consistently detected one binding site as well as one component of [H-3]DA uptake. We report here the identification of a novel partial inhibitor of [3H]DA uptake and DAT binding (SoRI-9804). [125I]RTI-55 binding to the DAT (mouse caudate, rat caudate, HEK cells expressing the cloned DAT), the 5-HT transporter (rat brain), and [3H]DA uptake (rat caudate synaptosomes) were conducted using published procedures. 4-[(Diphenylmethyl)amino]-2-phenylquinazoline (SoRI-9804) was essentially inactive at SERT binding and resolved two DAT binding components in all three tissues, having high affinity (mean K-i of 465 nM) for about 40% of the binding sites and an essentially immeasurable K-i (> 100 muM) for the remaining 60% of the binding sites. The [H-3]DA uptake experiments indicated that about 50% of uptake was SoRI-9804-sensitive. Saturation binding experiments showed that SoRI-9804 competitively inhibited [I-125]RTI-55 binding to the SoRI-9804-sensitive binding component. To determine if the two binding sites discriminated by SoRI-9804 were regulated by the MAP kinase pathway, rat caudate synaptosomes were incubated in the absence or presence of 10 muM of PD98059, which inhibits activation of the MAP kinase pathway. The results indicated that inhibition of MAPK/ERK kinase decreased the total B-max of the DAT by 90%. Treatment with PD98059 increased the proportion of the SoRI-9804-sensitive binding component from 68-80% of the total B-max. The PD98059 experiments suggest that inhibition of MAP kinase cannot explain the differential interaction of SoRI-9804 with the DAT. Viewed collectively, the present results indicate that SoRI-9804 discriminates two components of the DA transporter. Further studies will be needed to determine the underlying mechanism of this effect and if partial inhibition of DA uptake results in any unique behavioral effects. (C) 2002 Wiley-Liss, Inc. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. So Res Inst, Birmingham, AL 35255 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. FU NIDA NIH HHS [DA05477] NR 21 TC 13 Z9 14 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 2002 VL 43 IS 4 BP 268 EP 274 DI 10.1002/syn.10046 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 520FW UT WOS:000173771200007 PM 11835522 ER PT J AU Subramanian, AK Quinn, TC Kickler, TS Kasper, EK Tucker, PC AF Subramanian, AK Quinn, TC Kickler, TS Kasper, EK Tucker, PC TI Correlation of Chlamydia pneumoniae infection and severity of accelerated graft arteriosclerosis after cardiac transplantation SO TRANSPLANTATION LA English DT Article ID ALLOGRAFT VASCULOPATHY; ATHEROSCLEROSIS; DISEASE; TRACHOMATIS; PSITTACI; DONORS; IMPACT; CELLS; PCR AB Background. Chlamydia pneumoniae has been associated with atherosclerosis, although its role in the process is not clearly defined. Heart transplant recipients are known to have high titers of antibodies to C. pneumoniae, and the organism has bee recovered from the coronary arteries of both transplant recipients and donors. This study evaluated association between C. pneumoniae infection and accelerated graft arteriosclerosis (AGA), also known as cardiac allograft vasculopathy (CAV), after cardiac transplantation. Methods. A case-control study was performed with 54 heart transplant recipients at the Johns Hopkins Hospital. Severe cases had >50% luminal narrowing on cardiac catheterization, mild cases <50% narrowing, and controls were free of arteriosclerotic disease. Blood specimens were examined for C. pneumoniae serology and DNA detection by polymerase chain reaction (PCR) assays. Results. For every twofold increase in geometric mean C. pneumoniae immunoglobulin (Ig)G titer, the odds ratio for severe AGA versus controls was 3.13 (P=0.03) and for mild AGA versus control patients was 1.61 (P=0.45). On Kaplan-Meier survival analysis there was a nonsignificant trend toward faster development of CAV in patients with higher C. pneumoniae antibody titers. Overall, 29% of heart transplant patients evaluated had evidence of circulating C. pneumoniae DNA by PCR, without a statistical difference between groups. Conclusions. C. pneumoniae IgG titer correlates with severity of allograft arteriosclerosis after cardiac transplantation. Circulating C. pneumoniae DNA is detectable by PCR in up to 30% of cardiac transplant recipients, but this does not correlate with severity of allograft vasculopathy. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA. NIAID, NIH, Bethesda, MD 20814 USA. RP Subramanian, AK (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, 1830 E Monument St,Suite 8074, Baltimore, MD 21287 USA. FU NHLBI NIH HHS [F32 HL10300-01] NR 21 TC 15 Z9 17 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 15 PY 2002 VL 73 IS 5 BP 761 EP 764 DI 10.1097/00007890-200203150-00018 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 536TC UT WOS:000174717100018 PM 11907424 ER PT J AU Iosef, C Van Nguyen, T Jeong, KI Bengtsson, K Morein, B Kim, Y Chang, KO Azevedo, MSP Yuang, LJ Nielsen, P Saif, LJ AF Iosef, C Van Nguyen, T Jeong, KI Bengtsson, K Morein, B Kim, Y Chang, KO Azevedo, MSP Yuang, LJ Nielsen, P Saif, LJ TI Systemic and intestinal antibody secreting cell responses and protection in gnotobiotic pigs immunized orally with attenuated Wa human rotavirus and Wa 2/6-rotavirus-like-particles associated with immuno stimulating complexes SO VACCINE LA English DT Article DE immunostimulating-complexes (ISCOMs); rotavirus; virus-like-particle (VLP) vaccine ID HEAT-LABILE TOXIN; IMMUNOSTIMULATING COMPLEXES; INTRAMUSCULAR IMMUNIZATION; PRIMATE MODELS; MICE; PARTICLES; ISCOMS; VACCINE; INTRANASAL; FORMULATIONS AB The undesirable side effects and variable efficacy of some oral live rotavirus vaccines in infants have necessitated alternative vaccine approaches. We evaluated a recombinant RFVP2/WaVP6 rotavirus-like-particle (2/6VLP) oral vaccine, using an immunostimulating complex (ISCOM) matrix as adjuvant, in a gnotobiotic (Gn) pig model of human rotavirus (HRV) disease. The 2/6VLPs adhered to the ISCOM-matrix (2/6VLP-ISCOM) and were antigenic, but they failed to induce protection. However, when combined with attenuated (Att) HRV for oral priming, the 2/6VLP-ISCOM vaccine was effective as a booster and induced partial protection against virulent Wa HRV. The 250 mug 2/6VLP dose was more effective than 100 mug. The highest mean numbers of I-A antibody secreting cells evaluated by ELISPOT in intestinal lymphoid tissues were in pigs receiving AttHRV + 2/6VLP-ISCOM or three doses of AttHRV and were associated with the highest protection rates. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Ohio State Univ, Ohio Agr Res & Dev Ctr, Food Anim Hlth Res Program, Wooster, OH 44691 USA. Swedish Univ Agr Sci, Uppsala, Sweden. NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Saif, LJ (reprint author), Ohio State Univ, Ohio Agr Res & Dev Ctr, Food Anim Hlth Res Program, 1680 Madison Ave, Wooster, OH 44691 USA. EM saif.2@osu.edu RI Yuan, Lijuan/A-2468-2008 OI Yuan, Lijuan/0000-0003-0709-5228 FU NIAID NIH HHS [R01 AI33561, R01AI37111] NR 43 TC 34 Z9 37 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 15 PY 2002 VL 20 IS 13-14 BP 1741 EP 1753 AR PII S264-410X(02)00031-2 DI 10.1016/S0264-410X(02)00031-2 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 537QR UT WOS:000174771000010 PM 11906761 ER PT J AU Skiadopoulos, MH Tatem, JM Surman, SR Mitcho, Y Wu, SL Elkins, WR Murphy, BR AF Skiadopoulos, MH Tatem, JM Surman, SR Mitcho, Y Wu, SL Elkins, WR Murphy, BR TI The recombinant chimeric human parainfluenza virus type 1 vaccine candidate, rHPIV3-1cp45, is attenuated, immunogenic, and protective in African green monkeys SO VACCINE LA English DT Article DE chimeric vaccines; parainfluenza virus; rHPIV3-1cp45 ID RESPIRATORY SYNCYTIAL VIRUS; HEMAGGLUTININ-NEURAMINIDASE; FUSION GLYCOPROTEINS; PIV TYPE-3; BOVINE; PROTEINS; INFANTS; MUTANT; CHIMPANZEES; REPLICATION AB A recombinant live-attenuated chimeric human parainfluenza virus type I (HPIV1) candidate vaccine was previously generated by replacing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein open reading frames (ORFs) of the HPIV3 candidate vaccine, rHPIV3cp45, with those of wild-type HPIV1. Previously, this recombinant chimeric virus, designated rHPIV3-1 cp45, exhibited a greater level of the temperature sensitivity of replication in vitro and a greater level of attenuation of replication in the respiratory tract of immunized hamsters when compared to its HPIV3cp45 parent virus. In the present study, rHPIV3-1cp45 was evaluated for its level of attenuation and efficacy in African green monkeys (Cercopithecus aethiops), a primate in which both HPIV I and HPIV3 wild-type viruses replicate efficiently. The rHPIV3-1cp45 candidate vaccine was as restricted in replication in the upper and lower respiratory tract as its thoroughly characterized rHPIV3cp45 parent indicating that the attenuating mutations present in the rHPIV3cp45 backbone specified an appropriate level of attenuation of rHPIV3-1 ep45 for primates. The level to which rHPIV3-1 cp45 replicated in the respiratory tract of African green monkeys was also sufficient to induce a strong immune response to HPIV1 and provided protection against challenge with wild-type HPIV1. These results provide a basis for further evaluation of this HPIV1 candidate vaccine in humans. Published by Elsevier Science Ltd. C1 NIAID, NIH, Resp Viruses Sect, Infect Dis Lab, Bethesda, MD 20892 USA. Wyeth Lederle Vaccines, Pearl River, NY 10965 USA. NIAID, Infect Dis Lab, Exptl Primate Virol Sect, NIH, Bethesda, MD 20892 USA. RP Skiadopoulos, MH (reprint author), NIAID, NIH, Resp Viruses Sect, Infect Dis Lab, Bldg 50,Room 6511,50 S Dr MSC 8007, Bethesda, MD 20892 USA. NR 26 TC 14 Z9 14 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 15 PY 2002 VL 20 IS 13-14 BP 1846 EP 1852 AR PII S0264-410X(02)00038-5 DI 10.1016/S0264-410X(02)00038-5 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 537QR UT WOS:000174771000023 PM 11906774 ER PT J AU Griffin, DD Nakagomi, T Hoshino, Y Nakagomi, O Kirkwood, CD Parashar, UD Glass, RI Gentsch, JR AF Griffin, DD Nakagomi, T Hoshino, Y Nakagomi, O Kirkwood, CD Parashar, UD Glass, RI Gentsch, JR CA Natl Rotavirus Strain Surveillance TI Characterization of nontypeable rotavirus strains from the United States: Identification of a new rotavirus reassortant (P2A[6],G12) and rare P3[9] strains related to bovine rotaviruses SO VIROLOGY LA English DT Review ID POLYMERASE CHAIN-REACTION; CELL-CULTURE PROPAGATION; SUBGROUP-I SPECIFICITY; LONG RNA PATTERN; MONOCLONAL-ANTIBODIES; SEQUENCE-ANALYSIS; G-SEROTYPE; ANTIGENIC CHARACTERIZATION; NUCLEOTIDE-SEQUENCE; NONSTRUCTURAL GLYCOPROTEIN AB Among 1316 rotavirus specimens collected during strain surveillance in the United States from 1996 to 1999, most strains (95%) belonged to the common types (G1 to G4 and G9), while 5% were mixed infections of common serotypes, rare strains, or not completely typeable. In this report, 2 rare (P[9],G3) and 2 partially typeable (P[6],G?; P[9],G?) strains from that study were further characterized, The P[6] strain was virtually indistinguishable by hybridization analysis in 10 of its 11 gene segments with recently isolated P2A[6],G9 strains (e.g., U.S.1205 from the United States, but had a distinct VP7 gene homologous (94.7% aa and 90.2% nt) to the cognate gene from P1B[4],G12 reference strain L26. Thus, this serotype P2A[6],G12 strain represents a previously unrecognized reassortant. Three P3[9] strains were homologous (97.8-98.2% aa) in the VP8 region of VP4 to the P3[9],G3 feline-like reference strain AU-1, but had a high level of genome homology to Italian bovine-like, P3[9],G3 and P3[9],G6 rotavirus strains. Two of the U,S. P3[9] strains were confirmed to be type G3 (97.2-98.2% VP7 aa homology with reference G3 strain AU-1), while the other was most similar to Italian bovine-like strain PA151 (P3[9],G6), sharing 99.0% aa homology in VP7. Cross-neutralization studies confirmed all serotype assignments and represented the first detection of these rotavirus serotypes in the United States. The NSP4 genes of all U.S. P3[9] strains and rotavirus PA151 were most closely related to the bovine and equine branch within the DS-1 lineage, consistent with an animal origin, These results demonstrate that rare strains with P and G serotypes distinct from those of experimental rotavirus vaccines circulate in the United States, making it important to understand whether current vaccine candidates protect against these strains. (C) 2002 Elsevier Science (USA). C1 US Dept Hlth & Human Serv, Ctr Dis Control & Prevent, Div Viral & Rickettsial Dis, Viral Gastroenteritis Sect, Atlanta, GA 30333 USA. Akita Univ, Sch Med, Dept Microbiol, Akita 0108543, Japan. Natl Inst Allergy & Infect Dis, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. Royal Childrens Hosp, Murdoch Childrens Res Inst, Dept Gastroenterol & Clin Nutr, Melbourne, Vic, Australia. RP Gentsch, JR (reprint author), CDC, Viral Gastroentertis Sect, Mailstop G04 1600 Clifton Rd NE, Atlanta, GA 30333 USA. NR 102 TC 116 Z9 118 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2002 VL 294 IS 2 BP 256 EP 269 DI 10.1006/viro.2001.1333 PG 14 WC Virology SC Virology GA 542DA UT WOS:000175027200003 PM 12009867 ER PT J AU Earl, PL Wyatt, LS Montefiori, DC Bilska, M Woodward, R Markham, PD Malley, JD Vogel, TU Allen, TM Watkins, DI Miller, N Moss, B AF Earl, PL Wyatt, LS Montefiori, DC Bilska, M Woodward, R Markham, PD Malley, JD Vogel, TU Allen, TM Watkins, DI Miller, N Moss, B TI Comparison of vaccine strategies using recombinant env-gag-pol MVA with or without an oligomeric env protein boost in the SHIV rhesus macaque model SO VIROLOGY LA English DT Article DE SHIV89.6; SHIV-89.6P; vaccine; recombinant modified vaccinia virus Ankara; rhesus macaque; oligomeric env protein ID HUMAN-IMMUNODEFICIENCY-VIRUS; MUCOSAL IMMUNE-RESPONSES; T-LYMPHOCYTE RESPONSE; HIV-1 VACCINE; NEUTRALIZING ANTIBODY; VIRAL REPLICATION; DNA VACCINATION; PATHOGENIC SIV; ENVELOPE GENE; IMMUNIZATION AB Rhesus macaques were immunized with a replication-deficient vaccinia virus (MVA) expressing human immunodeficiency virus type 1 89.6 envelope (env) and SIV gagpol (MVA/SHIV89.6) with or without a protein boost consisting of soluble 89.6 env (gp140). Immunization with MVA/SHIV89.6 alone elicited binding antibodies in all animals and neutralizing antibodies in 5 of 15 animals, Both types of antibodies were enhanced by protein boosting In addition, CD8 cells exhibiting CM9 tetramer binding were detected in the subset of animals that were Mamu-A*01 positive. Animals were challenged intravenously with either SHIV-89.6 (Study 1) or the more pathogenic derivative SHIV-89.6P (Study 2). In Study 1, all control and vaccinated animals except one became infected. However, the levels of viremia were as follows controls (.) rMVA alone (.) rMVA + protein. The differences were statistically significant between immunized and control groups but not between the two immunized groups. In Study 2, all animals became infected; however, the vaccinated group exhibited a 5-fold reduction in peak viremia and a 10-fold reduction in the postacute phase viremia in comparison to the controls All of the controls required euthanasia by 10 months after challenger A relationship between vaccine-induced antibody titers and reduction in virus burden was observed in both studies. Thus, immunization with MVA/SHIV89.6 alone or with a protein boost stimulated both arms of the immune system and resulted in significant control of viremia and delayed progression to disease after challenge with SHIV-89.6P. (C) 2002 Elsevier Science (USA). C1 Lab Viral Dis, NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Div AIDS, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Adv Biosci Labs Inc, Kensington, MD USA. Univ Wisconsin, Wisconsin Regional Primate Res Ctr, Madison, WI 53706 USA. Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. RP Earl, PL (reprint author), Lab Viral Dis, NIH, Ctr Informat Technol, Bldg 4 Rm 236 4 Ctr Dr MSC 0445, Bethesda, MD 20892 USA. RI Allen, Todd/F-5473-2011 FU NIAID NIH HHS [AI85343] NR 64 TC 77 Z9 77 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 15 PY 2002 VL 294 IS 2 BP 270 EP 281 DI 10.1006/viro.2001.1345 PG 12 WC Virology SC Virology GA 542DA UT WOS:000175027200004 PM 12009868 ER PT J AU Techaarpornkul, S Collins, PL Peeples, ME AF Techaarpornkul, S Collins, PL Peeples, ME TI Respiratory syncytial virus with the fusion protein as its only viral glycoprotein is less dependent on cellular glycosaminoglycans for attachment than complete virus SO VIROLOGY LA English DT Article ID HERPES-SIMPLEX VIRUS; HEPARAN-SULFATE; IN-VITRO; CELLS; BINDING; MUTANT; GROWTH; PROTEOGLYCANS; BIOSYNTHESIS; INFECTIVITY AB Cell surface glycosaminoglycans (GAGS) are responsible for the majority of respiratory syncytial virus (RSV) attachment to cultured cells leading to infection. The viral glycoprotein G binds to GAGS and was thought to be the viral attachment protein, but more recently virus lacking the G protein was shown to be infectious in cell culture. We have compared the GAG dependence of a recombinant, green fluorescent protein-expressing virus containing the F protein as its only viral glycoprotein (rgRSV-F) to isogenic complete virus containing all three viral glycoproteins (rgRSV-SGF) Attachment and infection by each virus was found to be largely dependent on cell surface heparan sulfate (HS) based on the finding that both activities were inhibited by preincubation of virus with soluble HS, by removal of HS from target cells by enzymatic treatment or mutation, or by pretreatment of the target cells with basic fibroblast growth factor (bFGF), which binds HS. These results, coupled with the previous finding that SH is not involved in virion binding (S. Techaarpornkul, N. Barretto, and M. Peeples, 2001, J. Virol. 75, 6825-6834), suggest that, in the context of the virion, both the G and F proteins bind to HS, Interestingly, both rgRSV-F and rgRSV-SGF retained significant binding activity and infectivity despite these treatments, suggesting an alternate productive attachment and infection pathway. This property of GAG independence was particularly apparent for rgRSV-F virions, which retained nearly half of its attachment and infection activities in most of these experiments. Comparison of the attachment and infection activities of rgRSV-SGF and rgRSV-F virions with a Chinese hamster ovary cell line and a derivative thereof that is defective in GAG synthesis indicated that approximately 50% of rgRSV-SGF attachment is due to G protein-GAG binding, 25% to F protein-GAG binding, and 25% to an independent pathway This alternative pathway presumably is mediated by the sole remaining viral surface protein, F, although the formal possibility exists that some other virion-associated protein is involved. (C) 2002 Elsevier Science (USA). C1 Silpakorn Univ, Dept Biopharm, Lanzhou 730000, Peoples R China. Natl Inst Allergy & Infect Dis, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. RP Peeples, ME (reprint author), Silpakorn Univ, Dept Biopharm, Sanamchan Palace Campus, Lanzhou 730000, Peoples R China. FU NIAID NIH HHS [AI47213] NR 23 TC 71 Z9 74 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2002 VL 294 IS 2 BP 296 EP 304 DI 10.1006/viro.2001.1340 PG 9 WC Virology SC Virology GA 542DA UT WOS:000175027200007 PM 12009871 ER PT J AU Vousden, KH AF Vousden, KH TI Activation of the p53 tumor suppressor protein SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE p53; MDM2; tumor suppression; apoptosis; ubiquitination; subcellular localization; transcriptional activation ID C-TERMINAL DOMAIN; CELL-CYCLE ARREST; PROTEASOME-MEDIATED DEGRADATION; P53-DEPENDENT GENE ACTIVATION; INDUCIBLE FACTOR 1-ALPHA; NUCLEAR EXPORT SIGNAL; RING-FINGER DOMAIN; WILD-TYPE P53; DNA-DAMAGE; IN-VIVO AB The p53 tumor suppressor gene plays an important role in preventing cancer development, by arresting or killing potential tumor cells. Mutations within the p53 gene, leading to the loss of p53 activity, are found in about half of all human cancers, while many of the tumors that retain wild type p53 carry mutations in the pathways that allow full activation of p53. In either case, the result is a defect in the ability to induce a p53 response in cells undergoing oncogenic stress. Significant advances have been made recently in our understanding of the molecular pathways through which p53 activity is regulated, bringing with them fresh possibilities for the design of cancer therapies based on reactivation of the p53 response. Published by Elsevier Science B.V. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. NR 146 TC 262 Z9 278 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD MAR 14 PY 2002 VL 1602 IS 1 BP 47 EP 59 AR PII S0304-419X(02)00035-5 DI 10.1016/S0304-419X(02)00035-5 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 548PN UT WOS:000175397800003 PM 11960694 ER PT J AU Xu, LF Izenwasser, S Katz, JL Kopajtic, T Klein-Stevens, C Zhu, NJ Lomenzo, SA Winfield, L Trudell, ML AF Xu, LF Izenwasser, S Katz, JL Kopajtic, T Klein-Stevens, C Zhu, NJ Lomenzo, SA Winfield, L Trudell, ML TI Synthesis and biological evaluation of 2-substituted 3 beta-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACID METHYL-ESTERS; LIGAND-BINDING; SELECTIVE COMPOUNDS; HIGH-AFFINITY; COCAINE; ANALOGS; INHIBITION AB A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2beta-(R)-alcohol 10 over the 2beta-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse. C1 Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. Xavier Univ, Dept Chem, New Orleans, LA 70125 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33136 USA. RP Trudell, ML (reprint author), Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. RI Izenwasser, Sari/G-9193-2012 FU NIDA NIH HHS [DA11528] NR 32 TC 21 Z9 22 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 14 PY 2002 VL 45 IS 6 BP 1203 EP 1210 DI 10.1021/jm010453u PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 533AA UT WOS:000174506200006 PM 11881989 ER PT J AU Emond, P Vercouillie, J Innis, R Chalon, S Mavel, S Frangin, Y Halldin, C Besnard, JC Guilloteau, D AF Emond, P Vercouillie, J Innis, R Chalon, S Mavel, S Frangin, Y Halldin, C Besnard, JC Guilloteau, D TI Substituted diphenyl sulfides as selective serotonin transporter ligands: Synthesis and in vitro evaluation SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; I-123 IDAM; ALZHEIMERS-DISEASE; IN-VITRO; BINDING; BRAIN; RADIOLIGAND; SITES; MEMBRANES; RECEPTORS AB A series of diphenyl sulfide derivatives substituted at the 1-, 2'-, and 4'-positions has been synthesized and evaluated for their in vitro affinities at the dopamine, serotonin (SERT), and norepinephrine transporters. The examination of K-i values revealed that most of these derivatives have high affinity and selectivity for the SERT. Moreover, substitutions at these positions differently influence the SERT binding: (i) The nature of the substituent linked at the I-position critically influences the SERT affinity. (ii) Functions containing heteroatom at the 2'-position afford compounds with high SERT affinity. (iii) The nature of the substituent at the 4'-position slightly influences the SERT affinity whereas steric effect markedly decreases the SERT affinity. From this series, the most SERT selective derivatives (such as 8b, 8c, and 8g) are now evaluated for their potential as positron emission tomography imaging agents when labeled with carbon-11. C1 INSERM U316, Lab Biophys Med & Pharmaceut, F-37200 Tours, France. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Karolinska Hosp, Psychiat Sect, Dept Clin Neurosci, S-17176 Stockholm, Sweden. RP Emond, P (reprint author), INSERM U316, Lab Biophys Med & Pharmaceut, 31 Ave Monge, F-37200 Tours, France. RI Emond, Patrick/P-6994-2016; MAVEL, Sylvie/P-9001-2016; Chalon, Sylvie/G-2734-2013 OI Emond, Patrick/0000-0002-5324-2164; MAVEL, Sylvie/0000-0002-1424-2698; Chalon, Sylvie/0000-0003-1865-8380 FU NIMH NIH HHS [KO2MH01366, N01MH80005] NR 31 TC 33 Z9 34 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 14 PY 2002 VL 45 IS 6 BP 1253 EP 1258 DI 10.1021/jm010939a PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 533AA UT WOS:000174506200011 PM 11881994 ER PT J AU Hsin, LW Dersch, CM Baumann, MH Stafford, D Glowa, JR Rothman, RB Jacobson, AE Rice, KC AF Hsin, LW Dersch, CM Baumann, MH Stafford, D Glowa, JR Rothman, RB Jacobson, AE Rice, KC TI Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: Chiral hydroxyl-containing derivatives of 1[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 1-<2-ETHYL>-4-(3-PHENYLPROPYL)PIPERAZINES GBR-12935; RHESUS-MONKEYS; UPTAKE COMPLEX; BINDING; ANALOGS; RAT; INHIBITORS; PHARMACOLOGY; MEMBRANES; SEROTONIN AB In our search for long-acting agents for the treatment of cocaine abuse, a series of optically pure hydroxylated derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)-piperazine (1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) (GBR 12909 and GBR 12935, respectively) were synthesized and evaluated in vitro and in vivo. The enantiomers of the 2-hydroxylated analogues displayed substantial enantioselectivity. The S enantioniers displayed higher dopamine transporter (DAT) affinity and the R enantiomers were found to interact at the serotonin transporter (SERT) with higher affinity. The two-carbon spacer between the hydroxyl group and the piperazine ring was essential for enantioselectivity, and the length of the alkyl chain between the phenyl group and the piperazine ring influenced binding affinity and selectivity for the DAT and SERT. Phenylethyl analogues had a higher binding affinity for the SERT and a weaker affinity and selectivity for the DAT than the corresponding phenylpropyl analogues. Thus, (S)-(+)-1-[4-[2-[bis(4-fluorophenyl)methoxy] ethyl]piperazinyl]-3-phenylpropan- 2-ol (6) displayed the highest affinity to the,DAT, and (S)-(+)-1-[4- [2-(dipbenylmethoxy)ethyl]piperazinyl]-3-phenylpropan-2-ol (8) had the highest selectivity. The latter (8) is one of the most DAT selective ligands known. In accord with the in vitro data, 6 showed greater potency than 7 in elevating extracellular dopamine levels in a microdialysis assay and in inhibiting cocaine-maintained responding in rhesus monkeys. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH, Baltimore, MD 21224 USA. Louisiana State Univ, Med Ctr, Dept Pharmacol & Therapeut, Shreveport, LA 71130 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, Bldg 8,Room B1-23,8 Ctr Dr MSC 0815, Bethesda, MD 20892 USA. OI HSIN, LING-WEI/0000-0001-5018-4491 NR 36 TC 54 Z9 54 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 14 PY 2002 VL 45 IS 6 BP 1321 EP 1329 DI 10.1021/jm010430f PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 533AA UT WOS:000174506200018 PM 11882001 ER PT J AU Nelson, G Chandrashekar, J Hoon, MA Feng, LX Zhao, G Ryba, NJP Zuker, CS AF Nelson, G Chandrashekar, J Hoon, MA Feng, LX Zhao, G Ryba, NJP Zuker, CS TI An amino-acid taste receptor SO NATURE LA English DT Article ID GLUTAMATE RECEPTORS; MICE; G-ALPHA(16); RESPONSES; SACCHARIN; FAMILY AB The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances(1). Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals(2). This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses. C1 Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Zuker, CS (reprint author), Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 NR 27 TC 732 Z9 766 U1 18 U2 120 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 14 PY 2002 VL 416 IS 6877 BP 199 EP 202 DI 10.1038/nature726 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 530FR UT WOS:000174348100043 PM 11894099 ER PT J AU Lei, SB McBain, CJ AF Lei, SB McBain, CJ TI Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; CA2+-PERMEABLE AMPA RECEPTORS; CALCIUM-PERMEABLE AMPA; D-ASPARTATE RECEPTOR; HIPPOCAMPAL INTERNEURONS; RAT HIPPOCAMPUS; INWARD RECTIFICATION; SYNAPTIC ACTIVITY; PYRAMIDAL CELLS; SILENT SYNAPSES AB Dentate gyrus granule cells innervate inhibitory interneurons via a continuum of synapses comprised of either Ca2+-impermeable (CI) or Ca2+-permeable (CP) AMPA receptors. Synapses at the extreme ends of this continuum engage distinct postsynaptic responses, with activity at CI synapses being strongly influenced by NMDA receptor activation. NMDARs at CI synapses have a lower NR2B subunit composition and a higher open probability, which generate larger amplitude and more rapid EPSCs than their CP counterparts. A novel form of NMDAR-dependent long-term depression (iLTD) is associated with CI-mossy fiber synapses, whereas iLTD at CP synapses is dependent on Ca2+-permeable AMPA receptor activation. Induction of both forms of iLTD required elevation of postsynaptic calcium. Thus mossy fibers engage CA3 interneurons via multiple synapse types that will act to expand the computational repertoire of the mossy fiber-CA3 network. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. NR 58 TC 106 Z9 108 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 14 PY 2002 VL 33 IS 6 BP 921 EP 933 DI 10.1016/S0896-6273(02)00608-6 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 530ZK UT WOS:000174389600009 PM 11906698 ER PT J AU Horiguchi, N Takayama, H Toyoda, M Otsuka, T Fukusato, T Merlino, G Takagi, H Mori, M AF Horiguchi, N Takayama, H Toyoda, M Otsuka, T Fukusato, T Merlino, G Takagi, H Mori, M TI Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine SO ONCOGENE LA English DT Article DE HGF transgenic; hepatocellular carcinoma; c-Met; diethylnitrosamine; VEGF ID FACTOR SCATTER FACTOR; FULMINANT HEPATIC-FAILURE; FACTOR-ALPHA; HEPATOCELLULAR CARCINOMAS; ABNORMAL-DEVELOPMENT; LIVER-REGENERATION; MOLECULAR-CLONING; SOMATIC MUTATIONS; EPITHELIAL-CELLS; GENE-EXPRESSION AB Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported that HGF transgenic mice under the metallothionein gene promoter developed benign and malignant liver tumors spontaneously after 17 months of age. To elucidate the role of HGF in hepatocarcinogenesis, diethylnitrosamine (DEN) was administered to HGF transgenic mice. HGF overexpression accelerated DEN-induced hepatocarcinogenesis, often accompanied by abnormal blood vessel formation. In this study, 59% of transgenic mates (versus 20% of wild-type males) and 39% of transgenic females (versus 2% of wild-type females) developed either benign or malignant liver tumors by 48 weeks (P<0.005, P<0.001, respectively). Moreover, 33% of males and 23% of female transgenic mice developed hepatocellular carcinoma (HCC), while none of the wild-type mice developed HCC (P<0.001, P<0.005, respectively). Enhanced kinase activity of the HGF receptor, Met, was detected in most of these tumors. Expression of vascular endothelial growth factor (VEGF) was up-regulated in parallel with HGF transgene expression. Taken together, our results suggest that HGF promotes hepatocarcinogenesis through the autocrine activation of the HGF-Met signaling pathway in association with stimulation of angiogenesis by HGF itself and/or indirectly through VEGF. C1 Gunma Univ, Sch Med, Dept Internal Med 1, Gunma 3718511, Japan. Gunma Univ, Sch Med, Div Diagnost Pathol, Gunma 3718511, Japan. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Takagi, H (reprint author), Gunma Univ, Sch Med, Dept Internal Med 1, Showa Machi 3-39-15, Gunma 3718511, Japan. NR 65 TC 79 Z9 95 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 14 PY 2002 VL 21 IS 12 BP 1791 EP 1799 DI 10.1038/sj.onc.1205248 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 529DJ UT WOS:000174284500001 PM 11896611 ER PT J AU Finkeltov, I Kuhn, S Glaser, T Idelman, G Wright, JJ Roberts, CT Werner, H AF Finkeltov, I Kuhn, S Glaser, T Idelman, G Wright, JJ Roberts, CT Werner, H TI Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1 fusion protein SO ONCOGENE LA English DT Article DE DSRCT; IGF-I receptor; EWS; WT1; translocation ID ROUND-CELL TUMOR; HUMAN MYXOID CHONDROSARCOMA; WILMS-TUMOR; EWS GENE; EWINGS-SARCOMA; CHROMOSOME-TRANSLOCATION; PROMOTER ACTIVITY; MALIGNANT-MELANOMA; GENOMIC STRUCTURE; SUPPRESSOR WT1 AB The EWS family of genes is involved in numerous chromosomal translocations that are characteristic of a variety of sarcomas. A recently described member of this group is desmoplastic small round cell tumor (DSRCT), which is characterized by a recurrent t(11;22)(p13;q12) translocation that fuses the 5' exons of the EWS gene to the 3' exons of the WT1 gene. The originally described chimera comprises exons 1 - 7 of EWS and exons 8 - 10 of WT1. We have previously reported that the WT1 protein represses the expression of the IGF-I receptor gene, whereas the EWS(1 - 7)-WT 1(8 - 10) fusion protein activates IGF-I receptor gene expression. It has recently become apparent that EWS-WT1 chimeras produced in DSCRT are heterogeneous as a result of fusions of different regions of the EWS gene to the WT1 gene. We have recently characterized additional EWS-WT1 translocations that involve the juxtaposition of EWS exons 7 or 8 to WT1 exon 8, and an EWS-WT1 chimera that lacks EWS exon 6. The chimeric transcription factors encoded by these various translocations differ in their DNA-binding characteristics and their ability to transactivate the IGF-I receptor promoter. These data suggest that the molecular pathology of DSRCT is more complex than previously appreciated, and that this diversity may provide the foundation for predictive genotype-phenotype correlations in the future. C1 Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Ramat Aviv, Israel. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20889 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97201 USA. RP Werner, H (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Ramat Aviv, Israel. OI Roberts, Charles/0000-0003-1756-5772 FU NIDDK NIH HHS [DK50810] NR 48 TC 19 Z9 22 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 14 PY 2002 VL 21 IS 12 BP 1890 EP 1898 DI 10.1038/sj.onc.1205042 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 529DJ UT WOS:000174284500012 PM 11896622 ER PT J AU Mange, A Milhavet, O Umlauf, D Harris, D Lehmann, S AF Mange, A Milhavet, O Umlauf, D Harris, D Lehmann, S TI PrP-dependent cell adhesion in N2a neuroblastoma cells SO FEBS LETTERS LA English DT Article DE aggregation; intercellular adhesion; prion protein ID PRION PROTEIN EXPRESSION; SIGNAL-TRANSDUCTION; LAMININ; BINDING; SCRAPIE; MOLECULES; INTERACTS AB The cellular isoform of prion protein (PrPC) is a ubiquitous glycoprotein expressed by most tissues and with a biological function yet to be determined. Here, we have used a neuroblastoma cell model to investigate the involvement of PrP in cell adhesion. Incubation of single cell suspension induced cell-cell adhesion and formation of cell aggregates. Interestingly, cells overexpressing PrP exhibit increased cation-independent aggregation. Aggregation was reduced after phosphatidylinositol-specific phospholipase C release of the protein and by preincubation of cells with an antibody raised against the N-terminal part of PrPC. Our paradigm allows the study of the function of PrP as an intercellular adhesion molecule and a cell surface ligand or receptor. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 Inst Genet Humaine, CNRS UPR 1142, F-34396 Montpellier 05, France. NIA, NIH, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Lehmann, S (reprint author), Inst Genet Humaine, CNRS UPR 1142, 141 Rue Cardonille, F-34396 Montpellier 05, France. OI Mange, Alain/0000-0002-1566-9407 NR 28 TC 69 Z9 70 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 13 PY 2002 VL 514 IS 2-3 BP 159 EP 162 AR PII S0014-5793(02)02338-4 DI 10.1016/S0014-5793(02)02338-4 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 542AY UT WOS:000175022400009 PM 11943143 ER PT J AU Zametkin, AJ AF Zametkin, AJ TI Sexual orientation and suicide risk among teenagers - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIMH, Mood & Anxiety Disorder Program, Bethesda, MD 20892 USA. RP Zametkin, AJ (reprint author), NIMH, Mood & Anxiety Disorder Program, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 13 PY 2002 VL 287 IS 10 BP 1266 EP 1266 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 529YU UT WOS:000174329500023 ER PT J AU Han, MK Lin, P Paek, D Harvey, JJ Fuior, E Knutson, JR AF Han, MK Lin, P Paek, D Harvey, JJ Fuior, E Knutson, JR TI Fluorescence studies of pyrene maleimide-labeled translin: Excimer fluorescence indicates subunits associate in a tail-to-tail configuration to form octamer SO BIOCHEMISTRY LA English DT Article ID HOTSPOT BINDING-PROTEIN; CHROMOSOMAL TRANSLOCATIONS; DNA-BINDING; RNA-BINDING; DECAY; N-(1-PYRENE)MALEIMIDE; PROBE; GENE AB Translin is an octameric single-stranded DNA binding protein consisting of 228 amino acid residues per monomer. This protein contains two cysteine residues per monomer. Studies of reactions with DTNB show that both cysteines are reactive and exhibit biphasic reaction kinetics. Further studies with two site-directed mutants, C58S and C225S, confirm that Cys-58 reacts slowly while Cys-225 reacts quickly. Pyrene excimer emission was observed for pyrene maleimide-labeled C58S mutant. This was not observed, however, with the pyrene maleimide-labeled C225S mutant. DAS (decay associated spectra) revealed that all excited pyrene labels on C225 residues can form excimers with pyrenes of adjacent subunits within a few nanoseconds. Time-resolved emission anisotropy detects a rotational correlation time appropriate for octameric but not dimeric species. These results indicate proximity for the Cys-225 residues on adjacent monomers and that the subunits must interact in a tail-to-tail orientation. Moreover, disulfide bonds are not required for the formation of an octamer. C1 Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Han, MK (reprint author), Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. RI Paek, Domyung/D-5747-2012 NR 40 TC 17 Z9 17 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 12 PY 2002 VL 41 IS 10 BP 3468 EP 3476 DI 10.1021/bi015901e PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 530YQ UT WOS:000174387500021 PM 11876655 ER PT J AU Gaillard, WD Kopylev, L Weinstein, S Conry, J Pearl, PL Spanaki, MV Fazilat, S Fazilat, S Venzina, LG Dubovsky, E Theodore, WH AF Gaillard, WD Kopylev, L Weinstein, S Conry, J Pearl, PL Spanaki, MV Fazilat, S Fazilat, S Venzina, LG Dubovsky, E Theodore, WH TI Low incidence of abnormal (18)FDG-PET in children with new-onset partial epilepsy - A prospective study SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; POSITRON EMISSION TOMOGRAPHY; CEREBRAL GLUCOSE-METABOLISM; RESONANCE-IMAGING EVIDENCE; COMPLEX PARTIAL SEIZURES; HIPPOCAMPAL ATROPHY; FDG-PET; PRESURGICAL EVALUATION; FEBRILE CONVULSIONS; SURGICAL OUTCOMES AB Objective: Patients with refractory partial epilepsy often exhibit regional hypometabolism. It is unknown whether the metabolic abnormalities are present at seizure onset or develop over time. Methods: The authors studied 40 children within 1 year of their third unprovoked partial seizure with EEG, MRI, and [F-18]-fluorodeoxyglucose ((18)FDG)PET (mean age at seizure onset = 5.8 years, range 0.9 to 11.9 years; mean epilepsy duration = 1.1 years, range 0.3 to 2.3 years; mean number of seizures = 30, range 3 to 200). The authors excluded children with abnormal structural MRI, except four with mesial temporal sclerosis and two with subtle hippocampal dysgenesis. (18)FDG-PET was analyzed with a region of interest template. An absolute asymmetry index, \AI\, greater than 0.15 was considered abnormal. Results: Thirty-three children had a presumptive temporal lobe focus, five frontotemporal, and two frontal. Mean AI for all regions was not different from 10 normal young adults, even when children less likely to have a temporal focus were excluded. Eight of 40 children (20%) had focal hypometabolism, all restricted to the temporal lobe, especially inferior mesial and inferior lateral regions. Abnormalities were ipsilateral to the presumed temporal lobe ictal focus. Conclusions: Abnormalities of glucose utilization may be less common and profound in children with new-onset partial seizures than in adults with chronic partial epilepsy. Although these patients' prognosis is uncertain, resolution of epilepsy after three documented seizures is uncommon. If the subjects develop a higher incidence of hypometabolism in the future with planned follow-up studies, metabolic dysfunction may be related to persistent epilepsy rather than present at seizure onset. C1 George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neuroradiol, Washington, DC 20010 USA. NINCDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Biometry & Field Studies Branch, NIH, Bethesda, MD 20892 USA. RP Gaillard, WD (reprint author), George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NINDS NIH HHS [K08 NS01663] NR 47 TC 41 Z9 43 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 12 PY 2002 VL 58 IS 5 BP 717 EP 722 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 529LQ UT WOS:000174301300008 PM 11889233 ER PT J AU Plato, CC Galasko, D Garruto, RM Plato, M Gamst, A Craig, UK Torres, JM Wiederholt, W AF Plato, CC Galasko, D Garruto, RM Plato, M Gamst, A Craig, UK Torres, JM Wiederholt, W TI ALS and PDC of Guam - Forty-year follow-up SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; PARKINSONISM-DEMENTIA AB Background: It was noticed in the mid-1950s that the incidence of ALS and parkinsonism-dementia complex (PDC) were much higher on Guam than anywhere else in the world. In 1958, a registry of patients and controls was established to ascertain the familial and genetic aspects of these diseases. Patients and individually matched controls and their relatives were registered from 1958 to 1963. The registry was updated and analyzed in 1998 through 1999. Objective: To ascertain whether first-degree relatives of patients had a higher risk for developing ALS or PDC than relatives of controls. Methods: During the period of 1958 to 1963, 126 new patients and 126 individually matched controls and their respective first-degree relatives and spouses were evaluated neurologically and registered. Forty years later, the number of new cases among the patient and control relatives were compared to an expected number of new cases based on the age- and sex-specific incidence of ALS and PDC in the population at large. Results: From 1958 to 1999, there were 102 new ALS or PDC cases among relatives of patients and 33 among relatives of controls. These values were compared with the derived expected values. There were more observed than expected new cases among patients' relatives, and less observed cases than expected among the controls' relatives. Conclusions: Relatives of patients with ALS or PDC have significantly higher risks for developing the disease than the Guamanian population, whereas relatives of controls have significantly lower risks. C1 Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA. SUNY Binghamton, Dept Anthropol & Biol Sci, Binghamton, NY USA. NIH, Cent Nervous Syst Studies Lab, Bethesda, MD 20892 USA. Univ Guam, Mangilao, GU USA. Athi Media, San Diego, CA USA. RP Plato, CC (reprint author), Univ Calif San Diego, Sch Med, Dept Neurosci, 9500 Gilman Dr, La Jolla, CA 92093 USA. FU NIA NIH HHS [AG14382] NR 21 TC 48 Z9 50 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 12 PY 2002 VL 58 IS 5 BP 765 EP 773 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 529LQ UT WOS:000174301300015 PM 11889241 ER PT J AU Molloy, FM Shill, HA Kaelin-Lang, A Karp, BI AF Molloy, FM Shill, HA Kaelin-Lang, A Karp, BI TI Accuracy of muscle localization without EMG: Implications for treatment of limb dystonia SO NEUROLOGY LA English DT Article ID BOTULINUM TOXIN INJECTIONS; SPASMODIC TORTICOLLIS; CERVICAL DYSTONIA; DOUBLE-BLIND; DIFFUSION; TRIAL AB Although botulinum toxin is an effective treatment for focal dystonia, the importance of electromyography (EMG) in identifying muscles and guiding injections is unclear. The authors examined the accuracy of muscle localization in 38 muscles in patients with focal hand dystonia. without EMG guidance. Only 37% of needle placement attempts reached the target muscles or muscle fascicles. This study demonstrates that EMG guidance is needed for correct localization of desired muscles. C1 NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINCDS, Cort Physiol Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Karp, BI (reprint author), NINCDS, Human Motor Control Sect, NIH, Bldg 10,Rm 5S209,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. NR 10 TC 62 Z9 65 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 12 PY 2002 VL 58 IS 5 BP 805 EP 807 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 529LQ UT WOS:000174301300021 PM 11889247 ER PT J AU Goel, A Mazur, SJ Fattah, RJ Hartman, TL Turpin, JA Huang, MJ Rice, WG Appella, E Inman, JK AF Goel, A Mazur, SJ Fattah, RJ Hartman, TL Turpin, JA Huang, MJ Rice, WG Appella, E Inman, JK TI Benzamide-based thiolcarbamates: A new class of HIV-1NCp7 inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 NUCLEOCAPSID PROTEIN; ZINC FINGERS; ANTI-HIV; IN-VITRO; NONINFECTIOUS VIRUS; RNA; GAG; INFECTIVITY; BENZISOTHIAZOLONES AB The HIV-1 nucleocapsid protein NCp7, which contains two highly conserved zinc fingers, is being used as a novel target for AIDS therapy due to its pivotal role in viral replication and its mutationally intolerant nature. Herein we report a new class of NCp7 inhibitors that possess good antiviral activity with low cellular toxicity. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. So Res Inst, Infect Dis Res Dept, Frederick, MD 21702 USA. Achill Pharmaceut Inc, New Haven, CT 06511 USA. RP Inman, JK (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 66 Z9 67 U1 0 U2 6 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 11 PY 2002 VL 12 IS 5 BP 767 EP 770 AR PII S0960-894X(02)00007-0 DI 10.1016/S0960-894X(02)00007-0 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 532AM UT WOS:000174449500010 PM 11858998 ER PT J AU Vallone, D Pignatelli, M Grammatikopoulos, G Ruocco, L Bozzi, Y Westphal, H Borrelli, E Sadile, AG AF Vallone, D Pignatelli, M Grammatikopoulos, G Ruocco, L Bozzi, Y Westphal, H Borrelli, E Sadile, AG TI Activity, non-selective attention and emotionality in dopamine D2/D3 receptor knock-out mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Symposium on Dopamine Hypothesis of ADHD CY FEB 14-25, 2000 CL UNIV CASTILLA LA MANCHA, CASTILLA LA MANCHA, SPAIN HO UNIV CASTILLA LA MANCHA DE dopamine receptors; dopamine receptor mutants; knock-out mice; orienting; scanning times; genetic models; ADHD ID DEFICIT HYPERACTIVITY DISORDER; NONSELECTIVE ATTENTION; NITRIC-OXIDE; BEHAVIOR; NOVELTY; INHIBITOR; RESPONSES; RATS AB In order to assess the role of dopamine (DA) D2 and D3 receptors in the modulation of behaviour, we analysed exploration in a spatial novelty in mouse model systems. Genetically engineered mice mutants have been used that carry normal, partial or no expression of D2R, D3R, or both D2R/D3R (double mutants) DA receptor subtypes. Adult male mice were exposed for 30 min to a 1-Ate-maze. The behaviour was analysed for indices of activity, orienting (rearing frequency), scanning times (rearing duration) and defecation score (emotionality). D2R - / - and + / - as well as the D2R/D3R double homozygous mutants were less active than wild-type (WT) controls in travelled distance. In contrast D3R + / - were more active than WT mice in the first part of the test. As to orienting frequency, the D2R - / - were less active than WT during the entire test-period, whereas the D2 + / - mutants were less active than WT only in the second part of the test. Moreover, the D3R -/ - and + / - mutants showed less and more rearing frequency than WT, respectively, during the entire test. Finally, the D2/D3R - / - double mutants were also less active than WT during the entire test period. As to scanning times, D2R + and mutants were higher than WT during the entire test or only in the second part, respectively. The D3R + and were not different from WT, whereas the D2/D3R - / - double mutants showed shorter scanning times only in the first part of the test. As to emotionality index, the defecation score, was lower only in D3R + / - mutants. Thus, the dopamine D2 and D3 receptor subtypes appear to be differentially involved in the modulation of activity, orienting and scanning phases of attention. Lastly double mutation experiments reveal an interaction between D2R and D3R with the former prevailing on the latter. (C) 2002 Elsevier Science B.V. All rights reserved. C1 ULP, INSERM, CNRS, Inst Genet Mol Biol, Strasbourg, France. NIH, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. Univ Naples 2, Sect Human Physiol F Bottazzi, Dept Expt Med, Lab Neurophysiol Behav & Neural Networks, I-80138 Naples, Italy. RP Sadile, AG (reprint author), Univ Naples 2, Dept Expt Med, Sect Human Physiol, Lab Neurophysiol Behav & Neural Networks, Costantinopoli 16, I-80138 Naples, Italy. OI sadile, adolfo/0000-0003-2470-3328 FU Telethon [E.0513] NR 35 TC 29 Z9 32 U1 0 U2 3 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 10 PY 2002 VL 130 IS 1-2 SI SI BP 141 EP 148 AR PII S0166-4328(01)00428-4 DI 10.1016/S0166-4328(01)00428-4 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 536VF UT WOS:000174722000018 PM 11864730 ER PT J AU Shimamura, T Hsu, TC Colburn, NH Bejcek, BE AF Shimamura, T Hsu, TC Colburn, NH Bejcek, BE TI Activation of NF-kappa B is required for PDGF-B chain to transform NIH3T3 cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTORS; PHOSPHOLIPASE-C-GAMMA; FACTOR-BETA-RECEPTOR; BREAST-CANCER; IN-VIVO; PHOSPHATIDYLINOSITOL-3 KINASE; AUTOPHOSPHORYLATION SITES; CELLULAR-TRANSFORMATION; SELECTIVE-INHIBITION; MOUSE FIBROBLASTS AB Elucidating the secondary signaling molecules that are necessary for platelet-derived growth factor (PDGF) to stimulate tumor development will be crucial to the understanding and treatment of a variety of cancers. Several lines of evidence have indicated that the transcription factor NF-kappaB plays a central role in transformation induced by Ha-ras and Bcr-abl, but nothing is known concerning its role in transformation by PDGF. Here we demonstrate that transcription from a promoter containing NF-kappaB binding sequences as well as the DNA binding activity of NF-kappaB were increased in PDGF-B-chain-transformed mouse fibroblast cells. Focus formation of PDGF-B-chain-transformed mouse fibroblasts was suppressed by treatment with acetylsalicylic acid (ASA) and salicylic acid, which are known inhibitors of NF-kappaB activation, but other nonsteroidal anti-inflammatory drugs that do not have an effect on NF-kappaB activity did not affect focus formation in these cells. Furthermore, expression of a dominant negative mutant of IkappaBalpha, pMEIkappaBalpha67CJ, and a dominant negative mutant of p65, p65DeltaC, resulted in decreased focus formation and NF-kappaB activity. Therefore, the transcription factor NF-kappaB plays a vital role in PDGF-B chain transformation of mouse fibroblast cells, and the NF-kappaB activity is sensitive to treatment with ASA. (C) 2002 Elsevier Science (USA). C1 Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA. NCI, Basic Res Lab, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Bejcek, BE (reprint author), Western Michigan Univ, Dept Biol Sci, Kalamazoo, MI 49008 USA. FU NCI NIH HHS [R29CA69477] NR 67 TC 8 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAR 10 PY 2002 VL 274 IS 1 BP 157 EP 167 DI 10.1006/excr.2001.5449 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 531FZ UT WOS:000174406500017 PM 11855867 ER PT J AU Blagosklonny, MV AF Blagosklonny, MV TI P53: An ubiquitous target of anticancer drugs SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE p53; tumor suppressor; cancer; chemotherapy; anticancer strategies ID WILD-TYPE P53; HUMAN CANCER-CELLS; INDUCIBLE FACTOR 1-ALPHA; HUMAN TUMOR-CELLS; MUTANT P53; DNA-DAMAGE; PROTEASOME INHIBITION; FEEDBACK LOOP; IN-VIVO; THERAPEUTIC AGENTS AB The p53 tumor suppressor can induce growth arrest, apoptosis and cell senescence. Not surprisingly, p53 is an appealing target for therapeutic intervention. Although current anticancer agents do not directly interact with p53, these agents (including DNA damaging drugs, anti metabolites, microtubule-active drugs and inhibitors of the proteasome) cause accumulation of wt p53. Depending on the p53 status of cancer cells, diverse therapeutic strategies are under development. These include pharmacological rescue of mutant p53 function and reactivation of wt p53 in E6-expressing cells. For protection of normal cells, strategies range from abrogation of wt p53 induction, thereby decreasing the toxicity of DNA damaging agents, to activation of wt p53-dependent checkpoints, thereby protecting cells against cell cycle-dependent therapeutics. (C) 2002 Wiley-Liss, Inc. C1 NIH, NCI, Med Branch, Bethesda, MD 20892 USA. New York Med Coll, Dept Med, Valhalla, NY 10595 USA. RP Blagosklonny, MV (reprint author), NIH, NCI, Med Branch, Bldg 10,Room 12 N 226, Bethesda, MD 20892 USA. NR 109 TC 99 Z9 107 U1 2 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 10 PY 2002 VL 98 IS 2 BP 161 EP 166 DI 10.1002/ijc.10158 PG 6 WC Oncology SC Oncology GA 522ML UT WOS:000173901100001 PM 11857402 ER PT J AU Fichtenbaum, CJ Gerber, JG Rosenkranz, SL Segal, Y Aberg, JA Blaschke, T Alston, B Fang, F Kosel, B Aweeka, F AF Fichtenbaum, CJ Gerber, JG Rosenkranz, SL Segal, Y Aberg, JA Blaschke, T Alston, B Fang, F Kosel, B Aweeka, F CA NIAID AIDS Clinical Trials Grp TI Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047 SO AIDS LA English DT Article DE HIV infection; HMG-CoA reductase inhibitors; statins; protease inhibitors; drug interactions ID COA REDUCTASE INHIBITORS; BIOTRANSFORMATION PRODUCTS; HUMAN SERUM; RHABDOMYOLYSIS; SIMVASTATIN; ITRACONAZOLE; PRAVASTATIN; LOVASTATIN; HYPERLIPIDEMIA; ATORVASTATIN AB Objective: Lipid lowering therapy is used increasingly in persons with HIV infection in the absence of safety data or information on drug interactions with antiretroviral agents. The primary objectives of this study were to examine the effects of ritonavir (RTV) plus saquinavir soft-gel (SQVsgc) capsules on the pharmacokinetics of pravastatin, simvastatin, and atorvastatin, and the effect of pravastatin on the pharmacokinetics of nelfinavir (NFV) in order to determine clinically important drug-drug interactions. Design: Randomized, open-label study in healthy, HIV seronegative adults at AIDS Clinical Trials Units across the USA. Methods: Three groups of subjects (arms 1, 2, and 3) received pravastatin, simvastatin or atorvastatin (40 mg daily each) from days 1-4 and 15-18. In these groups, RTV 400 mg and SQVsgc 400 mg twice daily were given from days 4-18. A fourth group (arm 4) received NFV 1250 mg twice daily from days 1-14 with pravastatin 40 mg daily added from days 15-18. Statin and NFV levels were measured by liquid chromatography/tandem mass spectrometry. Results: Fifty-six subjects completed both pharmacokinetic study days. In arms 1-3, the median estimated area under the curves (AUC)(0-24) for the statins were: pravastatin (arm 1, n = 13), 151 and 75 ng.h/ml on days 4 and 18 (decline of 50% in presence of RTV/SQVsgc), respectively (P= 0.005); simvastatin (arm 2, n = 14), 17 and 548 ng.h/ml on days 4 and 18 (increase of 3059% in the presence of RTV/SQVsgc), respectively (P < 0.001); and total active atorvastatin (arm 3, n = 14), 167 and 289 ng.h/ml on days 4 and 18 (increase of 79% in the presence of RTV/SQVsgc), respectively (P < 0.001). In arm 4, the median estimated AUC(0-8) for NFV (24 319 versus 26 760 ng.h/ml; P=0.58) and its active M8 metabolite (15565 versus 14571 ng.h/m; P=0.63) were not statistically different from day 14 to day 18 (without or with pravastatin). Conclusions: Simvastatin should be avoided and atorvastatin may be used with caution in persons taking RTV and SQVsgc. Dose adjustment of pravastatin may be necessary with concomitant use of RTV and SQVsgc. Pravastatin does not alter the NFV pharmacokinetics, and thus appears to be safe for concomitant use. (C) 2001 Lippincott Williams Wilkins. C1 Univ Cincinnati, Coll Med, Cincinnati, OH USA. Washington Univ, St Louis, MO USA. Univ Colorado, Coll Hlth Sci, Denver, CO USA. Harvard Univ, Sch Publ Hlth, SDAC, Boston, MA 02115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Stanford Univ, Stanford, CA 94305 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Pharmacia & Upjohn Inc, Kalamazoo, MI 49001 USA. RP Fichtenbaum, CJ (reprint author), Univ Cincinnati, Coll Med, Holmes Hosp, Mail Locat 0405,Eden Ave & Albert Sabin Way, Cincinnati, OH 45267 USA. FU NCRR NIH HHS [5M01-RR-00051-37, 5M01-RR-00070-38, 5M01-RR-00083-37]; NIAID NIH HHS [AI-25903, AI-25897, AI-27666, AI-38855, AI-38858] NR 41 TC 199 Z9 206 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 8 PY 2002 VL 16 IS 4 BP 569 EP 577 DI 10.1097/00002030-200203080-00008 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 530PA UT WOS:000174367100008 PM 11873000 ER PT J AU Maher, BS Marazita, ML Zubenko, WN Spiker, DG Giles, DE Kaplan, BB Zubenko, GS AF Maher, BS Marazita, ML Zubenko, WN Spiker, DG Giles, DE Kaplan, BB Zubenko, GS TI Genetic segregation analysis of recurrent, early-onset major depression: Evidence for single major locus transmission SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE genetics; complex segregation analysis; major depression; recurrent mood; disorders; single major locus transmission ID AFFECTIVE-DISORDERS; PSYCHIATRIC-DISORDERS; UNIPOLAR DEPRESSION; BIPOLAR DISORDER; FAMILY HISTORY; TWIN; ILLNESS; RISK; SCHIZOPHRENIA; HERITABILITY AB Coordinated efforts are now underway to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders. These studies have focused on recurrent, early-onset MDD (RE-MDD), thought to be the most familial form of this disorder. The goal of this study was to conduct a complex segregation analysis of recurrent MDD and other major mood disorders aggregating in families identified by probands with RE-MDD. Eighty-one families were identified through probands over the age of 18 who met criteria for recurrent (greater than or equal to2 episodes), early-onset (less than or equal to25 years), nonpsychotic, unipolar MDD (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best-estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. The segregation analysis of recurrent MDD supported a sex-independent Mendelian codominant model. Analysis of major mood disorders supported a sex-independent Mendelian dominant model. Interestingly, inclusion of spousal residual correlations provided better fitting models for recurrent MDD but not the broader phenotype of major mood disorders. Unlike unipolar MDD, the lifetime prevalence of bipolar I disorder in this sample of families did not exceed the reported population prevalence [Zubenko et al., 2001]. Our results suggest that a major locus contributes to the expression of recurrent MDD and possibly other major mood disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). The absence of aggregation of bipolar I disorder in these families strongly suggests that while the genetic determinants of unipolar and bipolar disorders may overlap, they are not identical. Our findings illustrate the advantage of employing families identified by probands with RE-MDD in studies designed to detect susceptibility loci for unipolar MDD and related disorders. (C) 2002 Wiley-Liss, Inc. C1 Univ Pittsburgh, Sch Dent Med, Div Oral Biol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15213 USA. Univ Rochester, Sch Med, Dept Psychiat, Rochester, NY USA. Univ Rochester, Sch Med, Dept Neurol, Rochester, NY USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Mellon Coll Sci, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Zubenko, GS (reprint author), WPIC, Room E1230,3811 OHara ST, Pittsburgh, PA 15213 USA. RI Maher, Brion/F-9185-2010 FU NCRR NIH HHS [1-P41-RR03655]; NIMH NIH HHS [MH60866, MH48969, MH00540] NR 51 TC 24 Z9 25 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD MAR 8 PY 2002 VL 114 IS 2 BP 214 EP 221 DI 10.1002/ajmg.10158 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 523AU UT WOS:000173929800014 PM 11857584 ER PT J AU Hardy, J AF Hardy, J TI The real problem in association studies SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Letter C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,6C103, Bethesda, MD 20892 USA. RI Hardy, John/C-2451-2009 NR 1 TC 8 Z9 8 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD MAR 8 PY 2002 VL 114 IS 2 BP 253 EP 253 DI 10.1002/ajmg.10294 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 523AU UT WOS:000173929800020 PM 11857590 ER PT J AU Hofmann, A Tarasov, S Grella, M Ruvinov, S Nasr, F Filipowicz, W Wlodawer, A AF Hofmann, A Tarasov, S Grella, M Ruvinov, S Nasr, F Filipowicz, W Wlodawer, A TI Biophysical characterization of cyclic nucleotide phosphodiesterases SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cyclic nucleotide phosphodiesterases; isothermal titration calorimetry; sedimentation equilibrium analysis; ultracentrifugation; urea denaturation ID RIBOSE 1'',2''-CYCLIC PHOSPHATE; WHEAT-GERM; PURIFICATION; METABOLISM; MECHANISM; CLONING; YEAST AB We have compared selected biophysical properties of three phosphodiesterases, from Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli. All of them belong to a recently identified family of cyclic nucleotide phosphodiesterases. Experiments elucidating folding stability, protein fluorescence, oligomerization behavior, and the effects of substrates were conducted, revealing differences between the plant and the yeast protein. According to CD spectroscopy, the latter protein exhibits an (alpha + beta) fold rather than an (alpha/beta) fold as found with CPDase (A. thaliana). The redox-dependent structural reorganization recently found for the plant protein by X-ray crystallography could not be detected by CD spectroscopy due to its only marginal effect on the total percentage of helical content. However, in the present study a redox-dependent effect was also observed for the yeast CPDase. The enzymatic activity of wild type CPDase (A. thaliana) as well as of four mutants were characterized by isothermal titration calorimetry and the results prove the requirement of all four residues of the previously identified tandem signature motif for the catalytic function. Within the comparison of the three proteins in this study, the PDase Homolog/RNA ligase (E. coli) shares more similarities with the plant than with the yeast protein. C1 NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Struct Biophys Lab, Frederick, MD 21702 USA. NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Friedrich Miescher Inst Biomed Res, CH-4002 Basel, Switzerland. RP Hofmann, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Hofmann, Andreas/B-9515-2008 OI Hofmann, Andreas/0000-0003-4408-5467 NR 17 TC 8 Z9 9 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 8 PY 2002 VL 291 IS 4 BP 875 EP 883 DI 10.1006/bbrc.2002.6527 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 532EJ UT WOS:000174458400023 PM 11866446 ER PT J AU Montell, C Birnbaumer, L Flockerzi, V AF Montell, C Birnbaumer, L Flockerzi, V TI The TRP channels, a remarkably functional family SO CELL LA English DT Review AB TRIP cation channels display an extraordinary assortment of selectivities and activation mechanisms, some of which represent previously unrecognized modes for regulating ion channels. Moreover, the biological roles of TRP channels appear to be equally diverse and range from roles in pain perception to male aggression. C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Saarland, Inst Pharmakol & Toxikol, D-66421 Homburg, Germany. RP Montell, C (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. RI Marion-Poll, Frederic/D-8882-2011; OI Marion-Poll, Frederic/0000-0001-6824-0180; Montell, Craig/0000-0001-5637-1482 NR 20 TC 534 Z9 555 U1 0 U2 26 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAR 8 PY 2002 VL 108 IS 5 BP 595 EP 598 DI 10.1016/S0092-8674(02)00670-0 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 529TN UT WOS:000174314800004 PM 11893331 ER PT J AU Tong, HY Imahashi, K Steenbergen, C Murphy, E AF Tong, HY Imahashi, K Steenbergen, C Murphy, E TI Phosphorylation of glycogen synthase kinase-3 beta during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective SO CIRCULATION RESEARCH LA English DT Article ID CELL-SURVIVAL; TRANSCRIPTION AB We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3beta, we examined whether PC-induced phosphorylation and inhibition of GSK-3beta is important in PC by using two inhibitors of GSK-3beta, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3beta is protective and that this PI3-kinase-dependent signaling pathway may play an important role in ischemic preconditioning. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [HL-39752, R01 HL039752] NR 11 TC 253 Z9 269 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 8 PY 2002 VL 90 IS 4 BP 377 EP 379 DI 10.1161/01.RES.0000012567.95445.55 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 532PM UT WOS:000174484300006 PM 11884365 ER PT J AU Terskikh, AV Fradkov, AF Zaraisky, AG Kajava, AV Angres, B AF Terskikh, AV Fradkov, AF Zaraisky, AG Kajava, AV Angres, B TI Analysis of DsRed mutants - Space around the fluorophore accelerates fluorescence development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN; MUTAGENESIS; CORAL AB Earlier mutagenesis of the red fluorescent protein drFP583, also called DsRed, resulted in a mutant named Fluorescent Timer (Terskikh, A., Fradkov, A., Ermakova, G., Zaraisky, A., Tan, P., Kajava, A. V., Zhao, X., Lukyanov, S., Matz, M., Kim, S., Weissman, I., and Siebert, P. (2000) Science 290, 1585-1588). Further mutagenesis generated variants with novel and improved fluorescent properties. The mutant called AG4 exhibits only green fluorescence. The mutant, called E5up (V105A), shows complete fluorophore maturation, eventually eliminating residual green fluorescence present in DsRed. Finally, the mutant, called E57 (V105A, I161T, S197A), matures faster than DsRed as demonstrated in vitro with purified protein and in vivo with recombinant protein expressed in Escherichia coli and Xenopus leavis. Comparative analysis of the mutants in the context of the crystal structure of DsRed suggests that mutants with free space around the fluorophore mature faster and more completely. C1 Stanford Univ, Dept Pathol, Sch Med, Beckman Ctr, Stanford, CA 94305 USA. Russian Acad Sci, Shemiakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. BD Biosci Clontech, Palo Alto, CA 94303 USA. RP Terskikh, AV (reprint author), Stanford Univ, Dept Pathol, Sch Med, Beckman Ctr, 279 Campus Dr, Stanford, CA 94305 USA. RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 NR 18 TC 57 Z9 57 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2002 VL 277 IS 10 BP 7633 EP 7636 DI 10.1074/jbc.C100694200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000002 PM 11773062 ER PT J AU Hatters, DM Minton, AP Howlett, GJ AF Hatters, DM Minton, AP Howlett, GJ TI Macromolecular crowding accelerates amyloid formation by human apolipoprotein C-II SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE; PROTEINS; AGGREGATION; FIBRILLOGENESIS; CONSEQUENCES; EVOLUTION; PEPTIDES; ASSAY AB Human apolipoprotein C-II (apoC-H) slowly forms amyloid fibers in lipid-firee solutions at physiological pH and salt concentrations (Hatters, D. M., MacPhec, C. E., Lawrence, L. J., Sawyer, W. H., and Howlett, G. J. (2000) Biochemistry 39, 8276-8283). Measurements of the time dependence of solution turbidity, thioflavin T reactivity, and the amount of sedimentable aggregate reveal that the rate and extent of amyloid formation are significantly increased by the addition of an inert polymer, dextran T10, at concentrations exceeding 20 g/liter. High dextran concentrations do not alter the secondary structure of the protein, fiber morphology, or the thioflavin T and Congo Red binding capacity of apoC-H amyloid. Analytical ultracentrifugation studies show that monomeric apoC-II does not associate significantly with dextran. The observed dependence of the overall rate of amyloid formation on dextran concentration may be accounted for quantitatively by a simple model for nonspecific volume exclusion. The model predicts that an increase in the fractional volume occupancy of macromolecules in a physiological fluid can nonspecifically accelerate the formation of amyloid fibers by any amyloidogenic protein. C1 Univ Melbourne, Dept Biochem & Mol Biol, Russell Grimwade Sch Biochem & Mol Biol, Parkville, Vic 3010, Australia. NIDDK, Sect Phys Biochem, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Howlett, GJ (reprint author), Univ Melbourne, Dept Biochem & Mol Biol, Russell Grimwade Sch Biochem & Mol Biol, Parkville, Vic 3010, Australia. OI Hatters, Danny/0000-0002-9965-2847; Minton, Allen/0000-0001-8459-1247 NR 46 TC 169 Z9 172 U1 1 U2 26 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 8 PY 2002 VL 277 IS 10 BP 7824 EP 7830 DI 10.1074/jbc.M110429200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000027 PM 11751863 ER PT J AU Beard, WA Shock, DD Yang, XP DeLauder, SF Wilson, SH AF Beard, WA Shock, DD Yang, XP DeLauder, SF Wilson, SH TI Loss of DNA polymerase beta stacking interactions with templating purines, but not pyrimidines, alters catalytic efficiency and fidelity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; BASE EXCISION-REPAIR; CRYSTAL-STRUCTURE; NUCLEOTIDE INCORPORATION; TERNARY COMPLEXES; LARGE FRAGMENT; MINOR-GROOVE; ACTIVE-SITE; B-DNA; REPLICATION AB Structures of DNA polymerases bound with DNA reveal that the 5'-trajectory of the template strand is dramatically altered as it exits the polymerase active site. This distortion provides the polymerase access to the nascent base pair to interrogate proper Watson-Crick geometry. Upon binding a correct deoxynucleoside triphosphate, a-helix N of DNA polymerase 13 is observed to form one face of the binding pocket for the new base pair. Asp-276 and Lys-280 stack with the bases of the incoming nucleotide and template, respectively. To determine the role of Lys-280, site-directed mutants were constructed at this position, and the proteins were expressed and purified, and their catalytic efficiency and fidelity were assessed. The catalytic efficiency for single-nucleotide gap filling with the glycine mutant (K280G) was strongly diminished relative to wild type for templating purines (>15-fold) due to a decreased binding affinity for the incoming nucleotide. In contrast, catalytic efficiency was hardly affected by glycine substitution for templating pyrimidines (<4-fold). The fidelity of the glycine mutant was identical to the wild type enzyme for misinsertion opposite a template thymidine, whereas the fidelity of misinsertion opposite a template guanine was modestly altered. The nature of the Lys-280 side-chain substitution for thymidine triphosphate insertion (templating adenine) indicates that Lys-280 "stabilizes" templating purines through van der Waals interactions. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. N Carolina Cent Univ, Dept Chem, Durham, NC 27707 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 44 TC 63 Z9 63 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2002 VL 277 IS 10 BP 8235 EP 8242 DI 10.1074/jbc.M107286200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000078 PM 11756435 ER PT J AU Touz, MC Nores, MJ Slavin, I Carmona, C Conrad, JT Mowatt, MR Nash, TE Coronel, CE Lujan, HD AF Touz, MC Nores, MJ Slavin, I Carmona, C Conrad, JT Mowatt, MR Nash, TE Coronel, CE Lujan, HD TI The activity of a developmentally regulated cysteine proteinase is required for cyst wall formation in the primitive eukaryote Giardia lamblia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIPEPTIDYL PEPTIDASE-I; RIBOSOMAL-RNA; BREFELDIN-A; CATHEPSIN-C; EXPRESSION; DIFFERENTIATION; TROPHOZOITES; EXCYSTATION; ENCYSTATION; INVITRO AB Giardia is an intestinal parasite that belongs to the earliest diverging branch of the eukaryotic lineage of descent. Giardia undergoes adaptation for survival outside the host's intestine by differentiating into infective cysts. Encystation involves the synthesis and transport of cyst wall constituents to the plasma membrane for release and extracellular organization. Nevertheless, little is known about the molecular events related to cyst wall biogenesis in Giardia. Among the components of the cyst wall there are two proteins that we have previously identified and characterized: CWP1 (26 kDa) and CWP2 (39 kDa). Expression of these proteins is coordinately induced, and both concentrated within encystation-specific secretory vesicles before their extracellular polymerization. Although highly similar to each other at the amino terminus, CWP2 includes a COOH-terminal 121-amino acid extension. Here, we show that this extension, rich in basic residues, is cleaved from CWP2 before cyst wall formation by an intracellular cysteine proteinase activity, which is induced during encystation like CWPs. Specific inhibitors prevent release of cyst wall materials, abolishing cyst wall formation. We also report the purification, cloning, and characterization of the encystation-specific cysteine proteinase responsible for the proteolytic processing of CWP2, which is homologue to lysosomal cathepsin C. Encystation-specific cysteine proteinase ESCP possesses unique characteristics compared with cathepsins from higher eukaryotes, such as a transmembrane domain and a short cytoplasmic tail. These features make this enzyme the most divergent cathepsin C identified to date and provide new insights regarding cyst wall formation in Giardia. C1 Univ Nacl Cordoba, Fac Ciencias Med, Catedra Bioquim & Biol Mol, RA-5000 Cordoba, Argentina. Fac Ciencias, Unidad BIol Parasitaria, Montevideo 11600, Uruguay. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lujan, HD (reprint author), Univ Nacl Cordoba, Fac Ciencias Med, Catedra Bioquim & Biol Mol, Pabellon Argentina 2de Piso,Ciudad Univ, RA-5000 Cordoba, Argentina. NR 71 TC 77 Z9 78 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 8 PY 2002 VL 277 IS 10 BP 8474 EP 8481 DI 10.1074/jbc.M110250200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000108 PM 11773053 ER PT J AU Klotz, DM Hewitt, SC Ciana, P Raviscioni, M Lindzey, JK Foley, J Maggi, A DiAugustine, RP Korach, KS AF Klotz, DM Hewitt, SC Ciana, P Raviscioni, M Lindzey, JK Foley, J Maggi, A DiAugustine, RP Korach, KS TI Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; FACTOR-I; SIGNALING PATHWAYS; GENE-EXPRESSION; RAT UTERUS; ESTRADIOL; PHOSPHORYLATION; MOUSE; TRANSCRIPTION; BINDING AB In the uterus insulin-like growth factor-1 (IGF-1) signaling can be initiated by estradiol acting through its nuclear receptor (estrogen receptor (ER)) to stimulate the local synthesis of IGF-1. Conversely, in vitro studies have demonstrated that estradiol-independent ER transcriptional activity can be induced by IGF-1 signaling, providing evidence for a cross-talk mechanism between IGF-1 and ER. To investigate whether ERalpha is required for uterine responses to IGF-1 in vivo, both wild-type (WT) and ERalpha knockout (alphaERKO) mice were administered IGF-1, and various uterine responses to IGF-1 were compared. In both WT and alphaERKO mice, IGF-1 treatment resulted in phosphorylation of uterine IGF-1 receptor (IGF-1R) and formation of an IGF-1R/insulin receptor substrate-1/ phosphatidylinositol 3-kinase signaling complex. In addition, IGF-1 stimulated phosphorylation of uterine Akt and MAPK in both WT and alphaERKO mice. However, IGF-1 treatment stimulated BrdUrd incorporation and proliferating cell nuclear antigen expression in WT uteri only. To determine whether ERalpha can be activated in vivo by IGF-1 signaling, transgenic mice carrying a luciferase gene driven by two estrogen response elements (ERE-luciferase mice) were utilized. Treatment of ovariectomized ERE-luciferase mice with IGF-1 resulted in an increase in uterine luciferase activity that was attenuated in the presence of the ER antagonist ICI 182,780. Together these data demonstrate that 1) functional signaling proximal to IGF-1R is maintained in the alphaERKO mouse uterus, 2) ERalpha is necessary for IGF-1 induction of uterine nuclear proliferative responses, and 3) cross-talk between IGF-1R and ER signaling pathways exists in vivo. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy. Univ S Florida, Dept Biol, Tampa, FL 33620 USA. RP Korach, KS (reprint author), NIEHS, Lab Expt Pathol, NIH, POB 12233,Maildrop B3-02, Res Triangle Pk, NC 27709 USA. RI Ciana, Paolo /F-9224-2012; OI Korach, Kenneth/0000-0002-7765-418X NR 32 TC 198 Z9 206 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2002 VL 277 IS 10 BP 8531 EP 8537 DI 10.1074/jbc.M109592200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000115 PM 11751931 ER PT J AU O'Brien, KB O'Shea, JJ Carter-Su, C AF O'Brien, KB O'Shea, JJ Carter-Su, C TI SH2-B family members differentially regulate JAK family tyrosine kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INSULIN-RECEPTOR KINASE; MICE LACKING JAK3; GROWTH-HORMONE; ADAPTER PROTEIN; SIGNAL-TRANSDUCTION; C-CBL; MOLECULAR-CLONING; PROMOTER ACTIVITY; INTERFERON-GAMMA; PDGF RECEPTOR AB Activation of JAK tyrosine kinases is an essential step in cell signaling by multiple hormones, cytokines, and growth factors, including growth hormone (GH) and interferon-gamma. Previously, we identified SH2-1313 as a potent activator of JAK2 (Rui, L., and Carter-Su, C. (1999) Proc. Natl. Acad. Sci. U. S. A 96, 7172-7177). Here, we investigated whether the activation of JAK2 by SH2-Bbeta is specific to JAK2 and SH2-Bbeta or extends to other JAKs or other members of the SH2-1313 family. When SH2-1313 was overexpressed with JAK1 or JAK3, SH2-Bbeta failed to increase their activity. However, SH2-Bbeta bound to both and was tyrosyl-phosphorylated by JAK1. In contrast to SH2-Bbeta,6, APS decreased tyrosyl phosphorylation of GH-stimulated JAK2 as well as Stat5B, a substrate of JAK2. APS also decreased tyrosyl phosphorylation of JAK1, but did not affect the activity or tyrosyl phosphorylation of JAK3. Overexpressed APS bound to and was tyrosylphosphorylated by all three JAKs. Consistent with these data, in 3T3-F442A adipocytes, endogenous APS was tyrosyl-phosphorylated in response to GH and interferon-gamma. These results suggest that 1) SH2-Bbeta specifically activates JAK2, 2) APS negatively regulates both JAK2 and JAK1, and 3) both SH2-Bbeta and APS may serve as adapter proteins for all three JAKs independent of any role they have in JAK activity. C1 Univ Michigan, Sch Med, Dept Physiol, Ann Arbor, MI 48109 USA. NIAMS, NIH, Bethesda, MD 20892 USA. RP Carter-Su, C (reprint author), Univ Michigan, Sch Med, Dept Physiol, 6804 Med Sci 2,1301 E Catherine St, Ann Arbor, MI 48109 USA. FU NCI NIH HHS [T32CAO96760]; NIDDK NIH HHS [DK34171, DK54222, R01 DK034171, R01 DK054222] NR 67 TC 39 Z9 41 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2002 VL 277 IS 10 BP 8673 EP 8681 DI 10.1074/jbc.M109165200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528WR UT WOS:000174268000133 PM 11751854 ER PT J AU Liu, DG Gao, Y Wang, XZ Kelley, JA Burke, TR AF Liu, DG Gao, Y Wang, XZ Kelley, JA Burke, TR TI Enantioselective synthesis of N-alpha-Fmoc protected (2S,3R)-3-phenylpipecolic acid. A constrained phenylalanine analogue suitably protected for solid-phase peptide synthesis SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ASYMMETRIC-SYNTHESIS; AZIDATION; DESIGN AB Reported herein is the first enantioselective preparation of (2S,3R)-3-phenylpipecolic acid as a conformationally constrained phenylalanine analogue bearing N-a-protection suitable for solid-phase peptide synthesis. Stereochemistries at both the 2- and 3-positions are derived inductively from a single chiral center provided by the commercially available Evans chiral auxiliary, (4S)-4-benzyl-1,3-oxazolidin-2-one. By constraining phi and x(1) torsion angles, this novel amino acid analogue can serve as a useful tool for the induction of defined geometry in phenylalanine-containing peptides. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, Bldg 376,Boyles St,POB B, Frederick, MD 21702 USA. RI Burke, Terrence/N-2601-2014 NR 22 TC 13 Z9 13 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAR 8 PY 2002 VL 67 IS 5 BP 1448 EP 1452 DI 10.1021/jo010124+ PG 5 WC Chemistry, Organic SC Chemistry GA 531CV UT WOS:000174399200005 PM 11871872 ER PT J AU Junn, E Mouradian, MM AF Junn, E Mouradian, MM TI Human alpha-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine SO NEUROSCIENCE LETTERS LA English DT Article DE alpha-synuclein; reactive oxygen species; Parkinson's disease; dopamine; cell death ID PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; CELL-DEATH; AGGREGATION; MUTATION; GENE; GLUTATHIONE; SUPEROXIDE; TOXICITY AB alpha-Synuclein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Two point mutations in alpha-synuclein (A53T and A30P) are identified in few families with dominantly inherited PD, Yet the mechanism by which this protein is involved in nigral cell death remains poorly understood. Mounting evidence suggests the importance of oxidative stress in the pathogenesis of PD. Here we investigated the effects of wild-type and two mutant forms of alpha-synuclein on intracellular reactive oxygen species (ROS) levels using clonal SH-SY5Y cells engineered to over-express these proteins. All three cell lines, and particularly mutant alpha-synuclein-expressing cells, had increased ROS levels relative to control LacZ-engineered cells. In addition, cell viability was significantly curtailed following the exposure of all three alpha-synuclein-engineered cells to dopamine, but more so with mutant alpha-synuclein. These results suggest that over-expression of alpha-synuclein, and especially its mutant forms, exaggerates the vulnerability of neurons to dopamine-induced cell death through excess intracellular ROS generation. Thus, these findings provide a link between mutations or over-expression of alpha-synuclein and apoptosis of dopaminergic neurons by lowering the threshold of these cells to oxidative damage. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Mouradian, MM (reprint author), NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 32 TC 152 Z9 160 U1 0 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 8 PY 2002 VL 320 IS 3 BP 146 EP 150 AR PII S0304-3940(02)00016-2 DI 10.1016/S0304-3940(02)00016-2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 528KJ UT WOS:000174242700010 PM 11852183 ER PT J AU Rosenthal, J AF Rosenthal, J TI Curtain has fallen on hopes of legal bioprospecting - Local communities, too, could have benefited from better health care and conservation. SO NATURE LA English DT Letter C1 NIH, Div Int Training & Res, Fogarty Int Ctr, Bethesda, MD 20892 USA. Natl Sci Fdn, Arlington, VA 22230 USA. USDA, Washington, DC 20250 USA. RP Rosenthal, J (reprint author), NIH, Div Int Training & Res, Fogarty Int Ctr, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 1 TC 11 Z9 11 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 7 PY 2002 VL 416 IS 6876 BP 15 EP 15 DI 10.1038/416015a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 527WU UT WOS:000174211600014 PM 11882865 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, J TI Cell biology - Ripping up the nuclear envelope SO NATURE LA English DT Editorial Material ID MEMBRANE; MITOSIS C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. NR 13 TC 15 Z9 16 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 7 PY 2002 VL 416 IS 6876 BP 31 EP 32 DI 10.1038/416031a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 527WU UT WOS:000174211600025 PM 11882878 ER PT J AU Monti, P Campomenosi, P Ciribilli, Y Iannone, R Inga, A Abbondandolo, A Resnick, MA Fronza, G AF Monti, P Campomenosi, P Ciribilli, Y Iannone, R Inga, A Abbondandolo, A Resnick, MA Fronza, G TI Tumour p53 mutations exhibit promoter selective dominance over wild type p53 SO ONCOGENE LA English DT Article DE dominance; p53; mutation; yeast functional assay; p53 responsive element ID YEAST FUNCTIONAL ASSAY; CELL-LINES; MUTANT P53; PROTEIN; CANCER; DNA; IDENTIFICATION; INHIBITION; APOPTOSIS; ARREST AB The tumour suppressor gene p53 is frequently mutated in human cancer. Tumour derived p53 mutants are usually transcriptionally inactive, but some mutants retain the ability to transactivate a subset of p53 target genes. In addition to simple loss of function, some p53 mutants may be carcinogenic through a dominant negative mechanism. Aiming at a more general classification of p53 mutants into predictive functional categories it is important to determine (i) which p53 mutants are dominant, (ii) what features characterize dominant mutants and (iii) whether dominance is target gene specific. The ability of 71 p53 mutants to inhibit wild type p53 was determined using a simple yeast transcriptional assay. Approximately 30% of the mutants were dominant. They preferentially affect highly conserved amino acids (P < 0.005), which are frequently mutated in turnours (P < 0.005), and usually located near the DNA binding surface of the protein (P < 0.001). Different tumour-derived amino acid substitutions at the same codon usually have the same dominance phenotype. To determine whether the ability of p53 mutants to inhibit wild type p53 is target gene specific, the dominance towards p21, bax, and PIG3 binding sites was examined. Approximately 40% of the 45 mutants examined were dominant for the p21 (17/45) or PIG3 (20/45) responsive elements and 71% (32/45) were dominant for the bax responsive element. These differences are statistically significant (p21 vs bax, P < 0.003; bax vs PIG3, P < 0.02, Fisher's exact test) and defined a hierarchy of dominance. Finally, we extended the analysis to a group of mutants isolated in BRCA-associated tumours, some of which retained wild type level of transcription in yeast as well as in human cells, but show gain of function in transformation assays. Since transformation assays require transdominant inhibition of the endogenous wild type allele, one possible explanation for the behaviour of the BRCA-associated mutants is that they adopt conformations able to bind DNA alone but not in mixed tetramers with wild type p53. The yeast data do not support this explanation, because all BRCA-associated mutants that behaved as wild type in transcription assay were recessive in dominance assays. C1 Natl Canc Res Inst, IST, Mutagenesis Lab, I-16132 Genoa, Italy. Univ Insubria, DBSF, Human Genet Lab, Varese, Italy. NIEHS, Chromosome Stabil Grp, Res Triangle Pk, NC 27709 USA. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. RP Fronza, G (reprint author), Natl Canc Res Inst, IST, Mutagenesis Lab, Largo R Benzi 10, I-16132 Genoa, Italy. RI Campomenosi, Paola/C-9729-2011; OI Campomenosi, Paola/0000-0002-8853-1134 NR 27 TC 43 Z9 45 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 7 PY 2002 VL 21 IS 11 BP 1641 EP 1648 DI 10.1038/sj/onc/1205250 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 527XX UT WOS:000174214200002 PM 11896595 ER PT J AU Bohr, VA Stevnsner, T de Souza-Pinto, NC AF Bohr, VA Stevnsner, T de Souza-Pinto, NC TI Mitochondrial DNA repair of oxidative damage in mammalian cells SO GENE LA English DT Article; Proceedings Paper CT International Meeting on Mitochondria - Evolution, Genomics, Homeostasis and Pathology CY MAY 09-12, 2001 CL SELVA DI FASANO, ITALY DE DNA repair; BER; oxidative damage; mitochondrial DNA; nuclear DNA ID BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; RAT-LIVER; ESCHERICHIA-COLI; ABASIC SITES; GLYCOSYLASES; ENDONUCLEASE; 8-OXOGUANINE; PURIFICATION; ACCUMULATION AB Nuclear and mitochondrial DNA are constantly being exposed to damaging agents, from endogenous and exogenous sources. In particular, reactive oxygen species (ROS) are formed at high levels as by-products of the normal metabolism. Upon oxidative attack of DNA many DNA lesions are formed and oxidized bases are generated with high frequency. Mitochondrial DNA has been shown to accumulate high levels of 8-hydroxy-2'-deoxyguanosine, the product of hydroxylation of guanine at carbon 8, which is a mutagenic lesion. Most of these small base modifications are repaired by the base excision repair (BER) pathway. Despite the initial concept that mitochondria lack DNA repair, experimental evidences now show that mitochondria are very proficient in BER of oxidative DNA damage, and proteins necessary for this pathway have been isolated from mammalian mitochondria. Here, we examine the BER pathway with an emphasis on mtDNA repair. The molecular mechanisms involved in the formation and removal of oxidative damage from mitochondria are discussed. The pivotal role of the OGG1 glycosylase in removal of oxidized guanines from mtDNA will also be examined. Lastly, changes in mtDNA repair during the aging process and possible biological implications are discussed. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. Aarhus Univ, Danish Ctr Mol Gerontol, Dept Mol & Struct Biol, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Box 1,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 37 TC 116 Z9 120 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAR 6 PY 2002 VL 286 IS 1 BP 127 EP 134 AR PII S0378-1119(01)00813-7 DI 10.1016/S0378-1119(01)00813-7 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 544HR UT WOS:000175152600016 PM 11943468 ER PT J AU Wong, TY Klein, R Sharrett, AR Duncan, BB Couper, DJ Tielsch, JM Klein, BEK Hubbard, LD AF Wong, TY Klein, R Sharrett, AR Duncan, BB Couper, DJ Tielsch, JM Klein, BEK Hubbard, LD TI Retinal arteriolar narrowing and risk of coronary heart disease in men and women - The atherosclerosis risk in communities study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MYOCARDIAL-INFARCTION; ANGINA-PECTORIS; ARTERY DISEASE; CHEST PAIN; ANGIOGRAMS; MORTALITY; SEX AB Context Microvascular processes have been hypothesized to play a greater role in the development of coronary heart disease (CHD) in women than in men; however, prospective clinical data are limited. Objective To examine the association between retinal arteriolar narrowing, a marker of microvascular damage from hypertension and inflammation, and incident CHD in healthy middle-aged women and men. Design, Setting, and Participants The Atherosclerosis Risk in Communities Study, an ongoing prospective, population-based cohort study in 4 US communities initiated in 1987-1989. Retinal photographs were taken in 9648 women and men aged 51 to 72 years without CHD at the third examination (1993-1995). To quantify retinal arteriolar narrowing, the photographs were digitized, individual arteriolar and venular diameters were measured, and a summary arteriole-to-venule ratio (AVR) was calculated. Main Outcome Measure Risk of CHD associated with retinal arteriolar narrowing. Results During an average 3.5 years of follow-up, 84 women and 187 men experienced incident CHD events. In women, after controlling for mean arterial blood pressure averaged over the previous 6 years, diabetes, cigarette smoking, plasma lipid levels, and other risk factors, each SD decrease in the AVR was associated with an increased risk of any incident CHD (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.72) and of acute myocardial infarction (RR, 1.50; 95% CI, 1.10-2.04). In contrast, AVR was unrelated to any incident CHD in men (RR, 1,00; 95% CI, 0.84-1.18) or to acute myocardial infarction (RR, 1.08; 95% CI, 0.85-1.38). Conclusion Retinal arteriolar narrowing is related to risk of CHD in women but not in men, supporting a more prominent microvascular role in the development of CHD in women than in men. Future work is needed to confirm these findings. C1 Natl Univ Singapore, Dept Ophthalmol, Singapore 119260, Singapore. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. NHLBI, Bethesda, MD 20892 USA. Univ Fed Rio Grande Sul, Sch Med, Dept Social Med, Porto Alegre, RS, Brazil. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD USA. RP Wong, TY (reprint author), Natl Univ Singapore, Dept Ophthalmol, 10 Kent Ridge Crescent, Singapore 119260, Singapore. FU NHLBI NIH HHS [N01-HC-35125, N01-HC-35126, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 37 TC 374 Z9 383 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 6 PY 2002 VL 287 IS 9 BP 1153 EP 1159 DI 10.1001/jama.287.9.1153 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 527KV UT WOS:000174186000031 PM 11879113 ER PT J AU Vasan, RS Larson, MG Levy, D Leip, EP D'Agostino, RB Wolf, PA Kannel, WB Benjamin, EJ AF Vasan, RS Larson, MG Levy, D Leip, EP D'Agostino, RB Wolf, PA Kannel, WB Benjamin, EJ TI Prolonged PR interval is associated with increased risk of atrial fibrillation: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 125A EP 126A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700554 ER PT J AU Speir, E Yu, ZX Takeda, K Ferrans, VJ Muthuchamy, M Fananapazir, L AF Speir, E Yu, ZX Takeda, K Ferrans, VJ Muthuchamy, M Fananapazir, L TI Effect of estrogen on angiotensin receptors, matrix metalloproteinases, and left ventricular mass in a transgenic mouse model of human hypertrophic cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Texas A&M Univ, College Stn, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 131A EP 131A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700578 ER PT J AU Fleg, JL O'Connor, FC Becker, LC Townsend, S Clulow, J Gerstenblith, G Lakatta, EG AF Fleg, JL O'Connor, FC Becker, LC Townsend, S Clulow, J Gerstenblith, G Lakatta, EG TI Gender but not age affects cardiovascular performance during mental stress in healthy subjects 20-93 years old SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 138A EP 138A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700610 ER PT J AU Loredo, ML Tanowitz, HB Chandra, M Ferrans, VJ Shirani, J AF Loredo, ML Tanowitz, HB Chandra, M Ferrans, VJ Shirani, J TI Nitric oxide mediates myocyte apoptosis in experimental acute chagasic myocarditis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 161A EP 161A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700715 ER PT J AU Morshedi-Meibodi, A Evans, J Levy, D Larson, MG Vasan, R AF Morshedi-Meibodi, A Evans, J Levy, D Larson, MG Vasan, R TI Exercise-induced ventricular premature beats are associated with increased cardiovascular mortality: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 164A EP 164A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700726 ER PT J AU Kanchaiah, S Levy, D Evans, JC Benjamin, EJ Larson, MG Wilson, PW Kannel, WB Vasan, R AF Kanchaiah, S Levy, D Evans, JC Benjamin, EJ Larson, MG Wilson, PW Kannel, WB Vasan, R TI Impact of body mass index on the risk of heart failure: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 184A EP 184A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700818 ER PT J AU Fleg, JL Tehrani, R O'Connor, FE Wright, JG AF Fleg, JL Tehrani, R O'Connor, FE Wright, JG TI Blunted heart rate recovery fails to predict coronary events in apparently healthy individuals SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 189A EP 189A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700841 ER PT J AU Vasan, RS Larson, MG Leip, EP Benjamin, EJ Wang, TJ Sutherland, P Wilson, PW Levy, D AF Vasan, RS Larson, MG Leip, EP Benjamin, EJ Wang, TJ Sutherland, P Wilson, PW Levy, D TI Utility of natriuretic peptides for detecting left ventricular hypertrophy and dysfunction: The Framingham Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 201A EP 201A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700892 ER PT J AU Hill, JM Backer, MV Backer, JM Finkel, T AF Hill, JM Backer, MV Backer, JM Finkel, T TI Chimeric vascular endothelial growth factor fusion protein selectively inhibits Flk-1 endothelial progenitor cells SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 204A EP 204A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700907 ER PT J AU Rutter, MK Parise, H Larson, MG Benjamin, EJ Levy, D Meigs, JB Nesto, RW Wilson, PW Vasan, RS AF Rutter, MK Parise, H Larson, MG Benjamin, EJ Levy, D Meigs, JB Nesto, RW Wilson, PW Vasan, RS TI Insulin resistance is associated with left ventricular remodeling: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 207A EP 207A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700919 ER PT J AU Saucedo, JF Moursi, MM Anderson, RD Mendelsohn, FO Hermiller, JB Federici, R Zidar, J Greenbaum, AB Moon, T Whitehouse, MJ Annex, BH Lederman, R AF Saucedo, JF Moursi, MM Anderson, RD Mendelsohn, FO Hermiller, JB Federici, R Zidar, J Greenbaum, AB Moon, T Whitehouse, MJ Annex, BH Lederman, R TI Implications of smoking status on the response to therapeutic angiogenesis in peripheral artery disease: Findings from the therapeutic angiogenesis with FGF-2 for intermittent claudication (TRAFFIC) trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Univ Arkansas Med Sci, Little Rock, AR 72205 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 207A EP 207A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700918 ER PT J AU Zhu, JH Quyyumi, AA Wu, HS Rott, D Zalles-Ganley, A Ogunmakinwa, J Epstein, SE AF Zhu, JH Quyyumi, AA Wu, HS Rott, D Zalles-Ganley, A Ogunmakinwa, J Epstein, SE TI A potential protective role of heat shock protein 70 in atherogenesis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington, DC 20010 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 211A EP 211A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700937 ER PT J AU Campia, U Sullivan, G Bryant, MB Cardillo, C Panza, JA AF Campia, U Sullivan, G Bryant, MB Cardillo, C Panza, JA TI Effects of systemic hyperinsulinemia on flow-mediated dilation of the brachial artery in normal subjects SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 216A EP 216A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700961 ER PT J AU Halcox, JP Mincemoyer, R Zalos, G Quyyumi, AA AF Halcox, JP Mincemoyer, R Zalos, G Quyyumi, AA TI Heme oxygenase antagonism inhibits endothelium-dependent vasodilation in the normal human forearm circulation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 222A EP 222A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106700990 ER PT J AU Koh, EK Osako, G Schenke, W Cannon, RO AF Koh, EK Osako, G Schenke, W Cannon, RO TI Addition of statin attenuates the increase in C-reactive protein during estrogen replacement therapy in postmenopausal women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 238A EP 238A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701065 ER PT J AU Halcox, J Narayanan, S Prasad, A Satorius, C Schenke, WH Epstein, N Quyyumi, AA AF Halcox, J Narayanan, S Prasad, A Satorius, C Schenke, WH Epstein, N Quyyumi, AA TI Effect of the angiotensinogen M235T polymorphism on human coronary vascular endothelial function SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 239A EP 239A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701070 ER PT J AU Campia, U Cardillo, C Bryant, MB Panza, JA AF Campia, U Cardillo, C Bryant, MB Panza, JA TI Increased activity of endogenous endothelin-1 in patients with type 2 diabetes mellitus SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 258A EP 258A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701158 ER PT J AU Voltchikhina, SA Yacono, BC Cheng, L Lakatta, EG Talan, MI AF Voltchikhina, SA Yacono, BC Cheng, L Lakatta, EG Talan, MI TI Ventricular-arterial coupling in nondilated chronic heart failure following coronary artery ligation in mice SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 301A EP 301A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701352 ER PT J AU Mack, GK Wanitkun, S Mehwald, PS Zetts, AD Delmer, PR Lennon, D Sahn, DJ AF Mack, GK Wanitkun, S Mehwald, PS Zetts, AD Delmer, PR Lennon, D Sahn, DJ TI Calculation of cardiac output by measurement from tricuspid inflow using a 3-D digital color Doppler method: An in vivo validation study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 345A EP 345A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701552 ER PT J AU Christian, TF Llao, S Aletras, AH Balaban, RS Arai, AE AF Christian, TF Llao, S Aletras, AH Balaban, RS Arai, AE TI The importance of absolute quantitation for multislice MRI myocardial perfusion during vasodilator stress SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 348A EP 348A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701566 ER PT J AU Dick, AJ Guttman, MA Raman, VK Peters, DC Thompson, RB Lederman, RJ AF Dick, AJ Guttman, MA Raman, VK Peters, DC Thompson, RB Lederman, RJ TI Real-time MRI angioplasty using intravascular guidewire coils SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 352A EP 352A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701584 ER PT J AU Raman, VK Guttman, MA Dick, AJ Peters, DC Thompson, RB Lederman, RJ AF Raman, VK Guttman, MA Dick, AJ Peters, DC Thompson, RB Lederman, RJ TI Intravascular guidewire coil facilitated invasive real-time magnetic resonance arteriography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 352A EP 352A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701586 ER PT J AU Wang, HF Li, XK Jones, M Davies, CH Swanson-Birchill, JC Rusk, RA Schindera, ST Zetts, AD Lie, GR Sahn, DJ AF Wang, HF Li, XK Jones, M Davies, CH Swanson-Birchill, JC Rusk, RA Schindera, ST Zetts, AD Lie, GR Sahn, DJ TI Reconstructive three-dimensional tissue Doppler Imaging for quantifying left ventricular myocardial infarction area after coronary artery occlusion: An in vivo chronic animal study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 354A EP 355A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701596 ER PT J AU Watanabe, J Jones, M Shiota, T Tsujino, H Greenberg, NL Popovic, ZB Zetts, AD Qin, JX Cardon, LA Garcia, MJ Thomas, JD AF Watanabe, J Jones, M Shiota, T Tsujino, H Greenberg, NL Popovic, ZB Zetts, AD Qin, JX Cardon, LA Garcia, MJ Thomas, JD TI Color M-mode estimation of the spatial distribution of the diastolic intraventricular pressure gradient with a left ventricular aneurysm SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 364A EP 364A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701639 ER PT J AU Dilsizian, V Loredo, M Ferrans, VJ Jagoda, EM Eckelman, WC Shirani, J AF Dilsizian, V Loredo, M Ferrans, VJ Jagoda, EM Eckelman, WC Shirani, J TI Evidence for increased angiotensin II type 1 receptor immunoreactivity in peri-infarct myocardium of human explanted hearts SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 365A EP 365A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701641 ER PT J AU Chuang, ML Salton, CJ O'Donnell, CJ Kissinger, KV Levy, D Manning, WJ AF Chuang, ML Salton, CJ O'Donnell, CJ Kissinger, KV Levy, D Manning, WJ TI Criteria for concentric left ventricular geometry determined using magnetic resonance imaging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 368A EP 368A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701655 ER PT J AU Kim, YJ Jones, M Shiota, T Qin, JX Greenberg, NL Popovic, ZB Kwan, J Sitges, M Bauer, F Yang, H Cardon, LA Sachdev, V Griffin, BP Cosgrove, DM Thomas, JD AF Kim, YJ Jones, M Shiota, T Qin, JX Greenberg, NL Popovic, ZB Kwan, J Sitges, M Bauer, F Yang, H Cardon, LA Sachdev, V Griffin, BP Cosgrove, DM Thomas, JD TI Evaluation of left ventricular contractile function using noninvasively derived end-systolic elastance in mitral regurgitation: Experimental validation and clinical study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 372A EP 372A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701674 ER PT J AU Yang, H Jones, M Shiota, T Qin, JX Kim, YJ Daugherty, DW Popovic, Z Greenberg, NL Pu, M Cardon, LA Zetts, AD Thomas, JD AF Yang, H Jones, M Shiota, T Qin, JX Kim, YJ Daugherty, DW Popovic, Z Greenberg, NL Pu, M Cardon, LA Zetts, AD Thomas, JD TI Changes of mitral regurgitation severity under altered loading conditions and its relationship to pulmonary venous flow SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 384A EP 384A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701730 ER PT J AU Li, XK Jones, M Li, XN Zetts, AD Rusk, RA Mori, Y Davies, CH Mack, GK Sahn, DJ AF Li, XK Jones, M Li, XN Zetts, AD Rusk, RA Mori, Y Davies, CH Mack, GK Sahn, DJ TI Multi-threshold flow 3-D color Doppler reconstruction of velocity of the flow acceleration region for quantification of mitral regurgitation: A chronic animal model study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 395A EP 395A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701777 ER PT J AU Rusk, RA Mori, Y Irvine, T Kenny, A Zetts, AD Sachdev, V Sahn, DJ AF Rusk, RA Mori, Y Irvine, T Kenny, A Zetts, AD Sachdev, V Sahn, DJ TI Quantifying pulmonary regurgitation as the difference between RV and LV stroke volumes using real-rime three-dimensional echocardiography: Studies in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 403A EP 403A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701813 ER PT J AU Li, XK Jones, M Li, XN Zetts, AD Mack, GK Hashimoto, I Mori, Y Davies, CH Sahn, DJ AF Li, XK Jones, M Li, XN Zetts, AD Mack, GK Hashimoto, I Mori, Y Davies, CH Sahn, DJ TI A semiautomatic inter-aliasing distance method for quantifying aortic regurgitation using digital color Doppler M-mode computation: In vivo study in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 424A EP 424A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106701907 ER PT J AU Fox, C Evans, J Larson, M Kannel, W Levy, D AF Fox, C Evans, J Larson, M Kannel, W Levy, D TI Decreasing risk of sudden cardiac death: A role for both primary and secondary prevention SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2002 VL 39 IS 5 SU A BP 459A EP 460A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526AR UT WOS:000174106702067 ER PT J AU Shavers, VL Brown, ML AF Shavers, VL Brown, ML TI Racial and ethnic disparities in the receipt of cancer treatment SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID STAGE BREAST-CANCER; LOCALIZED PROSTATE-CANCER; SURGICAL ADJUVANT BREAST; BLACK-WHITE DIFFERENCES; AFRICAN-AMERICAN WOMEN; DISEASE-FREE SURVIVAL; CELL LUNG-CANCER; DATA-BASE REPORT; QUALITY-OF-LIFE; RADIATION-THERAPY AB A disproportionate number of cancer deaths occur among racial/ethnic minorities, particularly African Americans, who have a 33% higher risk of dying of cancer than whites. Although differences in incidence and stage of disease at diagnosis may contribute to racial disparities in mortality, evidence of racial disparities in the receipt of treatment of other chronic diseases raises questions about the possible role of inequities in the receipt of cancer treatment. To evaluate racial/ethnic disparities in the receipt of cancer treatment, we examined the published literature that addressed access/use of specific cancer treatment procedures, trends in patterns of use, or survival studies. We found evidence of racial disparities in receipt of definitive primary therapy, conservative therapy, and adjuvant therapy. These treatment differences could not be completely explained by racial/ethnic variation in clinically relevant factors. In many studies, these treatment differences were associated with an adverse impact on the health outcomes of racial/ethnic minorities, including more frequent recurrence, shorter disease-free survival, and higher mortality. Reducing the influence of nonclinical factors on the receipt of cancer treatment may, therefore, provide an important means of reducing racial/ethnic disparities in health. New data resources and improved study methodology are needed to better identify and quantify the full spectrum of nonclinical factors that contribute to the higher cancer mortality among racial/ethnic minorities and to develop strategies to facilitate receipt of appropriate cancer care for all patients. C1 NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Shavers, VL (reprint author), NIH, 6130 Execut Blvd,EPN 4005,MSC 7344, Bethesda, MD 20892 USA. NR 178 TC 503 Z9 508 U1 9 U2 27 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 6 PY 2002 VL 94 IS 5 BP 334 EP 357 PG 24 WC Oncology SC Oncology GA 527QU UT WOS:000174198700008 PM 11880473 ER PT J AU Dickert, N Emanuel, E Grady, C AF Dickert, N Emanuel, E Grady, C TI Paying research subjects: An analysis of current policies SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PAYMENT AB Background: Few data are available on guidelines used by research organizations to make decisions about paying subjects. Objective: To analyze existing guidance regarding payment of research subjects and to identify common characteristics and areas for further research. Design: Descriptive content analysis of policies. Measurements: Written policies and rules of thumb about paying subjects from 32 U.S. research organizations. Results: Of 32 organizations, 37.5% had written guidelines about paying subjects; all but 1 reported having rules of thumb. Few (18.8%) were able to provide a confident estimate of the proportion of studies that pay subjects. Organizations reported that investigators and institutional review boards make payment decisions and that both healthy and ill subjects in some studies are paid for their time (87%), for inconvenience (84%), for travel (68%), as incentive (58%), or for incurring risk (32%). Most organizations require that payment be prorated (84%) and described in the consent document (94%). Conclusions: Most organizations pay some research subjects, but few have written policies on payment. Because investigators and institutional review boards make payment decisions with little specific guidance, standards vary. C1 WG Magnuson Clin Ctr, Dept Clin Bioeth, NIH, Bethesda, MD 20892 USA. RP Grady, C (reprint author), WG Magnuson Clin Ctr, Dept Clin Bioeth, NIH, Bldg 1C118, Bethesda, MD 20892 USA. NR 15 TC 65 Z9 66 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 5 PY 2002 VL 136 IS 5 BP 368 EP 373 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 525VT UT WOS:000174095300004 PM 11874309 ER PT J AU Siebert, X Hummer, G AF Siebert, X Hummer, G TI Hydrophobicity maps of the N-peptide coiled coil of HIV-1 gp41 SO BIOCHEMISTRY LA English DT Article ID TRANSMEMBRANE PROTEIN GP41; LIGAND-BINDING SITES; CRYSTAL-STRUCTURE; ENTRY INHIBITORS; MEMBRANE-FUSION; POTENTIAL FUNCTIONS; MOLECULAR-DYNAMICS; DRUG DESIGN; TYPE-1 GP41; FORCE-FIELD AB Blocking HIV-1 viral entry into the host cell offers a promising new, strategy for interfering with the HIV-1 life cycle. A major target of inhibitor design is to prevent binding of fusogenic gp41 C-peptides to the trimeric coiled coil of fusion-active N-peptides. Here, we map the hydrophobic character of the binding surface of the IQN17 peptide, a soluble analogue of the N-peptide coiled coil. The local binding affinity for a hydrophobic probe is determined by three methods: a hydrophobic force field, and molecular dynamics in solution analyzed by test particle insertion and inhomogeneous information theory. The regions of highest calculated hydrophobicity overlap with the positions of the hydrophobic anchor residues of the native C-peptides, and of two known inhibitors. Additional binding sites not exploited by these inhibitors are identified, and modifications for enhancing their binding affinity are suggested. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 70 TC 24 Z9 24 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 5 PY 2002 VL 41 IS 9 BP 2956 EP 2961 DI 10.1021/bi0158526 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 527LL UT WOS:000174187500008 PM 11863433 ER PT J AU Fedorova, OV Talan, M Agalakova, NI Lakatta, EG Bagrov, AY AF Fedorova, OV Talan, M Agalakova, NI Lakatta, EG Bagrov, AY TI Endogenous ligand of alpha sodium pump, marinobufagenin, is a novel mediator of sodium chloride-dependent hypertension SO CIRCULATION LA English DT Article DE hypertension; Na+-K+-exchanging ATPase; sodium; bufadienolides; ouabain ID VOLUME EXPANSION; OUABAIN; RATS; NA,K-ATPASE; PLASMA; BUFODIENOLIDE; NA+,K+-ATPASE; INHIBITION; ATPASE AB Background-Digitalis-like sodium pump ligands (SPLs) effect natriuresis via inhibition of renal tubular Na+,K+-ATPase but may induce vasoconstriction. The present study investigated the potential roles of 2 putative endogenous SPLs, an ouabain-like compound (OLC) and an alpha(1) Na+,K+-ATPase inhibitor, marinobufagenin (MBG), in regulating natriuresis and blood pressure (BP) responses to sustained and acute NaCl loading in Dahl salt-sensitive rats (DS). Methods and Results-During 4 weeks of an 8% NaCl diet, DS exhibited a progressive increase in MBG renal excretion (66 +/- 13 pmol/24 hours at week 4 versus 11 +/- 1 pmol/24 hours at baseline, n=48), which paralleled an increase in systolic BP (174 +/- 10 mm Hg at week 4 versus 110 +/- 2 mm Hg at baseline). By contrast, OLC excretion peaked at week 1 and returned to baseline levels. Administration of an anti-MBG, but not anti-ouabain antibody, to DS after 3 weeks of a high NaCl diet lowered BP (139 +/- 7 versus 175 +/- 5 mm Hg, P<0.001, n=5). Acute NaCl loading (2 hours) of DS (n=5) increased MBG and OLC excretion and natriuresis. Pretreatment of acutely NaCl-loaded DS with an anti-MBG antibody (n=5) reduced the excretion of sodium and MBG but not that of OLC. An anti-ouabain antibody (n=5) reduced sodium excretion and both OLC and MBG. Conclusions-An initial transient stimulation of OLC induced by NaCl loading of DS precedes an MBG response. A sustained increase in MBG production in DS contributes to the chronic BP elevation induced by a sustained high NaCl intake. C1 NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 23 TC 99 Z9 103 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 5 PY 2002 VL 105 IS 9 BP 1122 EP 1127 DI 10.1161/hc0902.104710 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 530NK UT WOS:000174364100022 PM 11877366 ER PT J AU Lukoyanova, N VanLoock, MS Orlova, A Galkin, VE Wang, K Egelman, EH AF Lukoyanova, N VanLoock, MS Orlova, A Galkin, VE Wang, K Egelman, EH TI Each actin subunit has three nebulin binding sites: Implications for steric blocking SO CURRENT BIOLOGY LA English DT Article ID MUSCLE THIN-FILAMENTS; SKELETAL-MUSCLE; 3-DIMENSIONAL RECONSTRUCTION; MYOSIN SUBFRAGMENT-1; FRAGMENTS; PROTEIN; MODEL; ARCHITECTURE; TROPOMYOSIN; ANTIBODIES AB Nebulin is a giant protein that spans most of the muscle thin filament [1, 2]. Mutations in nebulin result in myopathies and dystrophies [3, 4]. Nebulin contains similar to200 copies of similar to35 residue modules, each believed to contain an actin binding site, organized into seven-module superrepeats [5, 6]. The strong correlation between the number of nebulin modules and the length of skeletal muscle thin filaments in different species suggests that nebulin determines thin filament length [2, 7, 8]. Little information exists about the interactions between intact nebulin and F-actin. More insight has come from working with fragments of nebulin, containing from one to hundreds of actin binding modules. However, the observed stoichiometry of binding between these fragments and actin has ranged from 0.4 to 13 modules per actin subunit [9-12]. We have used electron microscopy and a novel method of helical image analysis to characterize complexes of F-actin with a nebulin fragment. The fragment binds as an extended structure spanning three actin subunits and binding to different sites on each actin. Muscle regulation involves tropomyosin movement on the surface of actin, with binding in three states. Our results suggest the intriguing possibility that intact nebulin may also be able to occupy three different sites on F-actin. C1 Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. NIAMSD, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. RP Egelman, EH (reprint author), Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RI Egelman, Edward/A-2488-2009 NR 49 TC 49 Z9 50 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAR 5 PY 2002 VL 12 IS 5 BP 383 EP 388 AR PII S0960-9822(02)00678-4 DI 10.1016/S0960-9822(02)00678-4 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 528UH UT WOS:000174261700019 PM 11882289 ER PT J AU Van Houten, B Eisen, JA Hanawalt, PC AF Van Houten, B Eisen, JA Hanawalt, PC TI A cut above: Discovery of an alternative excision repair pathway in bacteria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ESCHERICHIA-COLI; GENOME SEQUENCE; DNA-DAMAGE; EXPRESSION; GENES; UVRB C1 Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Inst Genom Res, Inst Microbial Genom, Rockville, MD 20850 USA. RP Hanawalt, PC (reprint author), Stanford Univ, Dept Biol Sci, 371 Serra Mall, Stanford, CA 94305 USA. OI Eisen, Jonathan A./0000-0002-0159-2197 NR 25 TC 30 Z9 31 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 5 PY 2002 VL 99 IS 5 BP 2581 EP 2583 DI 10.1073/pnas.062062599 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600001 PM 11880612 ER PT J AU Tang, PT Cheng, TP Agnello, D Wu, CY Hissong, BD Watford, WT Ahn, HJ Galon, J Moss, J Vaughan, M O'Shea, JJ Gadina, M AF Tang, PT Cheng, TP Agnello, D Wu, CY Hissong, BD Watford, WT Ahn, HJ Galon, J Moss, J Vaughan, M O'Shea, JJ Gadina, M TI Cybr, a cytokine-inducible protein that binds cytohesin-1 and regulates its activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ADP-ribosylation factors; cytohesin-binding protein; PDZ domain; Sec7 domain; T cell ID ADP-RIBOSYLATION FACTOR; NUCLEOTIDE-EXCHANGE PROTEIN; CDNA MICROARRAYS; GENE; CLONING; FAMILY; CELLS AB Cytokines regulate lymphocyte development and differentiation, but precisely how they control these processes is still poorly understood. By using microarray technology to detect cytokine-induced genes, we identified a cDNA encoding Cybr, which was increased markedly in cells incubated with IL-2 and IL-12. The mRNA was most abundant in hematopoietic cells and tissues. The predicted amino acid sequence is similar to that of GRP-1-associated protein (GRASP), a recently identified retinoic acid-induced cytohesin-binding protein. Physical interaction, dependent on the coiled-coil domains of Cybr and cytohesin-1, was demonstrated by coimmunoprecipitation of the overexpressed proteins from 293T cells. Cytohesin-1, in addition to its role in cell adhesion, is a guanine nucleotide-exchange protein activator of ARF GTPases. Acceleration of guanosine 5'-O-(thiotriphosphate) binding to ARF by cytohesin-1 in vitro was enhanced by Cybr. Because the binding protein modified activation of ADP ribosylation factor by cytohesin-1, we designate this cytokine-inducible protein Cybr (cytohesin binder and regulator). C1 NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Natl Inst Hlth Res Scholar Program, Bethesda, MD 20892 USA. RP Gadina, M (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N252,10 Ctr Dr, Bethesda, MD 20892 USA. NR 24 TC 32 Z9 35 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 5 PY 2002 VL 99 IS 5 BP 2625 EP 2629 DI 10.1073/pnas.052712999 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600010 PM 11867758 ER PT J AU Dasgupta, A Darst, RP Martin, KJ Afshari, CA Auble, DT AF Dasgupta, A Darst, RP Martin, KJ Afshari, CA Auble, DT TI Mot1 activates and represses transcription by direct, ATPase-dependent mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TATA-BINDING PROTEIN; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; IN-VIVO; TBP BINDING; YEAST; DNA; COMPLEX; TFIIA AB Mot1 is an essential yeast Snf2/Swi2-related ATPase that exerts both positive and negative effects on gene expression. In vitro, Mot1 can disrupt TATA-binding protein-DNA complexes in an ATP-dependent reaction. This activity can explain Mot1-mediated transcriptional repression, but how Mot1 activates transcription is unknown. We demonstrate that, remarkably, Mot1 is localized in vivo to promoters for both Mot1-repressed and Mot1-activated genes. Moreover, Mot1 ATPase activity is required for both activation and repression of gene activity. These findings suggest a novel function for the Mot1 ATPase at activated genes, perhaps involving ATP-driven reorganization of the preinitiation complex. Mot1 regulates the expression of approximate to3% of yeast genes in cells grown in rich medium. Most of these genes are repressed by Mot1, consistent with Mot1's ATP-dependent TATA-binding protein-DNA dissociating activity. Additionally, approximate to77% of the Mot1-repressed genes are involved in the diauxic shift, stress response, mating, or sporulation. The gene sets controlled by NC2 and Srb10 are strongly correlated with the Mot1-controlled set, suggesting that these factors cooperate in transcriptional control on a global scale. C1 Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. NIEHS, Microarray Ctr, Res Triangle Pk, NC 27709 USA. RP Auble, DT (reprint author), Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, 1300 Jefferson Pk Ave,Room 6213, Charlottesville, VA 22908 USA. FU NIGMS NIH HHS [GM55763, R01 GM055763] NR 42 TC 68 Z9 70 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2002 VL 99 IS 5 BP 2666 EP 2671 DI 10.1073/pnas.052397899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600017 PM 11880621 ER PT J AU Gaussin, V Van de Putte, T Mishina, Y Hanks, MC Zwijsen, A Huylebroeck, D Behringer, RR Schneider, MD AF Gaussin, V Van de Putte, T Mishina, Y Hanks, MC Zwijsen, A Huylebroeck, D Behringer, RR Schneider, MD TI Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EARLY HEART DEVELOPMENT; MESENCHYMAL TRANSFORMATION; CELL-TRANSFORMATION; MOUSE EMBRYOGENESIS; IN-VIVO; EXPRESSION; GENE; MICE; INDUCTION; BMP2 AB Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGFbeta) superfamily, are persistently expressed during cardiac development, yet mice lacking type 11 or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGFbeta2, an established paracrine mediator of cushion morphogenesis, Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis. C1 Baylor Coll Med, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Katholieke Univ Leuven VIB, B-3000 Louvain, Belgium. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Procter & Gamble Co, Pharmaceut Hlth Care Res Ctr, Mason, OH 45040 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Schneider, MD (reprint author), Baylor Coll Med, Ctr Cardiovasc Dev, 1 Baylor Plaza,Room 506D, Houston, TX 77030 USA. EM michaels@bcm.tmc.edu OI Huylebroeck, Danny/0000-0003-4862-1079; Schneider, Michael/0000-0001-9645-1938 NR 41 TC 191 Z9 210 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 5 PY 2002 VL 99 IS 5 BP 2878 EP 2883 DI 10.1073/pnas.042390499 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600053 PM 11854453 ER PT J AU Pletnev, AG Putnak, R Speicher, J Wagar, EJ Vaughn, DW AF Pletnev, AG Putnak, R Speicher, J Wagar, EJ Vaughn, DW TI West Nile virus/dengue type 4 virus chimeras that are reduced in neurovirulence and peripheral virulence without loss of immunogenicity or protective efficacy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protective immunity; dengue virus; viral chimera ID TICK-BORNE ENCEPHALITIS; DENGUE TYPE-4; CONSTRUCTION; MICE; FLAVIVIRUS; CHALLENGE; CLEAVAGE; PROTEIN; STRAINS; VACCINE AB A candidate live attenuated vaccine strain was constructed for West Nile virus (WN), a neurotropic flavivirus that has recently emerged in the U.S. Considerable attenuation for mice was achieved by chimerization with dengue virus type 4 (DEN4). The genes for the structural premembrane and envelope proteins of DEN4 present in an infectious cDNA clone were replaced by the corresponding genes of WN strain NY99. Two of 18 cDNA clones of a WN/DEN4 chimera yielded full-length RNA transcripts that were infectious when transfected into susceptible cells. The two infectious clones shared a motif in the transmembrane signal domain located immediately downstream of the NS213-N53 protease cleavage site that separates the DEN4 capsid protein and the WIN premembrane protein of the chimera. This motif, Asp and Thr at a position 3 and 6 amino acids downstream of the cleavage site, respectively, was not present in the 16 noninfectious cDNA clones. The WN/DEN14 chimera was highly attenuated in mice compared with its WN parent; the chimera was at least 28,500 times less neurovirulent in suckling mice inoculated intracerebrally and at least 10,000 times less virulent in adult mice inoculated intraperitoneally. Nonetheless, the WN/DEN4 chimera and a deletion mutant derived from it were immunogenic and provided complete protection against lethal WN challenge. These observations provide the basis for pursuing the development of a live attenuated WIN vaccine. C1 NIAID, NIH, Lab Infect Dis, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Virus Dis, Silver Spring, MD 20910 USA. RP Pletnev, AG (reprint author), NIAID, NIH, Lab Infect Dis, Bldg 7 Rm 236 7 Ctr Dr MSC 0740, Bethesda, MD 20892 USA. NR 25 TC 83 Z9 90 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 5 PY 2002 VL 99 IS 5 BP 3036 EP 3041 DI 10.1073/pnas.022652799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600080 PM 11880643 ER PT J AU Oi, H Matsuura, D Miyake, M Ueno, M Takai, I Yamamoto, T Kubo, M Moss, J Noda, M AF Oi, H Matsuura, D Miyake, M Ueno, M Takai, I Yamamoto, T Kubo, M Moss, J Noda, M TI Identification in traditional herbal medications and confirmation by synthesis of factors that inhibit cholera toxin-induced fluid accumulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ADP-ribosylation; diarrheal disease; alternative medicine; cAMP; guanine nucleotide-binding proteins ID LABILE ENTERO-TOXIN; ESCHERICHIA-COLI; KDA PROTEIN; ACTIVATION; TANNINS AB Kampo formulations are traditional herbal medications used in China and Japan for many centuries to treat diarrheal diseases such as cholera. our studies were undertaken to identify and verify by chemical synthesis the active components that inhibited cholera toxin (CT), the virulence factor secreted by Vibrio cholerae, the causative agent of cholera. The Kampo formulation, Daio-kanzo-to, inhibited CT activities (i.e., ADP-ribosylation, Chinese hamster ovary cell elongation); in Daia-kanzo-to, Daio (Rhei rhizoma) was responsible for this effect. Among several components purified from Daio extract, rhubarb galloyl-tannin, a compound characterized by a polygallate structure, was the most effective. To define the active component, gallate analogues similar to rhubarb galloyltannin were synthesized. These gallate compounds inhibited all CT activities including ADP-ribosylation, elongation of Chinese hamster ovary cells, and importantly, fluid accumulation in ileal loops. Thus Kampo formulations or their gallate components might be effective adjunctive therapy with oral rehydration solution for the severe diarrhea of cholera. C1 Chiba Univ, Grad Sch Med, Dept Mol Infect, Chiba 2608670, Japan. Japan Immunores Labs, Takasaki, Gumma 3700021, Japan. Tsumura & Co, Tsumura Cent Res Labs, Ibaraki 3000700, Japan. Natl Heart Lung & Blood Inst, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Noda, M (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Infect, Chiba 2608670, Japan. NR 23 TC 43 Z9 43 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 5 PY 2002 VL 99 IS 5 BP 3042 EP 3046 DI 10.1073/pnas.052709499 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600081 PM 11854470 ER PT J AU Koo, HM VanBrocklin, M McWilliams, MJ Leppla, SH Duesbery, NS Vande Woude, GF AF Koo, HM VanBrocklin, M McWilliams, MJ Leppla, SH Duesbery, NS Vande Woude, GF TI Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTICANCER DRUG SCREEN; SIGNAL-TRANSDUCTION; FACTOR CLEAVES; INHIBITOR; PATHWAY; CANCER; LINES; IDENTIFICATION; MACROPHAGES; TOXINS AB Lethal factor, the principal virulence factor of Bacillus anthracis, inhibits mitogen-activated protein kinase (MAPK) signaling by proteolytically cleaving MAPK kinases. Edema factor, another component of anthrax toxin, is an adenylate cyclase, which increases intracellular cAMP. Inhibition of MAPK signaling with either anthrax lethal toxin (LeTx) or small molecule MAPK kinase inhibitors triggers apoptosis in human melanoma cells. Normal melanocytes do not undergo apoptosis in response to MAPK inhibition but arrest in the G, phase of the cell cycle. importantly, in vivo treatment of human melanoma xenograft tumors in athymic nude mice with LeTx results in significant or complete tumor regression without apparent side effects, suggesting that inhibiting the MAPK signaling pathway may be a useful strategy for treating melanoma. Additionally, interrupting MAPK signaling with LeTx and elevating cAMP with anthrax edema toxin in both melanoma cells and melanocytes lead to dramatic melanin production, perhaps explaining the formation of blackened eschars in cutaneous anthrax. C1 Van Andel Res Inst, Grand Rapids, MI 49503 USA. Natl Canc Inst, Frederick Canc Res & Dev Ctr, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. Natl Inst Dental Res, NIH, Bethesda, MD 20892 USA. RP Vande Woude, GF (reprint author), Van Andel Res Inst, 333 Bostwick NE, Grand Rapids, MI 49503 USA. OI DUESBERY, NICK/0000-0002-4258-5655 NR 30 TC 110 Z9 116 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 5 PY 2002 VL 99 IS 5 BP 3052 EP 3057 DI 10.1073/pnas.052707699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600083 PM 11867750 ER PT J AU Bera, TK Maitra, R Iavarone, C Salvatore, G Kumar, V Vincent, JJ Sathyanarayana, BK Duray, P Lee, BK Pastan, I AF Bera, TK Maitra, R Iavarone, C Salvatore, G Kumar, V Vincent, JJ Sathyanarayana, BK Duray, P Lee, BK Pastan, I TI PATE, a gene expressed in prostate cancer, normal prostate, and testis, identified by a functional genomic approach SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunotherapy; cancer vaccine; snake toxin; membrane protein ID REGULATORY PROTEIN CD59; DATABASE; RECEPTOR; ANTIGEN; DOMAIN; SEQUENCES; COMPLEX; CELLS; FOLD AB To identify target antigens for prostate cancer therapy, we have combined computer-based screening of the human expressed sequence tag database and experimental expression analysis to identify genes that are expressed in normal prostate and prostate cancer but not in essential human tissues. Using this approach, we identified a gene that is expressed specifically in prostate cancer, normal prostate, and testis. The gene has a 1.5-kb transcript that encodes a protein of 14 kDa. We named this gene PATE (expressed in prostate and testis). In situ hybridization shows that PATE mRNA is expressed in the epithelial cells of prostate cancers and in normal prostate. Transfection of the PATE cDNA with a Myc epitope tag into NIH 3T3 cells and subsequent cell fractionation analysis shows that the PATE protein is localized in the membrane fraction of the cell. Analysis of the amino acid sequence of PATE shows that it has structural similarities to a group of proteins known as three-finger toxins, which includes the extracellular domain of the type P transforming growth factor receptor. Restricted expression of PATE makes it a potential candidate for the immunotherapy of prostate cancer. C1 NCI, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Lab Mol Biol, NIH, Bldg 37 Rm 5106 37 Convent Dr Mol Simulat Ctr 426, Bethesda, MD 20892 USA. NR 29 TC 33 Z9 35 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 5 PY 2002 VL 99 IS 5 BP 3058 EP 3063 DI 10.1073/pnas.052713699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600084 PM 11880645 ER PT J AU Farci, P Strazzera, R Alter, HJ Farci, S Degioannis, D Coiana, A Peddis, G Usai, F Serra, G Chessa, L Diaz, G Balestrieri, A Purcell, RH AF Farci, P Strazzera, R Alter, HJ Farci, S Degioannis, D Coiana, A Peddis, G Usai, F Serra, G Chessa, L Diaz, G Balestrieri, A Purcell, RH TI Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AMINO-ACID SUBSTITUTIONS; QUASI-SPECIES NATURE; VIRUS-INFECTION; HYPERVARIABLE REGION-1; ALPHA-INTERFERON; NS5A REGION; HYPERIMMUNE SERUM; ANTIVIRAL THERAPY; FRENCH PATIENTS; HCV GENOME AB Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C1 Univ Cagliari, Dept Med Sci, I-09124 Cagliari, Italy. Univ Cagliari, Dept Cytomorphol, I-09124 Cagliari, Italy. NIAID, Lab Infect Dis, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. RP Farci, P (reprint author), Univ Cagliari, Dept Med Sci, Via San Giorgio 12, I-09124 Cagliari, Italy. RI Chessa, Luchino/H-7561-2012; OI Chessa, Luchino/0000-0002-9474-0995; Coiana, Alessandra/0000-0002-1039-5486 NR 53 TC 157 Z9 165 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 5 PY 2002 VL 99 IS 5 BP 3081 EP 3086 DI 10.1073/pnas.052712599 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600088 PM 11880647 ER PT J AU Licht, T Haskins, M Henthorn, P Kleiman, SE Bodine, DM Whitwam, T Puck, JM Gottesman, MM Melniczek, JR AF Licht, T Haskins, M Henthorn, P Kleiman, SE Bodine, DM Whitwam, T Puck, JM Gottesman, MM Melniczek, JR TI Drug selection with paclitaxel restores expression of linked IL-2 receptor gamma-chain and multidrug resistance (MDR1) transgenes in canine bone marrow SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; RIBOSOME ENTRY SITE; BICISTRONIC VECTOR; MEDIATED TRANSFER; GENE-THERAPY; LONG-TERM; IN-VIVO; RETROVIRUS; MICE AB Unstable expression of transferred genes is a major obstacle to successful gene therapy of hematopoietic diseases. We have investigated in a canine large-animal model whether expression of transduced genes can be recovered in vivo. Mixed-breed dogs had undergone autologous bone marrow transplantation (BMT) with stem cell factor and granulocyte- colony-stimulating factor-mobilized retrovirally marked hematopoietic cells. The bicistronic retroviral vector construct allowed for coexpression of MDR1 and human IL-2 receptor common gamma-chain cDNAs. The latter gene is deficient in X-linked severe combined immunodeficiency. After initial high-level expression, P-glycoprotein and the gamma-chain were undetectable in blood and bone marrow 17 months post-BMT. Six months later, one dog was treated i.v. with 125 mg/m(2) paclitaxel. Three administrations restored expression of the two linked genes to high levels in blood and bone marrow. Two dogs treated with higher paclitaxel doses died from myelosuppression after the first administration. As determined by flow cytometry, both genes were expressed in granulocytes, monocytes, and lymphocytes of the surviving animal. PCR analysis of DNA from peripheral blood confirmed that the retroviral cDNA was increased after paclitaxel treatment, suggesting enrichment of transduced cells. P-glycoprotein was detectable for more than 1 year after cessation of paclitaxel. Repeated analyses of blood and bone marrow aspirates gave no indication of hematopoietic disturbance after BMT with transduced cells and paclitaxel treatment. In summary, we have shown that with the use of a drug-selectable marker gene, chemotherapy can select for cells that express an otherwise nonselected therapeutic gene in blood and bone marrow. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Vet Med, Med Genet Sect, Philadelphia, PA 19104 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), Mayo Clin, Program Mol Med, Rochester, MN 55905 USA. FU NCRR NIH HHS [P40 RR002512, T32 RR007063, P40RR-02512, T32RR-07063]; NIAID NIH HHS [AI33177]; NIDDK NIH HHS [R01DK-32475] NR 35 TC 24 Z9 26 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 5 PY 2002 VL 99 IS 5 BP 3123 EP 3128 DI 10.1073/pnas.052712199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600095 PM 11867757 ER PT J AU Lee, SC Choi, S Lee, T Kim, HL Chin, H Shin, HS AF Lee, SC Choi, S Lee, T Kim, HL Chin, H Shin, HS TI Molecular basis of R-type calcium channels in central amygdala neurons of the mouse SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID KNOCK-OUT MICE; CA2+ CHANNELS; PERMEATION PROPERTIES; TRANSMITTER RELEASE; CONDITIONED FEAR; CENTRAL NUCLEUS; CURRENTS; RAT; STIMULATION; RESPONSES AB R-type Ca2+ channels play a critical role in coupling excitability to dendritic Ca2+ influx and neuronal secretion. Unlike other types of voltage-sensitive Ca2+ channels (L, N, P/Q, and T type), the molecular basis for the R-type Ca2+ channel is still unclear, thereby limiting further detailed analyses of R-type Ca2+ channel physiology. The prevailing hypothesis is that alpha(1E) (Ca(V)2.3) gene encodes for R-type Ca2+ channels, but the dearth of critical evidence has rendered this hypothesis controversial. Here we generated alpha(1E)-deficient mice (alpha(1E)-/-) and examined the status of voltage-sensitive Ca2+ currents in central amygdala (CeA) neurons that exhibit abundant alpha(1E) expression and R-type Ca2+ currents. The majority of R-type currents in CeA neurons were eliminated in alpha(1E)-/- mice whereas other Ca2+ channel types were unaffected. These data clearly indicate that the expression of alpha(1E) gene underlies R-type Ca2+ channels in CeA neurons. Furthermore, the alpha(1E)-/mice exhibited signs of enhanced fear as evidenced by their vigorous escaping behavior and aversion to open-field conditions. These latter findings imply a possible role of alpha(1E)-based R-type Ca2+ currents in amygdala physiology associated with fear. C1 Korea Inst Sci & Technol, Natl Creat Res Initiat Ctr Calcium & Learning, Seoul 136791, South Korea. Ewha Womans Univ, Ewha Inst Neurosci, Dept Neurosci, Seoul 110783, South Korea. Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea. Ewha Womans Univ, Coll Med, Dept Biochem, Seoul 158710, South Korea. NIH, Div Neurosci & Basic Behav Sci, Genet Res Branch, Bethesda, MD 20892 USA. RP Shin, HS (reprint author), Korea Inst Sci & Technol, Natl Creat Res Initiat Ctr Calcium & Learning, Seoul 136791, South Korea. EM shin@kist.re.kr NR 45 TC 47 Z9 48 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 5 PY 2002 VL 99 IS 5 BP 3276 EP 3281 DI 10.1073/pnas.052697799 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529DK UT WOS:000174284600121 PM 11854466 ER PT J AU Iwama, A Osawa, M Hirasawa, R Uchiyama, N Kaneko, S Onodera, M Shibuya, K Shibuya, A Vinson, C Tenen, DG Nakauchi, H AF Iwama, A Osawa, M Hirasawa, R Uchiyama, N Kaneko, S Onodera, M Shibuya, K Shibuya, A Vinson, C Tenen, DG Nakauchi, H TI Reciprocal roles for CCAAT/enhancer binding protein (C/EBP) and PU.1 transcription factors in Langerhans cell commitment SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE myeloid differentiation; lineage commitment; dendritic cells; eosinophils; domimant-negative C/EBP ID DENDRITIC CELLS; DEFICIENT MICE; TRANSFORMING GROWTH-FACTOR-BETA-1; HEMATOPOIETIC PROGENITORS; GENE-EXPRESSION; ALPHA; DIFFERENTIATION; LEUKEMIA; LINEAGE; GATA-1 AB Myeloid progenitor cells give rise to a variety of progenies including dendritic cells. However, the mechanism controlling the diversification of myeloid progenitors into each progeny is largely unknown. PU.1 and CCAAT/enhancing binding protein (C/EBP) family transcription factors have been characterized as key regulators for the development and function of the myeloid system. However, the roles of C/EBP transcription factors have not been fully identified because of functional redundancy among family members. Using high titer-retroviral infection, we demonstrate that a dominant-negative C/EBP completely blocked the granulocyte-macrophage commitment of human myeloid progenitors. Alternatively, Langerhans cell (LC) commitment was markedly facilitated in the absence of tumor necrosis factor (TNF)alpha, a strong inducer of LC development, whereas expression of wild-type C/EBP in myeloid progenitors promoted granulocytic differentiation, and completely inhibited TNF(alpha-dependent LC development. On the other hand, expression of wild-type PU.1 it) myeloid progenitors triggered LC development in the absence of TNFalpha, and its instructive effect was canceled by coexpressed C/EBP. Our findings establish reciprocal roles for C/EBP and PU.1 in LC development, and provide new insight into the molecular mechanism of LC development, which has not yet been well characterized. C1 JST, Core Res Evolutional Sci & Technol CREST Program, Inst Basic Med Sci, Dept Immunol, Tsukuba, Ibaraki 3058575, Japan. JST, PRESTO, Tsukuba, Ibaraki 3058575, Japan. Univ Tsukuba, Div Rheumatol, Tsukuba, Ibaraki 3058575, Japan. NCI, Biochem Lab, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Inst Med, Boston, MA 02115 USA. RIKEN, Res Ctr Allergy & Immunol, Yokohama, Kanagawa 2300045, Japan. RP Iwama, A (reprint author), Univ Tsukuba, Inst Basic Med Sci, Dept Immunol, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan. NR 38 TC 71 Z9 72 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 4 PY 2002 VL 195 IS 5 BP 547 EP 558 DI 10.1084/jem.20011465 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 560ZB UT WOS:000176110300003 PM 11877478 ER PT J AU de Beur, SMJ Streeten, EA Civelek, AC McCarthy, EF Uribe, L Marx, SJ Onobrakpeya, O Raisz, LG Watts, NB Sharon, M Levine, MA AF de Beur, SMJ Streeten, EA Civelek, AC McCarthy, EF Uribe, L Marx, SJ Onobrakpeya, O Raisz, LG Watts, NB Sharon, M Levine, MA TI Localisation of mesenchymal tumours by somatostatin receptor imaging SO LANCET LA English DT Article ID OSTEOMALACIA AB Oncogenic osteomalacia, an acquired hypophosphataemic syndrome associated with mesenchymal tumours, is characterised by hypophosphataemia secondary to inappropriate phosphaturia, reduced concentrations of serum calcitriol, and defective bone mineralisation. Removal of these tumours results in complete reversal of these biochemical defects. However, because these tumours are small, slow-growing, and frequently situated in unusual anatomical sites, conventional imaging techniques often fall to detect them. Since mesenchymal tumours express somatostatin receptors, we postulated that somatostatin analogues would be able to detect these tumours. We did Indium-111 labeled pentetreotide imaging in seven patients with oncogenic osteomalacia. In five patients, we identified a mesenchymal tumour, and clinical improvement occurred after tumour resection. Our findings suggest that In-111-pentetreotide imaging effectively detects occult mesenchymal tumours and facilitates surgical treatment of oncogenic osteomalacia. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Nucl Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Ilyssa Ctr Mol & Cellular Endocrinol, Baltimore, MD 21287 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. Washington Hosp Ctr, Dept Med, Washington, DC 20010 USA. NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH USA. RP de Beur, SMJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. EM sjandebe@mail.jhmi.edu OI Levine, Michael/0000-0003-0036-7809 NR 5 TC 77 Z9 78 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 2 PY 2002 VL 359 IS 9308 BP 761 EP 763 DI 10.1016/S0140-6736(02)07846-7 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 526DZ UT WOS:000174115200013 ER PT J AU Miller, FG AF Miller, FG TI Treatment of acute migraine SO LANCET LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 2 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAR 2 PY 2002 VL 359 IS 9308 BP 802 EP 802 DI 10.1016/S0140-6736(02)07867-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 526DZ UT WOS:000174115200056 PM 11888631 ER PT J AU Bucher, MH Evdokimov, AG Waugh, DS AF Bucher, MH Evdokimov, AG Waugh, DS TI Differential effects of short affinity tags on the crystallization of Pyrococcus furiosus maltodextrin-binding protein SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID ESCHERICHIA-COLI; RECOMBINANT PROTEINS; CRYSTAL-STRUCTURE; FUSION PROTEIN; PURIFICATION; EXPRESSION; STREPTAVIDIN; PEPTIDE; VIRUS; STRATEGIES AB Pyrococcus furiosus maltodextrin-binding protein readily forms large orthorhombic crystals that diffract to high resolution. This protein was used as a model system to investigate the influence of five short affinity tags (His(6), Arg(5), Strep tag II, FLAG tag and the biotin acceptor peptide) on the formation of protein crystals and their ability to diffract X-rays. The results indicate that the amino-acid sequence of the tag can have a profound effect on both of these parameters. Consequently, the ability to obtain diffracting crystals of a particular protein may depend as much on which affinity tag is selected as it does on whether an affinity tag is used at all. C1 NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. NR 35 TC 64 Z9 69 U1 0 U2 9 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAR PY 2002 VL 58 BP 392 EP 397 DI 10.1107/S0907444901021187 PN 3 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 528CQ UT WOS:000174227200002 PM 11856823 ER PT J AU Evdokimov, AG Tropea, JE Routzahn, KM Waugh, DS AF Evdokimov, AG Tropea, JE Routzahn, KM Waugh, DS TI Three-dimensional structure of the type III secretion chaperone SycE from Yersinia pestis SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID AERUGINOSA EXOENZYME-S; GRAM-NEGATIVE BACTERIA; PROTEIN; YOPE; ENTEROCOLITICA; VIRULENCE; PROGRAM; IDENTIFICATION; TRANSLOCATION; DELINEATION AB Many bacterial pathogens utilize a type III (contact-dependent) secretion system to inject cytotoxic effector proteins directly into host cells. This ingenious mechanism, designed for both bacterial offense and defense, has been studied most extensively in Yersinia spp. To be exported efficiently, at least three of the effectors (YopE, YopH and YopT) and several other proteins that transit the type III secretion pathway in Yersinia (YopN, YopD and YopB) must first form transient complexes with cognate-specific Yop chaperone (Syc) proteins. The cytotoxic effector YopE, a selective activator of mammalian Rho-family GTPases, associates with SycE. Here, the structure of Y. pestis SycE at 1.95 Angstrom resolution is reported. SycE possesses a novel fold with an unusual dimerization motif and an intriguing basic cavity located on the dyad axis of the dimer that may participate in its interaction with YopE. C1 NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. NR 44 TC 49 Z9 52 U1 2 U2 4 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAR PY 2002 VL 58 BP 398 EP 406 DI 10.1107/S090744490200015X PN 3 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 528CQ UT WOS:000174227200003 PM 11856824 ER PT J AU Dauter, Z Dauter, M Dodson, E AF Dauter, Z Dauter, M Dodson, E TI Jolly SAD SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID ANOMALOUS SCATTERING DATA; X-RAY-DIFFRACTION; MACROMOLECULAR STRUCTURES; ISOMORPHOUS REPLACEMENT; ATOMIC-RESOLUTION; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; PROTEIN; PHASE; REFINEMENT AB Examples of phasing macromolecular crystal structures based on single-wavelength anomalous dispersion (SAD) show that this approach is more powerful and may have more general application in structural biology than was anticipated. Better data-collection facilities and cryogenic techniques, coupled with powerful programs for data processing, phasing, density modification and automatic model building, means that the SAD approach may gain wide popularity owing to its simplicity, less stringent wavelength requirements and faster data collection and phasing than the multi-wavelength (MAD) approach. It can be performed at any wavelength where anomalous scattering can be observed, in many cases using laboratory X-ray sources. C1 Brookhaven Natl Lab, NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Brookhaven Natl Lab, SAIC Intramural Res Support Program, Upton, NY 11973 USA. Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England. RP Dauter, Z (reprint author), Brookhaven Natl Lab, NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Bldg 725A-X9, Upton, NY 11973 USA. EM dauter@bnl.gov NR 62 TC 162 Z9 165 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAR PY 2002 VL 58 BP 494 EP 506 DI 10.1107/S090744490200118X PN 3 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 528CQ UT WOS:000174227200015 PM 11856836 ER PT J AU Facchini, S Muellbacher, W Battaglia, F Boroojerdi, B Hallett, M AF Facchini, S Muellbacher, W Battaglia, F Boroojerdi, B Hallett, M TI Focal enhancement of motor cortex excitability during motor imagery: a transcranial magnetic stimulation study SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE transcranial magnetic stimulation; motor evoked potentials; motor imagery; primary motor cortex; cortical excitability ID POSITRON-EMISSION-TOMOGRAPHY; EVOKED-POTENTIALS MEPS; CORTICOSPINAL EXCITABILITY; MUSCLE RESPONSES; HAND MUSCLES; MOVEMENT; FACILITATION; PERFORMANCE; MODULATION; VOLUNTARY AB Objectives - In order to learn more about the physiology of the motor cortex during motor imagery, we evaluated the changes in excitability of two different hand muscle representations in the primary motor cortex (M1) of both hemispheres during two imagery conditions. Materials and methods - We applied focal transcranial magnetic stimulation (TMS) over each M1, recording motor evoked potentials (MEPs) from the contralateral abductor pollicis brevis (APB) and first dorsal interosseus (FDI) muscles during rest, imagery of contralateral thumb abduction (C-APB), and imagery of ipsilateral thumb abduction (I-APB). We obtained measures of motor threshold (MT), MEP recruitment curve (MEP-rc) and F waves. Results - Motor imagery compared with rest significantly decreased the MT and increased MEPs amplitude at stimulation intensities clearly above NIT in condition C-APB. but not in condition I-APB. These effects were not significantly different between right and left hemisphere. MEPs simultaneously recorded from the FDI. which was not involved in the task, did not show facilitatory effects. There were no significant changes in F wave amplitude during motor imagery compared with rest. Conclusions - Imagery of unilateral simple movements is associated with increased excitability only of a highly specific representation in the contralateral M1 and does not differ between hemispheres. C1 NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINCDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC-1428, Bethesda, MD 20892 USA. NR 32 TC 92 Z9 94 U1 2 U2 9 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD MAR PY 2002 VL 105 IS 3 BP 146 EP 151 DI 10.1034/j.1600-0404.2002.1o004.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 533ZR UT WOS:000174560600002 PM 11886355 ER PT J AU Oakley, F Khin, NA Parks, R Bauer, L Sunderland, T AF Oakley, F Khin, NA Parks, R Bauer, L Sunderland, T TI Improvement in activities of daily living in elderly following treatment for post-bereavement depression SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE activities of daily living; antidepressant treatment AB Objective: To determine if elderly bereaved depressed subjects display difficulty with activities of daily diving (ADL) and if their ADL difficulty improves with psychopharmacologic intervention. Method: The Assessment of Motor and Process Skills (AMPS). an ADL assessment measuring ADL motor and ADL process skills, was administered to a pilot sample of elderly persons with post-bereavement depression prior to psychopharmacologic intervention and subsequently during treatment response. Results: In the pretreatment phase. subjects displayed difficulty with ADL motor and ADL process skills that significantly improved during the treatment response phase. Conclusion: Results suggest that elderly bereaved depressed individuals demonstrated ADL difficulty that responds positively to psychopharmacologic intervention. C1 NIMH, Warren G Magnuson Clin Ctr, Occupat Therapy Sect, NIH, Bethesda, MD 20892 USA. NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nursing, Bethesda, MD 20892 USA. RP Oakley, F (reprint author), NIMH, Warren G Magnuson Clin Ctr, Occupat Therapy Sect, NIH, Bldg 10,Room 6s235,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. NR 14 TC 19 Z9 19 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD MAR PY 2002 VL 105 IS 3 BP 231 EP 234 DI 10.1034/j.1600-0447.2002.1sc021.x PG 4 WC Psychiatry SC Psychiatry GA 539PV UT WOS:000174880400011 PM 11939978 ER PT J AU Zhao, TM Bryant, MA Kindt, TJ Simpson, RM AF Zhao, TM Bryant, MA Kindt, TJ Simpson, RM TI Monoclonally integrated HTLV type 1 in epithelial cancers from rabbits infected with an HTLV type 1 molecular clone SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID T-CELL LEUKEMIA; VIRUS TYPE-I; TROPICAL SPASTIC PARAPARESIS; LYMPHOMA; PATIENT; DISEASE; MODEL; DNA; INFECTIVITY; PROVIRUS AB In addition to T cell leukemias and lymphomas, human T cell leukemia virus type 1 (HTLV-1) infection has been associated with nonhematologic malignancies and described as the cause of one case of small-cell lung carcinoma. Infected primary epithelial cells have been isolated from sweat gland and oral mucosae of HTLV-1-infected human patients. In the present study, epithelial neoplasms developed in two rabbits experimentally infected with a molecular clone of HTLV-1 (strain K30p). Serologic detection of anti-HTLV-1 and isolation of virus from blood lymphocytes at multiple time points postinjection established a course of chronic asymptomatic infection in both. One rabbit, infected fair 5.5 years after intramuscular injection of HTLV-1 DNA, developed a thymoma having features of medullary differentiation. HTLV-1 provirus was detected in both thymocytes and neoplastic epithelium isolated discretely, from the thymoma by laser capture microdissection. These findings provide the first experimental evidence of HTLV-1 disease after infection by HTLV-1 DNA injection. Endometrial adenocarcinoma occurred in a second rabbit 2.5 years after its inoculation with cell-associated virus. In this second case, an epithelial cell line derived ex vivo from a metastatic lesion produced virus in culture. In tumors from each of the two rabbits, the neoplastic epithelium was infected and harbored monoclonally integrated HTLV-1 provirus. Although monoclonal provirus integration alone does not establish retroviral cause of carcinogenesis unequivocally, these and other accumulating data indicate that there may be a role for HTLV-1 in diseases associated with infection of epithelia, including some epithelial cancers. C1 NIAID, Mol & Cellular Immunogenet Res Sect, Bethesda, MD 20892 USA. NIH, Diagnost & Res Serv Branch, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIAID, Infect Dis Pathogenesis Branch, Rockville, MD 20852 USA. RP Simpson, RM (reprint author), NCI, Comparat Mol Pathol Sect, Ctr Canc Res, 31 Ctr Dr,Room 3A11, Bethesda, MD 20892 USA. NR 45 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR 1 PY 2002 VL 18 IS 4 BP 253 EP 258 DI 10.1089/088922202753472829 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 524LX UT WOS:000174015800004 PM 11860672 ER PT J AU Flannery, BA Allen, JP Pettinati, HM Rohsenow, DJ Cisler, RA Litten, RZ AF Flannery, BA Allen, JP Pettinati, HM Rohsenow, DJ Cisler, RA Litten, RZ TI Using acquired knowledge and new technologies in alcoholism treatment trials SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Research-Society-on-Alcoholism CY JUN 23-28, 2001 CL MONTREAL, CANADA SP Res Soc Alcoholism DE biomarkers; compliance; alcohol craving; drinking measures; functional outcomes ID NALTREXONE; HEALTH AB This article represents the proceedings of a symposium held at the 2001 RSA meeting in Montreal, Canada. The organizer and chair was Barbara A. Flannery and the discussant was Rave Z. Litten. The presentations were (1) The use of biomarkers in alcohol-dependence treatment trials, by John P. Allen; (2) Strategies for enhancing patient compliance in clinical treatment trials, by Helen M. Pettinati; (3) The predictive utility of an alcohol-craving measure, by Barbara A. Flannery; () What should be the primary outcome measures in a clinical trial, by Damaris J. Rohsenow; (5) Innovative strategies for assessing functional outcomes in alcoholism treatment clinical trials, by Ron A. Cisler. C1 RTI Int, Ctr Interdisciplinary Subst Abuse Res, Res Triangle Pk, NC 27709 USA. NIAAA, Bethesda, MD USA. Univ Penn, Ctr Study Addict, Philadelphia, PA 19104 USA. Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. Univ Wisconsin, Ctr Addict & Behav Hlth Res, Milwaukee, WI 53201 USA. RP Flannery, BA (reprint author), RTI Int, Ctr Interdisciplinary Subst Abuse Res, POB 12194,3040 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. FU NIAAA NIH HHS [AA-08442, AA-11756, AA-08442-S2, AA-07850, AA-07517, AA-09544, AA-11773] NR 40 TC 16 Z9 16 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2002 VL 26 IS 3 BP 423 EP 429 DI 10.1111/j.1530-0277.2002.tb02556.x PG 7 WC Substance Abuse SC Substance Abuse GA 534WM UT WOS:000174612800019 PM 11923598 ER PT J AU Allhusen, V Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Jaeger, E Johnson, DJ Kelly, JF Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Robeson, W Spieker, S Vandell, DL Weinraub, M AF Allhusen, V Belsky, J Booth, C Bradley, R Brownell, CA Burchinal, M Caldwell, B Campbell, SB Clarke-Stewart, KA Cox, M Friedman, SL Hirsh-Pasek, K Huston, A Jaeger, E Johnson, DJ Kelly, JF Knoke, B Marshall, N McCartney, K O'Brien, M Owen, MT Payne, C Phillips, D Pianta, R Randolph, SM Robeson, W Spieker, S Vandell, DL Weinraub, M CA NICHD Early Child Care Res Network TI Early child care and children's development prior to school entry: Results from the NICHD Study of Early Child Care SO AMERICAN EDUCATIONAL RESEARCH JOURNAL LA English DT Article DE child care; day care; school readiness ID LANGUAGE-DEVELOPMENT; NONMATERNAL CARE; MOTHER-INFANT; QUALITY; ADJUSTMENT; EMPLOYMENT; ATTACHMENT; EXPERIENCE; OUTCOMES; FAMILY AB Effects of early child care on children's functioning at the age of 41/2 years wee a examined in the NICHD (National Institute of Child Health and Human Development) Study of Early Child Care, a prospective longitudinal study of more than 1,000 children. Even after controlling for multiple child and family characteristics, children's development was predicted by early child-care experience. Higher-quality child care, improvements in the quality of child care, and experience in center-type arrangements predicted better pre-academic skills and language performance at 41/2 years. More hours of care predicted higher levels of behavior problems according to caregivers. Effect sizes associated with early child-care experiences were evaluated in relation to effect sizes obtained for two other well-recognized influences on early development: parenting and poverty. The findings indicated the importance (and relative independence) of quantity, quality, and type of child care for children's development just prior to the time that children initiate formal schooling. C1 NICHHD, Early Child Care Res Network, CRMC, Rockville, MD 20852 USA. RP Allhusen, V (reprint author), NICHHD, Early Child Care Res Network, CRMC, 6100 Execut Blvd,4B05, Rockville, MD 20852 USA. RI Marshall, Nancy/C-3428-2012 NR 74 TC 281 Z9 282 U1 10 U2 69 PU AMER EDUCATIONAL RESEARCH ASSOC PI WASHINGTON PA 1230 17TH ST NW, WASHINGTON, DC 20036-3078 USA SN 0002-8312 J9 AM EDUC RES J JI Am. Educ. Res. J. PD SPR PY 2002 VL 39 IS 1 BP 133 EP 164 PG 32 WC Education & Educational Research SC Education & Educational Research GA 552CA UT WOS:000175599700006 ER PT J AU Baer, DJ Judd, JT Clevidence, BA Muesing, RA Campbell, WS Brown, ED Taylor, PR AF Baer, DJ Judd, JT Clevidence, BA Muesing, RA Campbell, WS Brown, ED Taylor, PR TI Moderate alcohol consumption lowers risk factors for cardiovascular disease in postmenopausal women fed a controlled diet SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE alcohol; LDL cholesterol; HDL cholesterol; triacylglycerols; postmenopausal women; triglycerides; cardiovascular disease ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE; PREMENOPAUSAL WOMEN; TRANSFER PROTEIN; PLASMA; MENOPAUSE; FAT; MEN; METABOLISM; LIPIDS AB Background: Moderate alcohol consumption (1-2 drinks/d) may decrease cardiovascular disease risk in postmenopausal women by improving lipid profiles. Objective: We measured the effect of moderate alcohol consumption on lipids and lipoproteins in postmenopausal women. Design: Postmenopausal women (n = 51) consumed 0 (control), 15 (1 drink), and 30 (2 drinks) g alcohol (ethanol)/d for 8 wk each as part of a controlled diet in a randomized crossover design. The control diet provided approximate to 15%, 53%, and 32% of energy from protein, carbohydrate, and fat, respectively. The energy provided from alcohol in the 15- and 30-g alcohol diets was replaced with energy from carbohydrate. Results: Compared with concentrations after the control diet, plasma LDL cholesterol decreased from 3.45 to 3.34 mmol/L (P = 0.04) and triacylglycerol from 1.43 to 1.34 mmol/L (P = 0,05) after 15 a alcohol/d. There were no additional significant decreases in either lipid after an increase in alcohol intake from 15 to 30 g/d. Compared with concentrations after the control diet, plasma HDL cholesterol increased nonsignificantly from 1.40 to 1.43 mmol/L after 15 g alcohol/d but increased to 1.48 mmol/L after 30 g alcohol/d (P = 0.02). Apolipoprotein A-I increased significantly and apolipoprotein B decreased significantly after 30 g alcoholld relative to the concentration after the control diet. Conclusions: Consumption of 15-30 g alcohol/d by postmenopausal women apparently decreases cardiovascular disease risk by improving lipid profiles. Plasma LDL-cholesterol and triacylglycerol concentrations improve after 15 g alcohol/d; plasma HDL cholesterol improves only after 30 g alcohol/d. C1 USDA ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. George Washington Univ, Med Ctr, Lipid Res Clin, Washington, DC USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Baer, DJ (reprint author), USDA ARS, Beltsville Human Nutr Res Ctr, Bldg 308,Room 213, Beltsville, MD 20705 USA. NR 43 TC 57 Z9 58 U1 3 U2 9 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2002 VL 75 IS 3 BP 593 EP 599 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 525NR UT WOS:000174078300021 PM 11864868 ER PT J AU Parker, AS Cerhan, JR Lynch, CF Ershow, AG Cantor, KR AF Parker, AS Cerhan, JR Lynch, CF Ershow, AG Cantor, KR TI Gender, alcohol consumption, and renal cell carcinoma SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; carcinoma; renal cell; case-control studies ID RISK-FACTORS; CANCER RISK; POSTMENOPAUSAL WOMEN; UNITED-STATES; MORTALITY; ESTROGEN; TOBACCO; SMOKING; DEATH AB The nature of the association between alcohol consumption and renal cell carcinoma (RCC) is not well understood, but there are indications of effect modification by gender. The authors report data from a population-based case-control study conducted in Iowa from 1986 to 1989. RCC cases (261 men and 145 women) were identified through the Iowa Cancer Registry, while controls (1,598 men and 831 women) were randomly selected from the general population, frequency matched on age and gender. Subjects provided detailed information on a mailed questionnaire regarding demographic, anthropometric, lifestyle, dietary, and medical history risk factors. In age-adjusted analysis, there was a decrease in risk for women who reported consuming more than three servings (median among drinkers) of alcohol per week (odds ratio = 0.5, 95% confidence interval: 0.2, 0.9) compared with never drinkers. No evidence of an association among men was noted (odds ratio = 1.1, 95% confidence interval: 0.8, 1.5). Multivariate adjustment for anthropometric, lifestyle, smoking, and dietary factors did not alter the findings. Analysis by type of alcohol suggested that the inverse association was strongest for beer consumption, but estimates were imprecise. These findings suggest an inverse association of alcohol consumption and RCC development among women but not among men. C1 Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Parker, AS (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. FU NCI NIH HHS [N01 CP5106, N01 CP85614] NR 34 TC 42 Z9 42 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 1 PY 2002 VL 155 IS 5 BP 455 EP 462 DI 10.1093/aje/155.5.455 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 526WX UT WOS:000174153800011 PM 11867357 ER PT J AU Sunderland, T AF Sunderland, T TI Strategies for treating Alzheimer's disease throughout the course of illness. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 SU 1 BP 20 EP 21 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 538CB UT WOS:000174795500060 ER PT J AU Lebowitz, BD AF Lebowitz, BD TI The unanticipated consequences of purposeful action. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 SU 1 BP 21 EP 21 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 538CB UT WOS:000174795500062 ER PT J AU Olin, JT Meyers, BS Alexopoulos, GS Katz, IR Lyketsos, CG Caine, ED Schneider, LS Lebowitz, BD AF Olin, JT Meyers, BS Alexopoulos, GS Katz, IR Lyketsos, CG Caine, ED Schneider, LS Lebowitz, BD TI NIMH provisional diagnostic criteria for depression of Alzheimer's disease. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD USA. Cornell Univ, White Plains, NY USA. Univ Penn, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Univ Rochester, Rochester, NY 14627 USA. Univ So Calif, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 SU 1 BP 28 EP 28 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 538CB UT WOS:000174795500081 ER PT J AU Bartels, SJ Finkel, SI Norquist, G AF Bartels, SJ Finkel, SI Norquist, G TI Integration of geriatric mental health services in primary care: Early results from the PROSPECT, IMPACT, PIC, and PRISMe studies. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 New Hampshire Dartmouth Psychiat Res Ctr, Lebanon, NH USA. Council Jewish Elderly, Leonard Schanfield Res Inst, Chicago, IL USA. NIMH, Div Serv & Intervent Res, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 4 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 SU 1 BP 33 EP 33 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 538CB UT WOS:000174795500096 ER PT J AU Olin, J AF Olin, J TI Emerging issues in the NIMH CATIE Alzheimer's disease effectiveness trial. SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 SU 1 BP 45 EP 46 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 538CB UT WOS:000174795500130 ER PT J AU Olin, JT Schneider, LS Katz, IR Meyers, BS Alexopoulos, GS Breitner, JC Bruce, ML Caine, ED Cummings, JL Devanand, DP Krishnan, KRR Lyketsos, CG Lyness, JM Rabins, PV Reynolds, CF Rovner, BW Steffens, DC Tariot, PN Lebowitz, BD AF Olin, JT Schneider, LS Katz, IR Meyers, BS Alexopoulos, GS Breitner, JC Bruce, ML Caine, ED Cummings, JL Devanand, DP Krishnan, KRR Lyketsos, CG Lyness, JM Rabins, PV Reynolds, CF Rovner, BW Steffens, DC Tariot, PN Lebowitz, BD TI Provisional diagnostic criteria for depression of Alzheimer disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article ID PREVALENCE AB The authors, a group of investigators with extensive research and clinical experience related to both late-life depression and Alzheimer disease (AD), propose provisional affective and behavioral inclusion and exclusion diagnostic criteria for Depression of AD. C1 NIMH, Geriatr Psychopharmacol Program, Adult & Geriatr Treatment & Prevent Intervent Res, Bethesda, MD 20892 USA. RP Olin, JT (reprint author), NIMH, Geriatr Psychopharmacol Program, Adult & Geriatr Treatment & Prevent Intervent Res, 6001 Execut Blvd,Room 7160 MSC 9635, Bethesda, MD 20892 USA. NR 6 TC 110 Z9 114 U1 0 U2 9 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 BP 125 EP 128 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 537AC UT WOS:000174733200003 PM 11925273 ER PT J AU Olin, JT Katz, IR Meyers, BS Schneider, LS Lebowitz, BD AF Olin, JT Katz, IR Meyers, BS Schneider, LS Lebowitz, BD TI Provisional diagnostic criteria for depression of Alzheimer disease - Rationale and background SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Review ID PRIMARY DEGENERATIVE DEMENTIA; BEHAVIOR RATING-SCALE; LATE-ONSET DEPRESSION; LATE-LIFE DEPRESSION; AGE-OF-ONSET; GERIATRIC DEPRESSION; DOUBLE-BLIND; MAJOR DEPRESSION; COGNITIVE DECLINE; ELDERLY PATIENTS AB This review provides the rationale and background for the development of diagnostic criteria for depression of Alzheimer disease (AD), including risk factors and neurobiological correlates, epidemiology, and clinical characteristics, along with course, assessment, treatment, economics, a description of the criteria, and future research directions. Overall, there is substantial research to suggest that the depression that may, co-occur with AD is different from other depressive disorders. Further research is needed to better define core symptoms, clinical course, and efficacy of treatments. C1 NIMH, Adult & Geriatr Treatment & Prevent Intervent Res, Rockville, MD USA. RP Olin, JT (reprint author), NIMH, 6001 Execut Blvd,Room 7160 MSC 9635, Bethesda, MD 20892 USA. FU NIMH NIH HHS [P30 MH52129]; PHS HHS [R37 MII51247] NR 127 TC 189 Z9 196 U1 4 U2 14 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR-APR PY 2002 VL 10 IS 2 BP 129 EP 141 DI 10.1176/appi.ajgp.10.2.129 PG 13 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 537AC UT WOS:000174733200004 PM 11925274 ER PT J AU DeBaun, MR Niemitz, EL McNeil, DE Brandenburg, SA Lee, MP Feinberg, AP AF DeBaun, MR Niemitz, EL McNeil, DE Brandenburg, SA Lee, MP Feinberg, AP TI Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WILMS-TUMOR; P57(KIP2); KVLQT1; IGF2; GENE; TRANSCRIPT; RELAXATION; MUTATIONS; TISSUE; LOCUS AB Beckwith-Wiedemann syndrome (BWS) is a congenital cancer-predisposition syndrome associated with embryonal cancers, macroglossia, macrosomia, ear pits or ear creases, and midline abdominal-wall defects. The most common constitutional abnormalities in BWS are epigenetic, involving abnormal methylation of either H19 or LIT1, which encode untranslated RNAs on 11p15. We hypothesized that different epigenetic alterations would be associated with specific phenotypes in BWS. To test this hypothesis, we performed a case-cohort study, using the BWS Registry. The cohort consisted of 92 patients with BWS and molecular analysis of both H19 and LIT1, and these patients showed the same frequency of clinical phenotypes as those patients in the Registry from whom biological samples were not available. The frequency of altered DNA methylation of H19 in patients with cancer was significantly higher, 56% (9/16), than the frequency in patients without cancer, 17% (13/76; P = .002), and cancer was not associated with LIT1 alterations. Furthermore, the frequency of altered DNA methylation of LIT1 in patients with midline abdominal-wall defects and macrosomia was significantly higher, 65% (41/63) and 60% (46/77), respectively, than in patients without such defects, 34% (10/29) and 18% (2/11), respectively (P = .012 and P = .002, respectively). Additionally, paternal uniparental disomy (UPD) of 11p15 was associated with hemihypertrophy (P = .003), cancer (P = .03), and hypoglycemia (P = .05). These results define an epigenotype- phenotype relationship in BWS, in which aberrant methylation of H19 and LIT1 and UPD are strongly associated with cancer risk and specific birth defects. C1 Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21204 USA. Johns Hopkins Univ, Sch Med, Predoctoral Program Human Genet, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Feinberg, AP (reprint author), Johns Hopkins Univ, Sch Med, Inst Med Genet, 1064 Ross,720 Rutland Ave, Baltimore, MD 21204 USA. FU NCI NIH HHS [R01 CA054358, CA54358, R37 CA054358, R37 CA054358-12] NR 32 TC 157 Z9 169 U1 0 U2 7 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 604 EP 611 DI 10.1086/338934 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000005 PM 11813134 ER PT J AU Niimi, T Munakata, M Keck-Waggoner, CL Popescu, NC Levitt, RC Hisada, M Kimura, S AF Niimi, T Munakata, M Keck-Waggoner, CL Popescu, NC Levitt, RC Hisada, M Kimura, S TI A polymorphism in the human UGRP1 gene promoter that regulates transcription is associated with an increased risk of asthma SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SUSCEPTIBILITY GENES; PROTEIN CC16; SERUM IGE; CELL; INFLAMMATION; ALLERGY AB Several traits associated with asthma phenotypes, such as high total serum immunoglobulin E and bronchial hyperresponsiveness, have been linked by numerous genome-screen studies and linkage analyses to markers on human chromosome 5q31-q34. In the present article, we describe UGRP1 (encoding uteroglobin-related protein 1) as one of asthma-susceptibility genes that is located on chromosome 5q31-q32. UGRP1 is a homodimeric secretory protein of 17 kDa and is expressed only in lung and trachea. The G-->A polymorphism was identified at -112 bp in the human UGRP1 gene promoter. The -112A allele is responsible for a 24% reduction in the promoter activity in relation to the -112G allele, as examined by transfection analysis. Electrophoretic mobility-shift analysis revealed that an unknown nuclear factor binds to the region around 5 112 bp. The binding affinity with the -112A oligonucleotide was reduced by approximately one half, as compared with the -112G oligonucleotide. In a case-control study using 169 Japanese individuals (84 patients with asthma and 85 healthy control individuals), those with a -112A allele (G/A or A/A) were 4.1 times more likely to have asthma than were those with the wild-type allele (G/G). C1 NCI, Met Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Fukushima Med Univ, Dept Pulm Med, Fukushima, Japan. Genaera Corp, Plymouth Meeting, PA USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Kimura, S (reprint author), NCI, Met Lab, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. NR 26 TC 42 Z9 48 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 718 EP 725 DI 10.1086/339272 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000014 PM 11813133 ER PT J AU De Sandre-Giovannoli, A Chaouch, M Kozlov, S Vallat, JM Tazir, M Kassouri, N Szepetowski, P Hammadouche, T Vandenberghe, A Stewart, CL Grid, D Levy, N AF De Sandre-Giovannoli, A Chaouch, M Kozlov, S Vallat, JM Tazir, M Kassouri, N Szepetowski, P Hammadouche, T Vandenberghe, A Stewart, CL Grid, D Levy, N TI Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; A-TYPE LAMIN; ZERO GENE; DISEASE TYPE-2; MUTATIONS; IDENTIFICATION; EXPRESSION; DOMINANT; FAMILY; MODEL AB The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes-NF-L and KIF1Bbeta-have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Z(max) = 4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1. C1 Fac Med de la Timone, INSERM, U491, Unite Genet Med & Dev, F-13385 Marseille 5, France. Hop Enfants La Timone, Dept Med Genet, Marseille, France. Inst Pasteur, Algiers, Algeria. NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. Ctr Hosp Univ Dupuytren, Serv Neuropathol, Limoges, France. Hop Antiquaille, Neurogenet Lab, Lyon, France. Genethon 3, Evry, France. RP Levy, N (reprint author), Fac Med de la Timone, INSERM, U491, Unite Genet Med & Dev, F-13385 Marseille 5, France. RI De Sandre-Giovannoli, Annachiara/L-5759-2016; LEVY, Nicolas/J-1632-2014 OI De Sandre-Giovannoli, Annachiara/0000-0002-2324-2462; LEVY, Nicolas/0000-0001-5171-6365 NR 37 TC 317 Z9 328 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 726 EP 736 DI 10.1086/339274 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000015 PM 11799477 ER PT J AU Collins-Schramm, HE Phillips, CM Operario, DJ Lee, JS Weber, JL Hanson, RL Knowler, WC Cooper, R Li, HZ Seldin, MF AF Collins-Schramm, HE Phillips, CM Operario, DJ Lee, JS Weber, JL Hanson, RL Knowler, WC Cooper, R Li, HZ Seldin, MF TI Ethnic-difference markers for use in mapping by admixture linkage disequilibrium SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ADMIXED POPULATIONS; MEXICAN-AMERICANS; DISEASE; TEXAS; RISK AB Mapping by admixture linkage disequilibrium (MALD) is a potentially powerful technique for the mapping of complex genetic diseases. The practical requirements of this method include (a) a set of markers spanning the genome that have large allele-frequency differences between the parental ethnicities contributing to the admixed population and (b) an understanding of the extent of admixture in the study population. To this end, a DNA-pooling technique was used to screen microsatellite and diallelic insertion/deletion markers for allele-frequency differences between putative representatives of the parental populations of the admixed Mexican American (MA) and African American (AA) populations. Markers with promising pooled differences were then confirmed by individual genotyping in both the parental and admixed populations. For the MA population, screening of >600 markers identified 151 ethnic-difference markers (EDMs) with delta > 0.30 (where delta is the absolute value of each allele-frequency differences between two populations, summed over all marker alleles and divided by two) that are likely to be useful for MALD analysis. For the AA population, analysis of >400 markers identified 97 EDMs. In addition, individual genotyping of these markers in Pima Amerindians, Yavapai Amerindians, European American (EA) individuals, Africans from Zimbabwe, MA individuals, and AA individuals, as well as comparison to the CEPH genotyping set, suggests that the differences between subpopulations of an ethnicity are small for many markers with large interethnic differences. Estimates of admixture that are based on individual genotyping of these markers are consistent with a 60% EA: 40% Amerindian contribution to MA populations and with a 20% EA: 80% African contribution to AA populations. Taken together, these data suggest that EDMs with large interpopulation and small intrapopulation differences can be readily identified for MALD studies in both AA and MA populations. C1 Univ Calif Davis, Dept Biol Chem & Med, Rowe Program Human Genet, Davis, CA 95616 USA. Marshfield Med Res Fdn, Ctr Med Genet, Marshfield, WI 54449 USA. NIDDKD, NIH, Phoenix, AZ USA. Loyola Univ, Dept Epidemiol & Prevent Med, Maywood, IL 60153 USA. RP Seldin, MF (reprint author), Univ Calif Davis, Dept Biol Chem & Med, Rowe Program Human Genet, 1 Shields Ave, Davis, CA 95616 USA. RI Phillips, Carolyn/E-8305-2011; Hanson, Robert/O-3238-2015 OI Phillips, Carolyn/0000-0002-6228-6468; Hanson, Robert/0000-0002-4252-7068 FU NHLBI NIH HHS [N01-HV-48141, HL45508, N01HV48141, R37 HL045508, R01-HV-62681]; NIDDK NIH HHS [U01-DK57249, U01 DK057249] NR 28 TC 100 Z9 102 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 737 EP 750 DI 10.1086/339368 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000016 PM 11845411 ER PT J AU Goldmuntz, E Bamford, R Karkera, JD dela Cruz, J Roessler, E Muenke, M AF Goldmuntz, E Bamford, R Karkera, JD dela Cruz, J Roessler, E Muenke, M TI CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LEFT-RIGHT AXIS; CARDIAC-MALFORMATIONS; GENE; FREQUENCY; DEFECTS; ZIC3 AB Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease-namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects-would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr MSC 1852,Bldg 10,Room 10C103, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL51533] NR 19 TC 99 Z9 102 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 776 EP 780 DI 10.1086/339079 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000021 PM 11799476 ER PT J AU Grice, DE Halmi, KA Fichter, MM Strober, M Woodside, DB Treasure, JT Kaplan, AS Magistretti, PJ Goldman, D Bulik, CM Kaye, WH Berrettini, WH AF Grice, DE Halmi, KA Fichter, MM Strober, M Woodside, DB Treasure, JT Kaplan, AS Magistretti, PJ Goldman, D Bulik, CM Kaye, WH Berrettini, WH TI Evidence for a susceptibility gene for anorexia nervosa on chromosome 1 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CONTROLLED FAMILY; BULIMIA-NERVOSA; DISORDERS; LINKAGE; POWER AB Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n = 37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p. C1 Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Cornell Univ, Dept Psychiat, White Plains, NY USA. Univ Munich, Hosp Behav Med, Klin Roseneck, Prien Am Chiemsee, Germany. Univ Calif Los Angeles, Inst Neuropsychiat, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Toronto, Toronto Hosp, Dept Psychiat, Toronto, ON, Canada. Univ Lausanne, Inst Physiol, Lausanne, Switzerland. Univ London Kings Coll, Inst Psychiat, London WC2R 2LS, England. NIAAA, Neurogenet Lab, Bethesda, MD USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Berrettini, WH (reprint author), Univ Penn, Dept Psychiat, Room 111,Clin Res Bldg,415 Curie Blvd, Philadelphia, PA 19104 USA. RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Treasure, Janet/0000-0003-0871-4596 NR 25 TC 128 Z9 131 U1 3 U2 11 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR PY 2002 VL 70 IS 3 BP 787 EP 792 DI 10.1086/339250 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 522DG UT WOS:000173880000023 PM 11799475 ER PT J AU Martin, SA Sandler, DP Harlow, SD Shore, DL Rowland, AS Alavanja, MCR AF Martin, SA Sandler, DP Harlow, SD Shore, DL Rowland, AS Alavanja, MCR TI Pesticide use and pesticide-related symptoms among black farmers in the agricultural health study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE African Americans; farmers; pesticides; exposure; health; occupational disease ID MORTALITY AB Background Health effects of pesticides have not been well studied in black farmers. We describe agricultural practices and pesticide-related symptoms in North Carolina black and white farmers participating in the Agricultural Health Study. Methods Self-administered questionnaires were completed by 891 black and 11,909 white farmers licensed to apply restricted pesticides. Regression models were used to compare characteristics by race. Results Black farmers reported lower lifetime pesticide use, less use of each class of pesticides (e.g., herbicides, insecticides), less use of high exposure application methods, and fewer pesticide-related symptoms such as headaches or dizziness, skin irritation, chest discomfort and feeling nervous or depressed than did white farmers. Conclusions Differences between black and white farmers may be explained by farm characteristics or economics. Despite lower use of pesticides, black farmers may have other work practices that affect exposure and risk. Am. J. Ind. Med. 41:202-209, 2002. Published 2002 Wiley-Liss, Inc(dagger). C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. Westat Corp, Durham, NC USA. NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, NIH, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI Sandler, Dale/0000-0002-6776-0018 NR 11 TC 12 Z9 12 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAR PY 2002 VL 41 IS 3 BP 202 EP 209 DI 10.1002/ajim.10046 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 526LP UT WOS:000174132200005 PM 11920964 ER PT J AU Jones, CA Francis, ME Eberhardt, MS Chavers, B Coresh, J Engelgau, M Kusek, JW Byrd-Holt, D Narayan, V Herman, WH Jones, CP Salive, M Agodoa, LY AF Jones, CA Francis, ME Eberhardt, MS Chavers, B Coresh, J Engelgau, M Kusek, JW Byrd-Holt, D Narayan, V Herman, WH Jones, CP Salive, M Agodoa, LY TI Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Third National Health and Nutrition Examination Survey (NHANES III); population survey; cross-sectional survey; prevalence; microalbuminuria (MA); proteinuria; albuminuria; random untimed urine; albumin-creatinine ratio (ACR); hypertension; diabetes ID URINARY ALBUMIN EXCRETION; DEPENDENT DIABETES-MELLITUS; CARDIOVASCULAR RISK-FACTORS; INSULIN-RESISTANCE SYNDROME; ESSENTIAL-HYPERTENSION; NONDIABETIC SUBJECTS; BLOOD-PRESSURE; RENAL-FUNCTION; CREATININE CLEARANCE; GENERAL-POPULATION AB Microalbuminuria (MA) is associated with adverse health outcomes in diabetic and hypertensive adults. The prevalence and clinical significance of MA in nondiabetic populations is less clear. The purpose of this study was to generate national estimates of the prevalence of MA in the US population. Untimed urinary albumin concentrations (UACs) and creatinine concentrations were evaluated in a nationally representative sample of 22,244 participants aged 6 years and older. Persons with hematuria and menstruating or pregnant women were excluded from analysis. The percent prevalence of clinical proteinuria (UAC greater than or equal to 300 mg/L) was similar for males and females. However, the prevalence of MA (urinary albumin-creatinine ratio [ACR], 30 to 299 mg/g) was significantly lower in males (6.1%) compared with females (9.7%). MA prevalence was greater in children than young adults and increased continuously starting at 40 years of age. MA prevalence was greater in non-Hispanic blacks and Mexican Americans aged 40 to 79 years compared with similar-aged non-Hispanic whites. MA prevalence was 28.8% in persons with previously diagnosed diabetes, 16.0% in those with hypertension, and 5.1% in those without diabetes, hypertension, cardiovascular disease, or elevated serum creatinine levels. In adults aged 40+ years, after excluding persons with clinical proteinuria, albuminuria (defined as ACR 30 mg/g) was independently associated with older age, non-Hispanic black and Mexican American ethnicity, diabetes, hypertension, and elevated serum creatinine concentration. MA is common, even among persons without diabetes or hypertension. Age, sex, race/ethnicity, and concomitant disease contribute to the variability of MA prevalence estimates. (C) 2002 by the National Kidney Foundation, Inc. C1 Joslin Diabet Ctr, Div Genet & Epidemiol, Sect Genet & Epidemiol, Boston, MA 02215 USA. Social & Sci Syst, Silver Spring, MD USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Epidemiol, Hyattsville, MD 20782 USA. Univ Minnesota, Sch Med, Dept Pediat, Minneapolis, MN 55455 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Dept Biostat & Med, Baltimore, MD USA. Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. NIDDKD, Clin Trials Program, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. Univ Michigan, Med Ctr, Dept Internal Med, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Epidemiol, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. Assoc Black Cardiologists Inc, Epidemiol & Clin Trials Ctr, Atlanta, GA USA. NHLBI, Div Epidemiol & Clin Applicat, Prevent Sci Res Grp, NIH, Bethesda, MD 20892 USA. NIDDKD, End Stage Renal Dis Program, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. NIDDKD, Minor Hlth Program, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Jones, CA (reprint author), Joslin Diabet Ctr, Div Genet & Epidemiol, Sect Genet & Epidemiol, Rm 368,1 Joslin Pl, Boston, MA 02215 USA. NR 69 TC 251 Z9 269 U1 1 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2002 VL 39 IS 3 BP 445 EP 459 DI 10.1053/ajkd.2002.31388 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 525UW UT WOS:000174093300001 PM 11877563 ER PT J AU Kusek, JW Greene, P Wang, SR Beck, G West, D Jamerson, K Agodoa, LY Faulkner, M Level, B AF Kusek, JW Greene, P Wang, SR Beck, G West, D Jamerson, K Agodoa, LY Faulkner, M Level, B CA African Amer Study Kidney Dis & Hy TI Cross-sectional study of health-related quality of life in African Americans with chronic renal insufficiency: The African American Study of Kidney Disease and Hypertension Trial SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE health-related quality of life (HRQL); chronic renal insufficiency (CRI); African Americans ID OF-LIFE; FUNCTIONAL STATUS; MEDICAL OUTCOMES; WHITEHALL-II; DIALYSIS; HEMODIALYSIS; INSTRUMENTS; SYMPTOMS; SF-36 AB We measured health-related quality of life (HRQL) by using the Medical Outcomes Study 36-Item Short-Form (SF-36) in a cross-sectional study of 1,094 African American men and women with mild to moderate chronic renal insufficiency (mean glomerular filtration rate, 45.7 mL/min/1.73 m(2)) caused by hypertension before randomization onto the African American Study of Kidney Disease and Hypertension (AASK) Trial. Scales contributing to physical health and a summary measure, the Physical Component Summary (PCs) score (mean, 43.4 +/- 10.9 [SD]), were significantly lower than scales relating to mental health and the Mental Component Summary (MCS) score (51.3 +/- 10.3). All scales (except Role-Physical) and the PCs and MCS were significantly higher in men (44.3 +/- 10.9 and 51.8 +/- 10.0, respectively) than women (41.9 +/- 10.8 and 50.5 +/- 10.6, respectively). In multivariate analysis, employment status, education level, household income, body mass index, comorbid medical conditions, years of hypertension, number of antihypertensive drugs prescribed, exercise status, and male sex were significant independent predictors of PCs. Fewer factors predicted MCS and included employment status, marital status, current smoking, age, comorbid medical conditions, and male sex. In the entire AASK cohort, mean scores for individual scales, except Mental Health, and the PCs were lower, but the mean MCS score was slightly higher than values for the US general population. Values for individual scales of the SF-36 and the PCs were substantially higher among AASK participants compared with African-American hemodialysis patients. Six of the eight scales were lower in the AASK cohort compared with groups of racially mixed and exclusively African-American hypertensive subjects. We conclude that physical aspects of quality of life are substantially reduced compared with mental components among AASK participants, and a number of demographic and clinical characteristics significantly impact on HRQL. (C) 2002 by the National Kidney Foundation, Inc. C1 NIDDKD, Div Kidney Urol & Hematol Dis, End Stage Renal Dis Program, Off Minor Hlth Coordinat,NIH, Bethesda, MD 20817 USA. Agcy Healthcare Res & Qual, Rockville, MD USA. Univ Alabama, Dept Prevent Med, Behav Med Unit, Birmingham, AL USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Michigan, Dept Internal Med, Div Hypertens, Ann Arbor, MI 48109 USA. Meharry Med Coll, Dept Internal Med, Div Nephrol, Nashville, TN 37208 USA. RP Kusek, JW (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, End Stage Renal Dis Program, Off Minor Hlth Coordinat,NIH, Rm 617,6707 Democracy Blvd, Bethesda, MD 20817 USA. FU NIDDK NIH HHS [U01 DK45388, U01 DK48645, U01 DK48652, U01 DK48677, U01 DK45386, U01 DK45381, U01 DK45426, U01 DK45373, U01 DK48669, U01 DK48643, U01 DK48648, U01 DK48659, U01 DK45430, U01 DK48682, U01 DK48689, U01 DK48621, U01 DK45387] NR 38 TC 65 Z9 68 U1 3 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2002 VL 39 IS 3 BP 513 EP 524 DI 10.1053/ajkd.2002.31401 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 525UW UT WOS:000174093300008 PM 11877570 ER PT J AU Carney, JA Stratakis, CA AF Carney, JA Stratakis, CA TI Familial paraganglioma and gastric stromal sarcoma: A new syndrome distinct from the Carney triad SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE paraganglioma; gastric stromal tumor; syndrome; familial; Carney triad; pheochromocytoma; catecholamines ID EXTRA-ADRENAL PARAGANGLIOMA; HEREDITARY GLOMUS TUMORS; NERVE GAN TUMOR; NONCHROMAFFIN PARAGANGLIOMAS; PULMONARY CHONDROMA; IMPRINTED GENE; MUTATIONS; COMPLEX; HEAD; NECK AB Paragangliomas may be inherited in an autosomal dominant manner either alone (as in PGL1, PGL2, and PGL3 syndromes) or as a component of a multiple tumor syndrome (as in von Hippel-Lindau disease and neurofibromatosis type 1). In this article, we describe 12 patients (7 male and 5 female) with an average age of 23 years from five unrelated families that manifested paraganglioma and gastric stromal sarcoma; the tumors were inherited in an apparent autosomal dominant manner, with incomplete penetrance. Seven patients had paraganglioma, four had paraganglioma and gastric stromal sarcoma, and one had gastric stromal sarcoma. The paraganglioma was multicentric and the gastric stromal sarcoma multifocal. Because of the rarity of gastric stromal sarcoma and its multifocality, the young age of the patients, and the unlikelihood of coincidental co-occurrence of paragangliomas and gastric stromal sarcomas, we suggest that a new syndrome exists with these two main components, a condition that is familial and distinct from the Carney triad. Published 2002 Wiley-Liss, Inc.(dagger). C1 Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Carney, JA (reprint author), Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, 200 1st St SW, Rochester, MN 55905 USA. NR 41 TC 152 Z9 159 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD MAR 1 PY 2002 VL 108 IS 2 BP 132 EP 139 DI 10.1002/ajmg.10235 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 524ZR UT WOS:000174043200006 PM 11857563 ER PT J AU Bytautiene, E Vedernikov, YP Saade, GR Romero, R Garfield, RE AF Bytautiene, E Vedernikov, YP Saade, GR Romero, R Garfield, RE TI Endogenous mast cell degranulation modulates cervical contractility in the guinea pig SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE mast cells; cervix; contractility; pregnancy; hypersensitivity ID FUNCTIONAL-CHARACTERISTICS; HUMAN MYOMETRIUM; SMOOTH-MUSCLE; HUMAN UTERUS; MEDIATORS; PROSTAGLANDINS; HISTAMINE; RATS AB OBJECTIVE: The purpose of this study was to investigate the effect of endogenous mast cell degranulation on the contractility of isolated cervical strips from nonpregnant and pregnant guinea pigs. STUDY DESIGN: Longitudinal cervical strips from nonpregnant and pregnant (mid and term) guinea pigs were used for isometric tension recording. Responses to the mast cell degranulating agent, compound 48/80, were compared in the absence or presence of different inhibitors and receptor antagonists. Concentration-response curves were obtained to histamine and 5-hydroxytryptamine in strips that were incubated with antagonists or solvent. RESULTS: Compound 48/80 and histamine significantly increased contractility of cervical strips in all 3 groups of animals. The inhibitor of mast cell degranulation significantly reduced responses to compound 48/80 and histamine-1 receptor antagonist reduced responses to histamine in all 3 groups. Histamine-1 receptor antagonist significantly inhibited responses to compound 48/80 in nonpregnant and mid pregnant guinea pigs. Histamine-2 receptor antagonist did not alter responses to compound 48/80 nor to histamine. The receptor antagonist 5-hydroxytryptamine-2 significantly inhibited cervical contractility that was induced by compound 48/80 in tissues from mid pregnant and term pregnant guinea pigs. Lipoxygenase inhibitor was effective in mid pregnant guinea pigs. Cyclooxygenase inhibitor, 5-hydroxytryptamine, and a combination of lipoxygenase and cyclooxygenase inhibitors had no effect on cervical contractility. CONCLUSION: The degranulation of mast cells releases histamine and other mediators that stimulate cervical contractility through histamine-1 receptors. Cervical infiltration and modulation of contractility by mast cells may play an important physiologic and/or pathologic role in the control of cervical function during pregnancy. C1 Univ Texas, Med Branch, Dept Obstet & Gynecol, Div Reprod Sci, Galveston, TX 77555 USA. NICHHD, Perinatol Res Branch, Bethesda, MD USA. RP Garfield, RE (reprint author), Univ Texas, Med Branch, Dept Obstet & Gynecol, Div Reprod Sci, 301 Univ Blvd,Rt J-62, Galveston, TX 77555 USA. NR 22 TC 29 Z9 31 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2002 VL 186 IS 3 BP 438 EP 445 DI 10.1067/mob.2002.120488 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 533WD UT WOS:000174552500018 PM 11904604 ER PT J AU Ramsey, PS Tamura, T Goldenberg, RL Mercer, BM Iams, JD Meis, PJ Moawad, AH Das, A Van Dorsten, JP Caritis, SN Thurnau, G Dombrowski, MP Miodovnik, M AF Ramsey, PS Tamura, T Goldenberg, RL Mercer, BM Iams, JD Meis, PJ Moawad, AH Das, A Van Dorsten, JP Caritis, SN Thurnau, G Dombrowski, MP Miodovnik, M CA Natl Inst Child Hlth & Human Dev M TI The Preterm Prediction Study: Elevated cervical ferritin levels at 22 to 24 weeks of gestation are associated with spontaneous preterm delivery in asymptomatic women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 47th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-30, 2000 CL CHICAGO, ILLINOIS SP Soc Gynecol Invest DE ferritin; acute-phase reactant; preterm delivery; pregnancy; inflammation ID AMNIOTIC-FLUID INFECTION; HISTOLOGIC CHORIOAMNIONITIS; PLACENTAL ISOFERRITIN; BACTERIAL VAGINOSIS; MONOCLONAL-ANTIBODY; PLASMA FERRITIN; SERUM FERRITIN; BIRTH; PREGNANCY; DISEASE AB OBJECTIVE: Low serum ferritin levels correlate with low iron stores, whereas high levels are associated with an acute-phase reaction. Our objective was to determine whether elevated levels of ferritin in the genital tract may be a potent marker to identify patients at risk for spontaneous preterm delivery. STUDY DESIGN: We performed a nested case-control study involving 182 women who had spontaneous preterm delivery and 182 term control subjects matched for race, parity, and recruitment center, and selected from 2929 women enrolled in the Preterm Prediction Study of the National Institute of Child Health and Development Maternal-Fetal Medicine Units Network. Cervical fluid ferritin was measured by use of radioimmunoassay. RESULTS. Cervical ferritin levels were significantly higher in women who subsequently had spontaneous early preterm delivery (<32 weeks, mean +/- SD, 37.7 +/- 31.1 vs 21.5 +/- 24.1 ng/mL, P = .002; and <35 weeks, 43.2 +/- 62.7 vs 28.2 +/- 36.7 ng/mL, P = .004) than in term controls. A cervical ferritin of >75th percentile in the controls (>35.5 ng/mL) was found in 52.9% (9/17) of the women delivered <29 weeks vs 17.7% (3/17) of the controls (odds ratio [OR] 5.3 [95% Cl 1.1-25.2]) and in 43.5% (20/46) of the women delivered <32 weeks versus 10.9% (5/46) of the controls (OR 6.3, 95% Cl 2.1-18.9). Cervical ferritin levels had a weaker association with spontaneous preterm delivery <35 weeks (OR 2.8 [95% Cl 1.5-5.1]) and <37 weeks (OR 1.6, 95% Cl 1.0-2.5]). Cervical ferritin levels correlated significantly with cervical lactoferrin, interleukin-6 (IL-6), and defensin levels. CONCLUSIONS: Elevated cervical ferritin levels at 22 to 24 weeks of gestation in asymptomatic women are associated with subsequent spontaneous preterm birth. The strong correlation of cervical ferritin with other inflammatory markers provides support for the hypothesis of infection as a mediator of preterm delivery. C1 NICHHD, Maternal Fetal Med Units Network, Bethesda, MD USA. RP Ramsey, PS (reprint author), Dept Obstet Gynecol, Div Maternal Fetal Med, 458 Old Hillman Bldg,619 19th St S, Birmingham, AL 35249 USA. OI caritis, steve/0000-0002-2169-0712 FU NICHD NIH HHS [HD19897, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917] NR 25 TC 19 Z9 19 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2002 VL 186 IS 3 BP 458 EP 463 DI 10.1067/mob.2002.121088 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 533WD UT WOS:000174552500021 PM 11904607 ER PT J AU Wang, EY Woodruff, TK Moawad, A AF Wang, EY Woodruff, TK Moawad, A CA Natl Inst Child Hlth & Human Dev M TI Follistatin-free activin A is not associated with preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE activin A; preterm birth ID INHIBIN-A; MATERNAL SERUM; FETAL MEMBRANES; HUMAN PLACENTA; HUMAN AMNION; BETA-A; PREDICTION; DELIVERY; WOMEN; PREECLAMPSIA AB OBJECTIVE: The purpose of this study was to determine whether follistatin-free activin A (an inhibin-related protein with rising serum levels before term labor) is associated with spontaneous preterm birth in an outpatient population. STUDY DESIGN: From 10 centers, 2929 women were enrolled in the Preterm Prediction Study. Plasma was isolated from blood samples obtained at 24 and 28 weeks of gestation and stored. A nested case-controlled study was performed; there were 197 women with spontaneous preterm birth before 37 weeks of gestation with 24-week samples and 142 cases with 28-week samples that were matched to an equal number of term control samples from each time point. A follistatin-free activin A enzyme-linked immunosorbent assay was performed, with results interpreted as positive or negative (defined as a value less than the assay limit of sensitivity). A comparison of follistatin-free activin A with other tests that were associated with spontaneous preterm birth (alpha-fetoprotein, alkaline phosphatase, cortisol, granulocyte colony-stimulating factor, fetal fibronectin, and cervical interleukin-6) was also performed. RESULTS: The odds ratio for associated spontaneous preterm birth at <37 weeks of gestation if the follistatin-free activin A result was positive was 1.16 at 24 weeks (95% Cl, 0.62-2.17) and 1.39 at 28 weeks (95% Cl, 0.68-2.84). A positive follistatin-free activin A result at either 24 or 28 weeks was not associated with a positive test for any of the other laboratory tests, except granulocyte colony-stimulating factor at 28 weeks' gestation. CONCLUSION: Follistatin-free activin A is not associated with spontaneous preterm birth in an asymptomatic outpatient population. Follistatin-free activin A may not be an appropriate screening marker for spontaneous preterm birth in the office setting. C1 Northwestern Univ, NICHHD, Maternal Fetal Med Units Network, Evanston, IL 60208 USA. Northwestern Univ, NICHHD, Maternal Fetal Med Units Network, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Northwestern Univ, Dept Neurobiol & Physiol, Chicago, IL 60611 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. RP Wang, EY (reprint author), Northwestern Univ, NICHHD, Maternal Fetal Med Units Network, Evanston, IL 60208 USA. FU NICHD NIH HHS [HD21414, HD19897, HD21410, HD21434, HD27860, HD27861, HD27869, HD27883, HD27889, HD27905, HD27915, HD27917, HD35708] NR 26 TC 7 Z9 7 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2002 VL 186 IS 3 BP 464 EP 469 DI 10.1067/mob.2002.121087 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 533WD UT WOS:000174552500022 PM 11904608 ER PT J AU Bauer, CR Shankaran, S Bada, HS Lester, B Wright, LL Krause-Steinrauf, H Smeriglio, VL Finnegan, LP Maza, PL Verter, J AF Bauer, CR Shankaran, S Bada, HS Lester, B Wright, LL Krause-Steinrauf, H Smeriglio, VL Finnegan, LP Maza, PL Verter, J TI The Maternal Lifestyle Study: Drug exposure during pregnancy and short-term maternal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE alcohol; cocaine; drug use; drug abuse; fetus; newborn; marijuana; maternal medical/health outcomes; NICHD Neonatal Research Network; opiates; perinatal; polydrug use; pregnancy; tobacco ID COCAINE USE AB OBJECTIVE: Reports of maternal effects resulting from drug exposure during pregnancy are inconsistent. The Maternal Lifestyle Study (MLS) is a multicenter, prospective, observational study that was initiated to better define the effects of exposure to illicit drugs during pregnancy on the mother, fetus, and infant. METHODS: Between May 1993 and May 1995, of 19,079 mother-infant dyads that were screened after delivery for cocaine and opiate exposure at four clinical centers (Brown University, University of Miami, University of Tennessee, Memphis, and Wayne State University), 16,988 (89%) met eligibility criteria and 11,811 (70%) of those eligible agreed to participate in the study. Exposure was defined as an admission of use of cocaine or opiates or both or the presence of cocaine or opiate metabolites in meconium as determined by use of gas chromatography-mass spectroscopy assay. Nonexposure was defined as a negative drug use history by interview and a negative immunoassay screen. When exposure could not be confirmed, such as when meconium was not obtained or was inadequate for confirmatory analysis, the mother-infant dyad was excluded (n = 3184). RESULTS: Of the mothers who consented to participate, 50% were African American, 38% were married, 64% were Medicaid recipients, and 95% had at least one prenatal care visit (median, 10 visits). Significant differences (P < .01) between cocaine-opiate exposed (n = 1185) and nonexposed (n = 7442) mothers included race (African American: 74.6% and 47.0%, respectively), mean age (29.6 and 26.1 years, respectively), and polydrug use including any combination of alcohol, tobacco, and/or marijuana (93% and 42%, respectively). Odds ratios (99% Cl) indicate that exposed mothers had a significantly higher risk (P <.001) of medical complications including syphilis 6.7 (4.8-9.6), gonorrhea 1.9 (1.3-3.0), and hepatitis 4.8 (2.6-8.91); psychiatric, nervous, and emotional disorders 4.0 (2.2-7.4); and abruptio placenta 2.3 (1.4-3.9). The odds of a positive test for human immunodeficiency virus were higher (available on 28% of the cohort) in the exposed group 8.2 (14.3-15.4). Seventeen cases of maternal acquired immunodeficiency syndrome (AIDS) were identified. Opiate exposure with its attendant needle use significantly increased the risk of hepatitis and AIDS. The number of hospitalizations during pregnancy did not differ between the exposure groups because similar to11 % of patients in each group were hospitalized at least once. However, violence as a cause of hospitalization was more common in the cocaine-exposed group, 19.6 (2.7-144.7). CONCLUSION: This observational study confirmed many of the reported adverse social and serious medical perinatal complications of mothers exposed to cocaine or opiates during pregnancy. The overall prevalence of these risk outcomes was lower than has been reported previously. C1 Univ Miami, Dept Pediat R131, Sch Med, Miami, FL 33101 USA. Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. Univ Tennessee, Memphis Coll Med, Dept Pediat, Memphis, TN USA. Brown Univ, Sch Med, Women & Infants Hosp, Dept Pediat, Providence, RI 02912 USA. NICHHD, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. Natl Inst Drug Abuse, Lexington, KY USA. NIH, Off Res Womens Hlth, Bethesda, MD USA. Adm Children Youth & Families, Washington, DC USA. RP Bauer, CR (reprint author), Univ Miami, Dept Pediat R131, Sch Med, POB 016960, Miami, FL 33101 USA. FU NICHD NIH HHS [U10 HD 21397, U10 HD 19897, U10 HD 21385, U10 HD 27856, U10 HD 27904] NR 25 TC 109 Z9 109 U1 1 U2 8 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2002 VL 186 IS 3 BP 487 EP 495 DI 10.1067/mob.2002.121073 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 533WD UT WOS:000174552500026 PM 11904612 ER PT J AU Okada, H Inoue, T Kanno, Y Kobayashi, T Watanabe, Y Kopp, JB Carey, RM Suzuki, H AF Okada, H Inoue, T Kanno, Y Kobayashi, T Watanabe, Y Kopp, JB Carey, RM Suzuki, H TI Interstitial fibroblast-like cells express renin-angiotensin system components in a fibrosing murine kidney SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; II TYPE-2 RECEPTOR; CONVERTING ENZYME; MATRIX PROTEINS; RENAL FIBROSIS; RAT-KIDNEY; MOUSE; MICE; LOCALIZATION; GENE AB Recently, the renin-angiotensin system (RAS) was implicated in organ fibrosis. However, few studies have examined the localization of RAS components, such as angiotensin H receptors, renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney. To localize these components in the fibrosing kidney, we used a murine model of renal fibrosis that shows an enhanced expression of angiotensin H type 1A receptor (ATAR) and AGTN. Our results indicate that the overall expression of angiotensin H type 2 receptor (AT(2)R) and ACE was attenuated in this model, whereas REN expression was unchanged. In addition to tubular epithelial cells that were positive for AT(1A)R, AT(2)R, REN, and AGTN, interstitial fibroblast-like cells expressed AT(1A)R, REN, AGTN, and ACE in the fibrosing kidney. The interstitial fibroblast-like cells that were positive for AT(1A)R mRNA were further characterized as positive for the expression of vimentin and transforming growth factor-beta1. These data provide strong evidence for a tubulointerstitial RAS within the fibrosing kidney, and a linkage between the RAS and renal fibro-genesis. C1 Saitama Med Coll, Dept Nephrol, Moroyama, Saitama 35004, Japan. NIDDKD, NIH, Kidney Dis Sect, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Suzuki, H (reprint author), Saitama Med Coll, Dept Nephrol, 38 Morohongo, Moroyama, Saitama 35004, Japan. OI Kopp, Jeffrey/0000-0001-9052-186X NR 32 TC 22 Z9 22 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2002 VL 160 IS 3 BP 765 EP 772 DI 10.1016/S0002-9440(10)64898-5 PG 8 WC Pathology SC Pathology GA 528QU UT WOS:000174255100003 PM 11891174 ER PT J AU Bissel, SJ Wang, GJ Ghosh, M Reinhart, TA Capuano, S Cole, KS Murphey-Corb, M Piatak, M Lifson, JD Wiley, CA AF Bissel, SJ Wang, GJ Ghosh, M Reinhart, TA Capuano, S Cole, KS Murphey-Corb, M Piatak, M Lifson, JD Wiley, CA TI Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA COMPLEX; DECREASED SYNAPTIC DENSITY; IN-SITU HYBRIDIZATION; HIV-INFECTION; CEREBROSPINAL-FLUID; RHESUS-MONKEYS; VIRAL LOAD; NONDEMENTED PATIENTS; ZIDOVUDINE TREATMENT AB Neurodegeneration observed in lentiviral-associated encephalitis has been linked to viral-infected and -activated central nervous system macrophages. We hypothesized that lentivirus, macrophages, or both lentivirus and macrophages within distinct microenvironments mediate synaptic damage. Using the simian immunodeficiency virus (SIV)-infected macaque model, we assessed the relationship between virus, macrophages, and neurological damage in multiple brain regions using laser confocal microscopy. In SIV-infected macaques with SIV encephalitis (SIVE), brain tissue concentrations of SIV RNA were 5 orders of magnitude greater than that observed in nonencephalitic animals. in SIVE, staining for postsynaptic protein microtubule-associated protein-2 was significantly decreased in the caudate, hippocampus, and frontal cortical gray matter compared to nonencephalitic controls, whereas staining for presynaptic protein synaptophysin was decreased in SIV-infected macaques with and without encephalitis. These data suggest that presynaptic damage occurs independent of pathological changes associated with SIVE, whereas postsynaptic damage is more tightly linked to regional presence of both activated and infected macrophages. C1 Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Infect Dis & Microbiol, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Microbiol, Pittsburgh, PA USA. NCI, Sci Applicat Int Corp, AIDS Vaccine Program, Lab Retroviral Pathogenesis, Frederick, MD 21701 USA. RP Wiley, CA (reprint author), A-515 UPMC Presbyterian,200 Lothrup St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [N01-CO-56000]; NIMH NIH HHS [R01 MH061205, K24 MH001717, MH01717, MH46790, MH61205]; NINDS NIH HHS [NS35731] NR 74 TC 32 Z9 32 U1 1 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2002 VL 160 IS 3 BP 927 EP 941 DI 10.1016/S0002-9440(10)64915-2 PG 15 WC Pathology SC Pathology GA 528QU UT WOS:000174255100020 PM 11891191 ER PT J AU Qu, W Diwan, BA Liu, J Goyer, RA Dawson, T Horton, JL Cherian, MG Waalkes, MP AF Qu, W Diwan, BA Liu, J Goyer, RA Dawson, T Horton, JL Cherian, MG Waalkes, MP TI The metallothionein-null phenotype is associated with heightened sensitivity to lead toxicity and an inability to form inclusion bodies SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID DEVELOPING RAT-KIDNEY; II GENES; PROTEIN; METALS; MICE; NEPHROTOXICITY; INDUCTION; EXPOSURE; AFFINITY; CADMIUM AB Susceptibility to lead toxicity in MT-null mice and cells, lacking the major forms of the metallothionein (MT) gene, was compared to wild-type (WT) mice or cells. Male MT-null and WT mice received lead in the drinking water (0 to 4000 ppm) for 10 to 20 weeks. Lead did not alter body weight in any group. Unlike WT mice, lead-treated MT-null mice showed dose-related nephromegaly. In addition, after lead exposure renal function was significantly diminished in MT-null mice In comparison to WT mice. MT-null mice accumulated less renal lead than WT mice and did not form lead inclusion bodies, which were present in the kidneys of WT mice. In gene array analysis, renal glutathione S-transferases were up-regulated after lead in MT-null mice only. In vitro studies on fibroblast cell lines derived from MT-null and WT mice showed that MT-null cells were much more sensitive to lead cytotoxicity. MT-null cells accumulated less lead and formed no inclusion bodies. The MT-null phenotype seems to preclude lead-induced Inclusion body formation and increases lead toxicity at the organ and cellular level despite reducing lead accumulation. This study reveals important roles for MT in chronic lead toxicity, lead accumulation, and inclusion bodyformation. C1 NIEHS, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. Univ Western Ontario, London, ON, Canada. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [N01-CO-56000] NR 47 TC 27 Z9 31 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2002 VL 160 IS 3 BP 1047 EP 1056 DI 10.1016/S0002-9440(10)64925-5 PG 10 WC Pathology SC Pathology GA 528QU UT WOS:000174255100030 PM 11891201 ER PT J AU Flanders, KC Sullivan, CD Fujii, M Sowers, A Anzano, MA Arabshahi, A Major, C Deng, CX Russo, A Mitchell, JB Roberts, AB AF Flanders, KC Sullivan, CD Fujii, M Sowers, A Anzano, MA Arabshahi, A Major, C Deng, CX Russo, A Mitchell, JB Roberts, AB TI Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; IN-VIVO; MYOFIBROBLASTIC PHENOTYPE; MOLECULAR MECHANISMS; TARGETED DISRUPTION; FIBROBLASTS AB Transforming growth factor-beta (TGF-beta) plays a central role in the pathogenesis of inflammatory and fibrotic diseases, including radiation-induced fibrosis. We previously reported that mice null for Smad3, a key downstream mediator of TGF-beta, show accelerated healing of cutaneous incisional wounds with reduced inflammation and accumulation of matrix. To determine if loss of Smad3 decreases radiation-induced injury, skin of Smad3+/+ [wild-type (WT)] and -/- [knockout (KO)] mice was exposed to a single dose of 30 to 50 Gy of gamma-irradiation. Six weeks later, skin from KO mice showed significantly less epidermal acanthosis and dermal influx of mast cells, macrophages, and neutrophils than skin from WT littermates. Skin from irradiated KO mice exhibited less immunoreactive TGF-beta and fewer myofibroblasts, suggesting that these mice will have a significantly reduced fibrotic response. Although irradiation induced no change in the immunohistochemical expression of the TGF-beta type I receptor, the epidermal expression of the type II receptor was lost after irradiation whereas its dermal expression remained high. Primary keratinocytes and dermal fibroblasts prepared from WT and KO mice showed similar survival when irradiated, as did mice exposed to whole-body irradiation. These results suggest that inhibition of Smad3 might decrease tissue damage and reduce fibrosis after exposure to ionizing irradiation. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Flanders, KC (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C-629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 66 TC 193 Z9 208 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2002 VL 160 IS 3 BP 1057 EP 1068 DI 10.1016/S0002-9440(10)64926-7 PG 12 WC Pathology SC Pathology GA 528QU UT WOS:000174255100031 PM 11891202 ER PT J AU Faletti, CJ Perrotti, N Taylor, SI Blazer-Yost, BL AF Faletti, CJ Perrotti, N Taylor, SI Blazer-Yost, BL TI sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na+ transport SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE insulin; antidiuretic hormone; aldosterone; amiloride; phosphoinositide pathway; epithelial Na+ channel; serum and glucocortoid-induced kinase ID EPITHELIAL SODIUM-CHANNELS; PROTEIN-KINASE; PHOSPHOINOSITIDE 3-KINASE; ALDOSTERONE; SERUM; ACTIVATION AB To study the role of sgk (serum, glucocorticoid-induced kinase) in hormonal regulation of Na+ transport mediated by the epithelial Na+ channel (ENaC), clonal cell lines stably expressing human sgk, an S422A sgk mutant, or a D222A sgk mutant were created in the background of the A6 model renal epithelial cell line. Expression of normal sgk results in a 3.5-fold enhancement of basal transport and potentiation of the natriferic response to antidiuretic hormone (ADH). Transfection of a S422A mutant form of sgk, which cannot be phosphorylated by phosphatidylinositol-dependent kinase (PDK)-2, results in a cell line that is indistinguishable from the parent line in basal and hormone-stimulated Na+ transport. The D222A sgk mutant, which lacks kinase activity, functions as a dominant-negative mutant inhibiting basal as well as peptide- and steroid hormone- stimulated Na+ transport. Thus sgk activity is necessary for ENaC-mediated Na+ transport. Phosphorylation and activation by PDK-2 are necessary for sgk stimulation of ENaC. Expression of normal sgk over endogenous levels results in a potentiated natriferic response to ADH, suggesting that the enzyme is a rate-limiting step for the hormone response. In contrast, sgk does not appear to be the rate-limiting step for the cellular response to aldosterone or insulin. C1 Indiana Univ Purdue Univ, Dept Biol, Indianapolis, IN 46202 USA. NIDDKD, Diabet Branch, Div Intramural Res, Bethesda, MD 20892 USA. Univ Catanzaro, Dipartimento Med Sperimentale & Clin G Salvatore, I-88100 Catanzaro, Italy. RP Blazer-Yost, BL (reprint author), Indiana Univ Purdue Univ, Dept Biol, SL 358,723 W Michigan St, Indianapolis, IN 46202 USA. RI chen, xuanlan/H-4158-2011 NR 24 TC 97 Z9 97 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD MAR PY 2002 VL 282 IS 3 BP C494 EP C500 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 520WJ UT WOS:000173806200009 PM 11832334 ER PT J AU Shafrir, Y Forgacs, G AF Shafrir, Y Forgacs, G TI Mechanotransduction through the cytoskeleton SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE intracellular signal transduction; computational model; mechanical energy transfer ID VASCULAR SMOOTH-MUSCLE; SIGNAL-TRANSDUCTION; CARDIAC MYOCYTES; ACTIN-FILAMENTS; GENE-EXPRESSION; CELLS; MICROTUBULES; LOCALIZATION; ACTIVATION; MEMBRANE AB We constructed a model cytoskeleton to investigate the proposal that this interconnected filamentous structure can act as a mechano- and signal transducer. The model cytoskeleton is composed of rigid rods representing actin filaments, which are connected with springs representing cross-linker molecules. The entire mesh is placed in viscous cytoplasm. The model eukaryotic cell is submitted to either shock wave-like or periodic mechanical perturbations at its membrane. We calculated the efficiency of this network to transmit energy to the nuclear wall as a function of cross-linker stiffness, cytoplasmic viscosity, and external stimulation frequency. We found that the cytoskeleton behaves as a tunable band filter: for given linker molecules, energy transmission peaks in a narrow range of stimulation frequencies. Most of the normal modes of the network are spread over the same frequency range. Outside this range, signals are practically unable to reach their destination. Changing the cellular ratios of linker molecules with different elastic characteristics can control the allowable frequency range and, with it, the efficiency of mechano-transduction. C1 Clarkson Univ, Dept Phys, Potsdam, NY 13676 USA. Univ Missouri, Dept Phys & Biol, Columbia, MO 65211 USA. RP Shafrir, Y (reprint author), NIH, Lab Expt & Computat Biol, Bethesda, MD 20892 USA. NR 48 TC 51 Z9 51 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD MAR PY 2002 VL 282 IS 3 BP C479 EP C486 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 520WJ UT WOS:000173806200007 PM 11832332 ER PT J AU Miller, DS Masereeuw, R Karnaky, KJ AF Miller, DS Masereeuw, R Karnaky, KJ TI Regulation of MRP2-mediated transport in shark rectal salt gland tubules SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE endothelin-1; multidrug resistance-associated protein isoform 2; protein kinase C ID MULTIDRUG-RESISTANCE; SQUALUS-ACANTHIAS; NATRIURETIC PEPTIDE; EXPORT PUMP; ENDOTHELIN; SECRETION; LOCALIZATION; CHLORIDE; RECEPTOR; MECHANISMS AB We examined endothelin-1 (ET-1) regulation of the xenobiotic efflux pump, multidrug resistance-associated protein isoform 2 (MRP2), in intact dogfish shark rectal salt gland tubules using a fluorescent substrate sulforhodamine 101 and confocal microscopy. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-lumen transport of sulforhodamine 101. These effects were prevented by an ETB receptor antagonist but not by an ETA receptor antagonist. Immunostaining with an antibody to mammalian ETB receptors showed specific localization to the basolateral membrane of the shark rectal gland epithelial cells. ET-1 effects on transport were blocked by a protein kinase C (PKC)-selective inhibitor, implicating PKC in ET-1 signaling. A protein kinase A (PKA)-selective inhibitor had no effect. Forskolin reduced luminal accumulation of sulforhodamine 101, but inhibition of PKA did not block the forskolin effect. Consistent with this observation, a cAMP analog that does not activate PKA reduced luminal accumulation of sulforhodamine 101. These results indicate that shark rectal gland transport on MRP2 is regulated by ET acting through an ETB receptor and PKC. In addition, cAMP affects transporter function through a PKA-independent mechanism, possibly by competition for transport. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, NL-6500 HB Nijmegen, Netherlands. Med Univ S Carolina, Dept Cell Biol & Anat, Charleston, SC 29425 USA. Med Univ S Carolina, Marine Biomed & Environm Sci Program, Charleston, SC 29425 USA. Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov RI Masereeuw, Roos/N-3582-2014 NR 22 TC 24 Z9 24 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAR PY 2002 VL 282 IS 3 BP R774 EP R781 PG 8 WC Physiology SC Physiology GA 520JR UT WOS:000173779200019 PM 11832398 ER PT J AU Regnauld, KL Leteurtre, E Gutkind, SJ Gespach, CP Emami, S AF Regnauld, KL Leteurtre, E Gutkind, SJ Gespach, CP Emami, S TI Activation of adenylyl cyclases, regulation of insulin status, and cell survival by G alpha olf in pancreatic beta-cells SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE G alpha olf subunit; apoptosis; diabetes; regeneration ID G-PROTEIN; MOLECULAR-CLONING; B-CELLS; RAT-BRAIN; EXPRESSION; CAMP; ISLETS; SECRETION; SUBUNITS; RECEPTOR AB Because we recently identified the Galphaolf subunit in rat pancreatic beta-cells, we investigated the downstream effectors and the biological functions of this G protein in HEK-293T cells and the insulin-secreting mouse betaTC-3 cell line. With the use of transient transfection of HEK-293T cells with constitutively activated Galphaolf (GalphaolfQ214L, i.e., AGalphaolf), together with expression vectors encoding the adenylyl cyclase (AC) isoforms (AC-I to -VIII and soluble AC), compared with cotransfections using AGalphas (GalphasR201C), we observed that AGalphaolf preferentially activates AC-I and -VIII, which are also expressed in beta-cells. Stable overexpression of wild-type or AGalphaolf in betaTC-3 cells resulted in partial attenuation of insulin secretion and biosynthesis, suggesting that chronic activation of the Galphaolf-signaling pathway is associated with beta-cell desensitization. In agreement, transfected betaTC-3 cells present a decreased insulin content with respect to parental cells, whereas the proinsulin convertases PC-1 and PC-2 were unaffected. Furthermore, betaTC-3-AGalphaolf cells are resistant to serum starvation-induced apoptosis. Our findings suggest that Galphaolf is involved in insulin status, cell survival, and regeneration of the insulin-secreting beta-cells during development and diabetes. C1 Hop St Antoine, INSERM, U482, F-75571 Paris 12, France. INSERM, U377, F-59045 Lille, France. NIDR, NIH, Bethesda, MD 20892 USA. RP Emami, S (reprint author), Hop St Antoine, INSERM, U482, F-75571 Paris 12, France. NR 46 TC 11 Z9 11 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAR PY 2002 VL 282 IS 3 BP R870 EP R880 PG 11 WC Physiology SC Physiology GA 520JR UT WOS:000173779200031 PM 11832410 ER PT J AU Bankir, L Ahloulay, M Devreotes, PN Parent, CA AF Bankir, L Ahloulay, M Devreotes, PN Parent, CA TI Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved? SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article; Proceedings Paper CT EB 2000 Meeting on the Extracellular ATP and cAMP as Paracrine and Interorgan regulators of Renal Function CY APR, 2000 CL SAN DIEGO, CA DE Dictyostelium discoideum; liver; adipose tissue; glucagon; epinephrine; parathyroid hormone; insulin; hypertension; hepatorenal syndrome; diabetes mellitus; sodium; phosphate ID CYCLIC ADENOSINE-MONOPHOSPHATE; GLOMERULAR-FILTRATION RATE; ESSENTIAL-HYPERTENSION; DICTYOSTELIUM-DISCOIDEUM; RENAL HEMODYNAMICS; GLY40SER MUTATION; CHEMOATTRACTANT RECEPTORS; ARGININE-VASOPRESSIN; PARATHYROID-HORMONE; INDUCED HYPERFILTRATION AB Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this "pancreato-hepatorenal cascade" indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulin-to-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide. Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism. cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues. C1 Inst Fer Moulin, INSERM, U367, F-75005 Paris, France. Hop Beaujon, INSERM, U481, F-92118 Clichy, France. Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bankir, L (reprint author), Inst Fer Moulin, INSERM, U367, 17 Rue Fer Moulin, F-75005 Paris, France. EM bankir@ifm.inserm.fr FU NIGMS NIH HHS [GM34933] NR 182 TC 45 Z9 47 U1 2 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F376 EP F392 PG 17 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100002 PM 11832418 ER PT J AU Breton, S Inoue, T Knepper, MA Brown, D AF Breton, S Inoue, T Knepper, MA Brown, D TI Antigen retrieval reveals widespread basolateral expression of syntaxin 3 in renal epithelia SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE soluble N-ethylmaleimide-sensitive factor attachment protein receptor; urinary tubule; basolateral membrane ID CANINE KIDNEY-CELLS; MEMBRANE-FUSION; TRANSPORT; SNARES; SPECIFICITY; RECEPTORS; VESICLES; DOCKING AB Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins play a key role in docking and fusion of intracellular transport vesicles and may regulate apical and basolateral membrane protein delivery in epithelial cells. In a previous study, syntaxin 3 (a target SNARE) protein was detectable in the kidney only in intercalated cells. We now report a more widespread distribution of syntaxin 3 in a variety of renal epithelial cells after antigen retrieval. Sections of rat kidney were treated with SDS and incubated with antisyntaxin 3 antibodies. Strong basolateral membrane staining was seen in descending and ascending thin limbs of Henle, thick ascending limbs of Henle, the macula densa, distal and connecting tubules, and all cells of the collecting duct including A- and B-intercalated cells. The papillary surface epithelium and the transitional epithelium of the ureter were also stained, but proximal tubules were negative. Western blotting revealed a strong signal at 37 kDa in all regions, and the antigen was restricted to membrane fractions. SDS treatment was not necessary to reveal syntaxin 3 in intercalated cells. These data show that syntaxin 3 might be involved in basolateral trafficking pathways in most renal epithelial cell types. The exclusive basolateral location of syntaxin 3 in situ, however, contrasts with the apical location of this SNARE protein in some kidney epithelial cells in culture. C1 Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Brown, D (reprint author), Massachusetts Gen Hosp E, Program Membrane Biol, Renal Unit, 149 13th St, Charlestown, MA 02129 USA. EM brown@receptor.mgh.harvard.edu FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [Z01-HL-01282-KE]; NIDDK NIH HHS [DK-42956] NR 23 TC 10 Z9 11 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F523 EP F529 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100019 PM 11832435 ER PT J AU Kim, YH Kim, DU Han, KH Jung, JY Sands, JM Knepper, MA Madsen, KM Kim, J AF Kim, YH Kim, DU Han, KH Jung, JY Sands, JM Knepper, MA Madsen, KM Kim, J TI Expression of urea transporters in the developing rat kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the American-Society-of-Nephrology CY NOV 01-08, 1999 CL MIAMI, FL SP Amer Soc Nephrol DE UT-A; UT-B; immunohistochemistry; urine concentration ID LONG-TERM REGULATION; BRATTLEBORO RATS; MESSENGER-RNA; VASA-RECTA; VASOPRESSIN; CLONING; LOCALIZATION; RECEPTOR; NEPHRON; SYSTEM AB Urea transport in the kidney is mediated by a family of transporter proteins that includes renal urea transporters (UT-A) and erythrocyte urea transporters (UT-B). Because newborn rats are not capable of producing concentrated urine, we examined the time of expression and the distribution of UT-A and UT-B in the developing rat kidney by light and electron microscopic immunocytochemistry. Kidneys from 16-, 18-, and 20-day-old fetuses, 1-, 4-, 7-, 14-, and 21-day-old pups, and adult animals were studied. In the adult kidney, UT-A was expressed intensely in the inner medullary collecting duct (IMCD) and terminal portion of the short-loop descending thin limb (DTL) and weakly in long-loop DTL in the outer part of the inner medulla. UT-A immunoreactivity was not present in the fetal kidney but was observed in the IMCD and DTL in 1-day-old pups. The intensity of UT-A immunostaining in the IMCD gradually increased during postnatal development. In 4- and 7-day-old pups, UT-A immunoreactivity was present in the DTL at the border between the outer and inner medulla. In 14- and 21-day-old pups, strong UT-A immunostaining was observed in the terminal part of short-loop DTL in the outer medulla, and weak labeling remained in long-loop DTL descending into the outer part of the inner medulla. In the adult kidney, there was intense staining for UT-B in descending vasa recta (DVR) and weak labeling of glomeruli. In the developing kidney, UT-B was first observed in the DVR of a 20-day-old fetus. After birth there was a striking increase in the number of UT-B-positive DVR, in association with the formation of vascular bundles. The intensity of immunostaining remained strong in the outer medulla but gradually decreased in the inner medulla. We conclude that the expression of urea transporters in short-loop DTL and DVR coincides with the development of the ability to produce a concentrated urine. C1 Catholic Univ, Coll Med, Dept Anat, Seoul 137701, South Korea. Emory Univ, Sch Med, Dept Med, Div Renal, Atlanta, GA 30322 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Florida, Dept Med, Gainesville, FL 32610 USA. RP Kim, J (reprint author), Catholic Univ, Coll Med, Dept Anat, 505 Banpo Dong, Seoul 137701, South Korea. EM jinkim@cmc.cuk.ac.kr FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NIDDK NIH HHS [R01 DK041707] NR 39 TC 50 Z9 51 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F530 EP F540 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100020 PM 11832436 ER PT J AU Mejia, R Wade, JB AF Mejia, R Wade, JB TI Immunomorphometric study of rat renal inner medulla SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE loop of Henle; urine-concentrating mechanism; inner medulla; aquaporin; chloride channel; urea channel ID THIN DESCENDING-LIMB; SODIUM-CHLORIDE; WATER TRANSPORT; ASCENDING LIMB; HENLES LOOP; VASOPRESSIN; CHANNEL; SYSTEM; KIDNEY; UREA AB We utilized immunofluorescent immunolabeling of renal tissue sections to identify and count tubules at specified depths of the rat renal inner medulla. We used primary antibodies to aquaporin-1 (AQP1; labeling thin descending limbs), aquaporin-2 (AQP2; labeling inner medullary collecting ducts), the rat kidney-specific chloride channel (ClC-K1; labeling thin ascending limbs), and von Willebrand factor (labeling descending vasa recta). Secondary antibodies conjugated to different fluorophores were used, giving up to a three-color display. Labeled structures were then identified and counted. At each level sampled in the inner medulla, many more thin limbs were labeled by ClC-K1 than AQP1. In addition, thin limbs were found to label with antibodies to ClC-K1 on both sides of their hairpin turns. We conclude that the descending thin limbs shift from expressing AQP1 to expressing ClC-K1 some distance before the point where they turn and begin to ascend. Mathematical models can use our quantitative data to explore implications for the urine-concentrating mechanism. C1 NIH, Math Res Branch, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. RP Mejia, R (reprint author), NIH, Math Res Branch, BSA Bldg,Suite 350, Bethesda, MD 20892 USA. EM ray@helix.nih.gov FU NIDDK NIH HHS [DK-32839] NR 31 TC 15 Z9 15 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F553 EP F557 PG 5 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100022 PM 11832438 ER PT J AU Notenboom, S Miller, DS Smits, P Russel, FGM Masereeuw, R AF Notenboom, S Miller, DS Smits, P Russel, FGM Masereeuw, R TI Role of NO in endothelin-regulated drug transport in the renal proximal tubule SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE multidrug resistance-associated protein 2; calcium; endothelin signaling; protein kinase C; xenobiotic transport; nitric oxide ID THICK ASCENDING LIMB; NITRIC-OXIDE; ORGANIC ANION; RAT-KIDNEY; CYCLOSPORINE-A; EXPORT PUMP; RECEPTOR; SECRETION; CELLS; EXPRESSION AB We previously demonstrated in intact killifish renal proximal tubules that endothelin (ET), acting through an ET(B) receptor and protein kinase C (PKC), reduced transport mediated by multidrug resistance-associated protein 2 (Mrp2), i.e., luminal accumulation of fluorescein methotrexate (FL-MTX) (Masereeuw R, Terlouw SA, Van Aubel RAMH, Russel FGM, and Miller DS. Mol Pharmacol 57: 59-67, 2000). In the present study, we used confocal microscopy and quantitative image analysis to measure Mrp2-mediated transport of FL-MTX in killifish tubules as an indicator of the status of this ET-fired, intracellular signaling pathway. Exposing tubules to sodium nitroprusside (SNP), a nitric oxide (NO) donor, signaled a reduction in luminal accumulation of FL-MTX, which suggested pathway activation. N(G)-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, blocked the action of ET-1 on transport. Because SNP effects on transport were blocked by bisindoylmaleide, a PKC-selective inhibitor, but not by RES-701-1, an ET(B)-receptor antagonist, generation of NO occurred after ET(B) receptor signaling but before PKC activation. NO generation was implicated in the actions of several nephrotoxicants, i.e., diatrizoate, gentamicin, amikacin, HgCl(2), and CdCl(2), each of which decreased Mrp2-mediated transport by activating ET signaling. For each nephrotoxicant, decreased FL-MTX transport was prevented when tubules were exposed to L-NMMA. ET-1 and each nephrotoxicant stimulated NO production by the tubules, as determined by a fluorescence-based assay. Together, the data show that NO generation follows ET binding to the basolateral ET(B) receptor and that, in activating the ET-signaling pathway, nephrotoxicants produce NO, a molecule that could contribute to subsequent toxic effects. C1 Univ Med Ctr Nijmegen, Dept Pharmacol & Toxicol, NL-6500 HB Nijmegen, Netherlands. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. RP Masereeuw, R (reprint author), Univ Med Ctr Nijmegen, Dept Pharmacol & Toxicol 233, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM R.Masereeuw@ncmls.kun.nl RI Russel, Frans/B-3184-2014; Masereeuw, Roos/N-3582-2014 OI Russel, Frans/0000-0002-7959-2314; NR 30 TC 32 Z9 32 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F458 EP F464 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100010 PM 11832426 ER PT J AU Yin, M Zhong, Z Connor, HD Bunzendahl, H Finn, WF Rusyn I Li, XL Raleigh, JA Mason, RP Thurman, RG AF Yin, M Zhong, Z Connor, HD Bunzendahl, H Finn, WF Rusyn, I Li, XL Raleigh, JA Mason, RP Thurman, RG TI Protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE kidney; hypoxia; rat ID HYPOXIC INJURY; PROXIMAL TUBULES; WARM ISCHEMIA; FREE-RADICALS; CELL INJURY; RAT; FAILURE; GLUTATHIONE; NEPHROPATHY; ADHESION AB Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion. The right kidney was removed before reperfusion. The postischemic glomerular filtration rate (GFR) showed that renal function was less impaired and recovered more quickly in rats receiving glycine. For example, at day 7, GFR in controls (0.31+/-0.03 ml.min(-1).100 g(-1)) was about one-half that of glycine-treated rats (0.61+/-0.06 ml.min(-1).100 g(-1), P<0.05). Furthermore, tubular injury and cast formation observed in controls was minimized by glycine (pathology score, 3.2 +/- 0.4 vs. 1.0 +/- 0.4, P<0.05). Urinary lactate dehydrogenase (LDH) concentration was elevated by ischemia-reperfusion in the control group (260+/-22 U/l), but values were significantly lower by about fourfold (60+/-30 U/l) in glycine-fed rats. Similarly, free radical production in urine was significantly lower in glycine-treated animals. Importantly, on postischemic day 1, binding of pimonidazole, an in vivo hypoxia marker, was increased in the outer medulla in controls; however, this phenomenon was prevented by glycine. Two weeks later, mild leukocyte infiltration and interstitial fibrosis were still observed in controls, but not in kidneys from glycine-treated rats. In conclusion, these results indicate that administration of glycine indeed reduces mild ischemia-reperfusion injury in the kidney in vivo, in part by decreasing initial damage and preventing chronic hypoxia. C1 Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Surg, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Nephrol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Zhong, Z (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. EM zzhong@med.unc.edu RI Rusyn, Ivan/S-2426-2016 NR 39 TC 44 Z9 48 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2002 VL 282 IS 3 BP F417 EP F423 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 520JQ UT WOS:000173779100005 PM 11832421 ER PT J AU Fee, E Brown, TM Lazarus, J Theerman, P AF Fee, E Brown, TM Lazarus, J Theerman, P TI Medical education for women, 1870 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. Univ Rochester, Dept Hist, Rochester, NY USA. NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2002 VL 92 IS 3 BP 363 EP 363 DI 10.2105/AJPH.92.3.363 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 525MU UT WOS:000174076200015 PM 11867309 ER PT J AU Hoppin, JA Umbach, DM London, SJ Alavanja, MCR Sandler, DP AF Hoppin, JA Umbach, DM London, SJ Alavanja, MCR Sandler, DP TI Chemical predictors of wheeze among farmer pesticide applicators in the agricultural health study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE wheeze; pesticides; organophosphates; paraquat; agricultural exposure ID RESPIRATORY SYMPTOMS; OCCUPATIONAL ASTHMA; PARAQUAT; WORKERS; INSECTICIDE; POPULATION; PREVALENCE; SELECTION; EXPOSURE; INDUSTRY AB Pesticides may contribute to respiratory symptoms among farmers. Using the Agricultural Health Study, a large cohort of certified pesticide applicators in Iowa and North Carolina, we explored the association between wheeze and pesticide use in the past year. Self-administered questionnaires contained items on 40 currently used pesticides and pesticide application practices. A total of 20,468 applicators, ranging in age from 16 to 88 years, provided complete information; 19% reported wheezing in the past year. Logistic regression models controlling for age, state, smoking, and history of asthma or atopy were used to evaluate associations between individual pesticides and wheeze. Among pesticides suspected to contribute to wheeze, paraquat, three organophosphates (parathion, malathion, and chlorpyrifos), and one thiocarbamate (S-ethyl-dipropylthiocarbamate [EPTC]) had elevated odds ratios (OR). Parathion had the highest OR (1.5, 95% confidence interval [CI] 1.0, 2.2). Chlorpyrifos, EPTC, paraquat, and parathion demonstrated significant dose-response trends. The herbicides, atrazine and alachlor, but not 2,4-D, were associated with wheeze. Atrazine had a significant dose-response trend with participants applying atrazine more than 20 days/year having an OR of 1.5 (95% CI 1.2, 1.9). Inclusion of crops and animals into these models did not significantly alter the observed OR. These associations, though small, suggest an independent role for specific pesticides in respiratory symptoms of farmers. C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. NCI, Occupat Epidemiol Branch, NIH, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. OI Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 NR 32 TC 94 Z9 95 U1 2 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 1 PY 2002 VL 165 IS 5 BP 683 EP 689 DI 10.1164/rccm.2106074 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 526LD UT WOS:000174131200013 PM 11874814 ER PT J AU Wilder, JA Olson, GK Chang, YC Kwon-Chung, KJ Lipscomb, MF AF Wilder, JA Olson, GK Chang, YC Kwon-Chung, KJ Lipscomb, MF TI Complementation of a capsule deficient Cryptococcus neoformans with CAP64 restores virulence in a murine lung infection SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID CELL-MEDIATED-IMMUNITY; T-SUPPRESSOR CELLS; IMMUNOLOGICAL-UNRESPONSIVENESS; SOLUBLE POLYSACCHARIDE; HUMAN-LYMPHOCYTES; NITRIC-OXIDE; NEUTROPHILS; MICE; PHAGOCYTOSIS; YEAST AB Cryptococcosis is a systemic infection in humans caused by the opportunistic fungal pathogen, Cryptococcus neoformans. The infection usually presents as chronic meningoencephalitis, but infects via the respiratory tract. A polysaccharide capsule is a major virulence factor, which allows the yeast to resist host defenses. However, the essential role of the capsule in allowing it to resist host defenses during the initial lung infection has not been clearly shown. A mutant acapsular C neoformans strain 602 was complemented with the CAP64 gene to obtain an encapsulated strain, TYCC38-602. TYCC38-602 persisted in the lungs of C.B-17 mice after intratracheal inoculation and disseminated to the brain, whereas the mutant acapsular 602 and the plasmid control transformant CIP3-602 strains grew less readily in the lung and were infrequently detected in the brain. T cell-mediated immunity, developed to the encapsulated organism, was required to control growth within the lungs and had a significant impact on numbers of yeasts detected in the brain. The parent acapsular strain, but not the transformant control, also required T cells for optimal inhibition of growth within the lung, but not for maintaining control of the colony-forming units (cfu) in the brain. In summary, the cryptococcal capsule plays an important role in lung virulence and dissemination to the brain, and intact immunity is required to control lung growth of the encapsulated yeast. C1 Univ New Mexico, Sch Med, Dept Pathol, BMSB, Albuquerque, NM 87131 USA. NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Lipscomb, MF (reprint author), Univ New Mexico, Sch Med, Dept Pathol, BMSB, 915 Stanford Dr NE, Albuquerque, NM 87131 USA. FU NHLBI NIH HHS [P50HL56384]; NIAID NIH HHS [R01AI21951] NR 40 TC 19 Z9 21 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAR PY 2002 VL 26 IS 3 BP 306 EP 314 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 528BD UT WOS:000174222800010 PM 11867339 ER PT J AU Kumaki, F Kawai, T Churg, A Galateau-Salle, FB Hasleton, P Henderson, D Roggli, V Travis, WD Cagle, PT Ferrans, VJ AF Kumaki, F Kawai, T Churg, A Galateau-Salle, FB Hasleton, P Henderson, D Roggli, V Travis, WD Cagle, PT Ferrans, VJ TI Expression of telomerase reverse transcriptase (TERT) in malignant mesotheliomas SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE telomerase; immunohistochemistry; malignant mesothelioma; pleuritis; benign mesothelial hyperplasia ID HUMAN PLEURAL MESOTHELIOMA; LUNG CANCERS; CELL; ASSOCIATION; BENIGN; TUMORS AB To evaluate the usefulness of determinations of telomerase activity for distinguishing malignant from benign mesothelial lesions, immunohistochemical (using a rabbit polyclonal antibody and the peroxidase method; n = 68) and in situ hybridization (using sense and antisense oligonucleotide probes; n = 46) studies were made on malignant mesotheliomas (epithelioid, 39; sarcomatoid, 18, including 2 of the desmoplastic type, and biphasic, 11) and 19 benign mesothelial lesions (benign mesothelial hyperplasia, 3; and reactive pleuritis, 16). In addition, biochemical studies of telomerase activity were made in 9 of the malignant mesotheliomas. Telomerase activity was detected histochemically in all but one of the malignant mesotheliomas, but only in one (pleuritis) of the benign lesions, in which it was present only in activated lymphocytes. Antisense hybridization signals indicated the presence of telomerase mRNA mainly in the cytoplasm of the malignant cells. Sense probes gave negative results. Biochemical determinations revealed a strong telomerase activity in the 9 malignant mesotheliomas examined. This study demonstrates the usefulness of immunohistochemical staining for the evaluation of mesotheliomas. The required immunostaining can be performed using paraffin sections of formalin-fixed tissues. C1 NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. Natl Def Med Coll, Tokorozawa, Saitama 359, Japan. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Caen, CHR, F-14032 Caen, France. Univ Manchester, Manchester, Lancs, England. Flinders Med Ctr, Bedford Pk, SA, Australia. Duke Univ, Med Ctr, Durham, NC USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Kumaki, F (reprint author), NHLBI, Pathol Sect, NIH, Bldg 10-2N240,10 Ctr Dr,MSC-1518, Bethesda, MD 20892 USA. RI Galateau Salle, Francoise/J-1530-2015 OI Galateau Salle, Francoise/0000-0003-3642-0165 NR 22 TC 32 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2002 VL 26 IS 3 BP 365 EP 370 DI 10.1097/00000478-200203000-00011 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 526LR UT WOS:000174132400011 PM 11859209 ER PT J AU Hypolite, IO Bucci, J Hshieh, P Cruess, D Agodoa, LYC Yuan, CM Taylor, AJ Abbott, KC AF Hypolite, IO Bucci, J Hshieh, P Cruess, D Agodoa, LYC Yuan, CM Taylor, AJ Abbott, KC TI Acute coronary syndromes after renal transplantation in patients with end-stage renal disease resulting from diabetes SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE acute coronary syndromes; congestive heart failure; diabetes mellitus; end-stage renal disease; hospitalization; myocardial infarction; renal transplant; unstable angina; USRDS ID DIALYSIS PATIENTS; PRIMARY HYPERPARATHYROIDISM; HEART-DISEASE; RISK-FACTORS; RECIPIENTS; COMPLICATIONS; MORTALITY; SURVIVAL AB Coronary heart disease is the leading cause of death in both diabetes mellitus and end-stage renal disease. Although renal transplantation is known to reduce mortality in end-stage renal disease, its effect on the incidence of acute coronary syndromes is unknown. Using data from the United States Renal Data System, we studied 11369 patients with end-stage renal disease due to diabetes enrolled on the renal and renal-pancreas transplant waiting list from 1 July 1994 to 30 June 1997. Cox nonproportional hazards regression models were used to calculate the adjusted, time-dependent relative risk for the most recent hospitalization for acute coronary syndromes (including acute myocardial infarction, unstable angina, or other acute coronary syndromes, ICD9 Code 410.x or 411.x) for a given patient in the study period. Demographics and comorbidities were controlled by using data from the medical evidence form (HCFA 2728). After renal transplantation, patients had an incidence of acute coronary syndromes of 0.79% per patient year, compared to 1.67% per patient year prior to transplantation. In comparison to maintenance dialysis, renal transplantation was independently associated with a lower risk for acute coronary syndromes (hazard ratio 0.38, 95% confidence interval, 0.30-0.49). Patients with end-stage renal disease due to diabetes on the renal transplant waiting list were much less likely to be hospitalized for acute coronary syndromes after renal transplantation. The reasons for this decreased risk should be the subject of further study. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD USA. USUHS, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 32 TC 20 Z9 21 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2002 VL 2 IS 3 BP 274 EP 281 DI 10.1034/j.1600-6143.2002.20313.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 547WN UT WOS:000175355900012 PM 12096791 ER PT J AU Valenzuela, JG AF Valenzuela, JG TI Editorial: Exploring the messages of the salivary glands of Ixodes ricinus SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material ID CUTANEOUS LEISHMANIASIS; AMBLYOMMA-AMERICANUM; BORRELIA-BURGDORFERI; HOST INTERACTIONS; TICK; TRANSMISSION; SCAPULARIS; RESISTANCE; ANTIGENS; IMMUNITY C1 NIAID, Lab Parasit Dis, Med Entomol Sect, NIH, Bethesda, MD 20892 USA. RP Valenzuela, JG (reprint author), NIAID, Lab Parasit Dis, Med Entomol Sect, NIH, 4 Ctr Dr,Bldg 4,Rm B2-12, Bethesda, MD 20892 USA. NR 21 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2002 VL 66 IS 3 BP 223 EP 224 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 573GH UT WOS:000176820600001 PM 12139211 ER PT J AU Sagara, I Sangare, D Dolo, G Guindo, A Sissoko, M Sogoba, M Niambele, MB Yalcoue, D Kaslow, DC Dicko, A Klion, AD Diallo, D Miller, LH Toure, Y Doumbo, O AF Sagara, I Sangare, D Dolo, G Guindo, A Sissoko, M Sogoba, M Niambele, MB Yalcoue, D Kaslow, DC Dicko, A Klion, AD Diallo, D Miller, LH Toure, Y Doumbo, O TI A high malaria reinfection rate in children and young adults living under a low entomological inoculation rate in a periurban area of Bamako, Mali SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PLASMODIUM-FALCIPARUM TRANSMISSION; WESTERN KENYA; AFRICA; EPIDEMIOLOGY; PREVALENCE; INFECTIONS; MORBIDITY; DISEASE; SITE AB In areas of intense malaria parasite transmission, preliminary studies of the rate of reinfection after curative therapy suggest that small sample size studies of vaccine efficacy are feasible. However, the effect of transmission rate, which may vary considerably between transmission seasons, on reinfection rate has not been assessed in areas of mesoendemicity with seasonal transmission. To address this question, the Plasmodium falciparum reinfection rate after curative therapy was measured in Sotuba, a Malian village with historically low transmission rates, as estimated by the entomological inoculation rate (EIR). The reinfection rate after curative Fansidar(TM) (sulfadoxine-pyrimethamine) treatment was 80.7% (88/109). The FIR during the 13-week study period (seasonal transmission) varied between 1 and 4.5 infected bites/person/month. The finding that reinfection rates were high despite low EIRs suggests that a low EIR may be sufficient to support small sample size vaccine efficacy trials in mesoendemic areas. C1 Univ Mali, Malaria Res & Training Ctr, Fac Med Pharm & Odonto Stomatol, Dept Epidemiol Affect Parasitaires, Bamako, Mali. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Sagara, I (reprint author), Univ Mali, Malaria Res & Training Ctr, Fac Med Pharm & Odonto Stomatol, Dept Epidemiol Affect Parasitaires, BP 1805, Bamako, Mali. OI Klion, Amy/0000-0002-4986-5326 NR 13 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAR PY 2002 VL 66 IS 3 BP 310 EP 313 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 573GH UT WOS:000176820600016 PM 12139226 ER PT J AU Gertz, MA Lacy, MQ Dispenzieri, A Cheson, BD Barlogie, B Kyle, RA Palladini, G Geyer, SM Merlini, G AF Gertz, MA Lacy, MQ Dispenzieri, A Cheson, BD Barlogie, B Kyle, RA Palladini, G Geyer, SM Merlini, G TI A multicenter phase II trial of 4 '-iodo-4 ' deoxydoxorubicin (IDOX) in primary amyloidosis (AL) SO AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS LA English DT Article DE amyloid; amyloidosis; anthracycline; cardiomyopathy; chemotherapy; nephrotic syndrome ID PRIMARY SYSTEMIC AMYLOIDOSIS; 4'-IODO-4'-DEOXYDOXORUBICIN; MELPHALAN; COLCHICINE; PREDNISONE AB Introduction. 4'-Iodo-4'-demydoxorubicin (IDOX) has been reported to bind to and lead to the catabolism of amyloid deposits. A multicenter stuck, attempted to develop a dosing schedule to confirm those results. Methods. Patients with biopsy-proven amyloidosis were required to have a cardiac ejection fraction > 50%, ventricular septal thickness < 20 mm, serum creatinine < 2.5 mg per dL, bilirubin < 2. 0 mg per dL, neutrophils > 1, 500 per muL, andplatelets > 100, 000 per uL. IDOX was administered intravenously over 1 hour at a dose of 15 mg per m, once a week for 4 consecutive weeks. This therapy was repeated every 3 months tip to 4 times. Results. Twenty-five previously treated and 15 untreated patients with primary, amyloidosis (AL) received therapy. Fifteen patients had > 3 g of protein per day in the urine. Eleven patients had an ejection fraction < 60%. One, 2, 3, 4, and 5 organ systems were involved in 22, 10, 4, 3, and 1 patients respectively. The median time between diagnosis and initiation of IDOX was 17.4 months. There were 6 responses (15%). Twelve of the patients have died. Conclusion. IDOX administered in this protocol was insufficiently active at the current dose. C1 Mayo Clin, Div Hematol & Internal Med, Rochester, MN 55905 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Arkansas Canc Res Ctr, Little Rock, AR USA. Univ Hosp IRCSS Policlin San Matteo, San Matteo, Italy. Mayo Clin, Biostat Sect, Rochester, MN USA. Univ Pavia, Dept Biochem, I-27100 Pavia, Italy. RP Gertz, MA (reprint author), Mayo Clin, Div Hematol & Internal Med, 200 1st St SW, Rochester, MN 55905 USA. RI Merlini, Giampaolo/A-3817-2008; Palladini, Giovanni/G-1763-2010; Geyer, Susan/E-3112-2011; OI Merlini, Giampaolo/0000-0001-7680-3254; Palladini, Giovanni/0000-0001-5994-5138; Dispenzieri, Angela/0000-0001-8780-9512 NR 16 TC 33 Z9 33 U1 0 U2 3 PU PARTHENON PUBLISHING GROUP PI LANCASTER PA RICHMOND HOUSE, WHITE CROSS, SOUTH ROAD, LANCASTER LA1 4XQ, ENGLAND SN 1350-6129 J9 AMYLOID JI Amyloid-J. Protein Fold. Disord. PD MAR PY 2002 VL 9 IS 1 BP 24 EP 30 DI 10.3109/13506120209072441 PG 7 WC Biochemistry & Molecular Biology; Medicine, General & Internal; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; General & Internal Medicine; Research & Experimental Medicine GA 549FB UT WOS:000175432900003 PM 12000194 ER PT J AU Hess, S Cassels, FJ Pannell, LK AF Hess, S Cassels, FJ Pannell, LK TI Identification and characterization of hydrophobic Escherichia coli virulence proteins by liquid chromatography-electrospray ionization mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE liquid chromatography-mass spectrometry; hydrophobic protein; virulence proteins; colonization factor; hexafluoroisopropanol; cyanogen bromide; peptide mapping; electrospray ionization mass spectrometry ID FACTOR ANTIGEN-I; COLONIZATION FACTOR; NUCLEOTIDE-SEQUENCE; DIARRHEA; GENES; PILI; HEXAFLUOROISOPROPANOL; PURIFICATION; PEPTIDES; FIMBRIAE AB Virulence of enterotoxicogenic Escherichia coli is mediated by rodlike, rigid, highly hydrophobic proteins designated fimbriae or colonization factors (CFs). More than 20 different colonization factors have been described so far using predominantly immunological and genetic methods. To characterize these hydrophobic proteins by liquid chromatography-mass spectrometry (LC-MS), different methodologies were explored. A novel LC-MS method was developed using hexafluoroisopropanol to maintain the hydrophobic proteins in solution. In addition, these proteins were digested with cyanogen bromide and peptide mapping by LC-MS was established. This technique was particularly useful in identification of closely related CFs. Both LC-MS and peptide mapping methodologies were found to be useful in characterizing highly hydrophobic CFs of E. coli. To search for molecular weights of mature proteins in the National Center for Biotechnology Information (NCBI) database, a new feature was developed and its applicability tested. The identification of a class of pathogenic virulence proteins, either intact or digested, is possible with molecular weight database searching. C1 NIDDKD, Struct Mass Spectrometry Facil, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Enter Infect, Div Communicable Dis & Immunol, Silver Spring, MD 20902 USA. RP Hess, S (reprint author), NIDDKD, Struct Mass Spectrometry Facil, Bioorgan Chem Lab, NIH, Bldg 8,Room B2A21, Bethesda, MD 20892 USA. RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 32 TC 12 Z9 12 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 1 PY 2002 VL 302 IS 1 BP 123 EP 130 DI 10.1006/abio.2001.5534 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 523WX UT WOS:000173981500016 PM 11846385 ER PT J AU Njoku, DB Shrestha, S Soloway, R Duray, PR Tsokos, M Abu-Asab, MS Pohl, LR West, AB AF Njoku, DB Shrestha, S Soloway, R Duray, PR Tsokos, M Abu-Asab, MS Pohl, LR West, AB TI Subcellular localization of trifluoroacetylated liver proteins in association with hepatitis following isoflurane SO ANESTHESIOLOGY LA English DT Article ID GLYBURIDE-INDUCED HEPATITIS; CYTOCHROME-P450 2E1; HALOTHANE HEPATITIS; HEPATOTOXICITY; ANESTHESIA; ENFLURANE; BIOTRANSFORMATION; METABOLISM; DESFLURANE; FAILURE C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. NCI, Lab Pathol Mol & Cellular Toxicol Sect, Pediat Tumor Biol & Ultrastruct Pathol Sect, Natl Heart Lung & Blood Inst Lab Mol Immunol NIH, Bethesda, MD USA. New York Univ, Med Ctr, Dept Pathol, New York, NY USA. Univ Texas, Med Branch, Dept Internal Med, Galveston, TX USA. RP Njoku, DB (reprint author), Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Blalock 960A 600 N Wolfe St, Baltimore, MD 21287 USA. OI Abu-Asab, Mones/0000-0002-4047-1232 NR 28 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2002 VL 96 IS 3 BP 757 EP 761 DI 10.1097/00000542-200203000-00036 PG 5 WC Anesthesiology SC Anesthesiology GA 526NH UT WOS:000174136200035 PM 11873055 ER PT J AU Zheng, G Freidlin, B Gastwirth, JL AF Zheng, G Freidlin, B Gastwirth, JL TI Robust TDT-type candidate-gene association tests SO ANNALS OF HUMAN GENETICS LA English DT Article ID HAPLOTYPE RELATIVE RISK; LINKAGE TESTS; AFFECTED SIBS; DISEQUILIBRIUM; POWER; SURVIVAL; PAIR; LOCI; IDDM; HLA AB In studies of association between genetic markers and a disease, the transmission disequilibrium test (TDT) has become a standard procedure. It was introduced originally as a test for linkage in the presence of association and can be used as a teat. for association raider appropriate assumptions. The power of the TDT test for association between a candidate gene and disease depends on the underlying genetic model and the TDT is the optimal test if the additive model holds. Related methods have been obtained for a given mode of inheritance (e.g. dominant or recessive). Quite often, however, the true model is unknown and selection of a single method of analysis is problematic, since use of a test optimal for one genetic model usually leads to a substantial loss of power if another genetic model is the true one. The general approach of efficiency robustness has suggested two types of robust procedures, which we apply to TDT-type association tests. When the plausible range of alternative models is wide (e.g. dominant through recessive) our results indicate that the maximum (MIX) of several test statistics, each of which is optimal for quite different models has good power under all genetic models. In situations where the set of possible models can be narrowed (e.g. dominant through additive) a simple linear combination also performs hell. In general, the MAX has better power properties than the TDT for the study of candidate genes when the mode of inheritance is unknown. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. George Washington Univ, Washington, DC USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr,MSC 7938, Bethesda, MD 20892 USA. NR 29 TC 25 Z9 25 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAR PY 2002 VL 66 BP 145 EP 155 DI 10.1017/S0003480002001045 PN 2 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 581VC UT WOS:000177313700004 PM 12174218 ER PT J AU Dosemeci, M Alavanja, MCR Rowland, AS Mage, D Zahm, SH Rothman, N Lubin, JH Hoppin, JA Sandler, DP Blair, A AF Dosemeci, M Alavanja, MCR Rowland, AS Mage, D Zahm, SH Rothman, N Lubin, JH Hoppin, JA Sandler, DP Blair, A TI A quantitative approach for estimating exposure to pesticides in the Agricultural Health Study SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE exposure assessment; pesticide exposure; agricultural exposures; farmers; pesticide applicators; occupational exposures ID NON-HODGKINS-LYMPHOMA; OCCUPATIONAL EXPOSURE; AERIAL APPLICATION; URINARY-EXCRETION; DERMAL EXPOSURE; HAND EXPOSURE; INSECTICIDES; RISK; FARMERS AB We developed a quantitative method to estimate long-term chemical-specific pesticide exposures in a large prospective cohort study of more than 58000 pesticide applicators in North Carolina and Iowa. An enrollment questionnaire was administered to applicators to collect basic time- and intensity-related information on pesticide exposure such as mixing condition, duration and frequency of application, application methods and personal protective equipment used. In addition, a detailed take-home questionnaire was administered to collect further intensity-related exposure information such as maintenance or repair of mixing and application equipment, work practices and personal hygiene. More than 40% of the enrolled applicators responded to this detailed take-home questionnaire. Two algorithms were developed to identify applicators' exposure scenarios using information from the enrollment and take-home questionnaires separately in the calculation of subject-specific intensity of exposure score to individual pesticides. The 'general algorithm' used four basic variables (i.e. mixing status, application method, equipment repair status and personal protective equipment use) from the enrollment questionnaire and measurement data from the published pesticide exposure literature to calculate estimated intensity of exposure to individual pesticides for each applicator. The 'detailed' algorithm was based on variables in the general algorithm plus additional exposure information from the take-home questionnaire, including types of mixing system used (i.e. enclosed or open), having a tractor with enclosed cab and/or charcoal filter, frequency of washing equipment after application, frequency of replacing old gloves, personal hygiene and changing clothes after a spill. Weighting factors applied in both algorithms were estimated using measurement data from the published pesticide exposure literature and professional judgment. For each study subject, chemical-specific lifetime cumulative pesticide exposure levels were derived by combining intensity of pesticide exposure as calculated by the two algorithms independently and duration/frequency of pesticide use from the questionnaire. Distributions of duration, intensity and cumulative exposure levels of 2,4-D and chlorpyrifus are presented by state, gender, age group and applicator type (i.e. farmer or commercial applicator) for the entire enrollment cohort and for the sub-cohort of applicators who responded to the take-home questionnaire. The distribution patterns of all basic exposure indices (i.e. intensity, duration and cumulative exposure to 2,4-D and chlorpyrifos) by state, gender, age and applicator type were almost identical in two study populations, indicating that the take-home questionnaire sub-cohort of applicators is representative of the entire cohort in terms of exposure. C1 NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27711 USA. Temple Univ, Inst Survey Res, Philadelphia, PA 19122 USA. RP Dosemeci, M (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 8002, Bethesda, MD 20892 USA. OI Mage, David/0000-0002-3880-566X; Sandler, Dale/0000-0002-6776-0018 NR 42 TC 127 Z9 131 U1 1 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD MAR PY 2002 VL 46 IS 2 BP 245 EP 260 DI 10.1093/annhyg/mef011 PG 16 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 532ZU UT WOS:000174505600013 PM 12074034 ER PT J AU Lublin, M Bartlett, DL Danforth, DN Kauffman, H Gallin, JI Malech, HL Shawker, T Choyke, P Kleiner, DE Schwartzentruber, DJ Chang, R DeCarlo, ES Holland, SM AF Lublin, M Bartlett, DL Danforth, DN Kauffman, H Gallin, JI Malech, HL Shawker, T Choyke, P Kleiner, DE Schwartzentruber, DJ Chang, R DeCarlo, ES Holland, SM TI Hepatic abscess in patients with chronic granulomatous disease SO ANNALS OF SURGERY LA English DT Article ID GASTROINTESTINAL COMPLICATIONS; SURGICAL IMPLICATIONS; CLINICAL-FEATURES; MANAGEMENT AB Objective To evaluate the clinical presentation, diagnostic procedures, and surgical management of hepatic abscesses in patients with chronic granulomatous disease Summary Background Data Chronic granulomatous disease is a rare inherited primary immunodeficiency in which phagocytes cannot destroy catalase-positive bacteria and fungi, Defects in the phagocytic cells' respiratory burst lead to life-threatening infections, including hepatic abscess. These abscesses are recurrent and often multiple and are treated differently from bacterial abscesses in patients without CGD. Methods Between 1980 and 2000, 61 cases of hepatic abscess in 22 patients with CGD were treated at the National Institutes of Health. Clinicopathologic features were investigated by retrospective review of the medical records, radiographs, and histopathology. Results Twelve of the 61 cases were primary hepatic abscesses. Twenty-nine of the cases were recurrent hepatic abscesses, and 20 cases were persistent hepatic abscesses. The median age at the time of initial hepatic abscess presentation was 14 years. Subjective fever was the most frequent presenting symptom, and the erythrocyte sedimentation rate was elevated in 98% of cases. Fifty-two cases were managed surgically and eight cases were managed with percutaneous drainage. One patient refused surgery. The surgical complication rate was 56%; however, there were no deaths directly related to the hepatic abscesses, Staphylococcus aureus was the most frequent organism identified in culture (88% of positive cultures). Aggressive surgery and antibiotics ultimately resulted in successful treatment of all patients. Conclusions Hepatic abscesses occurring in patients with CGD represent a difficult diagnostic and treatment challenge. Early excision and treatment with antibiotics directed against S. aureus is necessary. General surgeons should be aware of this rare immunodeficiency and should aggressively manage hepatic abscesses in these patients. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NCI, Dept Radiol, Ctr Clin, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Bartlett, DL (reprint author), NCI, Surg Branch, NIH, Bldg 10,Rm 2B38, Bethesda, MD 20892 USA. OI Kleiner, David/0000-0003-3442-4453 NR 18 TC 52 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2002 VL 235 IS 3 BP 383 EP 391 DI 10.1097/00000658-200203000-00010 PG 9 WC Surgery SC Surgery GA 527TQ UT WOS:000174204000010 PM 11882760 ER PT J AU Hasinoff, BB Takeda, K Ferrans, VJ Yu, ZX AF Hasinoff, BB Takeda, K Ferrans, VJ Yu, ZX TI The doxorubicin cardioprotective agent dexrazoxane (ICRF-187) induces endopolyploidy in rat neonatal myocytes through inhibition of DNA topoisomerase II SO ANTI-CANCER DRUGS LA English DT Article DE dexrazoxane; doxorubicin; endopolyploidy; ICRF-187; myocyte ID ANALOGS; CELLS AB Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-induced cardiotoxicity, Is also a potent catalytic Inhibitor of DNA topoisomerase II. In this study we showed that dexrazoxane Inhibited the division of neonatal rat ventricular myocytes in culture, and resulted In nuclear multilobulation (demonstrated by three-dimensional reconstruction of confocal images) and marked Increases In nuclear size and DNA ploidy levels (as shown by flow cytometry). It was concluded that dexrazoxane interfered with cell division In cardiac myocytes by virtue of Its ability to inhibit topoisomerase II. [(C) 2002 Lippincott Williams Wilkins.]. C1 Univ Manitoba, Fac Pharm, Winnipeg, MB R3T 2N2, Canada. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Hasinoff, BB (reprint author), Univ Manitoba, Fac Pharm, 50 Sifton Rd, Winnipeg, MB R3T 2N2, Canada. NR 11 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD MAR PY 2002 VL 13 IS 3 BP 255 EP 258 DI 10.1097/00001813-200203000-00007 PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 546YP UT WOS:000175304800007 PM 11984069 ER PT J AU Grem, JL Danenberg, KD Kao, V Danenberg, PV Nguyen, D AF Grem, JL Danenberg, KD Kao, V Danenberg, PV Nguyen, D TI Biochemical and molecular effects of UCN-01 in combination with 5-fluorodeoxyuridine in A431 human epidermoid cancer cells SO ANTI-CANCER DRUGS LA English DT Article DE 7-hydroxy-staurospaurine; DNA damage; fluoropyrimidines; thymidylate synthase; UCN-01 ID PROTEIN-KINASE-C; ANTICANCER DRUG SCREEN; COLON-CARCINOMA CELLS; THYMIDYLATE SYNTHASE; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; INTERFERON-GAMMA; GENE-EXPRESSION; BREAST-CANCER; STRAND BREAKS AB Concurrent and pre-exposure of A431 human epidermoid cancer cells to UCN-01, an Investigational anticancer drug, with 5-fluoro-2'-deoxyuridine (FdUrd), which targets thymidylate synthase, produced more than additive cytotoxicty. A 24-h exposure to 10 nM FdUrd led to inhibition of TS, a 2.5-fold Increase In total thymidylate synthase protein content, profound dTTP depletion and a 6.3-fold increase In the ratio of dATP to dTTP, but did not cause single-strand breaks in DNA. However, FdUrd enhanced UCN-01-associated DNA strand breaks. Concurrent thymidine exposure led to repletion of dTTP pools, and cytoprotection against FdUrd alone and with UCN-01. UCN-01 arrested cells In G(1), decreased the percentage of FdUrd-treated cells In S phase and reduced FdUrd-DNA Incorporation, suggesting the latter was not important for cytotoxicity. Delayed Induction of high molecular mass DNA fragmentation and poly(ADP-ribose) polymerase cleavage was observed with the combination of UCN-01 and FdUrd. These findings suggest that while FdUrd-mediated deoxynucleotide imbalance alone was Insufficient to induce apoptosis In this p53-mutant cell line, It magnified UCN-01's effects, most likely by Interfering with DNA repair. The clinical evaluation of UCN-01 combined with 5-fluoropyrimidines may be of interest. [(C) 2002 Lippincott Williams Wilkins.]. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Navy Med Oncol,Natl Naval Med Ctr, Bethesda, MD 20889 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. RP Grem, JL (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, Navy Med Oncol,Natl Naval Med Ctr, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 44 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD MAR PY 2002 VL 13 IS 3 BP 259 EP 270 DI 10.1097/00001813-200203000-00008 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 546YP UT WOS:000175304800008 PM 11984070 ER PT J AU Bekersky, I Fielding, RM Dressler, DE Lee, JW Buell, DN Walsh, TJ AF Bekersky, I Fielding, RM Dressler, DE Lee, JW Buell, DN Walsh, TJ TI Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ALTERED TISSUE DISTRIBUTION; FORMULATION; SAFETY; UNILAMELLAR; DOGS; RATS; NEUTROPENIA; CLEARANCE; TOLERANCE; ANIMALS AB The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h. The concentrations of AMB were determined by liquid chromatography tandem mass spectrometry (plasma, urine, feces) or high-performance liquid chromatography (HPLC) (plasma). Infusion-related side effects similar to those reported in patients, including nausea and back pain, were observed in both groups. Both formulations had triphasic plasma profiles with long terminal half-lives (liposomal AMB, 152 116 h; AMB-DOC, 127 30 h), but plasma concentrations were higher (P < 0.01) after administration of liposomal AMB (maximum concentration of drug in serum [C-max], 22.9 +/- 10 μg/ml) than those of AMB-DOC (C-max, 1.4 +/- 0.2 μg/ml). Liposomal AMB had a central compartment volume close to that of plasma (50 +/- 19 ml/kg) and a volume of distribution at steady state (V-ss) (774 +/- 550 ml/kg) smaller than the V-ss of AMB-DOC (1,807 +/- 239 ml/kg) (P < 0.01). Total clearances were similar (approximately 10 ml hr(-1) kg(-1)), but renal and fecal clearances of liposomal AMB were 10-fold lower than those of AMB-DOC (P < 0.01). Two-thirds of the AMB-DOC was excreted unchanged in the urine (20.6%) and feces (42.5%) with >90% accounted for in mass balance calculations at 1 week, suggesting that metabolism plays at most a minor role in AMB elimination. In contrast, < 10% of the liposomal AMB was excreted unchanged. No metabolites were observed by HPLC or mass spectrometry. In comparison to AMB-DOC, liposomal AMB produced higher plasma exposures and lower volumes of distribution and markedly decreased the excretion of unchanged drug in urine and feces. Thus, liposomal AMB significantly alters the excretion and mass balance of AMB. The ability of liposomes to sequester drugs in circulating liposomes and within deep tissue compartments may account for these differences. C1 Fujisawa Healthcare Inc, Deerfield, IL 60015 USA. Biol Serv, Boulder, CO USA. MDS Pharma Serv, Lincoln, NE USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Bekersky, I (reprint author), Fujisawa Healthcare Inc, 3 Pkwy N, Deerfield, IL 60015 USA. NR 35 TC 141 Z9 145 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2002 VL 46 IS 3 BP 828 EP 833 DI 10.1128/AAC.46.3.828-833.2002 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 522QR UT WOS:000173908900031 PM 11850268 ER PT J AU Bekersky, I Fielding, RM Dressler, DE Lee, JW Buell, DN Walsh, TJ AF Bekersky, I Fielding, RM Dressler, DE Lee, JW Buell, DN Walsh, TJ TI Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FORMULATION; UNILAMELLAR; AGGREGATION; CLEARANCE; SAFETY; LIPOPROTEINS; TOXICITY; ANIMALS AB Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and alpha(1)-acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 μg/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h(-1) kg(-1)) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes. C1 Fujisawa Healthcare Inc, Deerfield, IL 60015 USA. Biol Serv, Boulder, CO USA. MDS Pharma Serv, Lincoln, NE USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Bekersky, I (reprint author), Fujisawa Healthcare Inc, 3 Pkwy N, Deerfield, IL 60015 USA. NR 27 TC 107 Z9 112 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2002 VL 46 IS 3 BP 834 EP 840 DI 10.1128/AAC.46.3.834-840.2002 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 522QR UT WOS:000173908900032 PM 11850269 ER PT J AU Huheihel, M Salah, L Konson, A Manor, E Ford, M Marquez, VE Johns, DG Agbaria, R AF Huheihel, M Salah, L Konson, A Manor, E Ford, M Marquez, VE Johns, DG Agbaria, R TI Intracellular phosphorylation of N-methanocarbathymidine, a novel antiherpetic agent SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract C1 Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Pharmacol, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Fac Hlth Sci, Inst Appl Biosci, IL-84105 Beer Sheva, Israel. NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 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 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2002 VL 53 IS 3 SI SI MA 65 BP A55 EP A55 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 534KT UT WOS:000174586100066 ER PT J AU Margolis, L Grivel, JC Ito, Y Fitzgerald, W Lusso, P AF Margolis, L Grivel, JC Ito, Y Fitzgerald, W Lusso, P TI Mechanisms of differential pathogenesis of R5 and X4 HIV-1 variants in human lymphoid tissue. SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 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 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2002 VL 53 IS 3 SI SI MA 106 BP A68 EP A68 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 534KT UT WOS:000174586100111 ER PT J AU Rosenwirth, B Oostermeijer, H Steeneveld, E Koornstra, W ten Haaft, P Niphuis, H Doms, R Letvin, N Wagner, R Sutter, G Moss, B Liljestrom, P Heeney, JL AF Rosenwirth, B Oostermeijer, H Steeneveld, E Koornstra, W ten Haaft, P Niphuis, H Doms, R Letvin, N Wagner, R Sutter, G Moss, B Liljestrom, P Heeney, JL TI The chimeric combo vaccine strategy: a study evaluating immunogenicity and efficacy to protect against simian/human immunodeficiency virus infection in rhesus macaques. SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract C1 BPRC, Rijswijk, Netherlands. Univ Penn, Philadelphia, PA 19104 USA. Beth Israel Hosp, Boston, MA USA. Univ Regensburg, Inst Med Mikrobiol & Hyg, D-8400 Regensburg, Germany. GSF, Inst Mol Virol, Munich, Germany. NIAID, NIH, Bethesda, MD 20892 USA. Karolinska Inst, S-10401 Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2002 VL 53 IS 3 SI SI MA 39 BP A47 EP A47 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 534KT UT WOS:000174586100040 ER PT J AU Tomicic, MT Thust, R Sobol, RW Kaina, B AF Tomicic, MT Thust, R Sobol, RW Kaina, B TI DNA polymerase beta mediates protection of mammalian cells against ganciclovir-induced cyto- and genotoxicity: implications for gene therapy SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract C1 Univ Mainz, Inst Toxicol, D-6500 Mainz, Germany. Univ Jena, Inst Antiviral Chemotherapy, D-6900 Jena, Germany. NIEHS, Struct Biol Lab, Res Triangle Pk, NC USA. RI Sobol, Robert/E-4125-2013 OI Sobol, Robert/0000-0001-7385-3563 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 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2002 VL 53 IS 3 SI SI MA 93 BP A62 EP A62 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 534KT UT WOS:000174586100096 ER PT J AU Witvrouw, M Fikkert, V Van Maele, B Pannecouque, C Neamati, N Burke, TR Pais, G De Clercq, E Debyser, Z AF Witvrouw, M Fikkert, V Van Maele, B Pannecouque, C Neamati, N Burke, TR Pais, G De Clercq, E Debyser, Z TI Antiviral resistance to diketo acids is associated with the mutations T66I, L74M and S230R in the HIV-1 integrase gene SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract C1 Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. Univ So Calif, Los Angeles, CA 90089 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014 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 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAR PY 2002 VL 53 IS 3 SI SI MA 45 BP A48 EP A48 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 534KT UT WOS:000174586100045 ER PT J AU Upadhya, SC Chinta, SJ Pai, HV Boyd, MR Ravindranath, V AF Upadhya, SC Chinta, SJ Pai, HV Boyd, MR Ravindranath, V TI Toxicological consequences of differential regulation of cytochrome p450 Isoforms in rat brain regions by phenobarbital SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE brain; drug metabolism; cytochrome P450; psychoactive drugs; monooxygenase; neurotoxicity ID 9-METHOXY-N-2-METHYLELLIPTICINIUM ACETATE; MULTIPLE FORMS; CELL-LINES; IN-VITRO; EXPRESSION; PROTEINS; LOCALIZATION; CYTOTOXICITY; METABOLISM; ACTIVATION AB Cytochrome P4502B is an isoform of cytochrome P450 (P450) that is induced by the anticonvulsant drug phenobarbital. Here, we demonstrate the constitutive expression and predominant localization of CYP2B in neurons of rat brain. Administration of phenobarbital to rats resulted in selective induction of P450 levels in cortex and midbrain, while other regions were unaffected. Immunohistochemical localization of P4502B in brains of phenobarbital treated rats revealed localization of P4502B in neuronal cells, most predominantly the reticular neurons in midbrain. The anticancer agent 9-methoxy-N-methylellipticinium acetate (MMEA) has been shown to exhibit preferential neuronal toxicity in vitro. Pretreatment of rats with phenobarbital potentiated the toxicity of intrathecally administered MMEA in vivo, as seen by the degeneration of reticular neurons. Thus, induction of P450 in selective regions of brain by phenobarbital would profoundly influence xenobiotic metabolism in these regions, especially in clinical situations where phenobarbital is coadministered with other psychoactive drugs/xenobiotics. (C) 2002 Elsevier Science (USA). C1 Natl Brain Res Ctr, New Delhi 110067, India. Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. Natl Canc Inst, Ctr Canc Res, Mol Targets Drug Discovery Program, NIH, Ft Detrick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Brain Res Ctr, ICGEB Campus, New Delhi 110067, India. FU NIMH NIH HHS [MH55494] NR 33 TC 20 Z9 20 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAR 1 PY 2002 VL 399 IS 1 BP 56 EP 65 DI 10.1006/abbi.2001.2727 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 530QW UT WOS:000174371300007 PM 11883903 ER PT J AU Chan, LS Ahmed, AR Anhalt, GJ Bernauer, W Cooper, KD Elder, MJ Fine, JD Foster, S Ghohestani, R Hashimoto, T Hoang-Xuan, T Kirtschig, G Korman, NJ Lightman, S Lozado-Nur, F Marinkovich, MP Mondino, BJ Prost-Squarcioni, C Rogers, RS Setterfield, JF West, DP Wojnarowska, F Woodley, DT Yancey, KB Zillikens, D Zone, JJ AF Chan, LS Ahmed, AR Anhalt, GJ Bernauer, W Cooper, KD Elder, MJ Fine, JD Foster, S Ghohestani, R Hashimoto, T Hoang-Xuan, T Kirtschig, G Korman, NJ Lightman, S Lozado-Nur, F Marinkovich, MP Mondino, BJ Prost-Squarcioni, C Rogers, RS Setterfield, JF West, DP Wojnarowska, F Woodley, DT Yancey, KB Zillikens, D Zone, JJ TI The first international consensus on mucous membrane pemphigoid - Definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators SO ARCHIVES OF DERMATOLOGY LA English DT Article ID THIOPURINE METHYLTRANSFERASE ACTIVITY; INTRAVENOUS IMMUNOGLOBULIN THERAPY; SUBEPITHELIAL BLISTERING DISEASES; ORAL VESICULOEROSIVE DISEASES; BASEMENT-MEMBRANE; INDIRECT IMMUNOFLUORESCENCE; SUBEPIDERMAL BLISTERS; AUTOANTIBODIES REACT; CLINICAL VARIANTS; PASSIVE TRANSFER AB Objective: We aimed to develop consensus-based recommendations for streamlining medical communication among various health care professionals, to improve accuracy of diagnosis and treatment, and to facilitate future investigations for mucous membrane pemphigoid. Participants: Because of the highly specific nature of this group of diseases, the 26 invited participants included either international scholars in the field of mucous membrane pemphigoid or experts in cutaneous pharmacology representing the 3 medical disciplines ophthalmology, oral medicine, and dermatology. Evidence: The first author (L.S.C,) conducted a literature search. Based on the information obtained, inter-national experts who had contributed to the literature in the clinical care, diagnosis, and laboratory investigation for mucous membrane pemphigoid were invited to participate in a consensus meeting aimed at developing a consensus statement. Consensus Process: A consensus meeting was convened and conducted on May 10, 1999, in Chicago, 111, to discuss the relevant issues. The First author drafted die statement based on the consensus developed at the meeting and the participants' written comments. The draft was submitted to all participants for 3 separate rounds of review, and disagreements were reconciled based on literature evidence. The third and final statement incorporated all relevant evidence obtained in the literature search and the consensus developed by the participants. The final statement was approved and endorsed by all 26 participants. Conclusions: Specific consensus-based recommendations were made regarding the definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators for mucous membrane pemphigoid. A system of standard reporting for these patients was proposed to facilitate a uniform data collection. C1 Northwestern Univ, Sch Med, Dept Dermatol, Chicago, IL 60611 USA. Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Boston, MA 02115 USA. Johns Hopkins Med Inst, Dept Dermatol, Baltimore, MD 21205 USA. Univ Zurich, Dept Ophthalmol, Zurich, Switzerland. Case Western Reserve Univ, Sch Med, Dept Dermatol, Cleveland, OH 44106 USA. Christchurch Hosp, Dept Ophthalmol, Christchurch, New Zealand. Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Thomas Jefferson Med Coll, Dept Dermatol, Philadelphia, PA USA. Kurume Univ, Sch Med, Dept Dermatol, Fukuoka, Japan. Hop Bichat Claude Bernard, F-75877 Paris, France. Urije Univ, Dept Dermatol, Amsterdam, Netherlands. Moorfields Eye Hosp, London, England. UCL, Inst Ophthalmol, London, England. Univ Calif San Francisco, Sch Dent, Dept Stomatol, San Francisco, CA 94143 USA. Stanford Univ, Sch Med, Dept Dermatol, Stanford, CA 94305 USA. Vet Affairs Hlth Care Syst, Palo Alto, CA USA. Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Ophthalmol, Los Angeles, CA 90024 USA. Hop St Louis, Dept Dermatol, Paris, France. Hop St Louis, Policlin Dermatol, Paris, France. Mayo Clin, Dept Dermatol, Rochester, MN USA. St Thomas Hosp, St Johns Inst Dermatol, London, England. Churchill Hosp, Dept Dermatol, Oxford OX3 7LJ, England. Univ So Calif, Div Dermatol, Los Angeles, CA 90089 USA. NCI, Div Clin Sci, Dermatol Branch, NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Dermatol, D-8700 Wurzburg, Germany. Univ Utah, Dept Dermatol, Salt Lake City, UT USA. RP Chan, LS (reprint author), Northwestern Univ, Sch Med, Dept Dermatol, 675 N St Clair St,Suite 19-150, Chicago, IL 60611 USA. EM larrychan@northwestern.edu RI Zillikens, Detlef/C-8572-2011; OI West, Dennis/0000-0002-9107-6697 NR 95 TC 267 Z9 278 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X EI 1538-3652 J9 ARCH DERMATOL JI Arch. Dermatol. PD MAR PY 2002 VL 138 IS 3 BP 370 EP 379 DI 10.1001/archderm.138.3.370 PG 10 WC Dermatology SC Dermatology GA 530PC UT WOS:000174367300010 PM 11902988 ER PT J AU Charney, DS Nemeroff, CB Lewis, L Laden, SK Gorman, JM Laska, EM Borenstein, M Bowden, CL Caplan, A Emslie, GJ Evans, DL Geller, B Grabowski, LE Herson, J Kalin, NH Keck, PE Kirsch, I Krishnan, KRR Kupfer, DJ Makuch, RW Miller, FG Pardes, H Post, R Reynolds, MM Roberts, L Rosenbaum, JF Rosenstein, DL Rubinow, DR Rush, AJ Ryan, ND Sachs, GS Schatzberg, AF Solomon, S AF Charney, DS Nemeroff, CB Lewis, L Laden, SK Gorman, JM Laska, EM Borenstein, M Bowden, CL Caplan, A Emslie, GJ Evans, DL Geller, B Grabowski, LE Herson, J Kalin, NH Keck, PE Kirsch, I Krishnan, KRR Kupfer, DJ Makuch, RW Miller, FG Pardes, H Post, R Reynolds, MM Roberts, L Rosenbaum, JF Rosenstein, DL Rubinow, DR Rush, AJ Ryan, ND Sachs, GS Schatzberg, AF Solomon, S CA Consensus Dev Panel TI National depressive and manic-depressive association consensus statement on the use of placebo in clinical trials of mood disorders SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID BIOETHICS ADVISORY COMMISSION; ACUTE BIPOLAR MANIA; DOUBLE-BLIND; PSYCHIATRIC RESEARCH; MAJOR DEPRESSION; PROPHYLACTIC LITHIUM; RECURRENT DEPRESSION; INFORMED CONSENT; PATTERN-ANALYSIS; RESEARCH ETHICS AB A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active,control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research. C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. Natl Depress & Man Depress Assoc, Chicago, IL USA. Sci Therapeut Informat Inc, Springfield, NJ USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Albert Einstein Coll Med, Dept Psychiat, New York, NY USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. Univ Penn, Div Bioeth, Philadelphia, PA 19104 USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Washington Univ, Dept Psychiat, St Louis, MO USA. Appl Log Associates Inc, Houston, TX USA. Univ Wisconsin, Sch Med, Dept Psychiat, Madison, WI 53792 USA. Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. Univ Connecticut, Dept Psychol, Storrs, CT USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Yale Univ, Sch Med, New Haven, CT USA. New York Presbyterian Hosp, Dept Psychiat, New York, NY USA. Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Child & Adolescent Bipolar Fdn, Palo Alto, CA USA. RP Charney, DS (reprint author), NIMH, Intramural Res Program, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Rush, Augustus/0000-0003-2004-2382 NR 96 TC 75 Z9 75 U1 4 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAR PY 2002 VL 59 IS 3 BP 262 EP 270 DI 10.1001/archpsyc.59.3.262 PG 9 WC Psychiatry SC Psychiatry GA 529LK UT WOS:000174300800007 PM 11879164 ER PT J AU Chu, K Kang, DW Kim, DE Park, SH Roh, JK AF Chu, K Kang, DW Kim, DE Park, SH Roh, JK TI Diffusion-weighted and gradient echo magnetic resonance findings of hemichorea-hemiballismus associated with diabetic hyperglycemia - A hyperviscosity syndrome? SO ARCHIVES OF NEUROLOGY LA English DT Article ID MR-IMAGES; CHOREA; INTENSITY AB Background: The magnetic resonance (MR) imaging findings of hemichorea-hemiballismus (HCHB) associated with hyperglycemia are characterized by hyperintensities in the striatum on T1-weighted MR images and computed tomographic scans, with a mechanism of petechial hemorrhage considered to be responsible. Diffusion-weighted MR imaging (DWI) has been reported to detect early ischemic damage (cytotoxic edema) as bright areas of high signal intensity and vasogenic edema as areas of heterogeneous signal intensity. We report various DWI findings in 2 patients with hyperglycemia HCHB. Objectives: To describe the DWI and gradient echo findings and characterize the types of edema in HCHB associated with hyperglycemia. Setting: A tertiary referral center neurology department. Design and Methods: Two patients with HCHB associated with hyperglycemia underwent DWI, gradient echo imaging, and conventional MR imaging with gadolinium enhancement. The patients had an elevated serum glucose level on admission and a long history of uncontrolled diabetes, and the symptoms were controlled by dopamine receptor blocking agents. Initial DWIs were obtained 5 to 20 days after symptom onset. Apparent diffusion coefficient (ADC) values were measured in the abnormal lesions with visual inspection of DWI and T2-weighted echo planar images. Results: T1- and T2-weighted MR images and brain computed tomographic scans showed high signal intensities in the right head of the caudate nucleus and the putamen. Gradient echo images were normal. The DWIs showed bright high signal intensity in the corresponding lesions (patient 1), and the ADC values were decreased. The decrease in ADC and the high signal intensity on DWI persisted despite the disappearance of HCHB, even after 70 days. Conclusions: Gradient echo MR imaging findings were normal in HCHB with hyperglycemia, whereas DWI and the ADC map showed restricted diffusion, which suggests that hyperviscosity, not petechial hemorrhage, with cytotoxic edema can cause the observed MR abnormalities. C1 Seoul Natl Univ, Med Res Ctr, Dept Neurol, Seoul 151, South Korea. Seoul Natl Univ, Clin Res Inst, Seoul Natl Univ Hosp, Seoul 151, South Korea. Seoul Boramae Municpal Hosp, Dept Neurol, Seoul, South Korea. Natl Inst Neurol Disorders, Sect Stroke Diagnost & Therapeut, Bethesda, MD USA. RP Roh, JK (reprint author), Seoul Natl Univ, Med Res Ctr, Dept Neurol, Seoul 151, South Korea. RI Roh, Jae Kyu/J-5459-2012; Park, Seong Ho/J-5488-2012 NR 24 TC 78 Z9 91 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAR PY 2002 VL 59 IS 3 BP 448 EP 452 DI 10.1001/archneur.59.3.448 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 530YH UT WOS:000174386700015 PM 11890851 ER PT J AU Manolio, TA Bild, DE AF Manolio, TA Bild, DE TI Coronary calcium, race, and genes SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material ID RACIAL-DIFFERENCES; RISK-FACTORS; PREVALENCE C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2002 VL 22 IS 3 BP 359 EP 360 DI 10.1161/hq0302.105366 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 532FP UT WOS:000174461700001 PM 11884274 ER PT J AU Weyer, C Yudkin, JS Stehouwer, CDA Schalkwijk, CG Pratley, RE Tataranni, PA AF Weyer, C Yudkin, JS Stehouwer, CDA Schalkwijk, CG Pratley, RE Tataranni, PA TI Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians SO ATHEROSCLEROSIS LA English DT Article DE insulin resistance; obesity; atherosclerosis; glucose clamp; ethnicity ID C-REACTIVE PROTEIN; CELL-ADHESION MOLECULE-1; CORONARY-HEART-DISEASE; APPARENTLY HEALTHY-MEN; VON-WILLEBRAND-FACTOR; INNATE IMMUNE-SYSTEM; DIABETES-MELLITUS; E-SELECTIN; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK AB Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers or inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27 +/- I years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r = 0.71, 0.57, and 0.51. all P < 0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r = -0.65 and -0.46, both P < 0.001) and positively correlated with CRP! (r = 0.46, and 0.33, both P < 0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis. Published by Elsevier Science Ireland Ltd. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. UCL, Whittington Hosp, Diabet & Cardiovasc Dis Acad Unit, London, England. Vrije Univ Amsterdam, Acad Hosp, Dept Med, Amsterdam, Netherlands. Vrije Univ Amsterdam, Cardiovasc Res Inst, Amsterdam, Netherlands. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. EM cweyer@amylin.com RI Yudkin, John/C-1988-2008 NR 54 TC 130 Z9 142 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2002 VL 161 IS 1 BP 233 EP 242 AR PII S0021-9150(01)00626-8 DI 10.1016/S0021-9150(01)00626-8 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 532ZV UT WOS:000174505700026 PM 11882337 ER PT J AU Finney, LJ Iannotti, RJ AF Finney, LJ Iannotti, RJ TI Message framing and mammography screening: A theory-driven intervention SO BEHAVIORAL MEDICINE LA English DT Article DE breast cancer; mammography; message framing; prospect theory ID SELF-EXAMINATION; CERVICAL-CANCER; BREAST-CANCER; BEHAVIOR; INTENTIONS; DECISIONS; INVOLVEMENT; OPTIMISM; PERFORM; BELIEFS AB Although the rising incidence of breast cancer has prompted a surge of intervention strategies aimed at increasing women's use of mammography screening, the majority of patient-directed interventions have not been driven by relevant theoretical work on persuasive health communication. The authors evaluated an intervention derived from prospect theory that was designed to increase women's adherence to recommendations for annual mammography screening. They sent 1 of 3 reminder letters (positive frame, negative frame, or standard hospital prompt) to 929 randomly selected women who were due for mammography screening and had been identified as having either a positive or negative family history of breast cancer The primary hypothesis that women with a positive history would be more responsive to negatively framed messages, whereas women with a negative history would be more responsive to positively framed letters, was not confirmed The lack of support for predictions derived from prospect theory raises important questions about the generalizability of laboratory research to natural settings. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Finney, LJ (reprint author), Canc Prevent Fellowship Program, 6120 Executive Blvd,Suite T-41, Bethesda, MD 20892 USA. NR 33 TC 31 Z9 31 U1 3 U2 8 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0896-4289 J9 BEHAV MED JI Behav. Med. PD SPR PY 2002 VL 28 IS 1 BP 5 EP 14 PG 10 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 592MJ UT WOS:000177941200001 PM 12244644 ER PT J AU Cutler, DA Sullivan, T Marcus-Samuels, B Stewart, CL Reitman, ML AF Cutler, DA Sullivan, T Marcus-Samuels, B Stewart, CL Reitman, ML TI Characterization of adiposity and metabolism in Lmna-deficient mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE adipose tissue; lipodystrophy; animal models; lamin; diabetes ID FAMILIAL PARTIAL LIPODYSTROPHY; LAMIN A/C GENE; DREIFUSS MUSCULAR-DYSTROPHY; CAUSE AUTOSOMAL-DOMINANT; DUNNIGAN VARIETY; NUCLEAR LAMINS; DILATED CARDIOMYOPATHY; MISSENSE MUTATIONS; ROD DOMAIN; A-TYPE AB Dunnigan's Familial Partial Lipodystrophy (FPLD) is an autosomal dominant disease characterized by regional fat loss and insulin resistance. FPLD is caused by mutations in the LMNA gene, which encodes intermediate filaments of the nuclear lamina. Different LMNA mutations cause Emery-Dreifuss muscular dystrophy and/or a dilated cardiomyopathy. It is not known how LMNA mutations cause any of the disease phenotypes. Here we measure physical and metabolic characteristics of Lmna-/- and +/- mice to determine their usefulness as models for FPLD. Lmna-/- mice, which die prematurely of muscular dystrophy, have little fat, but do not show the insulin resistance characteristic of FPLD. Lmna+/- mice, despite treatment with a high fat diet, do not have decreased fat stores or metabolic features of FPLD. We also show, in mice, that Lmna transcripts are expressed at high levels in muscle and adipose tissue, but do not vary by body region or sex. In conclusion, Lmna+/- and -/- mice do not mimic Dunnigan's FPLD, and differential expression of lamins A and C does not appear to contribute to sex- or tissue-specific LMNA phenotypes. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. George Washington Univ, Grad Program Genet, Washington, DC 20052 USA. RP Reitman, ML (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 8N-250,10 Ctr Dr, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 NR 27 TC 43 Z9 46 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 1 PY 2002 VL 291 IS 3 BP 522 EP 527 DI 10.1006/bbrc.2002.6466 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 527TD UT WOS:000174202700013 PM 11855819 ER PT J AU Yan, B Raben, N Plotz, PH AF Yan, B Raben, N Plotz, PH TI Hes-1, a known transcriptional repressor, acts as a transcriptional activator for the human acid alpha-glucosidase gene in human fibroblast cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE acid alpha-glucosidase; glycogen storage disease type II; Hes-1; enhancer; intron; gene expression regulation ID LOOP-HELIX FACTORS; NEURONAL DIFFERENTIATION; NERVOUS-SYSTEM; MOLECULAR CHARACTERIZATION; REGULATES DIFFERENTIATION; NEGATIVE REGULATOR; DROSOPHILA-HAIRY; MAMMALIAN HAIRY; WRPW MOTIF; PROTEINS AB Hes-1, the mammalian homologue I of Drosophila hairy and Enhancer of split proteins, belongs to a family of basic helix-loop-helix proteins that are essential to neurogenesis, myogenesis, hematopoiesis, and sex determination. Hes-1 is a transcriptional repressor for a number of known genes including the human acid a-glucosidase (GAA) gene as we have previously shown in Hep G2 cells. The human GAA gene encodes the enzyme for glycogen breakdown in lysosomes, deficiency of which results in Glycogen Storage Disease type 11 (Pompe syndrome). Using constructs containing the DNA element that demonstrates repressive activity in Hep G2 cells and conditions in which the same transcription factors, Hes-1 and YY1, bind, we have shown that this element functions as an enhancer in human fibroblasts. Site-directed mutagenesis and overexpression of Hes-1 showed that Hes-1 functions as a transcriptional activator. The dual function of Hes-1 we have found is likely to contribute to the subtle tissue-specific control of this housekeeping gene. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Plotz, PH (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N244,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 TC 18 Z9 18 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 1 PY 2002 VL 291 IS 3 BP 582 EP 587 DI 10.1006/bbrc.2002.6483 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 527TD UT WOS:000174202700022 PM 11855828 ER PT J AU Otsuki, T Nagashima, T Komatsu, N Kirito, K Furukawa, Y Kobayashi, S Liu, JM Ozawa, K AF Otsuki, T Nagashima, T Komatsu, N Kirito, K Furukawa, Y Kobayashi, S Liu, JM Ozawa, K TI Phosphorylation of Fanconi anemia protein, FANCA, is regulated by Akt kinase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE FANCA; PKB/Akt; phosphorylation; serine/threonine ID NF-KAPPA-B; NUCLEAR ACCUMULATION; TRANSCRIPTION FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; LIPID PRODUCTS; CELL-SURVIVAL; GROWTH-FACTOR; GROUP-A; COMPLEMENTATION; PATHWAY AB Phsphorylation of the Fanconi anemia complementation group A (FANCA) protein is thought to be important for the function of the FA pathway. However, the kinase for FANCA (so-called FANCA-PK) remains to be identified. FANCA has a consensus sequence for Akt kinase near serine 1149 (Ser1149), suggesting that Akt can phosphorylate FANCA. We performed in vitro kinase assays using as substrate either a GST-fusion wild-type (WT) FANCA fragment or a GST-fusion FANCA fragment containing a mutation from serine to alanine at 1149 (FANCA-S1149A). These experiments confirmed that FANCA is phosphorylated at Ser 1149, in vitro. However, P-32-orthophosphate labeling experiments revealed that FANCA-S1149A was more efficiently phosphorylated than WT-FANCA. Furthermore, phosphorylation of wild-type FANCA was blocked by coexpression of a constitutively active (CA)-Akt and enhanced by a dominant-negative (DN) Akt. Our results suggest that Akt is a negative regulator of FANCA phosphorylation. (C) 2002 Elsevier Science (USA). C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Jichi Med Sch, Dept Hematol, Kawachi, Tochigi 3290498, Japan. Jichi Med Sch, Ctr Mol Med, Kawachi, Tochigi 3290498, Japan. Natl Def Med Coll, Dept Internal Med 3, Tokorozawa, Saitama 3590042, Japan. RP Liu, JM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103, Bethesda, MD 20892 USA. NR 41 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 1 PY 2002 VL 291 IS 3 BP 628 EP 634 DI 10.1006/bbrc.2002.6504 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 527TD UT WOS:000174202700030 PM 11855836 ER PT J AU Kim, SG Ravi, G Hoffmann, C Jung, YJ Kim, M Chen, AS Jacobson, KA AF Kim, SG Ravi, G Hoffmann, C Jung, YJ Kim, M Chen, AS Jacobson, KA TI p53-independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE adenosine receptor; antagonist; poly-ADP-ribose polymerase; CD95; APO-1; phospholipase C; HL-60; MOLT-4 ID A(3) RECEPTOR AGONISTS; P53-MEDIATED APOPTOSIS; MEDIATED APOPTOSIS; PHOSPHOLIPASE-C; MAST-CELLS; ACTIVATION; P53; EXPRESSION; HL-60; RAT AB A(3) adenosine receptor (A(3)AR) agonists have been reported to influence cell death and survival. The effects of an A3AR agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. C1-IB-MECA (greater than or equal to30 muM) increased the apoptotic fractions, as determined using fluorescence-activated cell sorting (FACS) analysis, and activated caspase 3 and poly-ADP-ribose-polymerase. Known messengers coupled to AJAR (phospholipase C and intracellular calcium) did not seem to play a role in the induction of apoptosis. Neither dantrolene nor BAPTA-AM affected the C1-IB-MECA-induced apoptosis. C1-IB-MECA failed to activate phospholipase C in HL-60 cells, while UTP activated it through endogenous P2Y(2) receptors. Induction of apoptosis during a 48 hr exposure to C1-IB-MECA was not prevented by the A3AR antagonists [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] (MRS 1220) or N-[9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1523). Furthermore, higher concentrations of MRS 1220, which would also antagonize A(1) and A(2A) receptors, were ineffective in preventing the apoptosis. Although 1l-IB-MECA has been shown in other systems to cause apoptosis through an A(3)AR-mediated mechanism, in these cells it appeared to be an adenosine receptor-independent effect, which required prolonged incubation. In both HL-60 and MOLT-4 cells, C1-IB-MECA induced the expression of Fas, a death receptor. This induction of Fas was not dependent upon p53, because p53 is not expressed in an active form in either HL-60 or MOLT-4 cells. C1-IB-MECA-induced apoptosis in HL-60 cells was augmented by an agonistic Fas antibody, CH-11, and this increase was suppressed by the antagonistic anti-Fas antibody ZB-4. Therefore, C1-IB-MECA induced apoptosis via a novel, p53-independent up-regulation of Fas. Published by Elsevier Science Inc. C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999] NR 42 TC 41 Z9 42 U1 1 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 1 PY 2002 VL 63 IS 5 BP 871 EP 880 AR PII S0006-2952(02)00839-0 DI 10.1016/S0006-2952(02)00839-0 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 543QX UT WOS:000175113600008 PM 11911839 ER PT J AU Wahde, M Klus, GT Bittner, ML Chen, YD Szallasi, Z AF Wahde, M Klus, GT Bittner, ML Chen, YD Szallasi, Z TI Assessing the significance of consistently mis-regulated genes in cancer associated gene expression matrices SO BIOINFORMATICS LA English DT Article ID PATTERNS AB Motivation: The simplest level of statistical analysis of cancer associated gene expression matrices is aimed at finding consistently up- or down-regulated genes within a given set of tumor samples. Considering the high level of gene expression diversity detected in cancer, one needs to assess the probability that the consistent mis-regulation of a given gene is due to chance. Furthermore, it is important to determine the required sample number that will ensure the meaningful statistical analysis of massively parallel gene expression measurements. Results: The probability of consistent mis-regulation is calculated in this paper for binarized gene expression data, using combinatorial considerations. For practical purposes, we also provide a set of accurate approximate formulas for determining the same probability in a computationally less intensive way. When the pool of mis-regulatable genes is restricted, the probability of consistent mis-regulation can be overestimated. We show, however, that this effect has little practical consequences for cancer associated gene expression measurements published in the literature. Finally, in order to aid experimental design, we have provided estimates on the required sample number that will ensure that the detected consistent mis-regulation is not due to chance. Our results suggest that less than 20 sufficiently diverse tumor samples may be enough to identify consistently mis-regulated genes in a statistically significant manner. C1 Chalmers Univ Technol, Div Mechatron, S-41296 Gothenburg, Sweden. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Childrens Hosp, Informat Program, Boston, MA USA. RP Wahde, M (reprint author), Chalmers Univ Technol, Div Mechatron, S-41296 Gothenburg, Sweden. NR 9 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR PY 2002 VL 18 IS 3 BP 389 EP 394 DI 10.1093/bioinformatics/18.3.389 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 536NH UT WOS:000174708500003 PM 11934737 ER PT J AU Goldman, D AF Goldman, D TI DBH and the functional taxonomy of major depressive disorder SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, Flow Bldg,Room 2,12501 Washington Ave, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 6 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2002 VL 51 IS 5 BP 347 EP 348 AR PII S0006-3223(02)01331-8 DI 10.1016/S0006-3223(02)01331-8 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 533CN UT WOS:000174512000001 PM 11904127 ER PT J AU Dunn, RT Kimbrell, TA Ketter, TA Frye, MA Willis, MW Luckenbaugh, DA Post, RM AF Dunn, RT Kimbrell, TA Ketter, TA Frye, MA Willis, MW Luckenbaugh, DA Post, RM TI Principal components of the beck depression inventory and regional cerebral metabolism in unipolar and bipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 151st Annual Meeting of the American-Psychiatric-Association CY MAY 30-JUN 05, 1998 CL TORONTO, CANADA SP Amer Psychiat Assoc DE Beck Depression Inventory; bipolar; unipolar; depression; cerebral metabolism; principal components analysis ID POSITRON EMISSION TOMOGRAPHY; FRONTAL-SUBCORTICAL CIRCUITS; SUBGENUAL PREFRONTAL CORTEX; BLOOD-FLOW; BASAL GANGLIA; MOOD DISORDERS; GLUCOSE-METABOLISM; MAJOR DEPRESSION; NEGATIVE SYMPTOMS; BRAIN METABOLISM AB Background: We determined clustering of depressive symptoms in a combined group of unipolar and patients with bipolar disorder using Principle Components Analysis of the Beck Depression Inventory. Then, comparing unipolars and bipolars, these symptom clusters were examined for interrelationships, and for relationships to regional cerebral metabolism for glucose measured by positron emission tomography. Methods: [F-18]-fluoro-deoxyglucose positron emission tomography scans and Beck Depression Inventory administered to 31 unipolars and 27 bipolars, all medicaton-free, mildly-to-severely depressed. BDI component and total scores were correlated with global cerebral metabolism for glucose, and voxel-by-voxel with cerebral metabolism for glucose corrected for multiple comparisons. Results: In both unipolars and bipolars, the psychomotor-anhedonia symptom cluster correlated with lower absolute metabolism in right insula, claustrum, anteroventral caudate/putamen, and temporal cortex, and with higher normalized metabolism in anterior cingulate. In unipolars, the negative cognitions cluster correlated with lower absolute metabolism bilaterally in frontal poles, and in right dorsolateral frontal cortex and supracallosal cingulate. Conclusions: Psychomotor anhedonia symptoms in unipolar and bipolar depression appear to have common, largely right-sided neural substrates, and these may be fundamental to the depressive syndrome in bipolars. In unipolars, but not bipolars, negative cognitions are associated with decreased frontal metabolism. Thus, different depressive symptom clusters may have different neural substrates in unipolars, but clusters and their substrates are convergent in bipolars. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, 10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. NR 75 TC 116 Z9 119 U1 4 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2002 VL 51 IS 5 BP 387 EP 399 AR PII S0006-3223(01)01244-6 DI 10.1016/S0006-3223(01)01244-6 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 533CN UT WOS:000174512000007 PM 11904133 ER PT J AU Oren, DA Desan, PH Boutros, N Anand, A Charney, DS AF Oren, DA Desan, PH Boutros, N Anand, A Charney, DS TI Effects of light on low nocturnal bilirubin in winter depression: A preliminary report SO BIOLOGICAL PSYCHIATRY LA English DT Article DE light; bilirubin; depression; circadian rhythms; seasonal affective disorder; photosensitive pigments ID SEASONAL AFFECTIVE-DISORDER; VISIBLE-LIGHT; PHOTOTRANSDUCTION; INDUCTION AB Background: The light-absorbing pigments involved in the induction of treatment of winter depression are unknown. It has been proposed that circulating bilirubin serves as a photoreceptor, in part because of its similarity to the chromophore of phytochrome, a primary time-setting plant molecule. Methods: We measured nocturnal bilirubin levels in nine patients with winter depression, and seven age- and gender-matched normal comparison volunteers. Results: Nocturnal bilirubin levels were lower in patients than in controls (p < .02), increased in both groups during the night (p < .0001), and increased in patients after 2 weeks of morning light treatment (p = .0009), which was accompanied by clinical improvement. Conclusions: Low nocturnal bilirubin levels may be associated with winter seasonal depression. (C) 2002 Society of Biological Psychiatry. C1 Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare System, Dept Psychiat, West Haven, CT 06516 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Oren, DA (reprint author), W Haven VA Med Ctr, 950 Campbell Ave, West Haven, CT 06516 USA. RI Anand, Amit/D-4232-2013 FU NIMH NIH HHS [MH-30929] NR 18 TC 13 Z9 13 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 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2002 VL 51 IS 5 BP 422 EP 425 AR PII S0006-3223(01)01342-9 DI 10.1016/S0006-3223(01)01254-9 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 533CN UT WOS:000174512000011 PM 11904137 ER PT J AU Dunson, DB Baird, DD AF Dunson, DB Baird, DD TI A proportional hazards model for incidence and induced remission of disease SO BIOMETRICS LA English DT Article DE carcinogenesis; disease remission; latent variable; proportional hazards; protective effect; survival analysis; time-dependent covariates ID RADIATION CARCINOGENESIS; STOCHASTIC-MODEL; CELL-DEATH; TIME; DISTRIBUTIONS; MULTIPLICITY; REGRESSION; CANCER; RISK; CURE AB To assess the protective effects of a time-varying covariate, we develop a stochastic model based on tumor biology. The model assumes that individuals have a Poisson-distributed pool of initiated clones, which progress through predetectable, detectable mortal and detectable immortal stags. Time-independent covariates are incorporated through a log-linear model for the expected number of clones, resulting in a proportional hazards model for disease onset. By allowing time-dependent covariates to induce clone death, with rate dependent on a clone's state, the model is flexible enough to accommodate delayed disease onset and remission or cure of preexisting disease. Inference uses Bayesian methods via Markov chain Monte Carlo. Theoretical properties are derived, and the approach is illustrated through analysis of the effects of childbirth on uterine leiomyoma (fibroids). C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. OI Baird, Donna/0000-0002-5544-2653 NR 26 TC 12 Z9 12 U1 0 U2 0 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2002 VL 58 IS 1 BP 71 EP 78 DI 10.1111/j.0006-341X.2002.00071.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 528DN UT WOS:000174229300009 PM 11890329 ER PT J AU Dunson, DB Dinse, GE AF Dunson, DB Dinse, GE TI Bayesian models for multivariate current status data with informative censoring SO BIOMETRICS LA English DT Article DE carcinogenicity experiment; interval censoring; Markov chain Monte Carlo algorithm; multistate stochastic model; multivariate survival data; tumor multiplicity ID PROPORTIONAL HAZARDS MODEL; GROUPED SURVIVAL-DATA; FAILURE TIME DATA; CARCINOGENICITY EXPERIMENTS; REGRESSION-ANALYSIS; MORTALITY; FRAILTY; TESTS AB Multivariate current status data, consist of indicators of whether each of several events occur by the time of a single examination. Our interest focuses on inferences about the joint distribution of the event times. Conventional methods for analysis of multiple event-time data cannot be used because all of the event times are censored and censoring may be informative. Within a given subject, we account for correlated event times through a subject-specific latent. variable, conditional upon which the various events are assumed to occur independently. We also assume that each event contributes independently to the hazard of censoring. Nonparametric step functions are used to characterize the baseline distributions of the different event tunes and of the examination times. Covariate and subject-specific effects are incorporated through generalized linear models. A Markov chain Monte Carlo algorithm is described for estimation of the posterior distributions of the unknowns. The methods are illustrated through application to multiple tumor site data from an animal carcinogenicity study. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 37 TC 25 Z9 25 U1 1 U2 10 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2002 VL 58 IS 1 BP 79 EP 88 DI 10.1111/j.0006-341X.2002.00079.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 528DN UT WOS:000174229300010 PM 11890330 ER PT J AU Xue, QL Bandeen-Roche, K AF Xue, QL Bandeen-Roche, K TI Combining complete multivariate outcomes with incomplete covariate information: A latent class approach SO BIOMETRICS LA English DT Article DE latent variable; measurement error; missing covariate; mixture model; multivariate categorical data; pseudo-maximum likelihood; screening program ID MAXIMUM-LIKELIHOOD ESTIMATION; MODELS AB This work was motivated by the need to combine outcome information from a reference population with risk factor information from a screened subpopulation in a setting where the analytic goal was to study the association between risk factors and multiple binary outcomes. To achieve such an analytic goal, this article proposes a two-stage latent class procedure that first summarizes the commonalities among outcomes using a reference population sample, then analyzes the association between outcomes and risk factors. It develops a pseudo-maximum likelihood approach to estimating model parameters. The performance of the proposed method is evaluated in a simulation study and in an illustrative analysis of data from the Women's Health and Aging Study, a recent investigation of the causes and course of disability in older women. Combining information in the proposed way is found to improve both accuracy and precision in summarizing multiple categorical outcomes, which effectively diminishes ambiguity and bias in making risk factor inferences. C1 Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Xue, QL (reprint author), Johns Hopkins Univ, Dept Epidemiol, 2024 E Monument St,Suite 2-904, Baltimore, MD 21205 USA. FU NIA NIH HHS [R01-AG-11703, R01-AG-12112]; NIMH NIH HHS [R01-MH-56639] NR 20 TC 8 Z9 8 U1 0 U2 2 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2002 VL 58 IS 1 BP 110 EP 120 DI 10.1111/j.0006-341X.2002.00110.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 528DN UT WOS:000174229300013 PM 11890305 ER PT J AU Stylianou, M Flournoy, N AF Stylianou, M Flournoy, N TI Dose finding using the biased coin up-and-down design and isotonic regression SO BIOMETRICS LA English DT Article DE adaptive designs; inference for stochastic processes; logistic regression; quantal estimation; random walk designs; response-driven designs; toxicity studies ID MAXIMUM-LIKELIHOOD; ESTIMATORS AB We are interested in finding a dose that has a prespecified toxicity rate in the target population. In this article, we investigate five estimators of the target dose to be used with the up-and-down biased coin design (BCD) introduced by Durham and Flournoy (1994, Statistical Decision Theory and Related Topics). These estimators are derived using maximum likelihood, weighted least squares, sample averages, and isotonic regression. A linearly interpolated isotonic regression estimate is shown to be simple to derive and to perform as well as or better than the other target dose estimators in terms of mean square error and average number of subjects needed for convergence in most scenarios studied. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. American Univ, Dept Math & Stat, Washington, DC 20016 USA. RP Stylianou, M (reprint author), NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. NR 18 TC 93 Z9 96 U1 0 U2 5 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2002 VL 58 IS 1 BP 171 EP 177 DI 10.1111/j.0006-341X.2002.00171.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 528DN UT WOS:000174229300020 PM 11890313 ER PT J AU Nakamura, C Kawasaki, N Miyataka, H Jayachandran, E Kim, IH Kirk, KL Taguchi, T Takeuchi, Y Hori, H Satoh, T AF Nakamura, C Kawasaki, N Miyataka, H Jayachandran, E Kim, IH Kirk, KL Taguchi, T Takeuchi, Y Hori, H Satoh, T TI Synthesis and biological activities of fluorinated chalcone derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID TUMOR-CELL-LINES; LIPID-PEROXIDATION; DIVERSE PANEL; 5-LIPOXYGENASE; LEUKOTRIENES; INHIBITION; MECHANISM; DRUGS; ASSAY AB We have designed and synthesized new 5-lipoxygenase inhibitors, fluorinated 3,4-dihydroxychalcones, and evaluated their biological activities with respect to antiperoxidation activity and in vitro antitumor activities. All fluorinated chalcones tested showed 5-lipoxygenase inhibition on rat basophilic leukemia-1 (RBL-1) cells and inhibitory action on Fe3+ -ADP induced NADPH-dependent lipid peroxidation in rat liver microsomes. The potencies were comparable or better to that of the lead 3,4-dihydroxychalcone. 6-Fluoro-3,4-dihydroxy-2',4'-dimethoxy chalcone (7) was the most effective compound in the in vitro assay using a human cancer cell line panel (HCC panel) consisting of 39 systems. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Tokushima Bunri Univ, Fac Pharmaceut Sci, Tokushima 7708514, Japan. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Tokyo Univ Pharm & Life Sci, Sch Pharm, Tokyo 1920392, Japan. Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. Univ Tokushima, Fac Engn, Dept Biol Sci & Technol, Tokushima 7708506, Japan. RP Miyataka, H (reprint author), Tokushima Bunri Univ, Fac Pharmaceut Sci, Yamashiro Cho, Tokushima 7708514, Japan. NR 21 TC 38 Z9 39 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR PY 2002 VL 10 IS 3 BP 699 EP 706 DI 10.1016/S0968-0896(01)00319-4 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 517CR UT WOS:000173594000027 PM 11814858 ER PT J AU Venkateswarlu, D Perera, L Darden, T Pedersen, LG AF Venkateswarlu, D Perera, L Darden, T Pedersen, LG TI Structure and dynamics of zymogen human blood coagulation factor X SO BIOPHYSICAL JOURNAL LA English DT Article ID GAMMA-CARBOXYGLUTAMIC ACID; FACTOR-FACTOR-VIIA; BOVINE FACTOR-X; TISSUE FACTOR; SUBSTRATE RECOGNITION; ACTIVE-SITE; PROTEIN-C; PROTHROMBINASE COMPLEX; SERINE PROTEASES; MEMBRANE-BINDING AB The solution structure and dynamics of the human coagulation factor X (FX) have been investigated to understand the key structural elements in the zymogenic form that participates in the activation process. The model was constructed based on the 2.3-Angstrom-resolution x-ray crystallographic structure of active-site inhibited human FXa (PDB:1XKA). The missing gamma-carboxyglutamic acid (GLA) and part of epidermal growth factor 1 (EGF1) domains of the light chain were modeled based on the template of GLA-EGF1 domains of the tissue factor (TF)-bound FVIIa structure (PDB:1DAN). The activation peptide and other missing segments of FX were introduced using homology modeling. The full calcium-bound model of FX was subjected to 6.2 ns of molecular dynamics simulation in aqueous medium using the AMBER6.0 package. We observed significant reorientation of the serine-protease (SP) domain upon activation leading to a compact multi-domain structure. The solution structure of zymogen appears to be in a well-extended conformation with the distance between the calcium ions in the GLA domain and the catalytic residues estimated to be similar to95 Angstrom in contrast to similar to83 Angstrom in the activated form. The latter is in close agreement with fluorescence studies on FXa. The S1-specificity residues near the catalytic triad show significant differences between the zymogen and activated structures. 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, Venable Hall,CB 3290, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013; Venkateswarlu, Divi/K-1815-2014 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861; Venkateswarlu, Divi/0000-0003-2481-7480 FU NHLBI NIH HHS [HL-06350] NR 65 TC 43 Z9 43 U1 1 U2 10 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR PY 2002 VL 82 IS 3 BP 1190 EP 1206 PG 17 WC Biophysics SC Biophysics GA 527DJ UT WOS:000174170700007 PM 11867437 ER PT J AU Dong, XX Ospeck, M Iwasa, KH AF Dong, XX Ospeck, M Iwasa, KH TI Piezoelectric reciprocal relationship of the membrane motor in the cochlear outer hair cell SO BIOPHYSICAL JOURNAL LA English DT Article ID FORCE GENERATION; GUINEA-PIG; CAPACITANCE; STIFFNESS; MOTILITY AB It has been shown that the membrane motor in the outer hair cell is driven by the membrane potential. Here we examine whether the motility satisfies the reciprocal relationship, the characteristic of piezoelectricity, by measuring charge displacement induced by stretching the cell with known force. The efficiency of inducing charge displacement was membrane potential dependent. The maximum efficiency of inducing charge displacement by force was similar to20 fC/nN for 50-mum-long lateral membrane. The efficiency per cell stretching was 0.1 pC/mum. We found that these values are consistent with the reciprocal relationship based on the voltage sensitivity of similar to20 nm/mV for 50-mum-long cell and force production of 0.1 nN/mV by the cell. We can thus conclude that the membrane motor in the outer hair cell satisfies a necessary condition for piezoelectricity and that the hair cell's piezoelectric coefficient of 20 fC/nN is four orders of magnitude greater than the best man-made material. C1 Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Dong, XX (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, Biophys Sect, NIH, Bethesda, MD 20892 USA. OI Iwasa, Kuni/0000-0002-9397-7704 NR 21 TC 50 Z9 51 U1 0 U2 1 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR PY 2002 VL 82 IS 3 BP 1254 EP 1259 PG 6 WC Biophysics SC Biophysics GA 527DJ UT WOS:000174170700012 PM 11867442 ER PT J AU Feller, SE Brown, CA Nizza, DT Gawrisch, K AF Feller, SE Brown, CA Nizza, DT Gawrisch, K TI Nuclear overhauser enhancement spectroscopy cross-relaxation rates and ethanol distribution across membranes SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; MAGNETIC-RESONANCE; LIPID BILAYERS; PHOSPHOLIPID-BILAYERS; COMPUTER-SIMULATION; HYDROCARBON CHAINS; ACYL-CHAIN; NMR; WATER; DIFFUSION AB Measurement of nuclear Overhauser enhancement spectroscopy cross-relaxation rates between ethanol and paimitoyloleoylphosphatidylcholine bilayers was combined with atomic-level molecular dynamics simulations. The molecular dynamics trajectories yielded autocorrelation functions of proton dipole-dipole interactions, and, consequently, relaxation times and cross-relaxation rates. These analyses allow the measured cross-relaxation rates to be interpreted in terms of relative interaction strengths with the various segments of the lipid molecule. We determined that cross-relaxation between ethanol and specific lipid resonances is primarily determined by the sites of interaction with some modulation due to lipid disorder and to local differences in intramolecular lipid dynamics. The rates scale linearly with the lifetime of temporary ethanol-lipid associations. Ethanol interacts with paimitoyloleoylphosphatidylcholine bilayers; primarily via hydrophilic interactions, in particular the formation of hydrogen bonds to the lipid phosphate group. There is a weak contribution to binding from hydrophobic interaction with lipid chain segments near the glycerol. However, the strength of hydrophobic interactions is insufficient to compensate for the energetic loss of locating ethanol in an exclusively hydrophobic environment, resulting in a probability of locating ethanol in the bilayer center that is three orders of magnitude lower than locating ethanol at the lipid/water interface. The low cross-relaxation rates between terminal methyl protons of hydrocarbon chains and ethanol are as much the result of infrequent chain upturns as of brief excursions of ethanol into the region of lipid hydrocarbon chains near the glycerol. The combination of nuclear magnetic resonance measurements and molecular dynamics simulations offers a general pathway to study the interaction of small molecules with the lipid matrix at atomic resolution. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Room 150, Rockville, MD 20852 USA. NR 35 TC 121 Z9 121 U1 0 U2 12 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR PY 2002 VL 82 IS 3 BP 1396 EP 1404 PG 9 WC Biophysics SC Biophysics GA 527DJ UT WOS:000174170700025 PM 11867455 ER PT J AU Chalovich, JM Yan, B Brenner, B Chen, YD AF Chalovich, JM Yan, B Brenner, B Chen, YD TI Modeling thin filament cooperativity - Response SO BIOPHYSICAL JOURNAL LA English DT Letter ID MYOSIN SUBFRAGMENT-1; REGULATED ACTIN; BINDING; TROPONIN; COMPLEX C1 E Carolina Univ, Brody Sch Med, Dept Biochem, Greenville, NC 27834 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20892 USA. Hannover Med Sch, Dept Mol & Cell Physiol, D-3000 Hannover, Germany. RP Chalovich, JM (reprint author), E Carolina Univ, Brody Sch Med, Dept Biochem, Greenville, NC 27834 USA. NR 17 TC 3 Z9 3 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR PY 2002 VL 82 IS 3 BP 1679 EP 1681 PG 3 WC Biophysics SC Biophysics GA 527DJ UT WOS:000174170700050 ER PT J AU Feng, LJ Novak, EK Hartnell, LM Bonifacino, JS Collinson, LM Swank, RT AF Feng, LJ Novak, EK Hartnell, LM Bonifacino, JS Collinson, LM Swank, RT TI The Hermansky-Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes SO BLOOD LA English DT Article ID STORAGE POOL DEFICIENCY; PALE EAR EP; MOUSE MODELS; INHERITED ABNORMALITIES; REGULATED SECRETION; PIGMENT MUTANT; AP-3 ADAPTER; MUTATION; DISORDERS; PROTEINS AB Hermansky-Pudiak syndrome (HPS) is an inherited hemorrhagic disease affecting the related subcellular organelles platelet dense granules, lysosomes, and melanosomes. The mouse genes for HIPS, pale ear and pearl, orthologous to the human HPS1 and HPS2 (ADTB3A) genes, encode a novel protein of unknown function and the beta(3)A subunit of the AP-3 adaptor complex, respectively. To test for In vivo interactions between these genes In the production and function of intracellular organelles, mice doubly homozygous for the 2 mutant genes were produced by appropriate breeding. Cooperation between the 2 genes In melanosome production was evident in increased hypopigmentation of the coat together with dramatic quantitative and qualitative alterations of melanosomes of the retinal pigment epithelium and choroid of double mutant mice. Lysosomal and platelet dense granule abnormalities, including hyposecretion of lysosomal enzymes from kidneys and depression of serotonin concentrations of platelet dense granules were likewise more severe in double than single mutants. Also, lysosomal enzyme concentrations were significantly increased In lungs of double mutant mice. Interaction between the 2 genes was specific in that effects on organelles were confined to melanosomes, lysosomes, and platelet dense granules. Together, the evidence indicates these 2 HPS genes function largely independently at the whole organism level to affect the production and function of all 3 organelles. Further, the increased lysosomal enzyme levels in lung of double mutant mice suggest a cause of a major clinical problem of HPS, lung fibrosis. Finally, doubly mutant HPS mice are a useful laboratory model for analysis of severe HPS phenotypes. C1 Roswell Pk Canc Inst, Mol & Cellular Biol Dept, Buffalo, NY 14263 USA. Albert Einstein Coll Med, Diabet Ctr, Bronx, NY USA. Natl Inst Child Hlth & Human Dev, Cell Biol & Metabol Branch, NIH, Bethesda, MD USA. Univ London Imperial Coll Sci & Technol, Fac Life Sci, Dept Biochem, London, England. RP Swank, RT (reprint author), Roswell Pk Canc Inst, Mol & Cellular Biol Dept, Carlton & Elm Sts, Buffalo, NY 14263 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 FU NCI NIH HHS [CA 16056]; NEI NIH HHS [EY12104]; NHLBI NIH HHS [HL31698, HL51480] NR 44 TC 45 Z9 46 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2002 VL 99 IS 5 BP 1651 EP 1658 PG 8 WC Hematology SC Hematology GA 524ZL UT WOS:000174042700022 PM 11861280 ER PT J AU Ma, YS Zeng, S Metcalfe, DD Akin, C Dimitrijevic, S Butterfield, JH McMahon, G Longley, BJ AF Ma, YS Zeng, S Metcalfe, DD Akin, C Dimitrijevic, S Butterfield, JH McMahon, G Longley, BJ TI The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations SO BLOOD LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Hematology CY DEC 01-05, 2000 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Hematol ID RECEPTOR TYROSINE KINASE; LIGAND-INDEPENDENT ACTIVATION; MAST-CELL LEUKEMIA; CATALYTIC DOMAIN; POINT MUTATION; LINE; IDENTIFICATION; ESTABLISHMENT AB Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either "enzymatic site" type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as "regulatory" type (FIT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, Inhibited wild-type and RT mutant KIT at 0.1 to 1 muM but did not significantly inhibit the Asp816VaI EST mutant associated with SAHM, even at 10 muM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical FIT mutation but which differ in that one also expresses the Asp816VaI EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the FIT mutant-only cell line. Neither compound suppressed activation of Asp816VaI EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816VaI mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its. natural ligand or by FIT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general, paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs. C1 Columbia Univ, Coll Phys & Surg, Sect Dermatopathol, Dept Dermatol, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Novartis, Basel, Switzerland. Mayo Clin & Mayo Fdn, Dept Allerg Dis, Rochester, MN 55905 USA. SUGEN, San Francisco, CA USA. RP Longley, BJ (reprint author), Columbia Univ, Coll Phys & Surg, Sect Dermatopathol, Dept Dermatol, 630 W 168th St, New York, NY 10032 USA. FU NIAMS NIH HHS [R01AR43356] NR 19 TC 335 Z9 345 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2002 VL 99 IS 5 BP 1741 EP 1744 DI 10.1182/blood.V99.5.1741 PG 4 WC Hematology SC Hematology GA 524ZL UT WOS:000174042700033 PM 11861291 ER PT J AU Bolan, CD Leitman, SF AF Bolan, CD Leitman, SF TI Management of anticoagulation-associated toxicity during large-volume leukapheresis of peripheral blood stem cell donors SO BLOOD LA English DT Letter C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Bolan, CD (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. NR 9 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 1 PY 2002 VL 99 IS 5 BP 1878 EP 1878 DI 10.1182/blood.V99.5.1878 PG 1 WC Hematology SC Hematology GA 524ZL UT WOS:000174042700058 PM 11871390 ER PT J AU Schiffmann, R Mankin, H Dambrosia, JM Xavier, RJ Kreps, C Hill, SC Barton, NW Rosenthal, DI AF Schiffmann, R Mankin, H Dambrosia, JM Xavier, RJ Kreps, C Hill, SC Barton, NW Rosenthal, DI TI Decreased bone density in splenectomized Gaucher patients receiving enzyme replacement therapy SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article ID MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; SEVERE SKELETAL INVOLVEMENT; POSTMENOPAUSAL WOMEN; MINERAL DENSITY; QUANTITATIVE CT; LUMBAR SPINE; DISEASE; MARROW; OSTEOPOROSIS; ALENDRONATE AB Little is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectornized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxy vitamin D-3; 0.25-3.0 mug/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7-12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1-6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after [he first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant, effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease. (C) 2002 Elsevier Science (USA). C1 NINCDS, Dev & Metab Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Orthopaed Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med & Mol Biol, Boston, MA 02114 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Schiffmann, R (reprint author), NINCDS, Dev & Metab Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 35 TC 42 Z9 42 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR PY 2002 VL 28 IS 2 BP 288 EP 296 DI 10.1006/bcmd.2002.0517 PG 9 WC Hematology SC Hematology GA 565HC UT WOS:000176362900024 PM 12064924 ER PT J AU Hausler, KD Horwood, NJ Uren, A Ellis, J Lengel, C Martin, TJ Rubin, JS Gillespie, MT AF Hausler, KD Horwood, NJ Uren, A Ellis, J Lengel, C Martin, TJ Rubin, JS Gillespie, MT TI Secreted frizzled-related protein (sFRP-1) binds to RANKL to inhibit osteoclast formation SO BONE LA English DT Meeting Abstract C1 St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia. NCI, NIH, Bethesda, MD 20892 USA. RI Horwood, Nicole/B-4351-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR PY 2002 VL 30 IS 3 SU S MA C130 BP 33S EP 33S PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 530FB UT WOS:000174345000131 ER PT J AU Watkins, KE Vargha-Khadem, F Ashburner, J Passingham, RE Connelly, A Friston, KJ Frackowiak, RSJ Mishkin, M Gadian, DG AF Watkins, KE Vargha-Khadem, F Ashburner, J Passingham, RE Connelly, A Friston, KJ Frackowiak, RSJ Mishkin, M Gadian, DG TI MRI analysis of an inherited speech and language disorder: structural brain abnormalities SO BRAIN LA English DT Article DE developmental language disorders; verbal dyspraxia; caudate nucleus; morphometry; genetics ID TEMPORAL-LOBE EPILEPSY; DEVELOPMENTAL DYSLEXIA; COGNITIVE DEFICITS; CHILDREN; MOTOR; DISEASE; SCHIZOPHRENIA; ARTICULATION; NEUROANATOMY; MORPHOMETRY AB Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family. C1 UCL, Sch Med, Dev Cognit Neurosci Unit, London W1N 8AA, England. UCL, Sch Med, Inst Child Hlth, Radiol & Phys Unit, London W1N 8AA, England. UCL, Sch Med, Wellcome Dept Cognit Neurol, Inst Neurol, London W1N 8AA, England. Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Watkins, KE (reprint author), McGill Univ, Montreal Neurol Inst, Cognit Neurosci Unit, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. EM kwatkins@bic.mni.mcgill.ca RI Gadian, David/C-4961-2008; Vargha-Khadem, Faraneh/C-2558-2008; Friston, Karl/D-9230-2011; Watkins, Kate/A-6559-2012; Connelly, Alan/A-9065-2013; Frackowiak, Richard/I-1809-2013; Frackowiak, Richard/H-4383-2011; Ashburner, John/I-3757-2013 OI Friston, Karl/0000-0001-7984-8909; Frackowiak, Richard/0000-0002-3151-822X; Watkins, Kate/0000-0002-2621-482X; Ashburner, John/0000-0001-7605-2518 NR 46 TC 197 Z9 199 U1 2 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAR PY 2002 VL 125 BP 465 EP 478 DI 10.1093/brain/awf057 PN 3 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 530MP UT WOS:000174361700004 PM 11872605 ER PT J AU Maurer-Spurej, E Dyker, K Gahl, WA Devine, DV AF Maurer-Spurej, E Dyker, K Gahl, WA Devine, DV TI A novel immunocytochemical assay for the detection of serotonin in platelets SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE blood platelets; serotonin; fluorescence; selective scrotonin reuptake inhibitors; Hermansky-Pudlak syndrome ID HERMANSKY-PUDLAK-SYNDROME; STORAGE POOL DEFICIENCY; LIQUID-CHROMATOGRAPHY; ELECTROCHEMICAL DETECTION; VESICLE FORMATION; DENSE GRANULES; WHOLE-BLOOD; PLASMA; METABOLITES; MUTATIONS AB A method for the rapid, inexpensive and easy detection of platelet serotonin (5-hydroxytryptamine, 5-HT) is riot currently available. Consequently, many patients suffering from unresolved platelet-related bleeding disorders are not examined for a possible platelet 5-HT deficiency. The direct measurement of 5-HT concentration with high-performance liquid chromatography (HPLC) or serotonin enzyme-linked immunosorbent assay (ELISA) is costly and highly demanding. Indirect methods, which determine the content of ATP or calcium with lumi-aggregometry or electron microscopy, rely upon tire assumption that the ATP or calcium concentration is equivalent to that of 5-HT. We have developed a fluorescence-based assay for 5-HT that can be performed within 2 h on fresh or frozen samples using a fluorescence microscope or a flow cytometer. The assay requires only 0.2 ml of platelet-rich plasma and might therefore be of particular interest for paediatric patients. Samples from control and patient donors were analysed for 5-HT with the new immunocytochemical assay in comparison with HPLC and/or 5-HT ELISA. Patients with Hermansky-Pudlak syndrome were readily identified. The new assay was also reliable in cases where the 5-HT content of dense granules was not correlated with the calcium or ATP content, such as in Calcium deficiency or in the presence of selective serotonin reuptake inhibitors. C1 Univ British Columbia, Dept Pathol, Vancouver, BC V6T 2B5, Canada. Canadian Blood Serv, Vancouver, BC, Canada. Univ British Columbia, Dept Med, Vancouver, BC V6T 2B5, Canada. NIH, Bethesda, MD 20892 USA. RP Maurer-Spurej, E (reprint author), Univ British Columbia, Dept Pathol, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 24 TC 18 Z9 19 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2002 VL 116 IS 3 BP 604 EP 611 DI 10.1046/j.0007-1048.2001.03302.x PG 8 WC Hematology SC Hematology GA 527ZF UT WOS:000174217500017 PM 11849219 ER PT J AU Fricker, G Nobmann, S Miller, DS AF Fricker, G Nobmann, S Miller, DS TI Permeability of porcine blood brain barrier to somatostatin analogues SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE blood brain barriers; cancer; central nervous system; confocal microscopy; Mrp2; octreotide; p-glycoprotein; somatostatin ID CENTRAL-NERVOUS-SYSTEM; RENAL PROXIMAL TUBULE; P-GLYCOPROTEIN; MULTIDRUG TRANSPORTER; OCTREOTIDE; PEPTIDES; OCTAPEPTIDE; EFFLUX; TUMORS; ABSORPTION AB 1 Transport of a fluorescent somatostatin analogue (NBD-octreotide) across freshly isolated functionally intact capillaries from porcine brain was visualized by confocal microscopy and quantitated by image analysis. 2 Luminal accumulation of NBD-octreotide showed all characteristics of specific and energy-dependent transport. Steady-state luminal fluorescence averaged 2-3 times cellular fluorescence and was reduced to cellular levels when metabolism was inhibited by NaCN. 3 The accumulation of NBD-octreotide in capillary lumens was inhibited in a concentration-dependent manner by unlabelled octreotide, by verapamil, PSC-833 and cyclosporin A, potent inhibitors of p-glycoprotein, and by leucotriene C-4, a strong modulator of Mrp2. Conversely, unlabelled octreotide reduced luminal accumulation of fluorescent BODIPY-verapanlil oil glycoprotein and of fluorescein-methotrexate, on Mrp2, None of the inhibitors used significantly reduced cellular accumulation of the fluorescent substrates. 4 Together, the data are consistent with octreotide being transported across the luminal membrane of porcine brain capillaries by both P-gp and Mrp2. providing further evidence that both transporters contribute substantially to the active barrier function of this endothelium. British Journal of Pharmacology (2002). C1 Univ Heidelberg, Inst Pharmazeut Technol & Biopharm, INF 366, D-69120 Heidelberg, Germany. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Fricker, G (reprint author), Univ Heidelberg, Inst Pharmazeut Technol & Biopharm, INF 366, D-69120 Heidelberg, Germany. NR 28 TC 32 Z9 33 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAR PY 2002 VL 135 IS 5 BP 1308 EP 1314 DI 10.1038/sj.bjp.0704557 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 530XN UT WOS:000174384400028 PM 11877340 ER PT J AU Gavins, FNE Gao, J Murphy, PM Flower, RJ Perretti, M AF Gavins, FNE Gao, J Murphy, PM Flower, RJ Perretti, M TI Annexin 1 peptide protects against ischaemia reperfusion in the mouse mesentery SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract C1 Univ London St Bartholomews Hosp Med Coll, Coll Med, William Harvey Res Inst, London EC1M 6BQ, England. NIAID, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAR PY 2002 VL 135 SU S MA 198P PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 533QN UT WOS:000174541900048 ER PT J AU Anisimov, SV Bokheler, KR Khavinson, VK Anisimov, VN AF Anisimov, SV Bokheler, KR Khavinson, VK Anisimov, VN TI Studies of the effects of vilon and epithalon on gene expression in mouse heart using DNA-microarray technology SO BULLETIN OF EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE gene expression; DNA-microarray; peptides; Vilon; epithalon ID PINEAL PEPTIDE PREPARATION; LIFE-SPAN; MICE; MELATONIN; DOMAIN AB Expression of 15,247 clones from a cDNA library in the heart of mice receiving Vilon and Epithalon was studied by DNA-microarray technology. We revealed 300 clones (1.94% of the total count), whose expression changed more than by 2 times. Vilon changed expression of 36 clones, while Epithalon modulated expression of 98 clones. Combined treatment with Vilon and Epithalon changed expression of 144 clones. Vilon alone or in combination with Epithalon activated expression of 157 clones (maximally by 6.13 times) and inhibited expression of 23 clones (maximally by 2.79 times). Epithalon alone or in combination with Vilon activated expression of 194 clones (maximally by 6.61 times) and inhibited expression of 48 clones (maximally by 2.71 times). Our results demonstrate the specific effects of Epithalon and Vilon on gene expression. C1 Russian Acad Med Sci, St Petersburg Inst Bioregulat & Gerontol, Northwestern Div, St Petersburg, Russia. NIA, Baltimore, MD 21224 USA. Minist Publ Hlth Russia, NN Petrov Inst Oncol, St Petersburg, Russia. RI Khavinson, Vladimir/N-9908-2014 OI Khavinson, Vladimir/0000-0001-7547-7725 NR 15 TC 3 Z9 4 U1 0 U2 0 PU CONSULTANTS BUREAU PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0007-4888 J9 B EXP BIOL MED+ JI Bull. Exp. Biol. Med. PD MAR PY 2002 VL 133 IS 3 BP 293 EP 299 DI 10.1023/A:1015859322630 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 593ZX UT WOS:000178025300027 PM 12360356 ER PT J AU Wood, CM Wilson, P Bergman, HL Bergman, AN Laurent, P Otiang'a-Owiti, G Walsh, PJ AF Wood, CM Wilson, P Bergman, HL Bergman, AN Laurent, P Otiang'a-Owiti, G Walsh, PJ TI Ionoregulatory strategies and the role of urea in the Magadi tilapia (Alcolapia grahami) SO CANADIAN JOURNAL OF ZOOLOGY-REVUE CANADIENNE DE ZOOLOGIE LA English DT Article ID OREOCHROMIS-ALCALICUS-GRAHAMI; EXTREMELY ALKALINE ENVIRONMENT; FRESH-WATER; OPERCULAR EPITHELIUM; FISH; GILL; LAKE; MORPHOLOGY; EXCRETION; TRANSPORT AB The unique ureotelic tilapia Alcolapia grahami lives in the highly alkaline and saline waters of Lake Magadi, Kenya (pH similar to10.0, alkalinity similar to380 mmolL(-1), Na+ similar to350 mmolL(-1), Cl- similar to110 mmolL(-1), osmolality similar to580 mosmolkg(-1)). In 100% lake water, the Magadi tilapia maintained plasma Na+, Cl-, and osmolality at levels typical of marine teleosts and drank the medium at 8.01 +/- 1.29 mLkg(-1)h(-1). Gill chloride cells were predominantly of the sea water type (recessed, with apical pits) but a few freshwater-type chloride cells (surficial, with flat apical exposure) were also present. Whole-body Na+ and Cl- concentrations were relatively high and exhibited larger relative changes in response to salinity transfers than did plasma ions. All fish succumbed upon acute transfer to 1% lake water, but tolerated acute transfer to 10% lake water well, and gradual long-term acclimation to both 10 and 1% lake water without change in plasma cortisol. Plasma osmolytes were here maintained at levels typical of freshwater teleosts. Curiously, drinking continued at the same rate in fish adapted to 1% lake water, but chloride cells were now exclusively of the freshwater type. Significant mortality and elevated cortisol occurred after acute transfer to 200% lake water. However, the fish survived well during gradual adaptation to 200% lake water, although plasma cortisol remained chronically elevated. Urea levels accounted for only 2-3% of internal osmolality in 100% lake water but responded to a greater extent than plasma ions during exposure to 10 and 200% lake water, decreasing by 28-42% in the former and increasing by over 500% in the latter relative to simultaneous-control values. Urea thereby played a small but significant role (up to 8% of internal osmolality) in osmoregulation. C1 McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS,Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Trent Univ, Dept Chem, Wildlife Forens DNA Lab, Peterborough, ON K9J 7B8, Canada. Univ Wyoming, Dept Zool & Physiol, Laramie, WY 82071 USA. CNRS, Ctr Ecol & Physiol Energet, F-67037 Strasbourg, France. Univ Nairobi, Dept Vet Anat, Nairobi, Kenya. RP Wood, CM (reprint author), McMaster Univ, Dept Biol, 1280 Main St W, Hamilton, ON L8S 4K1, Canada. NR 48 TC 11 Z9 11 U1 2 U2 12 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0008-4301 J9 CAN J ZOOL JI Can. J. Zool.-Rev. Can. Zool. PD MAR PY 2002 VL 80 IS 3 BP 503 EP 515 DI 10.1139/Z02-019 PG 13 WC Zoology SC Zoology GA 541XG UT WOS:000175011400013 ER PT J AU Macpherson, GR Ng, SSW Lakhani, NJ Price, DK Venitz, J Figg, WD AF Macpherson, GR Ng, SSW Lakhani, NJ Price, DK Venitz, J Figg, WD TI Antiangiogenesis therapeutic strategies in prostate cancer SO CANCER AND METASTASIS REVIEWS LA English DT Review DE angiogenesis; prostate cancer; thalidomide; endostatin; carboxyamido-triazole; 2-methoxyestradiol ID ENDOTHELIAL GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; ANGIOGENESIS INHIBITOR TNP-470; PHASE-II TRIAL; ENDOGENOUS ESTROGEN METABOLITE; MEDIATED SIGNAL-TRANSDUCTION; CALCIUM INFLUX INHIBITOR; SUPPRESSES TUMOR-GROWTH; VERSUS-HOST DISEASE; CARBOXYAMIDO-TRIAZOLE AB It is now well documented that tumor progression from its early stages to an advanced metastatic state requires the recruitment of new vasculature. The reliance on angiogenesis by tumors renders them susceptible to agents that can interfere with the angiogenic process. Recent interest in the therapeutic potential of using angiogenesis as a target mechanism for anticancer therapy has led to the identification of various antiangiogenic agents that interfere at various stages of the process. This review is a summary of recent progress in the identification and characterization of antiangiogenesis agents with a focus on their utility with respect to prostate cancer. Though we focus on prostate cancer, this knowledge is relevant to any cancer that involves angiogenesis. C1 NCI, Mol Pharmacol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Ctr Canc Res, NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 145 TC 10 Z9 12 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD MAR PY 2002 VL 21 IS 1 BP 93 EP 106 DI 10.1023/A:1020128708223 PG 14 WC Oncology SC Oncology GA 591JA UT WOS:000177874900007 PM 12400998 ER PT J AU Blagosklonny, MV Robey, R Sheikh, MS Fojo, T AF Blagosklonny, MV Robey, R Sheikh, MS Fojo, T TI Paclitaxel-induced FasL-independent apoptosis and slow (non-apoptotic) cell death SO CANCER BIOLOGY & THERAPY LA English DT Article DE microtubule-active drugs; caspases; mitotic slippage; multinucleation ID DRUG-RESISTANCE; LEUKEMIA-CELLS; MEDIATED APOPTOSIS; CASPASE ACTIVATION; DNA FRAGMENTATION; CROSS-RESISTANCE; INHIBITION; MITOCHONDRIA; LIGAND; P53 AB Microtubule-active drugs, including paclitaxel (Taxol, PTX), cause mitotic arrest, and this can result in apoptosis. A recently study has reported that PTX mediates apoptosis by upregulating FasL in Jurkat and MDA-231 cells. In contrast to the previous report, we found that anti-FasL antibodies failed to inhibit PTX-induced apoptosis in Jurkat cells. In MDA-231 cells, neither FasL nor PTX induced apoptosis. In these cells, PTX caused slow cell death without activation of caspase-3 or -8 or PARP cleavage. Doxorubicin at cytostatic concentrations did not affect FasL-induced apoptosis but inhibited PTX-induced apoptosis in Jurkat cells. Following PTX-induced mitotic arrest Jurkat cells undergo apoptosis, whereas MDA-MB-231 cells exit mitosis and form multinucleated cells which then die in a slower nonapoptotic manner. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. New York Med Coll, Dept Med, Valhalla, NY 10595 USA. SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA. RP Blagosklonny, MV (reprint author), New York Med Coll, Dept Med, Brander Canc Res Inst, 19 Bradhurst Ave, Hawthorne, NY 10532 USA. NR 24 TC 36 Z9 39 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR-APR PY 2002 VL 1 IS 2 BP 113 EP 117 PG 5 WC Oncology SC Oncology GA 637UV UT WOS:000180532900004 PM 12170770 ER PT J AU Amundson, SA Patterson, A Do, KT Fornace, AJ AF Amundson, SA Patterson, A Do, KT Fornace, AJ TI A nucleotide excision repair master-switch: p53 regulated coordinate induction of global genomic repair genes SO CANCER BIOLOGY & THERAPY LA English DT Article DE DNA repair; gene induction; ionizing radiation; XP; GADD45a ID THYMIDINE KINASE LOCUS; CELL-CYCLE CHECKPOINT; DECREASED DNA-REPAIR; TUMOR-SUPPRESSOR; DAMAGING AGENTS; TRANSCRIBED STRAND; PYRIMIDINE DIMERS; CDNA MICROARRAY; GADD45 PROTEIN; UV-IRRADIATION AB The tumor suppressor gene p53 is mutated in many human cancers. One of its major roles is as a transcription factor, and its many effector genes control key cellular processes including cell cycle checkpoints and apoptosis. An important role in DNA repair is also emerging for both p53 itself and some of its effector genes. The products of two p53-regulated genes, GADD45a and DDB2, are now known to participate in the global genomic repair (GGR) sub-pathway of nucleotide excision repair (NER). We recently reported the induction of a third GGR gene, XPC, following exposure of normal human peripheral blood lymphocytes to gamma-rays. We now show that XPC is induced in a variety of human cell lines in response to both ionizing and ultra-violet (UV) radiation and alkylating agents, and that this induction requires wild-type p53. C1 NCI, NIH, Div Basic Sci, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, NIH, Div Basic Sci, 37 Convent Dr,Bldg 37,RM 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 40 TC 60 Z9 62 U1 0 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR-APR PY 2002 VL 1 IS 2 BP 145 EP 149 PG 5 WC Oncology SC Oncology GA 637UV UT WOS:000180532900010 PM 12170774 ER PT J AU Mariotto, A Capocaccia, R Verdecchia, A Micheli, A Feuer, EJ Pickle, L Clegg, LMX AF Mariotto, A Capocaccia, R Verdecchia, A Micheli, A Feuer, EJ Pickle, L Clegg, LMX TI Projecting SEER cancer survival rates to the US: an ecological regression approach SO CANCER CAUSES & CONTROL LA English DT Article DE cancer survival; ecological models; SEER; socioeconomic and demographic factors ID SURVEILLANCE; BREAST; TRENDS AB Objectives: Cancer survival information is available only in areas covered by cancer registration. The objective of this study is to project cancer survival for the entire US as well as states from survival data from the National Cancer Institute's Surveillance, Epidemiology. and End Results (SEER) program. Methods: Five-year breast, prostate, and colorectal cancer relative survival rates from SEER are regressed on socioeconomic, demographic, and health variables at the county level. These models are first validated by comparing the observed rates with projected rates for counties not used in the estimation process. Results: Education was the best indicator of longer cancer survival. Other important predictors of the geographical variability of survival varied by cancer site. Better survival was predicted for breast and prostate than for colorectal cancer. CONCLUSIONS: Data from cancer registries can be used in ecological models to provide national and state estimates of patients' survival rates. These estimates are useful in targeting areas in which to promote earlier diagnosis or improved access to care, and may also aid in monitoring the quality of survival data collected by individual cancer registries. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Ist Super Sanita, Dept Epidemiol, I-00161 Rome, Italy. Ist Nazl Tumori, Div Epidemiol, I-20133 Milan, Italy. RP Mariotto, A (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Suite 504,MSC 8317, Bethesda, MD 20892 USA. OI Micheli, Andrea/0000-0002-4558-4754 NR 20 TC 48 Z9 49 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2002 VL 13 IS 2 BP 101 EP 111 DI 10.1023/A:1014380323037 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 534EM UT WOS:000174571700001 PM 11936816 ER PT J AU Luce, D Leclerc, A Begin, D Demers, PA Gerin, M Orlowski, E Kogevinas, M Belli, S Bugel, I Bolm-Audorff, U Brinton, LA Comba, P Hardell, L Hayes, RB Magnani, C Merler, E Preston-Martin, S Vaughan, TL Zheng, W Boffetta, P AF Luce, D Leclerc, A Begin, D Demers, PA Gerin, M Orlowski, E Kogevinas, M Belli, S Bugel, I Bolm-Audorff, U Brinton, LA Comba, P Hardell, L Hayes, RB Magnani, C Merler, E Preston-Martin, S Vaughan, TL Zheng, W Boffetta, P TI Sinonasal cancer and occupational exposures: a pooled analysis of 12 case-control studies SO CANCER CAUSES & CONTROL LA English DT Article DE adenocarcinoma; asbestos; case-control studies; formaldehyde; occupational exposures; sinonasal cancer; squamous cell carcinoma; textile dust ID WOOD DUST EXPOSURE; PARA-NASAL SINUSES; SQUAMOUS-CELL CANCERS; PARANASAL SINUSES; CAVITY; FORMALDEHYDE; NOSE; TEXTILE; ADENOCARCINOMA; REANALYSIS AB Objective: In order to examine the associations between sinonasal cancer and occupational exposures other than wood dust and leather dust, the data from 12 case-control studies conducted in seven countries were pooled and reanalyzed. Methods: The pooled data set included 195 adenocarcinoma cases (169 men and 26 women), 432 squamous cell carcinomas (330 men and 102 women), and 3136 controls (2349 men and 787 women). Occupational exposures to formaldehyde, silica dust, textile dust, coal dust, flour dust, asbestos, and man-made vitreous fibers were assessed with a job-exposure matrix. Odds ratios (ORs) were adjusted for age, study, wood dust, and leather dust, or other occupational exposures when relevant. 95% confidence intervals (CIs) were estimated by unconditional logistic regression. Results: A significantly increased risk of adenocarcinoma was associated with exposure to formaldehyde. The ORs for the highest level of exposure were 3.0 (CI = 1.5-5.7) among men and 6.2 (CI = 2.0-19.7) among women. An elevated risk of squamous cell carcinoma was observed among men (OR = 2.5, CI = 0.6-10.1) and women (OR = 3.5, CI = 1.2-10.5) with a high probability of exposure to formaldehyde. Exposure to textile dust was associated with non-significantly elevated risk of adenocarcinoma, among women only: the OR for the high level of cumulative exposure was 2.5 (CI = 0.7-9.0). High level of asbestos exposure was associated with a significantly increased risk of squamous cell carcinoma among men (OR = 1.6, CI = 1.1-2.3). Conclusions: The results of this pooled analysis support the hypothesis that occupational exposure to formaldehyde increases the risk of sinonasal cancer. particularly of adenocarcinoma. They also indicate an elevated risk of adenocarcinoma among women exposed to textile dust, and suggest that exposure to asbestos may increase the risk of squamous cell carcinoma. C1 Hop Natl St Maurice, INSERM, U88, F-94415 St Maurice, France. Univ Montreal, Montreal, PQ, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. INSERM E9909, Creteil, France. Inst Municipal Invest Med, E-08003 Barcelona, Spain. Inst Super Sanita, Rome, Italy. Hess Minist Frauen Arbeit & Sozialordnung, Wiesbaden, Germany. NCI, Bethesda, MD 20892 USA. Orebro Med Ctr Hosp, S-70185 Orebro, Sweden. Univ Turin, Turin, Italy. Ctr Studio & Prevenz Oncol, Florence, Italy. Univ So Calif, Los Angeles, CA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Vanderbilt Univ, Nashville, TN USA. Int Agcy Res Canc, F-69372 Lyon, France. RP Luce, D (reprint author), Hop Natl St Maurice, INSERM, U88, 14 Rue Val Dosne, F-94415 St Maurice, France. EM d.luce@st-maurice.inserm.fr RI Brinton, Louise/G-7486-2015; LUCE, Daniele/J-9125-2015; Kogevinas, Manolis/C-3918-2017; OI Brinton, Louise/0000-0003-3853-8562; Luce, Daniele/0000-0002-1708-4584 NR 39 TC 65 Z9 69 U1 2 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2002 VL 13 IS 2 BP 147 EP 157 DI 10.1023/A:1014350004255 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 534EM UT WOS:000174571700006 PM 11936821 ER PT J AU Schroeder, JC Olshan, AF Baric, R Dent, GA Weinberg, CR Yount, B Cerhan, JR Lynch, CF Schuman, LM Tolbert, PE Rothman, N Cantor, KP Blair, A AF Schroeder, JC Olshan, AF Baric, R Dent, GA Weinberg, CR Yount, B Cerhan, JR Lynch, CF Schuman, LM Tolbert, PE Rothman, N Cantor, KP Blair, A TI A case-control study of tobacco use and other non-occupational risk factors for t(14;18) subtypes of non-Hodgkin's lymphoma (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE bcl-2; epidemiology; lymphoma; molecular genes; non-Hodgkin; tobacco; translocation (genetics) ID POLYMERASE CHAIN-REACTION; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MINIMAL RESIDUAL DISEASE; HAIR DYE USE; FOLLICULAR LYMPHOMA; CIGARETTE-SMOKING; MULTIPLE-MYELOMA; GENE REARRANGEMENTS; 14-18 TRANSLOCATION; STRUCTURAL-ANALYSIS AB Objective: Non-Hodgkin's lymphoma (NHL) encompasses diverse subtypes, and analyzing NHL as a single outcome may mask associations. In a new approach we evaluated associations with subtypes defined by the t(14;18) translocation, reasoning that cases within these subtypes would have more common risk factors than all NHL combined. Methods: Archival biopsies from cases in a population-based NHL study were assayed for t(14;18) using polymerase chain reaction amplification. Exposures in 68 t(14;18)-positive and 114-negative cases were compared with 1245 controls. The expectation-maximization algorithm was used to fit polytomous regression models based on all available information, including data from 440 unclassified cases. Results: Family history of hemolymphatic cancer was associated with t(14;18)-negative NHL (odds ratio (OR) 21.4, 95% confidence interval (CI) 1.4-3.9), but not t(14;18)-positive NHL. Cigarette smoking was weakly associated with t(14;18)-positive NHL (OR 1.7, CI 0.9-3.3), but ORs decreased as smoking increased. Chewing tobacco was associated with t(14;18)-positive NHL, particularly when used before age 18 (OR 2.5, CI 1.0-6.0, 13 exposed cases). Odds ratios for both case-subtypes were doubled among hair-dye users. Conclusions: Cigarette smoking was not clearly associated with t(14;18)-positive NHL. Family history may be a marker for factors that act specifically through t(14;18)-negative pathogenic mechanisms. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Mayo Clin, Hlth Sci Res, Rochester, MN USA. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. Univ Minnesota, Dept Epidemiol, Minneapolis, MN USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Schroeder, JC (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RI Tolbert, Paige/A-5676-2015 FU NCI NIH HHS [K07 CA64220, R03CA71617, N01-CP-11020] NR 67 TC 30 Z9 30 U1 2 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2002 VL 13 IS 2 BP 159 EP 168 DI 10.1023/A:1014397920185 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 534EM UT WOS:000174571700007 PM 11936822 ER PT J AU Staudt, LM AF Staudt, LM TI It's ALL in the diagnosis SO CANCER CELL LA English DT Editorial Material ID ACUTE LYMPHOBLASTIC-LEUKEMIA C1 NCI, Metab Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Canc Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 8 TC 17 Z9 18 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAR PY 2002 VL 1 IS 2 BP 109 EP 110 DI 10.1016/S1535-6108(02)00036-3 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TG UT WOS:000178350800001 PM 12086866 ER PT J AU Choyke, PL Knopp, MV Libutti, SK AF Choyke, PL Knopp, MV Libutti, SK TI Special techniques for imaging blood flow to tumors SO CANCER JOURNAL LA English DT Article DE cancer; imaging; MRI; PET; ultrasound; flow ID POSITRON-EMISSION-TOMOGRAPHY; LUNG NODULE ENHANCEMENT; CONTRAST ENHANCEMENT; BREAST-TUMORS; MICROVESSEL DENSITY; CERVICAL-CARCINOMA; CT MEASUREMENTS; ANGIOGENESIS; DOPPLER; COLOR AB In this review, the current imaging methods of assessing tumor perfusion are discussed and compared. Because most of the techniques depend on the administration of contrast agents, we first consider some general principles underlying the fate of contrast agents and their behavior inside the unique vascular environment of tumors. C1 NIH, Dept Radiol, Warren Grant Magnusen Clin Ctr, Bethesda, MD 20892 USA. Natl Canc Inst, Ctr Canc Res, Surg Branch, NIH, Bethesda, MD USA. RP Choyke, PL (reprint author), NIH, Dept Radiol, Warren Grant Magnusen Clin Ctr, Bldg 10 Rm 1C660, Bethesda, MD 20892 USA. RI Knopp, Michael/E-3410-2011 OI Knopp, Michael/0000-0001-9543-2962 NR 56 TC 13 Z9 14 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAR-APR PY 2002 VL 8 IS 2 BP 109 EP 118 DI 10.1097/00130404-200203000-00005 PG 10 WC Oncology SC Oncology GA 542HL UT WOS:000175037400005 PM 11999945 ER PT J AU Carroll, NM Alexander, HR AF Carroll, NM Alexander, HR TI Isolation perfusion of the liver SO CANCER JOURNAL LA English DT Article DE Isolation perfusion; hepatic metastases; tumor necrosis factor; melphalan ID TUMOR-NECROSIS-FACTOR; ISOLATED HEPATIC PERFUSION; ISOLATED HYPERTHERMIC LIVER; PROSPECTIVE RANDOMIZED TRIAL; COLORECTAL-CANCER; FACTOR-ALPHA; UVEAL MELANOMA; PHASE-I; SYSTEMIC FLUOROURACIL; ARTERIAL CHEMOTHERAPY AB Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melpha-lan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver, In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases. C1 NCI, Surg Branch, Surg Metabolism Sect, NIH, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, Surg Metabolism Sect, NIH, Bldg 10 Rm 2B07, Bethesda, MD 20892 USA. NR 72 TC 8 Z9 8 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAR-APR PY 2002 VL 8 IS 2 BP 181 EP 193 DI 10.1097/00130404-200203000-00012 PG 13 WC Oncology SC Oncology GA 542HL UT WOS:000175037400012 PM 12004803 ER PT J AU Mousses, S Bubendorf, L Wagner, U Hostetter, G Kononen, J Cornelison, R Goldberger, N Elkahloun, AG Willi, N Koivisto, P Ferhle, W Raffeld, M Sauter, G Kallioniemi, OP AF Mousses, S Bubendorf, L Wagner, U Hostetter, G Kononen, J Cornelison, R Goldberger, N Elkahloun, AG Willi, N Koivisto, P Ferhle, W Raffeld, M Sauter, G Kallioniemi, OP TI Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays SO CANCER RESEARCH LA English DT Article ID COMPLEMENTARY-DNA; BINDING PROTEIN; MU-CRYSTALLIN; IN-VIVO; S100P; EXPRESSION; XENOGRAFT; ANDROGEN; OVEREXPRESSION; CARCINOMA AB To explore molecular mechanisms of prostate cancer progression, we applied tissue microarrays (TMAs) to analyze expression of candidate gene targets discovered by cDNA microarray analysis of the CWR22 xenograft model system. A TMA with 544 clinical specimens from different stages of disease progression was probed by mRNA in situ hybridization and protein immunohistochemistry. There was an excellent correlation (r = 0.96; n = 16) between the expression levels of the genes in the xenografts by cDNA microarray and mRNA in situ hybridization on a TMA. One of the most highly overexpressed genes in hormone-refractory CWR22R xenografts was the S100P gene. This gene, coding for a calcium signaling molecule implicated in the loss of senescence, was also significantly associated with progression in clinical tumors by TMA analysis (P < 0.001), suggesting dysregulation of this pathway in hormone-refractory and metastatic prostate cancers. Conversely, two genes that were down-regulated during tumor progression in the CWR22 model system were validated in vivo: crystallin μ (CRYM) and a LIM-domain protein LMO4 both showed significantly lower mRNA levels in hormone-refractory tumors as compared with primary tumors (P < 0.001). These results illustrate a strategy for rapid clinical validation at the mRNA and protein level of gene targets found to be differentially expressed in cDNA microarray experiments of model systems of cancer. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Tampere Univ Hosp, Canc Genet Lab, Tampere 33521, Finland. NCI, Dept Pathol, NIH, Bethesda, MD 20850 USA. RP Kallioniemi, OP (reprint author), NHGRI, Canc Genet Branch, NIH, 50 S Dr,Bldg 50,Room 5318,MSC 8000, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 FU NCI NIH HHS [CA57179] NR 24 TC 124 Z9 131 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2002 VL 62 IS 5 BP 1256 EP 1260 PG 5 WC Oncology SC Oncology GA 530AP UT WOS:000174333700005 PM 11888886 ER PT J AU Kurooka, M Nuovo, GJ Caligiuri, MA Nabel, GJ AF Kurooka, M Nuovo, GJ Caligiuri, MA Nabel, GJ TI Cellular localization and function of Fas ligand (CD95L) in tumors SO CANCER RESEARCH LA English DT Article ID COLON-CANCER CELLS; IMMUNE PRIVILEGE; EXPRESSION; APOPTOSIS; COUNTERATTACK; GENE AB The localization of CD95L in different cell types within tumors has not been well defined, and its role in tumor growth is uncertain. In this study, CD95L expression and its contribution to tumor growth are evaluated using genetic polymorphisms and adoptive transfer in genetically deficient mice. CD95L was detected in tumors in vivo at levels up to 10(4)-fold higher than those in cell culture and predominantly in host tumor-infiltrating macrophages, but not in tumor cells. Adoptive transfer into genetically deficient mice revealed that host CD95-CD95L function did not alter tumor growth, demonstrating that CD95L alone does not affect tumor growth. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3005, Bethesda, MD 20892 USA. NR 20 TC 13 Z9 14 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 1 PY 2002 VL 62 IS 5 BP 1261 EP 1265 PG 5 WC Oncology SC Oncology GA 530AP UT WOS:000174333700006 PM 11888887 ER PT J AU Mambo, E Nyaga, SG Bohr, VA Evans, MK AF Mambo, E Nyaga, SG Bohr, VA Evans, MK TI Defective repair of 8-hydroxyguanine in mitochondria of MCF-7 and MDA-MB-468 human breast cancer cell lines SO CANCER RESEARCH LA English DT Article ID OXIDATIVE DNA-DAMAGE; BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; THYMINE GLYCOL; HOGG1 GENE; P53 GENE; 8-OXOGUANINE; GLYCOSYLASE; MUTATIONS AB Breast cancer is one of the major causes of mortality among women in the United States. Although the causes of breast cancer remain unclear, it has been speculated that DNA base damage may lead to mutations that subsequently can be carcinogenic. Recently, defective oxidative DNA damage repair has been implicated in breast tumorigenesis. The major oxidative DNA lesion, 8-hydroxyguanine (8-oxoG), is increased in breast cancer, suggesting that this lesion may play a crucial role in the etiology of breast cancer. However, it is not known whether the repair of 8-oxoG or other oxidative base lesions is altered during breast carcinogenesis. We examined the ability of nuclear and mitochondrial extracts of two human breast cancer cell lines, MCF-7 and MDA-MB-468, to repair 8-oxoG lesion. We report that mitochondrial extracts from the two breast cancer cell lines are defective in the base excision repair of 8-oxoG relative to two noncancer cell lines. We also show that the incision activity of 8-oxoG was significantly lower in mitochondrial than in nuclear extracts in the breast cancer cell lines. The defective mitochondrial repair activity was not attributable to lower levels of human 8-hydroxyguanine DNA glycosylase, the base excision repair enzyme known to incise 8-oxoG in DNA. The repair of thymine glycol, another major oxidative DNA base lesion that blocks transcription and causes cell death, was similar in cancer and noncancer cells. Furthermore, nuclear extracts incised thymine glycol with a much higher efficiency than 8-oxoG. These data provide evidence for defective repair of 8-oxoG in mitochondria of MCF-7 and MDA-MB-468 breast cancer cell lines. These results may implicate 8-oxoG repair mechanisms in mitochondria of certain breast cancers. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. NR 50 TC 30 Z9 32 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 1 PY 2002 VL 62 IS 5 BP 1349 EP 1355 PG 7 WC Oncology SC Oncology GA 530AP UT WOS:000174333700023 PM 11888904 ER PT J AU Patel, V Lahusen, T Sy, T Sausville, EA Gutkind, JS Senderowicz, AM AF Patel, V Lahusen, T Sy, T Sausville, EA Gutkind, JS Senderowicz, AM TI Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest SO CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; ANTITUMOR-ACTIVITY; INDUCED APOPTOSIS; CDK INHIBITORS; BREAST-CANCER; MILTEFOSINE; HEAD; NECK; P21; P21(CIP1/WAF1) AB Alkylphospholipids (ALKs) are a novel class of antineoplastic compounds that display potent antiproliferative activity against several in vitro and in vivo human tumor models. However, the mechanism by which these agents exert this desired effect is still unclear. In this study, we investigated the effect of perifosine, a p.o.-bioavailable ALK, on the cell cycle kinetics of immortalized keratinocytes (HaCaT) as well as head and neck squamous carcinoma cells. All cells were sensitive to the antiproliferative properties of perifosine with an IC50 of similar to0.6-8.9 muM. Cell cycle arrest at the G(1)-S and G(2)-M boundaries was observed in HN12, HN30, and HaCaT cells independent of p53 function, and this effect was preceded by loss in cdc2 and cyclin-dependent kinase (cdk) 2 activity. Analysis of cdk complexes in vitro demonstrated that perifosine, up to 20 muM, did not directly interfere with these enzymes. However, aphidicolin-synchronized HN12 cells released in the presence of perifosine (10 muM) demonstrated increased expression of total p21(WAF1) and increased association of p21(WAF1) with cyclin-cdk complexes resulting in reduced cdc2 activity. HCT116 isogenic cell lines were used to assess the role of p21(WAF1) induction by perifosine. This compound (20 muM) induced both G(1)-S and G(2)-M cell cycle arrest, together with p21(WAF1) expression in both p53 wild-type and p53(-/-) clones. By contrast, p21(-/-) variants demonstrated no p21(WAF1) induction or cell cycle arrest. Similar results were obtained with other ALK congeners (miltefosine and edelfosine). These data, therefore, indicate that perifosine blocks cell cycle progression of head and neck squamous carcinoma cells at G(1)-S and G(2)-M by inducing p21(WAF1), irrespective of p53 function, and may be exploited clinically because the majority of human malignancies harbor p53 mutations. C1 NICDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), NICDR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 53 TC 79 Z9 79 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2002 VL 62 IS 5 BP 1401 EP 1409 PG 9 WC Oncology SC Oncology GA 530AP UT WOS:000174333700031 PM 11888912 ER PT J AU Ichinose, M Liu, XH Hagihara, N Youle, RJ AF Ichinose, M Liu, XH Hagihara, N Youle, RJ TI Extracellular bad fused to toxin transport domains induces apoptosis SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE B/AKT; DIPHTHERIA-TOXIN; PROSTATE-CANCER; CELL-SURVIVAL; TUMOR-SUPPRESSOR; BH3 DOMAIN; PSEUDOMONAS EXOTOXIN; GLIOMA-CELLS; IN-VIVO; PHOSPHORYLATION AB Bad, a proapoptotic member of the Bcl-2 family, is inactivated by phosphorylation, and this loss of activity may contribute to the malignancy of certain types of tumors such as glioblastoma and prostate cancer. To determine whether extracellular Bad can be delivered into cells via cell surface receptor binding and induce apoptosis, we genetically fused the mouse Bad gene to the gene for the translocation and receptor-binding domains of diphtheria toxin (DTTR). The purified Bad (wild-type)-DTTR protein showed cytotoxicity to human glioma cells in a dose-dependent manner. Bad phosphorylation sites at codons 112 and 136 were mutated from serine to alanine to prevent Bad inactivation by kinases and to increase the toxicity of Bad. The Bad (S112A S136A)-DTTR protein was at least 5 times more toxic than Bad (wild-type)-DTTR with an IC50 of 5 x 10(-8) M. The Bad (S112A S136A)-DTTR protein altered the subcellular distribution of Bcl-X-L, indicating that it enters the cell cytoplasm and binds Bcl-X-L. Bad (S112D S136A)-DTTR, mutated to mimic phosphorylation of Bad, showed lower toxicity than either Bad (wild-type)-DTTR or Bad (S112A S136A)-DTTR, additionally indicating that Bad-DTTR must bind Bcl-X-L to stimulate apoptosis. We conclude that extracellular Bad can be delivered into cells via the transport domain of a bacterial toxin and may be used to induce apoptosis. C1 NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINCDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 10,Room 5D-37,MSC 1414,10 Ctr Dr, Bethesda, MD 20892 USA. NR 51 TC 14 Z9 15 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 1 PY 2002 VL 62 IS 5 BP 1433 EP 1438 PG 6 WC Oncology SC Oncology GA 530AP UT WOS:000174333700035 PM 11888916 ER PT J AU Barazi, HO Zhou, LG Templeton, NS Krutzsch, HC Roberts, DD AF Barazi, HO Zhou, LG Templeton, NS Krutzsch, HC Roberts, DD TI Identification of heat shock protein 60 as a molecular mediator of alpha 3 beta 1 integrin activation SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; GROWTH-FACTOR-I; SIGNAL-TRANSDUCTION; ALPHA(3)BETA(1) INTEGRIN; CARCINOMA CELLS; TYROSINE PHOSPHORYLATION; MATRIX PROTEINS; MAMMALIAN-CELLS; BONE-MATRIX; T-CELLS AB The alpha3beta1 integrin is involved in the adhesion of metastatic breast cancer cells to the lymph nodes and to osteoblasts in the bone. Regulation of the affinity or avidity of integrins for their ligands may result from conformational changes induced by changes in the microenvironment of the integrin. Two surface proteins, 55 and 32 kDa, coimmunoprecipitated with the alpha3beta1 integrin from breast carcinoma cells. The 55-kDa protein preferentially associated with the active form of the alpha3beta1 integrin. The protein was identified as HSP60 using two-dimensional electrophoresis and mass spectrometry and confirmed by reimmunoprecipitation of the integrin immune complex with an anti-HSP60 antibody. In cell spreading assays on a thrombospondin-1 substrate, addition of exogenous-recombinant HSP60 was sufficient to specifically activate alpha3beta1 integrin but not to activate function of alpha2beta1, alphavbeta3, alpha4beta1, or alpha5beta1 integrins. Furthermore, mizoribine, an HSP60-binding drug, blocked activation of the alpha3beta1 integrin induced by insulin-like growth factor 1 (IGF1) or exogenous recombinant HSP60 and inhibited the association of HSP60 with the integrin. Additionally, inhibiting the surface expression of endogenous HSP60 by nonactin inhibited activation of the alpha3beta1 integrin by IGF1. These data demonstrate that HSP60 binding is sufficient to activate alpha3beta1 integrin function and suggest that association of endogenous HSP60 with alpha3beta1 integrin is necessary for IGF1-induced activation. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10 Room 2A33,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 71 TC 65 Z9 69 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2002 VL 62 IS 5 BP 1541 EP 1548 PG 8 WC Oncology SC Oncology GA 530AP UT WOS:000174333700052 PM 11888933 ER PT J AU Shibata, A Parsonnet, J Longacre, TA Garcia, MI Puligandla, B Davis, RE Vogelman, JH Orentreich, N Habel, LA AF Shibata, A Parsonnet, J Longacre, TA Garcia, MI Puligandla, B Davis, RE Vogelman, JH Orentreich, N Habel, LA TI CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma SO CARCINOGENESIS LA English DT Article ID MOLECULAR EPIDEMIOLOGY; INTESTINAL METAPLASIA; EPITHELIAL-CELLS; INVERSE RELATION; CANCER; CARCINOMA; RISK; STRAINS; BLADDER; CARCINOGENESIS AB Infection with Helicobacter pylori (H. pylori) increases stomach cancer risk. Helicobacter pylori strains with the cag pathogenicity island (PAI) induce more severe inflammation in the gastric epithelium and are more strongly associated with stomach cancer risk than strains lacking the PAI. We examined whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains. DNA from 105 microdissected tumor specimens was analyzed for mutation in exons 5-8 of the p53 gene by polymerase chain reaction-based single-strand conformation polymorphism followed by direct DNA sequencing. Enzyme-linked immunosorbent assays for IgG antibodies against H. pylori and CagA were performed on sera collected 2-31 years prior to cancer diagnosis. Tumors from CagA(+) subjects were significantly more likely to have p53 mutations than tumors from CagA(-) subjects (including H. pylori(-) and H. pylori(+)/CagA(-)): odds ratio = 3.72; 95% confidence interval, 1.06-13.07 after adjustment for histologic type and anatomic subsite of tumor and age at diagnosis and sex of subjects. Mutations were predominantly insertions and deletions (43%) as well as transition mutations at CpG dinucleotides (33%). The data suggest that CagA(+) H. pylori infection, when compared with CagA(-) infection or the absence of H. pylori infection, is associated with a higher prevalence of p53 mutation in gastric adenocarcinoma. C1 Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. Kaiser Permanente Med Care Program, Dept Pathol, Oakland, CA 94611 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. Orentreich Fdn Advancement Sci Inc, Cold Spring Harbor, NY 10516 USA. RP Shibata, A (reprint author), Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. FU NCI NIH HHS [R35 CA 48761, R01 CA 73011] NR 55 TC 42 Z9 47 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2002 VL 23 IS 3 BP 419 EP 424 DI 10.1093/carcin/23.3.419 PG 6 WC Oncology SC Oncology GA 536PD UT WOS:000174710400006 PM 11895856 ER PT J AU Baek, SJ Wilson, LC Eling, TE AF Baek, SJ Wilson, LC Eling, TE TI Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53 SO CARCINOGENESIS LA English DT Article ID CANCER CHEMOPREVENTIVE ACTIVITY; BETA SUPERFAMILY MEMBER; CELL-CYCLE ARREST; TUMOR-GROWTH; APOPTOSIS; WINE; INHIBITION; GRAPES; TRANSCRIPTION; INDUCTION AB Dietary phenolic substances including resveratrol, a stillbene compound, are found in several fruits and vegetables, and these compounds have been reported to have anti-oxidant, anti-inflammatory and antitumorigenic activities. However, the molecular mechanisms underlying the antitumorigenic or chemopreventive activities of these compounds remain largely unknown. The expression of NAG-1 [non-steroidal anti-inflammatory (NSAID) drug-activated gene-1], a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with pro-apoptotic and antitumorigenic activities. Here, we have demonstrated that resveratrol induces NAG-1 expression and apoptosis in a concentration-dependent manner. Resveratrol increases the expression of p53, tumor suppressor protein, prior to NAG-1 induction, indicating that NAG-1 expression by resveratrol is mediated by p53 expression. We also show that the p53 binding sites within the promoter region of NAG-1 play a pivotal role to control NAG-1 expression by resveratrol. Derivatives of resveratrol were examined for NAG-1 induction, and the data suggest that resveratrol-induced NAG-1 and p53 induction is not dependent on its anti-oxidant activity. The data may provide linkage between p53, NAG-1 and resveratrol, and in part, a new clue to the molecular mechanism of the antitumorigenic activity of natural polyphenolic compounds. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI Baek, Seung/0000-0001-7866-7778 NR 32 TC 143 Z9 145 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2002 VL 23 IS 3 BP 425 EP 434 DI 10.1093/carcin/23.3.425 PG 10 WC Oncology SC Oncology GA 536PD UT WOS:000174710400007 PM 11895857 ER PT J AU Grossman, PM Han, ZG Palasis, M Barry, JJ Lederman, RJ AF Grossman, PM Han, ZG Palasis, M Barry, JJ Lederman, RJ TI Incomplete retention after direct myocardial injection SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE catheter; endomyocardial; gene transfer; intramyocardial drug administration ID NEUTRON-ACTIVATION ANALYSIS; FIBROBLAST-GROWTH-FACTOR; GENE-TRANSFER; BLOOD-FLOW; ANGIOGENESIS; DELIVERY; INTRACORONARY; HEART; REVASCULARIZATION; EFFICIENT AB Direct intramyocardial injection may permit local delivery of protein and gene therapy agents for myocardial and coronary artery disease. Little is known about the immediate fate of materials administered via percutaneous endomyocardial catheters or via surgical epicardial injection. In this study, we use a novel method to evaluate the acute retention of agents injected directly into the myocardium. compare epicardial with the percutaneous endocardial and postmortem delivery, and evaluate the influence of injectate volume on myocardial retention. Fifteen 40-50 kg pigs underwent overlapping myocardial injections using a percutaneous endomyocardial catheter, an epicardial needle via an open chest, and epicardial needle postmortem. Multiple distinct 15 mu neutron-activated microsphere species were used as tracers. Two or three myocardial walls were injected in each animal using 3.5 mm, 27-28 gauge needles at varying injectate volumes. Animals were sacrificed immediately. Myocardial walls were divided and multiple microsphere species were quantified. In an additional study, nine 70 kg pigs underwent percutaneous endomyocardial injections with replication-deficient adenovirus encoding for the production of lac-Z. The injectate volume was varied, while the viral particle number remained constant. The animals were sacrificed 5 days after the percutaneous injections; the heart, liver, and spleen were collected for beta-galactosidase activity. Endomyocardial injection was associated with 43% +/- 15% microsphere retention. compared with 15% +/- 21% (P < 0.01) retention of open chest epicardial injection and 89% +/- 60% (P < 0.01) for postmortem injection. Reducing the injectate volume from 100 to 10 muL improved microsphere retention (P = 0.01). There was a trend toward improved viral transfection associated with smaller injection volumes. Despite direct intramyocardial administration, a significant fraction of injectate is not retained locally. Catheter-based needle endomyocardial injection is associated with equivalent or superior injectate retention compared with open chest epicardial injection. Proportionately, more injectate may be retained at lower volumes. Loss may involve a combination of channel leakage, venous, and lymphatic return. (C) 2002 Wiley-Liss, Inc. C1 Univ Michigan, Hlth Syst, Dept Internal Med, Div Cardiol, Ann Arbor, MI USA. Boston Sci Corp, Natick, MA USA. RP Lederman, RJ (reprint author), Natl Heart Lung & Blood Inst, NIH, Bldg 10 Rm 2C713 MSC1538, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 NR 27 TC 76 Z9 82 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 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAR PY 2002 VL 55 IS 3 BP 392 EP 397 DI 10.1002/ccd.10136 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 526CC UT WOS:000174110000024 PM 11870950 ER PT J AU Blagosklonny, MV Campisi, J Keyomarsi, K Medrano, EE AF Blagosklonny, Mikhail V. Campisi, Judith Keyomarsi, Khandan Medrano, Estela E. TI No Restriction Points in Life and Science SO CELL CYCLE LA English DT Editorial Material C1 [Blagosklonny, Mikhail V.] NIH, Bethesda, MD 20892 USA. [Blagosklonny, Mikhail V.] New York Med Coll, Valhalla, NY 10595 USA. [Campisi, Judith] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Keyomarsi, Khandan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Medrano, Estela E.] Baylor Coll Med, Houston, TX 77030 USA. RP Blagosklonny, MV (reprint author), New York Med Coll, Brander Canc Res Inst, Dept Med, 19 Bradhurst Ave, Hawthorne, NY 10532 USA. EM mikhailb@mail.nih.gov NR 13 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD MAR-APR PY 2002 VL 1 IS 2 BP 100 EP 102 DI 10.4161/cc.1.2.107 PG 3 WC Cell Biology SC Cell Biology GA V40PW UT WOS:000209491500001 PM 12429915 ER PT J AU Blagosklonny, MV Pardee, AB AF Blagosklonny, Mikhail V. Pardee, Arthur B. TI The Restriction Point of the Cell Cycle SO CELL CYCLE LA English DT Review DE Cell cycle; Cyclins; Growth factors; Oncogenes AB As formulated in 1974, the concept of the restriction point of the cell cycle was based on cell biological experiments, yet allowing accurate molecular predictions and spurring a search for the restriction factor. Although cyclin D meets the criteria of the R-factor, the picture as outlined here is more interesting and far more complex. We discuss the relationship between the restriction knot and DNA damage-checkpoints. Finally, we discuss how loss of the restriction point in cancer leads to loss of checkpoint control and to insensitivity to antimitogens including some mechanism-based anticancer therapeutics. C1 [Blagosklonny, Mikhail V.] NCI, NIH, Bethesda, MD 20892 USA. [Blagosklonny, Mikhail V.] New York Med Coll, Brander Canc Res Inst, Hawthorne, NY 10532 USA. [Pardee, Arthur B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pardee, Arthur B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Blagosklonny, MV (reprint author), New York Med Coll, Brander Canc Res Inst, Dept Med, 19 Bradhurst Ave, Hawthorne, NY 10532 USA. EM mikhailb@mail.nih.gov NR 138 TC 202 Z9 217 U1 1 U2 8 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD MAR-APR PY 2002 VL 1 IS 2 BP 103 EP 110 DI 10.4161/cc.1.2.108 PG 8 WC Cell Biology SC Cell Biology GA V40PW UT WOS:000209491500002 PM 12429916 ER PT J AU Yang, YA Tang, BW Robinson, G Hennighausen, L Brodie, SG Deng, CX Wakefield, LM AF Yang, YA Tang, BW Robinson, G Hennighausen, L Brodie, SG Deng, CX Wakefield, LM TI Smad3 in the mammary epithelium has a nonredundant role in the induction of apoptosis, but not in the regulation of proliferation or differentiation by transforming growth factor-beta SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID BREAST-CANCER CELLS; TGF-BETA; II RECEPTOR; TARGETED DISRUPTION; MICE; GLAND; EXPRESSION; GROWTH-FACTOR-BETA-1; HYPERPLASIA; METASTASES AB Transforming growth factor-beta (TGF-beta) regulates proliferation, morphogenesis, and functional differentiation in the mammary gland and plays complex roles in mammary tumorigenesis. Here we show that the signaling mediators Smad1-Smad5 are expressed at all stages of mammary gland development. To begin to investigate which Smads mediate which TGF-beta responses, we have analyzed mammary gland development in Smad3 null mice. Smad3 null virgin females showed delayed mammary gland development. However, this phenotype was secondary to ovarian insufficiency because Smad3 null mammary epithelium developed normally in hormonally supplemented Smad3 null mice or when transplanted into wild-type hosts. Absence of Smad3 had no effect on the ability of TGF-beta to inhibit the growth of mammary epithelial cells in culture, and no compensatory changes in expression or activation of Smad2 were seen in the Smad3 null epithelium. A small but significant decrease in apoptotic cells was seen in involuting glands from Smad3 null transplants. The results suggest that epithelial Smad3 is dispensable for TGF-beta effects on proliferation and differentiation in the mammary gland, but that it contributes in a nonredundant manner to the induction of apoptosis. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Wakefield, LM (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. RI Robinson, Gertraud/I-2136-2012; deng, chuxia/N-6713-2016 NR 36 TC 42 Z9 45 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD MAR PY 2002 VL 13 IS 3 BP 123 EP 130 PG 8 WC Cell Biology SC Cell Biology GA 539HF UT WOS:000174863900004 PM 11959813 ER PT J AU Mongini, PKA Tolani, S Fattah, RJ Inman, JK AF Mongini, PKA Tolani, S Fattah, RJ Inman, JK TI Antigen receptor triggered upregulation of CD86 and CD80 in human B cells: augmenting role of the CD21/CD19 co-stimulatory complex and IL-4 SO CELLULAR IMMUNOLOGY LA English DT Article DE B cell; human; cellular activation; co-stimulatory molecules; CD86; CD21; IL-4; complement ID T-DEPENDENT ANTIGEN; ANTIBODY-RESPONSE; IMMUNE-RESPONSE; CROSS-LINKING; MEMBRANE IGM; COSTIMULATORY MOLECULES; LYMPHOCYTE RESPONSES; AFFINITY MATURATION; GERMINAL-CENTERS; MAST-CELLS AB The impact of BCR:CD21 co-engagement on B cell expression of molecules critical for T cell activation was investigated with receptor-specific mAbs, conjugated to high MW dextran as stimulatory ligands. In the absence of IL-4, BCR:CD21 co-ligation augmented BCR-triggered CD86 only under conditions of very low BCR ligand dose or affinity, and CD80 was minimally induced by BCR and/or CD21 crosslinking. In the presence of IL-4, BCR:CD21 co-ligation augmented CD86 and CD80 expression under conditions of greater BCR engagement. However, with very high level BCR engagement, no bonus effect of BCR:CD21 crosslinking was observed. Co-ligation-promoted CD86 and CD80 expression was associated with heightened B cell activation of resting allo-genetic T cells. The data suggest that co-clustering of BCR and the CD21/CD19 co-stimulatory complex following B cell engagement with C3d-bound microbial or self-antigens will enhance B cell recruitment of T cell help only when IL-4 is present and/or BCR engagement is very limiting. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Hosp Joint Dis & Med Ctr, Dept Rheumatol, New York, NY 10003 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, Dept Pathol, New York, NY 10016 USA. NIH, Lab Inununol, Bethesda, MD 20892 USA. RP Mongini, PKA (reprint author), Hosp Joint Dis & Med Ctr, Dept Rheumatol, 301 E 17th St, New York, NY 10003 USA. FU NIGMS NIH HHS [GM-35174] NR 70 TC 21 Z9 23 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD MAR-APR PY 2002 VL 216 IS 1-2 BP 50 EP 64 AR PII S0008-8749(02)00512-9 DI 10.1016/S0008-8749(02)00512-9 PG 15 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 622ZA UT WOS:000179677100007 PM 12381350 ER PT J AU Resjo, S Goransson, O Harndahl, L Zolnierowicz, S Manganiello, V Degerman, E AF Resjo, S Goransson, O Harndahl, L Zolnierowicz, S Manganiello, V Degerman, E TI Protein phosphatase 2A is the main phosphatase involved in the regulation of protein kinase B in rat adipocytes SO CELLULAR SIGNALLING LA English DT Article DE okadaic acid; calyculin A; insulin signalling; antilipolysis; protein phosphatase; PP2A; PDE3B ID NUCLEOTIDE PHOSPHODIESTERASE 3B; INSULIN-INDUCED PHOSPHORYLATION; GLYCOGEN-SYNTHASE KINASE-3; HORMONE-SENSITIVE LIPASE; RABBIT-SKELETAL-MUSCLE; OKADAIC ACID; CALYCULIN-A; MEMBRANE TRANSLOCATION; ADIPOSE-TISSUE; IN-VITRO AB In adipocytes, protein kinase B (PKB) has been suggested to be the enzyme that phosphorylates phosphodiesterase 3B (PDE3B), a key enzyme in insulin's antilipolytic signalling pathway. In order to screen for PKB phosphatases, adipocyte homogenates were fractionated using ion-exchange chromatography and analysed for PKB phosphatase activities. PKB phosphatase activity eluted as one main peak, which cocluted with serine/threonine phosphatases (PP)2A. In addition, adipocytes were incubated with inhibitors of PP. Incubation of adipocytes with 1 muM okadaic acid inhibited PP2A by 75% and PP I activity by only 17%, while 1 muM tautomycin inhibited PP1 activity by 54% and PP2A by only 7%. Okadaic acid, but not tautomycin, induced the activation of both PKBalpha and PKBbeta. Finally, PP2A subunits were found in several subcellular compartments, including plasma membranes (PM) where the phosphorylation of PKB is thought to occur. In summary, our results suggest that PP2A is the principal phosphatase that dephosphorylates PKB in adipocytes. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Lund Univ, Biomed Ctr, SE-22184 Lund, Sweden. UG MUG, Intercollegiate Fac Biotechnol, PL-80822 Gdansk, Poland. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Resjo, S (reprint author), Lund Univ, Biomed Ctr, C11, SE-22184 Lund, Sweden. NR 57 TC 89 Z9 93 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD MAR PY 2002 VL 14 IS 3 BP 231 EP 238 DI 10.1016/S0898-6568(01)00238-8 PG 8 WC Cell Biology SC Cell Biology GA 517VN UT WOS:000173631100007 PM 11812651 ER PT J AU Kowara, R Karaczyn, AA Fivash, MJ Kasprzak, KS AF Kowara, R Karaczyn, AA Fivash, MJ Kasprzak, KS TI In vitro inhibition of the enzymatic activity of tumor suppressor FHIT gene product by carcinogenic transition metals SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID NITRIC-OXIDE; PROTEIN; BINDING; APOPTOSIS; COPPER; CANCER; TUMORIGENICITY; REPLACEMENT; EXPRESSION; COMPLEXES AB FHIT (Fragile Histidine Triad) is a human tumor suppressor gene. The Fhit protein is believed to inhibit tumor growth by inducing apoptosis through interaction with diadenosine triphosphate (APA). The latter is first sequestered and eventually hydrolyzed by Fhit to ADP and AMP. Thus, the balance between the cellular APA level and Fhit enzymatic activity may affect cell death or survival. Increasing the Ap(3)A level, e.g., by inhibition of the enzyme, should prevent apoptosis and thus sustain tumorigenesis. To test if certain carcinogenic transition metals could inhibit the enzymatic activity of Fhit, purified human Fhit protein [30 nM in 1.25 mM poly(vinylpyrrolidone)], expressed in and isolated from E. coli, was incubated at pH 6.8 (50 mM HEPES buffer in 150 mM NaCl) with 120 muM Ap3A in the presence of 5 mM Mg(II) (activating cation) and 0-100 muM Ni(II), Cu(II), Zn(II), Cd(II), Co(II), Cr(III), As(III), or As(V). The reaction mixtures were analyzed by HPLC. The results revealed a strong inhibitory potential of Cu(II) [0.4], followed by Ni(II) [3.5] : Zn(II) [7.0] much greater than Cr(III) [73] > Cd(II) [98] much greater than Co(II) [432] [the numbers in brackets are IC50 values, muM]. As(III) and As(V) had no effect. As revealed by spectrophotometry, mass spectrometry, and gel electrophoresis, the exceptionally strong inhibition by Cu (II) was associated with Fhit dimerization through formation of a disulfide bond. The other metals and also H2O2 and NO did not cause the dimerization. Thus, the effect of Cu(II) must be due to its reaction with Cys-39 bearing the only thiol group in Fhit monomer. Since Cys-39 is not readily accessible in the Fhit molecule, the reaction is most likely facilitated by conformational changes which follow the coordination of Cu(II) by the surface histidines 35, 94, and/or 96. The observed inhibition of Fhit may be mechanistically involved in metal-mediated toxicity and carcinogenesis. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, Data Management Serv Inc, Frederick, MD 21702 USA. Med Acad Gdansk, Dept Clin Biochem, PL-80211 Gdansk, Poland. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Room 205E, Frederick, MD 21702 USA. NR 34 TC 9 Z9 10 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAR PY 2002 VL 15 IS 3 BP 319 EP 325 DI 10.1021/tx010112j PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 536AR UT WOS:000174679000005 PM 11896678 ER PT J AU Pacheco-Rodriguez, G Kristof, AS Stevens, LA Zhang, Y Crooks, D Moss, J AF Pacheco-Rodriguez, G Kristof, AS Stevens, LA Zhang, Y Crooks, D Moss, J TI Genetics and gene expression in Lymphangioleiomyomatosis SO CHEST LA English DT Article; Proceedings Paper CT 44th Annual Thomas L Petty Aspen Lung Conference CY JUN 06-09, 2001 CL ASPEN, COLORADO DE lymphangioleiomyomatosis; tuberous sclerosis complex ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; PRODUCT; LYMPHANGIOMYOMATOSIS; CT; DIAGNOSIS; HAMARTIN; PROTEINS; FAMILY; CELLS AB Lymphangioleiomyomatosis (LAM) is a disease of unknown etiology that is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) in the lung, which leads to cystic parenchymal destruction and progressive respiratory failure. Recent evidence suggests that the proliferative and invasive nature of LAM cells may be due, in part, to somatic mutations in the TSC2 gene, which has been implicated in the pathogenesis of tuberous sclerosis complex. Here, we describe the clinical and molecular characteristics of LAM, as well as the efforts now under way to understand the genetic and biochemical factors that lead to progressive pulmonary destruction and, ultimately, to lung transplantation or death. C1 NHLBI, NIH, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, NIH, Pulm Crit Care Med Branch, 10 Ctr Dr,Bldg 10,Room 6 D05,MSC 1590, Bethesda, MD 20892 USA. NR 46 TC 18 Z9 19 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2002 VL 121 IS 3 SU S BP 56S EP 60S DI 10.1378/chest.121.3_suppl.56S PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 532NH UT WOS:000174481400038 PM 11893686 ER PT J AU Thornberry, J Bhaskar, B Krulewitch, CJ Wesley, B Hubbard, ML Das, A Foudin, L Adamson, M AF Thornberry, J Bhaskar, B Krulewitch, CJ Wesley, B Hubbard, ML Das, A Foudin, L Adamson, M TI Audio computerized self-report interview use in prenatal clinics SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Article DE computer interview; computer screening; pregnancy; alcohol use screening; patient attitudes ID ALCOHOL-USE; RISK-DRINKING; PREGNANCY; BEHAVIOR AB Computer interviewing to obtain sensitive information is not a new concept. However, concerns about the acceptance of computers in disadvantaged populations with potentially low literacy led us to combine audio- and touch-screen technologies with an audio computerized self-report interview to obtain information about alcohol use. This study evaluated acceptance and ease of use by a disadvantaged population of pregnant women in the District of Columbia. Patients attending an initial visit at prenatal clinics answered questions anonymously about their consumption of alcoholic beverages and other personal information. The questionnaire was programmed on a laptop computer. The computer administered the recorded questions via earphones, as well as displayed them on the screen, and patients answered by touching the computer screen. Results were immediately available. A total of 507 women were interviewed, who were primarily African American, non-Hispanic, and never married. Nearly 24% did not complete a high school education, 43% were unemployed, and 30% received public assistance. Most of the women (59%) used computers occasionally (a few days a month) or never. Nearly all patients (96%) reported that the computer was not difficult to use, and approximately 90% liked answering the questions by computer. The study demonstrates that using computers to screen for alcohol use in disadvantaged pregnant populations is feasible and acceptable to the patients. C1 Res Triangle Inst, Rockville, MD 20852 USA. Univ Maryland, Baltimore Sch Nursing, Dept Childrens Womens & Family Hlth, Baltimore, MD 20742 USA. Howard Univ, Coll Med, Dept Obstet & Gynecol, Washington, DC USA. Natl Inst Alcohol Abuse & Alcoholism, NIH, Bethesda, MD USA. RP Thornberry, J (reprint author), Res Triangle Inst, 6110 Execut Blvd,Suite 420, Rockville, MD 20852 USA. FU NICHD NIH HHS [U18-HD30445, U18-HD30447, U18-HD30450, U18-HD30454, U18-HD30458, U18-HD31206, U18-HD31919] NR 24 TC 24 Z9 24 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1538-2931 EI 1538-9774 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD MAR-APR PY 2002 VL 20 IS 2 BP 46 EP 52 DI 10.1097/00024665-200203000-00009 PG 7 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA 571GN UT WOS:000176709800004 PM 11984122 ER PT J AU Everhart, JE Kruszon-Moran, D Perez-Perez, G AF Everhart, JE Kruszon-Moran, D Perez-Perez, G TI Reliability of Helicobacter pylori and CagA serological assays SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID GASTRIC-CANCER; UNITED-STATES; INFECTION; DIAGNOSIS; POPULATION; ACCURACY; TESTS; RISK; ADENOCARCINOMA; SEROPREVALENCE AB Background serological assays for Helicobacter pylori are commonly used without knowledge of reliability. This information is needed to define the ability of serological tests to determine either new cases of infection or loss of infection in longitudinal studies. We evaluated the reproducibility and the interrelationships of serological test results for H. pylori and cytotoxin-associated gene product A (CagA) enzyme-linked immunoassays within a subset of participants in a population-based study. Stored samples from 1,229 participants in the third U.S. National Health and Nutrition Examination Survey were replicate serologically tested for H. pylori and CagA. Overall disagreement was 3.4% between duplicate tests for H. pylori (or 2.3% if equivocal results were disregarded). Six percent of samples positive on the first test had an immune serum ratio at least 30% lower on repeat testing. The odds ratio for H. pylori seropositivity on retesting was 2.8 (95% confidence interval [CI] = 1.8 to 4.5) when CagA serology was positive versus when it was negative. CagA antibody was found among 47.8% of H. pylori-equivocal and 7.0% of H. pylori-negative samples. CagA-positive yet H. pylori-negative samples were more likely to occur among Mexican Americans (odds ratio, 5.2; 95% CI = 2.4 to 11.4) and non-Hispanic blacks (odds ratio, 5.5; 95% CI = 2.3 to 13.0) than among non-Hispanic whites. Relying on repeated H. pylori serological tests over time to determine infection rates may result in in is interpretation due to limits in test reproducibility. CagA testing may have a role in verifying infection. C1 NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. Vanderbilt Univ, Nashville, TN 37235 USA. RP Everhart, JE (reprint author), NIDDKD, Div Digest Dis & Nutr, 2 Democracy Plaza,Rm 673,6707 Democracy Blvd,MSC, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK-6-2202] NR 31 TC 22 Z9 23 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD MAR PY 2002 VL 9 IS 2 BP 412 EP 416 DI 10.1128/CDLI.9.2.412-416.2002 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 532EA UT WOS:000174457600034 PM 11874887 ER PT J AU Sandor, V Bakke, S Robey, RW Kang, MH Blagosklonny, MV Bender, J Brooks, R Piekarz, RL Tucker, E Figg, WD Chan, KK Goldspiel, B Fojo, AT Balcerzak, SP Bates, SE AF Sandor, V Bakke, S Robey, RW Kang, MH Blagosklonny, MV Bender, J Brooks, R Piekarz, RL Tucker, E Figg, WD Chan, KK Goldspiel, B Fojo, AT Balcerzak, SP Bates, SE TI Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms SO CLINICAL CANCER RESEARCH LA English DT Article ID CHROMOBACTERIUM-VIOLACEUM NO-968; ACUTE PROMYELOCYTIC LEUKEMIA; RETINOIC ACID; DIFFERENTIATING AGENTS; RESISTANCE GENE; CELL-LINES; EXPRESSION; CANCER; MODULATION; BUTYRATE AB Purpose: The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity. Patients and Methods: Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m(2), and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m(2). Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method. Results: Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m(2). The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (I patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m(2)). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t(1/2alpha) and t(1/2beta) at a dose of 17.8 mg/m(2) was: 8.6 literS/m(2), 11.6 liters/h/m(2), 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249-577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells. Conclusion: The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m2. The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and I patient obtained a partial response. The recommended Phase 11 dose is 17.8 mg/m(2) administered on day I and 5 of a 21-day cycle. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Clin Ctr, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. McGill Univ, Sir Mortimer B Davis Jewish Hosp, Montreal, PQ H3T 1E2, Canada. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 34 TC 430 Z9 446 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR PY 2002 VL 8 IS 3 BP 718 EP 728 PG 11 WC Oncology SC Oncology GA 531EP UT WOS:000174403300013 PM 11895901 ER PT J AU Assersohn, L Gangi, L Zhao, YD Dowsett, M Simon, R Powles, TJ Liu, ET AF Assersohn, L Gangi, L Zhao, YD Dowsett, M Simon, R Powles, TJ Liu, ET TI The feasibility of using fine needle aspiration from primary breast cancers for cDNA microarray analyses SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION PATTERNS; TRANSCRIPTIONAL PROGRAM; YEAST; THERAPY; MARKERS AB Purpose: Our aims in this pilot study were to determine whether fine needle aspirates (FNAs) provide a sufficient quantity of mRNA for cDNA microarray analysis, produce a set of quality control criteria to accept individual arrays, and determine whether gene expression profiles obtained from FNAs were representative of the source tumor. Experimental Design: Twenty-seven women with breast cancer for treatment with primary surgery had a FNA before and at the time of surgery, and a portion of excised tumor was taken for array analysis. Control experiments were performed using two Ewing's sarcoma xenograft models. mRNA was extracted from the samples and hybridized with the reference (MCF7 cell line) on cDNA microarrays. Statistical methods were applied to identify acceptability criteria for the arrays. Results: Statistical analyses demonstrated that an adequate array could be identified by calculating the SD of the log of fluorescence intensities from the arrays. Using this criterion, only 4 of the 27 patients (15%) had FNA samples suitable for array analysis. Gene expression profiles from the FNAs closely resembled that of the corresponding source tumors and were clearly distinguished from FNAs derived from the xenografts. Conclusions: SD is a useful quality index for the clinical application of cDNA microarrays. This "proof of principle" study demonstrates that FNAs from primary breast cancers can be used for microarray analysis, although without amplification, it is feasible in only a small proportion of patients. For this to be clinically useful, validated amplification techniques for FNA samples are probably required. C1 Royal Marsden Hosp, Breast Unit, Sutton SM2 5PT, Surrey, England. NCI, Div Clin Sci, Microarray Facil, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Powles, TJ (reprint author), Royal Marsden Hosp, Breast Unit, Downs Rd, Sutton SM2 5PT, Surrey, England. EM trevor.powles@rmh.nthames.nhs.uk RI Liu, Edison/C-4141-2008 NR 19 TC 58 Z9 60 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR PY 2002 VL 8 IS 3 BP 794 EP 801 PG 8 WC Oncology SC Oncology GA 531EP UT WOS:000174403300023 PM 11895911 ER PT J AU Walsh, TJ Rex, JH AF Walsh, TJ Rex, JH TI All catheter-related candidemia is not the same: Assessment of the balance between the risks and benefits of removal of vascular catheters SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID HOSPITAL-ACQUIRED CANDIDEMIA; INFECTIONS; EPIDEMIOLOGY; COLONIZATION; CANDIDIASIS; MANAGEMENT; PREVENTION; FUNGEMIA; CANCER C1 NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Univ Texas, Sch Med, Ctr Study Emerging & Reemerging Pathogens, Dept Internal Med,Div Infect Dis, Houston, TX USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bldg 10,Room 13N240,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 52 Z9 53 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2002 VL 34 IS 5 BP 600 EP 602 DI 10.1086/338715 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 518PT UT WOS:000173677600006 PM 11810604 ER PT J AU Abbott, KC Agodoa, LY AF Abbott, KC Agodoa, LY TI Polycystic kidney disease at end-stage renal disease in the United States: patient characteristics and survival SO CLINICAL NEPHROLOGY LA English DT Article DE polycystic kidney disease; Caucasian; female; EPO; peritoneal dialysis; transplantation; complications; dialysis; USRDS; age; albumin; hemoglobin; weight; dysrhythmias; mortality; frequency ID PERITONEAL-DIALYSIS; HEMODIALYSIS AB Background: The patient characteristics and mortality associated with autosomal dominant polycystic kidney disease have not been characterized fora national sample of end-stage renal disease (ESRD) patients. Methods: 375,152 patients in the United States Renal Data System were initiated on ESRD therapy (including patients who eventually received renal transplants) between January 1, 1992 and June 30, 1997 and analyzed in an historical cohort study of polycystic kidney disease. Results: Of the study population, 5,799 (1.5%) had polycystic kidney disease. In logistic regression, polycystic kidney disease was associated with Caucasian race (odds ratio 3.31, 95%; CI, 3.09 - 3.54), women (1.10, 1.04 - 1.16), receipt of renal transplant (4.15, 3.87 - 4.45), peritoneal dialysis (vs. hemodialysis, 1.37, 1.27 - 1.49), younger age, and more recent year of first treatment for ESRD. Use of pre-dialysis EPO but not the level of serum hemoglobin at initiation of ESRD was significantly higher in patients with polycystic kidney disease. Patients with polycystic kidney disease had lower mortality compared to patients with other causes of ESRD, but patients with polycystic kidney disease had a higher adjusted risk of mortality associated with hemodialysis (vs. peritoneal dialysis) compared to patients with other causes of ESRD (hazard ratio 1.40, 1.13 - 1.75). Conclusions: Hematocrit at presentation to ESRD was not significantly different in patients with polycystic kidney disease compared with patients with other causes of ESRD. Peritoneal dialysis is a more frequent modality than hemodialysis in patients with polycystic kidney disease, and patients with polycystic kidney disease had an adjusted survival benefit associated with peritoneal dialysis, compared to patients with other causes of renal disease. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 16 TC 22 Z9 22 U1 0 U2 0 PU DUSTRI-VERLAG DR KARL FEISTLE PI OBERHACHING PA BAJUWARENRING 4, D-82041 OBERHACHING, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD MAR PY 2002 VL 57 IS 3 BP 208 EP 214 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 529NY UT WOS:000174306600005 PM 11924752 ER PT J AU Abernethy, DR Pezzullo, J Mascelli, MA Frederick, B Kleiman, NS Freedman, J AF Abernethy, DR Pezzullo, J Mascelli, MA Frederick, B Kleiman, NS Freedman, J TI Pharmacodynamics of abciximab during angioplasty: Comparison to healthy subjects SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PLATELET ACTIVATION; CORONARY ANGIOPLASTY; MONOCLONAL-ANTIBODY; RECEPTOR; 7E3; PATHOGENESIS; AGGREGATION; HEPARIN AB Objectives: Our objectives were to compare and contrast abciximab concentration-effect relationships in healthy volunteer participants with those in patients with coronary atherosclerosis undergoing elective coronary angioplasty. We also aimed to establish abciximab plasma concentrations associated with 80% inhibition of platelet aggregation. Methods. Abciximab clearance and concentration-effect relationships were determined from two separate clinical studies, one in 30 healthy subjects aged 21 to 66 years and the other in 32 patients aged 44 to 74 years before they underwent elective coronary angioplasty. After abciximab administration, abciximab plasma concentrations, platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy, and degree of inhibition of platelet aggregation in the presence of 5-mumol/L and 20-mumol/L adenosine diphosphate was determined. With an E-max (receptor occupancy) or inhibitory E-max (inhibition of platelet aggregation) model, abciximab concentrations required for 80% receptor occupancy and 80% inhibition of platelet aggregation were determined. Results: Abciximab steady-state clearance in healthy participants was 183 +/- 72 ml/min (mean +/- SD), and single-dose clearance in patients undergoing angioplasty was 405 240 ml/min (mean SD). Abciximab concentration required for 80% GP Hb/Ma receptor occupancy was 35.2 t 2.4 versus 72.8 +/- 6.4 ng/ml in healthy participants versus patients (P <.01). Concentrations required for 80% inhibition of platelet aggregation stimulated by 5-μmol/L adenosine diphosphate were 25.6 +/- 1.6 versus 68.9 +/- 9.2 ng/ml (P <.01). Similarly, the concentrations required for 80% inhibition of platelet ag'aregation stimulated by 20- mumol/L adenosine diphosphate were 56.0 +/- 3.2 versus 141 +/- 16.8 ng/ml (P <.01). Conclusion: Approximately 2-fold greater abciximab exposure is required to achieve the same degree of GP Ilb/IIIa occupancy and inhibition of platelet aggregation in patients undergoing angioplasty as compared with healthy participants. The difference between groups may be related either to different states of basal platelet activation or to the effect of heparin that patients received as part of the angioplasty procedure. A therapeutic concentration range for patients is 100 to 175 ng/ml, because this is the concentration consistent with >80% inhibition of platelet aggregation when 20-mumol/L adenosine diphosphate is used as the aggregating stimulus. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Georgetown Univ, Sch Med, Div Clin Pharmacol, Washington, DC USA. Centocor Inc, Malvern, PA 19355 USA. Baylor Coll Med, Div Cardiol, Houston, TX 77030 USA. RP Abernethy, DR (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIA NIH HHS [AG08226] NR 19 TC 15 Z9 16 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2002 VL 71 IS 3 BP 186 EP 195 DI 10.1067/mcp.2002.121775 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 538RX UT WOS:000174829800009 PM 11907493 ER PT J AU Boone, TB Kusek, JW Nyberg, LM Steele, G Pashos, C Grossman, M Diokno, A Bull, S Albrecht, D AF Boone, TB Kusek, JW Nyberg, LM Steele, G Pashos, C Grossman, M Diokno, A Bull, S Albrecht, D TI Treatment patterns and associated symptom improvement during six months of care for overactive bladder: A prospective, observational study SO CLINICAL THERAPEUTICS LA English DT Article DE overactive bladder; urge urinary incontinence; treatment satisfaction; resource utilization; observational study ID URGE URINARY-INCONTINENCE; QUALITY-OF-LIFE; RELEASE OXYBUTYNIN; WOMEN; STRESS; THERAPY AB Background. Several pharmacologic and nonpharmacologic interventions are available for the treatment of symptoms of overactive bladder (OAB). The relationship between type of initial intervention and subsequent symptom improvement and resource utilization has not been explored in detail. Objective: The purpose of this study was to assess (1) the proportion of patients continuing with their initially prescribed treatment for OAB 3 and 6 months after the initial evaluation and (2) the relationship between actual treatment patterns, symptom improvement, and number of physician office visits. Methods: A total of 31 physicians enrolled patients with OAB for this 6-month prospective, observational study. Baseline data on OAB symptom severity and OAB management strategies were obtained and initial treatment(s) were prescribed by physicians during a routine office visit. Follow-up data on symptom changes, treatment changes, number of physician office visits, and the frequency of absorbent pad use were collected via telephone interviews with patients 3 and 6 months after the initial visit. Stepwise logistic regression was used to assess the relationship between patient characteristics, prescription of medication, and symptom improvement. Results: A total of 213 patients were enrolled; 122 (57.3%) and 100 (46.9%) patients provided follow-up data at the 3-month and 6-month assessments, respectively. The mean age was 61.2 years; 85.2% of patients were female, and 77.7% were white. OAB symptom improvement was significantly related to being prescribed medication (odds ratio [OR], 4.3; 95% CI, 1.8-9.9) and the mean number of daily leakage incidents at baseline (OR, 3.2; 95% CI, 1.2-8.4). Although patients who were prescribed drugs at baseline tended to have fewer physician office visits and were less likely to be prescribed nondrug interventions than patients who were not treated initially with drugs, these differences were not statistically significant. Conclusions: Pharmacologic treatment for symptoms of OAB appears to be associated with greater symptom improvement than nonpharmacologic treatment. Larger studies of experimental design are needed to determine whether patients treated with medication use fewer nondrug interventions and require fewer physician office visits than patients treated without medication. C1 Baylor Coll Med, Houston, TX 77030 USA. NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. ABT Associates Clin Trials, Cambridge, MA USA. Strateg Advantage Inc, Wellesley, MA USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Alza Corp, Mt View, CA USA. RP Boone, TB (reprint author), Baylor Coll Med, Houston, TX 77030 USA. NR 26 TC 8 Z9 8 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD MAR PY 2002 VL 24 IS 3 BP 397 EP 408 DI 10.1016/S0149-2918(02)85041-X PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 537BG UT WOS:000174736500005 PM 11952023 ER PT J AU Mulshine, JL Cuttitta, F Tockman, MS De Luca, LM AF Mulshine, JL Cuttitta, F Tockman, MS De Luca, LM TI Lung cancer evolution to preinvasive management SO CLINICS IN CHEST MEDICINE LA English DT Article ID NUCLEAR RIBONUCLEOPROTEIN A2/B1; 2ND PRIMARY TUMORS; BRONCHIAL EPITHELIUM; ACTION PROJECT; RETINOIC ACID; CARCINOMA; ISOTRETINOIN; EXPRESSION; CELLS; OVEREXPRESSION AB The refinement of spiral CT provides an attractive tool for routinely detecting early lung cancer. Clinical trials will be mounted to evaluate critically the utility of this approach. Because the volume of newly detected cancer is so much smaller than what is routinely found with the chest radiograph, a reconsideration of all aspects of how we manage this cancer will be essential to establish complementary clinical managements for CT-detected early lung cancer. Learning how to efficiently and effectively detect and manage presymptomatic lung cancer is an exciting and demanding new challenge. C1 NCI, Intervent Sect, Med Branch, Ctr Canc Res,Ctr Clin,NIH, Bethesda, MD 20892 USA. Univ S Florida, Tampa, FL USA. H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. NCI, Differentiat Control Sect, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect, Med Branch, Ctr Canc Res,Ctr Clin,NIH, Bldg 10,Room 12N 226, Bethesda, MD 20892 USA. EM mulshinj@mail.nih.gov NR 50 TC 16 Z9 17 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-5231 J9 CLIN CHEST MED JI Clin. Chest Med. PD MAR PY 2002 VL 23 IS 1 BP 37 EP + DI 10.1016/S0272-5231(03)00058-3 PG 14 WC Respiratory System SC Respiratory System GA 532UN UT WOS:000174493600004 PM 11901918 ER PT J AU Tsilou, ET Rubin, BI Reed, GF Iwata, F Gahl, W Kaiser-Kupfer, MI AF Tsilou, ET Rubin, BI Reed, GF Iwata, F Gahl, W Kaiser-Kupfer, MI TI Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis SO CORNEA LA English DT Article DE crystalline keratopathy; cystinosis; cystinosis complications ID CORNEAL CRYSTALS; CYSTEAMINE; CHILDREN AB Purpose. As a result of successful renal transplantation, patients with nephropathic cystinosis are now, living into adulthood. As these patients age, anterior segment ocular complications. other than deposition of corneal crystals, become more evident. With our experience with 172 patients followed up at the National Institutes of Health between 1976 and 2000, the prevalence of anterior segment complications in nephropathic cystinosis was determined. Methods. A cross-sectional examination of age-specific prevalence was performed with logistic regression analysis of prevalence change with age. Results. Besides the corneal crystals apparent in all age groups, superficial punctate keratopathy, filamentary keratopathy, severe peripheral corneal neovascularization. band keratopathy, and posterior synechiae with iris thickening and transillumination were noted in the older age groups. The prevalence increased with age for each complication. Conclusions. As patients with cystinosis grow older. more severe ophthalmic manifestations become evident. It remains to be seen how the prevalence of these complications will be altered by early initiation of oral and topical cysteamine therapy. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Tsilou, ET (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 10 Ctr Dr,MSC-1860,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. NR 13 TC 15 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD MAR PY 2002 VL 21 IS 2 BP 173 EP 176 DI 10.1097/00003226-200203000-00009 PG 4 WC Ophthalmology SC Ophthalmology GA 525XT UT WOS:000174099900009 PM 11862089 ER PT J AU Pattabiraman, N AF Pattabiraman, N TI Analysis of ligand-macromolecule contacts: Computational methods SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID HIV-1 REVERSE-TRANSCRIPTASE; OCCLUDED MOLECULAR-SURFACE; PROTEIN STRUCTURES; FREE-ENERGY; CRYSTAL-STRUCTURE; INHIBITOR DESIGN; COMPLEXES; PACKING; BINDING; GRAPHICS AB Due to the many technological advancements in biology and development of new fields such as biotechnology and bioinformatics, our knowledge of cellular functions has been growing rapidly; and Biology has entered the Information Age. Along with the technological advancements has come a rapid increase in identification of biomolecular targets involved in diseases. Recently, structure-based drug design studies have emphasized integration of the clinical, cellular, biochemical, structural, and biophysical knowledge of the target. Due to advances in sequencing the human genome, in chemical synthesis and structure determination of biological targets using X-ray and NMR techniques, and in high-performance computing, many scientists from both experimental and theoretical fields focus on structure-based drug design. As scientists in such wide-ranging disciplines, we must understand the data from and educate one another about the strengths and weaknesses of our various disciplines. Since 1990, we have been using computers to visually evaluate ligand binding. In this review, the author will focus on computational methods that not only visualize but also quantify the nature and strength of ligand-macromolecule contacts. Such quantification can be very useful both for medicinal chemists to design ligands and for molecular biologists to design rational protein design experiments to study the effect of amino acid changes on ligand binding. C1 NCI, SAIC, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Pattabiraman, N (reprint author), AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850 USA. FU NCI NIH HHS [N01-CO-56000] NR 31 TC 4 Z9 4 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD MAR PY 2002 VL 9 IS 5 BP 609 EP 621 DI 10.2174/0929867024606957 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 538TN UT WOS:000174831300005 PM 11945127 ER PT J AU Kingston, DGI Newman, DJ AF Kingston, DGI Newman, DJ TI Mother nature's combinatorial libraries; their influence on the synthesis of drugs SO CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT LA English DT Review DE cell cycle inhibitor; natural products; privileged structures; tubulin interactive agents ID CYCLIN-DEPENDENT KINASE; VANCOMYCIN-RESISTANT BACTERIA; GROWTH-FACTOR-RECEPTOR; MICROTUBULE-STABILIZING AGENTS; BIOSYNTHETIC GENE-CLUSTER; SOLUTION-PHASE SYNTHESIS; TYROSINE KINASE; BIOLOGICAL EVALUATION; PRIVILEGED STRUCTURES; SORANGIUM-CELLULOSUM AB Natural products or secondary metabolites, whether from the microbial, plant or marine worlds, represent the results Of evolutionary pressures to preserve and enhance the life of their producing organism. They have evolved into structurally and usually stereochemically complex compounds with specific bioactivities. They thus represent a diverse 'combinatorial library' that may have potential pharmaceutical use. In principle, the combination of this diverse library with the methods of combinatorial chemistry could lead to an unlimited supply of diverse and complex structures, and is recommended as a fruitful approach for future drug development. Examples of the application of combinatorial methods to nature's combinatorial library will be presented and discussed, with an emphasis on the antitumor, anti-infective and pain control disease areas. C1 Virginia Polytech Inst & State Univ, Dept Chem, Blacksburg, VA 24061 USA. NCI, Nat Prod Branch, Dev Therapeut Program, Frederick, MD 21702 USA. RP Kingston, DGI (reprint author), Virginia Polytech Inst & State Univ, Dept Chem, M-C 0212, Blacksburg, VA 24061 USA. OI Kingston, David/0000-0001-8944-246X NR 96 TC 35 Z9 36 U1 0 U2 3 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1367-6733 J9 CURR OPIN DRUG DI DE JI Curr. Opin. Drug Discov. Dev. PD MAR PY 2002 VL 5 IS 2 BP 304 EP 316 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 651NG UT WOS:000181325600015 PM 11926137 ER PT J AU Miller, JL AF Miller, JL TI Hemoglobin switching and modulation: genes, cells, and signals SO CURRENT OPINION IN HEMATOLOGY LA English DT Article ID BETA-GLOBIN GENE; GROWTH-FACTOR-BETA; ERYTHROID-CELLS; TRANSGENIC MICE; DEVELOPMENTAL SPECIFICITY; FETAL; EXPRESSION; ERYTHROPOIESIS; TRANSCRIPTION; CHROMATIN AB A detailed understanding of hemoglobin production in erythroid cells is of fundamental clinical importance for the treatment of hemoglobinopathies. Several hundred scientific reports and dozens of reviews describe this intriguing topic of research. Early studies demonstrated the temporal nature of a hemoglobin-switching phenomenon during development in the circulating erythrocytes of humans. The focus then shifted from descriptive to experimental analyses and model systems in an effort to define the switching mechanisms. The application of molecular biology in those experimental models has been a primary focus for the last two decades. Today, advances in the fields of stem cell biology and signal transduction are being integrated with those genetic studies. Genomic and proteomic approaches are also being developed to provide a more robust description of the biologic variables involved. This review highlights recent advances in erythroid genetics and cellular biology with an emphasis upon the modulation of fetal hemoglobin expression during the maturation of adult human erythrocytes. Curr Opin Hematol 2002, 9:87-92 (C) 2002 Lippincott Williams Wilkins, Inc. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Room 9B17, Bethesda, MD 20892 USA. NR 64 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD MAR PY 2002 VL 9 IS 2 BP 87 EP 92 AR UNSP ISSN 1065-6251 DI 10.1097/00062752-200203000-00001 PG 6 WC Hematology SC Hematology GA 524VT UT WOS:000174034100001 PM 11844989 ER PT J AU Atkinson, JC Diamond, F Eichmiller, F Selwitz, R Jones, G AF Atkinson, JC Diamond, F Eichmiller, F Selwitz, R Jones, G TI Stability of bisphenol A, triethylene-glycol dimethacrylate, and bisphenol A dimethacrylate in whole saliva SO DENTAL MATERIALS LA English DT Article DE bisphenol a; bisphenol A dimethacrylate; saliva; dental material; dental sealant ID ENVIRONMENTAL ESTROGEN BISPHENOL; IN-VITRO; DENTAL COMPOSITES; CELL-LINE; EXPOSURE; GROWTH; BIODEGRADATION; SEALANTS; RELEASE; VIVO AB Objectives: This study investigated the stability of compounds of dental sealant materials in a salivary matrix. Methods: Various amounts of bisphenol A (BPA), bisphenol A dimethacrylate (BIS-DMA) or triethylene-glycol dimethacrylate (TEGDMA) were added to whole salivary samples, and stored at -70degreesC or -20degreesC for up to 4 months. In other experiments, four separate whole salivary or water samples with BIS-DMA (200 ng/ml) were incubated for 0, 1, 2, 4 or 24 h at 37degreesC. Levels of analytes were determined by capillary gas chromatography/mass spectrophotometry (GC/MS) and high-performance liquid chromatography (HPLC). Results: BPA was stable under all tested conditions. Samples originally containing BIS-DMA had high levels of BPA and almost no BIS-DMA after 4 months at -20degreesC. Salivary samples incubated at 37degreesC originally containing only BIS-DMA (200 ng/ml) demonstrated rapid decreases of BIS-DMA and increases of BPA. By 24 h, the mean BIS-DMA concentration fell to 21.8 (25) ng/ml, while BPA increased to 100 (48) ng/ml. Only slight decreases in BIS-DMA and no BPA were present in the water samples incubated at 37degreesC. BPA, BIS-DMA, and TEGDMA were stable if salivary samples were stored at -70degreesC. Acidification of salivary samples prevented the breakdown of BIS-DMA. Significance: BIS-DMA is converted rapidly to BPA in the presence of whole saliva. This could account for the findings of BPA in clinical samples collected after the placement of certain sealant products. Decreasing salivary pH and temperature can slow this process and this method should be used for clinical studies of salivary BPA leached from restorative materials. (C) 2002 Academy of Dental Materials. Published by Elsevier Science Ltd. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Natl Med Serv, Willow Grove, PA USA. Paffenbarger Res Ctr, Amer Dent Assoc Hlth Fdn, Gaithersburg, MD USA. Natl Inst Dent & Craniofacial Res, Off Sci Policy & Anal, Bethesda, MD USA. USN, Dent Res Inst, Great Lakes, IL USA. RP Atkinson, JC (reprint author), Univ Maryland, Baltimore Coll Dent Surg, Dept Clin Affairs, Room 3E-32,666 W Baltimore St, Baltimore, MD 21201 USA. NR 21 TC 34 Z9 35 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0109-5641 J9 DENT MATER JI Dent. Mater. PD MAR PY 2002 VL 18 IS 2 BP 128 EP 135 AR PII S-0109-5641(01)00031-8 DI 10.1016/S0109-5641(01)00031-8 PG 8 WC Dentistry, Oral Surgery & Medicine; Materials Science, Biomaterials SC Dentistry, Oral Surgery & Medicine; Materials Science GA 529RD UT WOS:000174311600005 PM 11755591 ER PT J AU Wagner, KU Boulanger, CA Henry, MD Sgagias, M Hennighausen, L Smith, GH AF Wagner, KU Boulanger, CA Henry, MD Sgagias, M Hennighausen, L Smith, GH TI An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal SO DEVELOPMENT LA English DT Article DE mammary gland; cre recombinase; epithelium; parity; stem cells; involution; differentiation; mouse ID ACIDIC PROTEIN GENE; MYOEPITHELIAL CELLS; TRANSGENIC MICE; GLAND; BREAST; DIFFERENTIATION; EXPRESSION; LACTATION; CARCINOGENESIS; MORPHOGENESIS AB Mammary gland biologists have long assumed that differentiated secretory epithelial cells undergo programmed cell death at the end of lactation and that the alveolar compartment is reconstituted from undifferentiated precursor cells in subsequent pregnancies. It is generally agreed that the remodeled gland in a parous animal resembles that of a mature virgin at the morphological level. However, several physiological differences have been noted in comparing the responses of mammary epithelia from nulliparous versus parous females to hormonal stimulation and carcinogenic agents. We present genetic evidence that an involuted mammary gland is fundamentally different from a virgin gland, despite its close morphological resemblance. This difference results from the formation of a new mammary epithelial cell population that originates from differentiating cells during pregnancy. In contrast to the majority of fully committed alveolar cells, this epithelial population does not undergo cell death during involution or remodeling after lactation. We show that these cells can function as alveolar progenitors in subsequent pregnancies and that they can play an important role in functional adaptation in genetically engineered mice, which exhibit a reversion of a lactation-deficient phenotype in multiparous animals. In transplantation studies, this parity-induced epithelial population shows the capacity for self-renewal and contributes significantly to the reconstitution of the resulting mammary outgrowth (i.e. ductal morphogenesis and lobulogenesis). We propose that this parity-induced population contributes importantly to the biological differences between the mammary glands of parous and nulliparous females. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. NCI, Basic Res Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Wagner, KU (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 986805 Nebraska Med Ctr,Rm 8009, Omaha, NE 68198 USA. RI Wagner, Kay-Uwe/B-6044-2009 NR 53 TC 180 Z9 184 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR PY 2002 VL 129 IS 6 BP 1377 EP 1386 PG 10 WC Developmental Biology SC Developmental Biology GA 538PJ UT WOS:000174824000009 PM 11880347 ER PT J AU Lartillot, N Lespinet, O Vervoort, M Adoutte, A AF Lartillot, N Lespinet, O Vervoort, M Adoutte, A TI Expression pattern of Brachyury in the mollusc Patella vulgata suggests a conserved role in the establishments of the AP axis in Bilateria SO DEVELOPMENT LA English DT Article DE Brachyury; mollusc; gastrulation; AP axis; teloblast; Patella vulgata ID MOUSE T-GENE; SEA-URCHIN; DROSOPHILA BRACHYENTERON; DORSOVENTRAL POLARITY; HEMICHORDATE EMBRYOS; BASAL DEUTEROSTOMES; ZEBRAFISH HOMOLOG; CELL-LINEAGE; D-QUADRANT; MESODERM AB We report the characterisation of a Brachyury ortholog (PvuBra) in the marine gastropod Patella vulgata. :In this mollusc, the embryo displays an equal cleavage pattern until the 32-cell stage. There, an inductive event takes place that sets up the bilateral symmetry, by specifying one of the four initially equipotent vegetal macromeres as the posterior pole of all subsequent morphogenesis. This macromere, usually designated as 3D, will subsequently act as an organiser. We show that 3D expresses PvuBra as soon as its fate is determined. As reported for another mollusc (J. D. Lambert and L. M. Nagy (2001) Development 128, 4556), we found that 3D determination and activity also involve the activation of the MAP kinase ERK, and we further show that PvuBra expression in 3D requires ERK activity. PvuBra expression then rapidly spreads to neighbouring cells that cleave in a bilateral fashion and whose progeny will constitute the posterior edge of the blastopore during gastrulation, suggesting a role for PvuBra in regulating cell movements and cleavage morphology in Patella. Until the completion of gastrulation, PvuBra expression is maintained at the posterior pole, and along the developing anterior-posterior axis. Comparing this expression pattern with what is known in other Bilateria, we advocate that Brachyury might have a conserved role in the regulation of anterior-posterior patterning among Bilateria, through the maintenance of a posterior growth zone, suggesting that a teloblastic mode of axis formation might be ancestral to the Bilateria. C1 CNRS, Ctr Genet Mol, F-91198 Gif Sur Yvette, France. NIH, Bethesda, MD 20894 USA. RP Lartillot, N (reprint author), CNRS, Ctr Genet Mol, Batiment 26,Ave Terrasse, F-91198 Gif Sur Yvette, France. RI Lespinet, Olivier/C-1235-2008 OI Lespinet, Olivier/0000-0002-4961-7461 NR 54 TC 63 Z9 63 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR PY 2002 VL 129 IS 6 BP 1411 EP 1421 PG 11 WC Developmental Biology SC Developmental Biology GA 538PJ UT WOS:000174824000012 PM 11880350 ER PT J AU Miyamoto, T Kawahara, A Teufel, A Mukhopadhyay, M Zhao, YG Dawid, IB Westphal, H AF Miyamoto, T Kawahara, A Teufel, A Mukhopadhyay, M Zhao, YG Dawid, IB Westphal, H TI Mbx, a novel mouse homeobox gene SO DEVELOPMENT GENES AND EVOLUTION LA English DT Article DE Mbx; homeobox; midbrain AB The homeobox gene Mbx is thought to play important roles in the development of eyes and tectum in zebrafish. We isolated mouse Mbx cDNA and analyzed its expression pattern during early mouse embryogenesis. Expression is predominantly restricted to the midbrain region at E9.5. At subsequent stages of development, Mbx transcripts were also found in the forebrain in addition to midbrain. Thus, the Mbx gene provides a useful molecular marker for early mouse midbrain development and may play a critical role in brain development. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NR 11 TC 11 Z9 12 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0949-944X J9 DEV GENES EVOL JI Dev. Genes Evol. PD MAR PY 2002 VL 212 IS 2 BP 104 EP 106 DI 10.1007/s00427-002-0217-4 PG 3 WC Cell Biology; Evolutionary Biology; Developmental Biology SC Cell Biology; Evolutionary Biology; Developmental Biology GA 541TV UT WOS:000175001400007 PM 11914943 ER PT J AU Chiao, E Fisher, P Crisponi, L Deiana, M Dragatsis, I Schlessinger, D Pilia, G Efstratiadis, A AF Chiao, E Fisher, P Crisponi, L Deiana, M Dragatsis, I Schlessinger, D Pilia, G Efstratiadis, A TI Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling SO DEVELOPMENTAL BIOLOGY LA English DT Review DE growth; proteoglycans; glypican; insulin-like growth factor; Simpson-Golabi-Behmel syndrome ID GROWTH-FACTOR-II; BECKWITH-WIEDEMANN-SYNDROME; HEPARAN-SULFATE PROTEOGLYCANS; AMNIOTIC SAC PUNCTURE; MICE LACKING; MUTANT MICE; GPC3 GENE; TARGETED DISRUPTION; PERINATAL LETHALITY; MOLECULAR-BIOLOGY AB The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBSI, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBSI features (omphalocele and skeletal defects) were manifested. However, results from a detailed comparative analysis of growth patterns in double mutants lacking GPC3 and also IGF2, IGF1, or the type I IGF receptor (IGFIR) provided conclusive genetic evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by sequestering or downregulating an IGF ligand. Nevertheless, our data are compatible with a model positing that there is downstream convergence of the independent signaling pathways in which either IGFs or (indirectly) GPC3 participate. (C) 2002 Elsevier Science (USA). C1 Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. CNR, Ist Ric Talassemie & Anemie Mediterranee, Cagliari, Italy. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Efstratiadis, A (reprint author), Columbia Univ, Russ Berrie Med Sci Pavil,1150 St Nicholas Ave, New York, NY 10032 USA. FU NCI NIH HHS [CA75553]; NICHD NIH HHS [HD34526]; NIMH NIH HHS [MH50733] NR 130 TC 68 Z9 70 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 1 PY 2002 VL 243 IS 1 BP 185 EP 206 DI 10.1006/dbio.2001.0554 PG 22 WC Developmental Biology SC Developmental Biology GA 527PU UT WOS:000174195600015 PM 11846487 ER PT J AU Xu, D Rovira, II Finkel, T AF Xu, D Rovira, II Finkel, T TI Oxidants painting the cysteine chapel: Redox regulation of PTPs SO DEVELOPMENTAL CELL LA English DT Editorial Material ID PROTEIN-TYROSINE PHOSPHATASES; EPIDERMAL GROWTH-FACTOR; REVERSIBLE INACTIVATION; HYDROGEN-PEROXIDE; GENERATION AB Growth factors and cytokines appear to stimulate the intracellular production of reactive oxygen species (ROS). Evidence suggests that this alteration in the cellular redox state is essential for downstream signaling, but the precise mechanism has remained elusive. A new study now demonstrates that ligand-stimulated intracellular hydrogen peroxide can specifically and reversibly regulate the activity of protein tyrosine phosphatases. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Xu, D (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 114 Z9 116 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAR PY 2002 VL 2 IS 3 BP 251 EP 252 DI 10.1016/S1534-5807(02)00132-6 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 548KV UT WOS:000175387900001 PM 11879627 ER PT J AU Akagi, K Park, EK Mood, K Daar, IO AF Akagi, K Park, EK Mood, K Daar, IO TI Docking protein SNT1 is a critical mediator of fibroblast growth factor signaling during Xenopus embryonic development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE SNTI; FRS-2; fibroblast growth factor receptor; mesoderm; xenopus ID MAP KINASE; MESODERM INDUCTION; FACTOR RECEPTOR; TYROSINE-PHOSPHATASE; CELL-DIFFERENTIATION; PC12 CELLS; FGF; BINDING; EXPRESSION; ACTIVATION AB The docking protein SNT1/ FRS2 (fibroblast growth factor receptor substrate 2) is implicated in the transmission of extracellular signals from several growth factor receptors to the mitogen-activated protein (MAP) kinase signaling cascade, but its biological function during development is not well characterized. Here, we show that the Xenopus homolog of mammalian SNT1/FRS-2 (XSNT1) plays a critical role in the appropriate formation of mesoderm-derived tissue during embryogenesis. XSNT1 has an expression pattern that is quite similar to the fibroblast growth factor receptor-1 (FGFR1) during Xenopus development. Ectopic expression of XSNT1 markedly enhanced the embryonic defects induced by an activated FGF receptor, and increased the MAP kinase activity as well as the expression of a mesodermal marker in response to FGF receptor signaling. A loss-of-function study using antisense XSNT1 morpholino oligonucleotides (XSNT-AS) shows severe malformation of trunk and posterior structures. Moreover, XSNT-AS disrupts muscle and notochord formation, and inhibits FGFR-induced ALAP kinase activation. In ectodermal explants, XSNT-AS blocks FGFR-mediated induction of mesoderm and the accompanying elongation movements. Our results indicate that XSNT1 is a critical mediator of FGF signaling and is required for early Xenopus development. (C) 2002 Wiley-Liss, Inc. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Daar, IO (reprint author), NCI, Regulat Cell Growth Lab, Bldg 560,Room 22-3, Frederick, MD 21702 USA. OI Daar, Ira/0000-0003-2657-526X NR 62 TC 8 Z9 8 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAR PY 2002 VL 223 IS 2 BP 216 EP 228 DI 10.1002/dvdy.10048 PG 13 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 517XK UT WOS:000173635600005 PM 11836786 ER PT J AU Tufan, AC Daumer, KM Tuan, RS AF Tufan, AC Daumer, KM Tuan, RS TI Frizzled-7 and limb mesenchymal chondrogenesis: Effect of misexpression and involvement of N-cadherin SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Chfz-1; Chfz-7; limb chondrogenesis; cellular condensation; N-cadherin ID AGGLUTININ AFFINITY-CHROMATOGRAPHY; IN-VITRO CHARACTERIZATION; TISSUE POLARITY; BETA-CATENIN; TRANSMEMBRANE DOMAINS; SIGNAL-TRANSDUCTION; MICROMASS CULTURES; PATTERN-FORMATION; GENE-EXPRESSION; LECTIN BINDING AB Products of the Frizzled family of tissue polarity genes have been identified as putative receptors for the Wnt family of signaling molecules. Wnt-signaling is implicated in the regulation of limb mesenchymal chondrogenesis, and our recent study indicates that N-cadherin and related activities are functionally involved in Wnt-7a-mediated inhibition of chondrogenesis. By using an in vitro high-density micromass culture system of chick limb mesenchymal cells, we have analyzed the spatiotemporal expression patterns and the effects on chondrogenesis of RCAS retroviral-mediated misexpression of Chfz-1 and Chfz-7, two Frizzled genes implicated in chondrogenic regulation. Chfz-1 expression was localized at areas surrounding the cartilaginous nodules at all time points examined, whereas Chfz-7 expression was limited to cellular aggregates during initial mesenchymal condensation, and subsequently was down-regulated from the centers toward the periphery of cartilage nodules at the time of chondrogenic differentiation, resembling the pattern of N-cadherin expression. Chondrogenesis in vitro was inhibited and limited to a smaller area of the culture upon misexpression of Chfz-7, but not affected by Chfz-1 misexpression. Analyses of cellular condensation and chondrogenic differentiation showed that the inhibitory action of Chfz-7 is unlikely to be at the chondrogenic differentiation step, but instead affects the earlier precartilage aggregate formation event. At 24 hr, expression of N-cadherin, a key component of the cellular condensation phase of chondrogenesis, was delayed/suppressed in Chfz-7 misexpressing cultures, and was limited to a significantly smaller cellular condensation area within the entire culture at 48 hr, when compared with control cultures. Chfz-1 misexpressing cultures appeared similar to control cultures at all time points. However, neither Chfz-1 nor Chfz-7 misexpression affected mesenchymal cell proliferation in vitro. These results suggest that Chfz-7 is active in regulating N-cadherin expression during the process of limb mesenchymal chondrogenesis and that Chfz-1 and Chfz-7 are involved in different Wnt-signaling pathways. (C) 2002 Wiley-Liss, Inc. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 13,3W17,MSC 5755, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIDCR NIH HHS [DE16864]; NIEHS NIH HHS [ES07005] NR 52 TC 28 Z9 28 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAR PY 2002 VL 223 IS 2 BP 241 EP 253 DI 10.1002/dvdy.10046 PG 13 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 517XK UT WOS:000173635600007 PM 11836788 ER PT J AU Shima, Y Copeland, NG Gilbert, DJ Jenkins, NA Chisaka, O Takeichi, M Uemura, T AF Shima, Y Copeland, NG Gilbert, DJ Jenkins, NA Chisaka, O Takeichi, M Uemura, T TI Differential expression of the seven-pass transmembrane cadherin genes Celsr1-3 and distribution of the Celsr2 protein during mouse development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE cadherin superfamily; Celsr; Flamingo; mouse development; in situ hybridization; immunohistochemistry; gene mapping ID CHROMOSOMAL LOCALIZATION; NERVOUS-SYSTEM; CELL POLARITY; DROSOPHILA; RECEPTOR; FLAMINGO; GASTRULATION; IDENTIFICATION; ORGANIZATION; SUPERFAMILY AB Drosophila Flamingo (Fmi) is an evolutionally conserved seven-pass transmembrane receptor of the cadherin superfamily. Fmi plays multiple roles in patterning neuronal processes and epithelial planar cell polarity. To explore the in vivo roles of Fmi homologs in mammals, we previously cloned one of the mouse homologs, mouse flamingo1/Celsr2. Here, we report the results of our study of its embryonic and postnatal expression patterns together with those of two other paralogs, Celsr1 and Celsr3. Celsr1-3 expression was initiated broadly in the nervous system at early developmental stages, and each paralog showed characteristic expression patterns in the developing CNS. These genes were also expressed in several other organs, including the cochlea, where hair cells develop planar polarity, the kidney, and the whisker. The Celsr2 protein was distributed at intercellular boundaries in the whisker and on processes of neuronal cells such as hippocampal pyramidal cells, Purkinje cells, and olfactory neurons. Celsr2 is mapped to a distal region of the mouse chromosome 3. We discussed possible functions of seven-pass transmembrane cadherins in mouse development. (C) 2002 Wiley-Liss, Inc. C1 Kyoto Univ, Inst Virus Res, Dept Mol Genet, Lab Mol Genet,Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Sch Sci, Dept Biophys, Sakyo Ku, Kyoto, Japan. NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. Kyoto Univ, Grad Sch Biostudies, Sakyo Ku, Kyoto, Japan. Japan Sci & Technol Corp, CREST, Tokyo, Japan. RP Uemura, T (reprint author), Kyoto Univ, Inst Virus Res, Dept Mol Genet, Lab Mol Genet,Sakyo Ku, Kyoto 6068507, Japan. RI Takeichi, Masatoshi/G-5903-2012 OI Takeichi, Masatoshi/0000-0002-9931-3378 NR 47 TC 56 Z9 57 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAR PY 2002 VL 223 IS 3 BP 321 EP 332 DI 10.1002/dvdy.10054 PG 12 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 528CX UT WOS:000174227800002 PM 11891983 ER PT J AU Drake, SK Bourdon, E Wehr, NB Levine, RL Backlund, PS Yergey, AL Rouault, TA AF Drake, SK Bourdon, E Wehr, NB Levine, RL Backlund, PS Yergey, AL Rouault, TA TI Numerous proteins in mammalian cells are prone to iron-dependent oxidation and proteasomal degradation SO DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE iron; oxidation; carbonyl; proteasome; iron regulatory protein 2 (IRP2); degradation; aging; neurodegeneration; inclusions; heat shock proteins ID CARBOXYL-TERMINAL HYDROLASE; REGULATORY PROTEIN-2; MASS-SPECTROMETRY; NEURODEGENERATIVE DISEASES; SACCHAROMYCES-CEREVISIAE; MOLECULAR CHAPERONE; OXIDIZED PROTEINS; HYDROGEN-PEROXIDE; STRESS-RESPONSE; BINDING-SITE AB The mechanisms that underlie iron toxicity in cells and organisms are poorly understood. Previous studies of regulation of the cytosolic iron sensor, iron-regulatory protein 2 (IRP2), indicate that iron-dependent oxidation triggers ubiquitination and proteasomal degradation of IRP2. To determine if oxidization by iron is involved in degradation of other proteins, we have used a carbonyl assay to identify oxidized proteins in lysates from RD4 cells treated with either an iron source or iron chelator. Protein lysates from iron-loaded or iron-depleted cells were resolved on two-dimensional gels and these iron manipulations were also repeated in the presence of proteasomal inhibitors. Eleven abundant proteins were identified as prone to iron-dependent oxidation and subsequent proteasomal degradation. These proteins included two putative iron-binding proteins, hNFU1 and calreticulin; two proteins involved in metabolism of hydrogen peroxide, peroxiredoxin 2 and superoxide dismutase 1; and several proteins identified in inclusions in neurodegenerative diseases, including HSP27, UCHL1, actin and tropomyosin. Our results indicate that cells can recognize and selectively eliminate iron-dependently oxidized proteins, but unlike IRP2, levels of these proteins do not significantly decrease in iron-treated cells. As iron overload is a feature of many human neurological diseases, further characterization of the process of degradation of iron-dependently oxidized proteins may yield insights into mechanisms of human disease. Copyright (C) 2002 S. Karger AG, Basel. C1 NICHHD, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), 9000 Rockville Pike,Bldg 18 Rm 101, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 67 TC 18 Z9 18 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-5866 J9 DEV NEUROSCI-BASEL JI Dev. Neurosci. PD MAR-JUN PY 2002 VL 24 IS 2-3 BP 114 EP 124 DI 10.1159/000065693 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 613QN UT WOS:000179143100005 PM 12401949 ER PT J AU Nelson, EE Alberts, JR AF Nelson, EE Alberts, JR TI Gastric saline infusion reduces ultrasonic vocalizations and brown fat activity in suckling rat pups SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE ultrasonic vocalization; intragastric infusion; thermogenesis ID ADIPOSE-TISSUE THERMOGENESIS; 10-DAY-OLD RATS; INFANT RATS; FOOD-INTAKE; COLD-EXPOSURE; CHOLECYSTOKININ; OXYTOCIN; INHIBITION; INGESTION; RESPONSES AB Under standard conditions involving isolation and cooling, it has been documented that intraoral infusion of milk and injection of the intestinal peptide cholecystokinin (CCK) result in (in attenuation in ultrasonic, vocalizations (USV) emitted by infant rat pups. One of the most effective stimuli in inhibiting ingestion in suckling rat pups is gastric, distension, but the effect of gastric distension on USV production has not been reported. In this experiment, we subjected infant rats to intragastric infusion of isotonic saline (2% body weight) to produce a natural level of gastric, distension and hydration. We found that this stimulus resulted in a powerful reduction in USV emissions in isolated 10-day-old rats. In a subsequent experiment, we found that gastric saline infusion also diminished brown adipose tissue (BAT) thermogenesis. There were different time courses of the gastric saline infusion effects on BAT thermogenesis and oil USV emissions, however suggesting that these processes may be independently regulated. We hypothesize that this stimulus induces a transient activation of the parasympathetic nervous system, which overrides the sympathetic control of BAT and USV production, (C) 2002 Wiley Periodicals. Inc. C1 Indiana Univ, Dept Psychol, Bloomington, IN 47405 USA. RP Nelson, EE (reprint author), NIMH, Mood & Anxiety Disorders Program, Bldg 1,RM B3-10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Nelson, Eric/B-8980-2008 OI Nelson, Eric/0000-0002-3376-2453 FU NIMH NIH HHS [MH 28355] NR 39 TC 5 Z9 5 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD MAR PY 2002 VL 40 IS 2 BP 160 EP 167 DI 10.1002/dev.10019 PG 8 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 529RR UT WOS:000174312800007 PM 11857330 ER PT J AU Mei, J Holst, LS Landstrom, TR Holm, C Brindley, D Manganiello, V Degerman, E AF Mei, J Holst, LS Landstrom, TR Holm, C Brindley, D Manganiello, V Degerman, E TI C-2-ceramide influences the expression and insulin-mediated regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 adipocytes SO DIABETES LA English DT Article ID NECROSIS-FACTOR-ALPHA; HORMONE-SENSITIVE LIPASE; RAT ADIPOSE-TISSUE; FREE FATTY-ACIDS; AMP PHOSPHODIESTERASE; PROTEIN-KINASE; CAMP-PHOSPHODIESTERASE; PHOSPHATIDYLINOSITOL 3-KINASE; DIFFERENT MECHANISMS; GLUCOSE-TRANSPORT AB Cyclic nucleotide phosphodiesterase (PDE) 3B plays an important role in the antilipolytic action of insulin and, thereby, the release of fatty acids from adipocytes. Increased concentrations of circulating fatty acids as a result of elevated or unrestrained lipolysis cause insulin resistance. The lipolytic action of tumor necrosis factor (TNF)-alpha is thought to be one of the mechanisms by which TNF-alpha. induces insulin resistance. Ceramide is the suggested second messenger of TNF-alpha action, and in this study, we used 3T3-L1 adipocytes to investigate the effects of C-2-ceramide (a short-chain ceramide analog) on the expression and regulation of PDE3B and lipolysis. Incubation of adipocytes with 100 mumol/l C-2-ceramide (N-acetyl-sphingosine) resulted in a time-dependent decrease of PDE3B activity, accompanied by decreased PDE3B protein expression. C-2-ceramide, in a time- and dose-dependent manner, stimulated lipolysis, an effect that was blocked by H-89, an inhibitor of protein kinase A. These ceramide effects were prevented by 20 mumol/l troglitazone, an antidiabetic drug. In addition to downregulation of PDE3B, the antilipolytic action of insulin was decreased by ceramide treatment. These results, together with data from other studies on PDE3B and lipolysis in diabetic humans and animals, suggest a novel pathway by which ceramide induces insulin resistance. Furthermore, PDE3B is demonstrated to be a target for troglitazone action in adipocytes. C1 Lund Univ, Dept Cell & Mol Biol, Sect Mol Signalling, S-22184 Lund, Sweden. Univ Alberta, Dept Biochem, Edmonton, AB, Canada. Univ Alberta, Lipid Biol Grp, Edmonton, AB, Canada. NHLBI, Sect Biochem Physiol, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Mei, J (reprint author), Lund Univ, Dept Cell & Mol Biol, Sect Mol Signalling, BMC C11, S-22184 Lund, Sweden. NR 60 TC 16 Z9 19 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2002 VL 51 IS 3 BP 631 EP 637 DI 10.2337/diabetes.51.3.631 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527CD UT WOS:000174167400011 PM 11872660 ER PT J AU Harris, ML Cowie, CC Gu, K Francis, ME Flegal, K Eberhardt, MS AF Harris, ML Cowie, CC Gu, K Francis, ME Flegal, K Eberhardt, MS TI Higher fasting insulin but lower fasting C-peptide levels in African Americans in the US population SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE insulin; C-peptide; African American; Mexican American ID DEPENDENT DIABETES-MELLITUS; NON-HISPANIC WHITES; HIGH-RISK; ATHEROSCLEROSIS RISK; ETHNIC-DIFFERENCES; MEXICAN-AMERICANS; FAT DISTRIBUTION; GLUCOSE; SECRETION; NIDDM AB Background Fasting serum insulin and fasting serum C-peptide are risk factors for developing type 2 diabetes. Because of the higher incidence of type 2 diabetes in African Americans and Hispanic Americans, it is likely that these groups may differ from non-Hispanic whites in their levels of insulin and C-peptide. Methods We analyzed data from a nationally representative sample of adults in the US population for whom sociodemographic, clinical, and laboratory information were obtained. The data were used to describe distributions of fasting insulin and fasting C-peptide in non-Hispanic white, non-Hispanic black, and Mexican American men and women aged greater than or equal to 20 years without a medical history of diabetes. Results Among men, Mexican Americans had higher insulin values than non-Hispanic whites and blacks. Among women, both Mexican Americans and blacks had higher insulin values than whites. For C-peptide, differences by sex and race-ethnicity paralleled those seen for fasting insulin with the exception that black men had significantly lower C-peptide values than whites and Mexican Americans. After adjustment for age, fasting plasma glucose (FPG), body mass index (BMI), and waist-to-hip ratio (WHR), the higher levels for insulin in blacks and Mexican Americans remained; both black men and women had significantly lower C-peptide values than whites and Mexican Americans. The molar ratio of fasting C-peptide to fasting insulin was similar for men and women in each race-ethnic group. However, blacks had substantially lower ratios than whites and Mexican Americans. Conclusions We found wide variations in fasting insulin and fasting C-peptide levels by race and ethnicity in US adults that were not explained by confounding factors, primarily measures of obesity. Most notably, the higher fasting insulin and lower fasting C-peptide levels in blacks implies that there is a derangement in insulin clearance and an impairment in beta-cell function in blacks compared with whites and Mexican Americans. Published in 2002 by John Wiley Sons, Ltd. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Bethesda, MD USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Cowie, CC (reprint author), NIDDKD, NIH, 6707 Democracy Blvd,Suite 691, Bethesda, MD 20892 USA. RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 24 TC 22 Z9 22 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1520-7552 J9 DIABETES METAB RES JI Diabetes-Metab. Res. Rev. PD MAR-APR PY 2002 VL 18 IS 2 BP 149 EP 155 DI 10.1002/dmrr.273 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 547MN UT WOS:000175336300009 PM 11994907 ER PT J AU Cohen, OJ Fauci, AS AF Cohen, OJ Fauci, AS TI Current strategies in the treatment of HIV infection SO DM DISEASE-A-MONTH LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; PNEUMOCYSTIS-CARINII PNEUMONIA; PLACEBO-CONTROLLED TRIAL; AIDS-RELATED COMPLEX; T-CELL RESPONSES; REVERSE-TRANSCRIPTASE INHIBITORS; CD4 LYMPHOCYTE COUNT; COMBINATION THERAPY; VIRAL-LOAD C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Cohen, OJ (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 152 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0011-5029 J9 DM-DIS MON JI DM-Dis.-a-Mon. PD MAR PY 2002 VL 48 IS 3 BP 150 EP 184 DI 10.1067/mda.2002.124659 PG 35 WC Medicine, General & Internal SC General & Internal Medicine GA 555VQ UT WOS:000175814300002 ER PT J AU Olden, K AF Olden, K TI New opportunities in toxicology in the post-genomic era SO DRUG DISCOVERY TODAY LA English DT Editorial Material ID TOXICOGENOMICS; SEQUENCE C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NIH, Dept Hlth & Human Serv, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM olden@niehs.nih.gov NR 14 TC 8 Z9 11 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAR 1 PY 2002 VL 7 IS 5 BP 273 EP 276 AR PII 1359-6446(02)02120-1 DI 10.1016/S1359-6446(01)02120-1 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525WP UT WOS:000174097300001 PM 11854041 ER PT J AU Usmani, KA Rose, RL Goldstein, JA Taylor, WG Brimfield, AA Hodgson, E AF Usmani, KA Rose, RL Goldstein, JA Taylor, WG Brimfield, AA Hodgson, E TI In vitro human metabolism and interactions of repellent N,N-diethyl-M-toluamide SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID LIVER-MICROSOMES; RAT-LIVER; DEET; N,N-DIETHYL-META-TOLUAMIDE; IDENTIFICATION; QUANTITATION; ABSORPTION; EXCRETION; TOXICITY AB Oxidative metabolism of the insect repellent N,N-diethyl-m-toluamide (DEET) by pooled human liver microsomes (HLM), rat liver microsomes (RLM), and mouse liver microsomes (MLM) was investigated. DEET is metabolized by cytochromes P450 (P450s) leading to the production of a ring methyl oxidation product, N,N-diethyl-m-hydroxymethylbenzamide (BALC), and an N-deethylated product, N-ethyl-m-toluamide (ET). Both the affinities and intrinsic clearance of HLM for ring hydroxylation are greater than those for N-deethylation. Pooled HLM show significantly lower affinities (K-m) than RLM for metabolism of DEET to either of the primary metabolites (BALC and ET). Among 15 cDNA-expressed P450 enzymes examined, CYP1A2, 2B6, 2D6*1 (Val(374)), and 2E1 metabolized DEET to the BALC metabolite, whereas CYP3A4, 3A5, 2A6, and 2C19 produced the ET metabolite. CYP2B6 is the principal cytochrome P450 involved in the metabolism of DEET to its major BALC metabolite, whereas CYP2C19 had the greatest activity for the formation of the ET metabolite. Use of phenotyped HLMs demonstrated that individuals with high levels of CYP2B6, 3A4, 2C19, and 2A6 have the greatest potential to metabolize DEET. Mice treated with DEET demonstrated induced levels of the CYP2B family, increased hydroxylation, and a 2.4-fold increase in the metabolism of chlorpyrifos to chlorpyrifos-oxon, a potent anticholinesterase. Preincubation of human CYP2B6 with chlorpyrifos completely inhibited the metabolism of DEET. Preincubation of human or rodent microsomes with chlorpyrifos, permethrin, and pyridostigmine bromide alone or in combination can lead to either stimulation or inhibition of DEET metabolism. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Saskatoon Res Ctr, Saskatoon, SK, Canada. USA, Med Res Inst Chem Def, Aberdeen Proving Ground, MD 21010 USA. RP Hodgson, E (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Box 7633, Raleigh, NC 27695 USA. RI Goldstein, Joyce/A-6681-2012 NR 27 TC 54 Z9 55 U1 4 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD MAR PY 2002 VL 30 IS 3 BP 289 EP 294 AR UNSP 577/966312 DI 10.1124/dmd.30.3.289 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525FR UT WOS:000174058700011 PM 11854147 ER PT J AU Zheng, H Jiang, C Chiu, MH Covey, JM Chan, KK AF Zheng, H Jiang, C Chiu, MH Covey, JM Chan, KK TI Chiral pharmacokinetics and inversion of enantiomers of a new quinoxaline topoisomerase II beta poison in the rat SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID IBUPROFEN ENANTIOMERS; XK469 AB XK469 (NSC 697887; (+/-)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIbeta poison. Both R(+) and S(-) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral high-performance liquid chromatography assay, pharmacokinetics of R(+)-, S(-)-, and (+/-)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(-)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t(1/2beta) for the R-isomer of 24.7 h being significantly longer than 4.2 In, the mean t(1/2beta) for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(+)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected. C1 Ohio State Univ, Coll Med, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Natl Canc Inst, Toxicol & Pharmacol Branch, Rockville, MD USA. RP Chan, KK (reprint author), Ohio State Univ, Coll Med, Ctr Comprehens Canc, Room 308,410 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CM-57201] NR 16 TC 13 Z9 13 U1 2 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD MAR PY 2002 VL 30 IS 3 BP 344 EP 348 AR UNSP 572/964308 DI 10.1124/dmd.30.3.344 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525FR UT WOS:000174058700020 PM 11854156 ER PT J AU Watts, NR Conway, JF Cheng, NQ Stahl, SJ Belnap, DM Steven, AC Wingfield, PT AF Watts, NR Conway, JF Cheng, NQ Stahl, SJ Belnap, DM Steven, AC Wingfield, PT TI The morphogenic linker peptide of HBV capsid protein forms a mobile array on the interior surface SO EMBO JOURNAL LA English DT Article DE core antigen; cryo-electron microscopy; hepatitis B virus; nucleic acid packaging; nucleocapsid morphogenesis ID HEPATITIS-B VIRUS; CORE PROTEIN; CRYOELECTRON MICROSCOPY; DENSITY MAPS; ELECTRON CRYOMICROSCOPY; ESCHERICHIA-COLI; C-TERMINUS; E-ANTIGEN; PARTICLES; RESOLUTION AB Many capsid proteins have peptides that influence their assembly. In hepatitis B virus capsid protein, the peptide STLPETTNV, linking the shell-forming 'core' domain and the nucleic acid-binding 'protamine' domain, has such a role. We have studied its morphogenic properties by permuting its sequence, substituting it with an extraneous peptide, deleting it to directly fuse the core and protamine domains and assembling core domain dimers with added linker peptides. The peptide was found to be necessary for the assembly of protamine domain-containing capsids, although its size-determining effect tolerates some modifications. Although largely invisible in a capsid crystal structure, we could visualize linker peptides by cryo-EM difference imaging: they emerge on the inner surface and extend from the capsid protein dimer interface towards the adjacent symmetry axis. A closely sequence-similar peptide in cellobiose dehydrogenase, which has an extended conformation, offers a plausible prototype. We propose that linker peptides are attached to the capsid inner surface as hinged struts, forming a mobile array, an arrangement with implications for morphogenesis and the management of encapsidated nucleic acid. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. Inst Biol Struct JP Ebel, F-38027 Grenoble, France. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bldg 50,Room 1517,50 S Dr,MSC 8025, Bethesda, MD 20892 USA. RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 NR 45 TC 47 Z9 50 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 1 PY 2002 VL 21 IS 5 BP 876 EP 884 DI 10.1093/emboj/21.5.876 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 530NR UT WOS:000174365400003 PM 11867516 ER PT J AU Baron, GS Wehrly, K Dorward, DW Chesebro, B Caughey, B AF Baron, GS Wehrly, K Dorward, DW Chesebro, B Caughey, B TI Conversion of raft associated prion protein to the protease-resistant state requires insertion of PrP-res (PrPSc) into contiguous membranes SO EMBO JOURNAL LA English DT Article DE microsomes; PEG; PI-PLC; PrP; raft ID GPI-ANCHORED PROTEINS; CREUTZFELDT-JAKOB-DISEASE; SCRAPIE-ASSOCIATED FORM; NEUROBLASTOMA-CELLS; AMYLOID PLAQUES; CULTURED-CELLS; INFECTED MICE; ISOFORM; BRAIN; PHOSPHOLIPASE AB Prion protein (PrP) is usually attached to membranes by a glycosylphosphatidylinositol-anchor that associates with detergent-resistant membranes (DRMs), or rafts. To model the molecular processes that might occur during the initial infection of cells with exogenous transmissible spongiform encephalopathy (TSE) agents, we examined the effect of membrane association on the conversion of the normal protease-sensitive PrP isoform (PrP-sen) to the protease-resistant isoform (PrP-res). A cell-free conversion reaction approximating physiological conditions was used, which contained purified DRMs as a source of PrP-sen and brain microsomes from scrapie-infected mice as a source of PrP-res. Interestingly, DRM-associated PrP-sen was not converted to PrP-res until the PrP-sen was either released from DRMs by treatment with phosphatidylinositol-specific phospholipase C (PI-PLC), or the combined membrane fractions were treated with the membrane-fusing agent polyethylene glycol (PEG). PEG-assisted conversion was optimal at pH 6-7, and acid pre-treating the DRMs was not sufficient to permit conversion without PI-PLC or PEG, arguing against late endosomes/lysosomes as primary compartments for PrP conversion. These observations raise the possibility that generation of new PrP-res during TSE infection requires (i) removal of PrP-sen from target cells; (ii) an exchange of membranes between cells; or (iii) insertion of incoming PrP-res into the raft domains of recipient cells. C1 NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. NR 66 TC 192 Z9 199 U1 2 U2 4 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 1 PY 2002 VL 21 IS 5 BP 1031 EP 1040 DI 10.1093/emboj/21.5.1031 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 530NR UT WOS:000174365400018 PM 11867531 ER PT J AU Koch, CA Mauro, D Walther, MM Linehan, WM Vortmeyer, AO Jaffe, R Pacak, K Chrousos, GP Zhuang, ZP Lubensky, IA AF Koch, CA Mauro, D Walther, MM Linehan, WM Vortmeyer, AO Jaffe, R Pacak, K Chrousos, GP Zhuang, ZP Lubensky, IA TI Pheochromocytoma in von Hippel-Lindau disease: Distinct histopathologic phenotype compared to pheochromocytoma in multiple endocrine neoplasia type 2 SO ENDOCRINE PATHOLOGY LA English DT Article DE pheochromocytoma; adrenal; von Hippel-Lindau disease; multiple endocrine neoplasia type 2; sporadic; histopathology ID TUMOR-SUPPRESSOR GENE; FAMILIAL PHEOCHROMOCYTOMA; VONHIPPELLINDAU DISEASE; RECKLINGHAUSENS-DISEASE; RET PROTOONCOGENE; SPORADIC PHEOCHROMOCYTOMA; GERMLINE MUTATIONS; FOLLOW-UP; VHL GENE; NEUROFIBROMATOSIS AB Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel-Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL pheochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas. C1 Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reproduct Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Pathol Lab, Bethesda, MD 20892 USA. RP Lubensky, IA (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 54 TC 37 Z9 38 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD SPR PY 2002 VL 13 IS 1 BP 17 EP 27 DI 10.1385/EP:13:1:17 PG 11 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 564MG UT WOS:000176317700002 PM 12114747 ER PT J AU Arnold, JT Isaacs, JT AF Arnold, JT Isaacs, JT TI Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault SO ENDOCRINE-RELATED CANCER LA English DT Article ID MESENCHYMAL-EPITHELIAL INTERACTIONS; KERATINOCYTE GROWTH-FACTOR; HUMAN BENIGN; ADENOCARCINOMA SYSTEM; EXTRACELLULAR-MATRIX; RECEPTOR ACTIVATION; BREAST-CANCER; TISSUE; FIBROBLASTS; RAT AB The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote 'It is not the cell itself that is disorderly, but its relationship with the rest of the tissue'. We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention. C1 NCCAM, NIH, Bethesda, MD 20892 USA. Johns Hopkins Oncol, Baltimore, MD 21231 USA. RP Arnold, JT (reprint author), NCCAM, NIH, 8 W Dr MSC 2669,Qtrs 15B1, Bethesda, MD 20892 USA. FU NCI NIH HHS [P30 CA006973] NR 88 TC 151 Z9 156 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD MAR PY 2002 VL 9 IS 1 BP 61 EP 73 DI 10.1677/erc.0.0090061 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 540QJ UT WOS:000174939400005 PM 11914183 ER PT J AU Napolitano, G Bucci, I Giuliani, C Massafra, C Di Petta, C DeVangelio, E Singer, DS Monaco, F Kohn, LD AF Napolitano, G Bucci, I Giuliani, C Massafra, C Di Petta, C DeVangelio, E Singer, DS Monaco, F Kohn, LD TI High glucose levels increase major histocompatibility complex class I gene expression in thyroid cells and amplify interferon-gamma action SO ENDOCRINOLOGY LA English DT Article ID NF-KAPPA-B; DEPENDENT DIABETES-MELLITUS; TRANSCRIPTION FACTOR-I; INNATE IMMUNE-SYSTEM; BETA-CELLS; THYROTROPIN; INSULIN; DISEASE; KINASE; AUTOIMMUNITY AB Increased major histocompatibility complex (MHC class I gene expression in target tissues may be relevant to the pathogenesis of autoimmune diseases. In this study, we questioned whether high glucose levels might increase MHC class I levels and thereby contribute to autoimmune complications. We used thyrocytes in continuous culture, because there is an increased incidence of autoimmune thyroiditis in type 2 diabetics and because transcriptional regulation of MHC class I is well studied in these cells. Northern analysis and flow cytometry showed that 20 and 30 MM D-glucose up-regulated MHC class I expression and that the glucose effect was addi. tive to and independent of interferon-gamma. The effect was specific, because L-glucose did not modify class I expression. The glucose acted transcriptionally, requiring both enhancer A and a cAMP-response element-like element located in the hormone-sensitive region of the MHC class I 5'flanking region. These elements are different from those activated by interferon-gamma. High glucose levels increase formation of the MOD-1 complex with enhancer A, MOD-1 is a heterodimer of fra-2 and the p50 subunit of NF-KB. Both TSH and insulin are required for full expression of the glucose activity in thyrocytes. The glucose effect is partially blocked by wortmannin, suggesting involvement of the PI3K signal system. The data support the possibility that high serum glucose levels in type 2 diabetic patients may increase MHC class I levels in target tissues and contribute to autoimmune complications of the disease. C1 Ohio Univ, Edison Biotechnol Inst, Athens, OH 45701 USA. Univ G DAnnunzio, Chair Endocrinol, I-66100 Chieti, Italy. Univ G DAnnunzio, Dept Med & Sci Aging, I-66100 Chieti, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Kohn, LD (reprint author), Ohio Univ, Edison Biotechnol Inst, Ridges Bldg 25, Athens, OH 45701 USA. EM kohnl@ohio.edu NR 58 TC 8 Z9 9 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2002 VL 143 IS 3 BP 1008 EP 1017 DI 10.1210/en.143.3.1008 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 524WA UT WOS:000174034800032 PM 11861526 ER PT J AU Zhang, BJ Kusano, K Zerfas, P Iacangelo, A Young, WS Gainer, H AF Zhang, BJ Kusano, K Zerfas, P Iacangelo, A Young, WS Gainer, H TI Targeting of green fluorescent protein to secretory granules in oxytocin magnocellular neurons and its secretion from neurohypophysial nerve terminals in transgenic mice SO ENDOCRINOLOGY LA English DT Article ID CELL-SPECIFIC EXPRESSION; RAT NEUROHYPOPHYSIS; HORMONE NEURONS; VASOPRESSINERGIC NEURONS; INTRACELLULAR CALCIUM; STIMULATED RELEASE; SUPRAOPTIC NUCLEUS; LACTATING RATS; CA2+ CHANNELS; NEUROPHYSIN AB Oxytocin (OT) is a hypothalamic nonapeptide that is synthesized as part of a larger precursor protein that also contains an approximately 10-kDa protein called neurophysin at its C-terminus. This precursor protein is trafficked through the regulated secretory pathway into secretory granules and then axonally transported to and secreted from nerve terminals in the neural lobe of the pituitary. In this paper, we show that the AI-03 transgene that contains enhanced green fluorescent protein (EGFP) fused to the end of the neurophysin at the C-terminus of the OT pre-prohormone, is expressed sclectively in OT-magnocellular neurons and is trafficked to secretory granules in transgenic mice. The EGFP-containing secretory granules are then transported to OT-neurosecretory terminals in the neurohypophysis, where the EGFP fluorescence undergoes depolarization-induced calcium-dependent secretion. The endogenous fluorescence in the neural lobes is sufficiently intense to image secretory events in individual OT nerve terminals (neurosecretosomes) isolated from the posterior pituitaries in these transgenic mice. C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINCDS, Electron Microscope Facil, NIH, Bethesda, MD 20892 USA. NIMH, Sect Neural Gene Express, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINCDS, Neurochem Lab, NIH, Bldg 36,Room 4D04, Bethesda, MD 20892 USA. RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 NR 61 TC 30 Z9 31 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2002 VL 143 IS 3 BP 1036 EP 1046 DI 10.1210/en.143.3.1036 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 524WA UT WOS:000174034800035 PM 11861530 ER PT J AU Vgontzas, AN Chrousos, GP AF Vgontzas, AN Chrousos, GP TI Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; TUMOR-NECROSIS-FACTOR; EYE-MOVEMENT SLEEP; SLOW-WAVE SLEEP; HEALTHY-MEN; CLINICAL IMPLICATIONS; DAYTIME SLEEPINESS; CHRONIC INSOMNIA; GROWTH-HORMONE; FACTOR-ALPHA AB Sleep is an important component of mammalian homeostasis, vital for our survival. Sleep disorders are common in the general population and are associated with significant medical, psychologic, and social disturbances. Sleep, in particular deep sleep, has an inhibiting influence on the hypothalamic-pituitary-adrenal (HPA) axis, whereas activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. Insomnia, the most common sleep disorder, is associated with a 24-hour increase of corticotropin and cortisol secretion, consistent with a disorder of central nervous system hyperarousal. Sleepiness and fatigue are very prevalent in the general population, and recent studies have demonstrated that the proinflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) are elevated in disorders associated with excessive daytime sleepiness, such as sleep apnea, narcolepsy, and idiopathic hypersomnia. Sleep deprivation leads to sleepiness and daytime hypersecretion of IL-6. Combined, these findings suggest that the HPA axis stimulates arousal whereas IL-6 and TNF-alpha are possible mediators of excessive daytime sleepiness in humans. C1 Penn State Univ, Dept Psychiat, Coll Med, Hershey, PA 17033 USA. NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Vgontzas, AN (reprint author), Penn State Univ, Dept Psychiat, Coll Med, H073 500 Univ Dr, Hershey, PA 17033 USA. NR 87 TC 167 Z9 176 U1 1 U2 18 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD MAR PY 2002 VL 31 IS 1 BP 15 EP + AR PII S0889-8529(01)00005-6 DI 10.1016/S0889-8529(01)00005-6 PG 24 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557RX UT WOS:000175922900003 PM 12055986 ER PT J AU Gold, PW Gabry, KE Yasuda, MR Chrousos, GP AF Gold, PW Gabry, KE Yasuda, MR Chrousos, GP TI Divergent endocrine abnormalities in melancholic and atypical depression: clinical and pathophysiologic implications SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Review ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL AXIS; PLASMA NOREPINEPHRINE LEVELS; SYMPATHETIC NERVOUS-SYSTEM; MEDIAL PREFRONTAL CORTEX; CORONARY HEART-DISEASE; MESSENGER-RNA LEVELS; CEREBRAL BLOOD-FLOW; MAJOR DEPRESSION; CEREBROSPINAL-FLUID AB Mediators of neuroendocrine and autonomic function seem to play important roles in the core symptoms of major depression. Although centrally directed corticotropin-releasing hormones and norepinephrine contribute to core symptoms such as alterations in anxiety, arousal, and mood, they also exert significant potentially clinically relevant effects on key processes that proceed in the periphery. Thus, the core clinical manifestations of major depression may represent a fraction of a complicated systemic illness that not only influences thought and feeling, but also the processes involved in premature cardiovascular disease, osteoporosis, and premature death. Subdividing patients with major depression into meaningful biologic subgroups will facilitate the elucidation of the mechanisms that underlie the central and peripheral manifestations of major depressive illness. C1 NIMH, Clin Endocrinol Branch, Intramural Res Program, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Gold, PW (reprint author), NIMH, Clin Endocrinol Branch, Intramural Res Program, Bethesda, MD 20892 USA. NR 119 TC 62 Z9 65 U1 3 U2 8 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD MAR PY 2002 VL 31 IS 1 BP 37 EP + AR PII S0889-8529(01)00022-6 DI 10.1016/S0889-8529(01)00022-6 PG 27 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557RX UT WOS:000175922900004 PM 12055990 ER PT J AU Nagata, T Nakamori, M Iwahashi, M Yamaue, H AF Nagata, T Nakamori, M Iwahashi, M Yamaue, H TI Overexpression of pyrimidine nucleoside phosphorylase enhances the sensitivity to 5 '-deoxy-5-fluorouridine in tumour cells in vitro and in vivo SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE pyrimidine nucleoside phosphorylase (PyNPase); 5 '-deoxy-5-fluorouridine (5 '-DFUR); gene therapy ID ADVANCED COLORECTAL-CANCER; GROWTH-FACTOR ACTIVITY; THYMIDINE-PHOSPHORYLASE; PHASE-II; INFUSION FLUOROURACIL; THERAPEUTIC EFFICACY; COLORIMETRIC ASSAY; TGF-ALPHA; IN-VIVO; 5-FLUOROURACIL AB 5-Fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR), a prodrug of 5-FU, are representative of the chemotherapeutic agents for colorectal adenocarcinomas. Pyrimidine nucleoside phosphorylase (PyNPase) catalyses the conversion of 5'-DFUR to 5-FU, the activated form. Murine adenocarcinoma CT26 cells were transfected with human PYN Pase cDNA. The engineered transfectants producing PyNPase augmented the response to 5'-DFUR in vitro and in giro. Animals were administered by means of intraperitoneal (i.p.) injection, and not orally, in order to obtain a better efficiency of absorption. The tumours of the transfected cells nearly all disappeared, even following treatment with quite a small amount of the anticancer agent. The animals injected with the tranfected cells were protected against subsequent challenge with the parental tumour cell line. These findings demonstrate that PyNPase gene transfection increases the sensitivity to 5'-DFUR, and thereby decreases the toxicity of the agent. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Wakayama Sch Med, Dept Surg 2, Kimiidera, Japan. RP Nagata, T (reprint author), NIAMSD, NIH, Autoimmun Branch, Bldg 10,6D46,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 TC 17 Z9 21 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2002 VL 38 IS 5 BP 712 EP 717 AR PII S0959-8049(01)00469-5 DI 10.1016/S0959-8049(01)00469-5 PG 6 WC Oncology SC Oncology GA 546PT UT WOS:000175283100019 PM 11916555 ER PT J AU Abrams, JS AF Abrams, JS TI Restructuring NCI-sponsored clinical trials in the USA SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2002 VL 38 SU 3 MA 323 BP S127 EP S127 DI 10.1016/S0959-8049(02)80409-9 PG 1 WC Oncology SC Oncology GA 542PE UT WOS:000175052800328 ER PT J AU Sotiriou, C Neo, SY McShane, L Korn, E Harris, AL Liu, ET AF Sotiriou, C Neo, SY McShane, L Korn, E Harris, AL Liu, ET TI cDNA microarray gene expression profiles as a potential prognostic and predictive tool for an improved management of breast cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 Free Univ Brussels, Inst Jules Bordet, Brussels, Belgium. Genome Inst Singapore, Singapore, Singapore. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Weatherall Inst Mol Med, Imperial Canc Res Fund, Mol Oncol Lab, Oxford OX3 9DU, England. RI Liu, Edison/C-4141-2008 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2002 VL 38 SU 3 MA 460 BP S164 EP S164 DI 10.1016/S0959-8049(02)80546-9 PG 1 WC Oncology SC Oncology GA 542PE UT WOS:000175052800462 ER PT J AU van Leeuwen, FE Hooning, MJ Aleman, BMP Travis, LB AF van Leeuwen, FE Hooning, MJ Aleman, BMP Travis, LB TI Second cancer risk following breast cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract ID ADJUVANT CHEMOTHERAPY; CONTRALATERAL BREAST; ENDOMETRIAL CANCER; LUNG-CANCER; THERAPY; RADIOTHERAPY; LEUKEMIA C1 Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2002 VL 38 SU 3 MA E14 BP S28 EP S30 PG 3 WC Oncology SC Oncology GA 542PE UT WOS:000175052800015 ER PT J AU Koch, CA Vortmeyer, A Diallo, R Poremba, C Giordano, TJ Sanders, D Bornstein, SR Chrousos, GP Pacak, K AF Koch, CA Vortmeyer, A Diallo, R Poremba, C Giordano, TJ Sanders, D Bornstein, SR Chrousos, GP Pacak, K TI Survivin: a novel neuroendocrine marker for pheochromocytoma SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; ANTI-APOPTOSIS GENE; CANCER; EXPRESSION; DISEASE; TYPE-2; NEUROBLASTOMA; CARCINOMAS; PROGNOSIS; PROTEINS AB Objective: To study survivin expression in human adrenal medulla and in benign and malignant pheochromocytoma tissue as a tool to predict tumor metastatic potential and prognosis. Design: Blinded study to assess the role of the anti-survivin antibody in chromaffin cells. Methods: We performed immunohistochemistry with a purified rabbit-polyclonal anti-survivin antibody on 39 formalin-fixed and paraffin-embedded pheochromocytoma/paraganglioma specimens, and on 10 normal adrenal medulla samples from patients unaffected by a chromaffin cell tumor. Fourteen samples were from 14 patients with benign pheochromocytoma (<8 year follow-up, mean 5.2 years), 18 specimens were from 12 patients with malignant pheochromocytoma (<13 year follow-up, mean 6.3 years), 5 samples were from 2 patients with malignant paraganglioma (<6 year follow-up, mean 4 years), and 2 specimens from 2 patients with benign paraganglioma (<7 year follow-up, mean 5.5 years). Malignancy was defined by metastases in non-chromaffin tissues. Staining intensity with the anti-survivin antibody was scored from 0 (none) to 3+ (heavy). Tissues from human kidney, breast, and melanoma served as controls. Results: All pheochromocytoma/paraganglioma specimens stained either 2+ or 3+. By analysis of variance (ANOVA), there was no statistically significant difference between the staining intensity of benign and malignant samples. All normal adrenal medulla specimens stained positively with anti-survivin but to a lesser degree than the chromaffin cell tumors (P < 0.01). Conclusions: Based on these findings, we conclude that (i) survivin may represent a novel neuroendocrine marker for chromaffin cell tumors, and (ii) survivin does not appear to reliably distinguish benign from malignant pheochromocytomas/paragangliomas and thus does not identify patients at risk of recurrent disease. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Munster, Gerhard Domagk Inst Pathol, D-4400 Munster, Germany. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. Univ Dusseldorf, Dept Endocrinol, D-4000 Dusseldorf, Germany. RP Koch, CA (reprint author), NICHD, PREB, NIH, Bldg 10,Rm 9D42, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242; Giordano, Thomas/0000-0003-0641-8873 NR 27 TC 30 Z9 39 U1 0 U2 1 PU BIO SCIENTIFICA LTD PI BRISTOL PA 16 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD MAR PY 2002 VL 146 IS 3 BP 381 EP 388 DI 10.1530/eje.0.1460381 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 606PT UT WOS:000178742900015 PM 11888845 ER PT J AU Choi, YN Simon-Stoos, K Puck, JM AF Choi, YN Simon-Stoos, K Puck, JM TI Hypo-active variant of IL-2 and associated decreased T cell activation contribute to impaired apoptosis in autoimmune prone MRL mice SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE autoimmune; MRL; T cell; apoptosis; IL-2 ID FAS-MEDIATED APOPTOSIS; MUTANT-GENE LPR; LYMPHOPROLIFERATIVE SYNDROME; MOUSE INTERLEUKIN-2; BIOLOGICAL-ACTIVITY; CONCANAVALIN-A; MUTATIONS; DEATH; STRAINS; SUSCEPTIBILITY AB Apoptosis of activated lymphocytes is crucial to the maintenance of immune homeostasis and self-tolerance, as demonstrated by the well-known autoimmune MRL/pr mouse lacking the death receptor Fas. However, even MRL+/+ activated T cells have a resistance to Fas-mediated apoptosis as compared to T cells from the non-autoimmune FVB/N strain. To understand the molecular mechanisms underlying these strain differences, we studied biochemical characteristics of T cells upon activation. Compared to FVB/N T cells, MRL T cells under-expressed procaspase-3 but over-expressed FLIPL. In addition, up-regulation of Bcl-X-L, IL-2, and CD25 was diminished in MRL cells, suggesting inadequate T cell activation. Upon finding that MRL, like other autoimmune strains NOD and SJL, has a hypo-active variant of the IL-2 gene, we added wild-type murine recombinanat (mr)IL-2 during activation. Exogenous mrIL-2 restored MRL apoptosis to the level of FVB/N; in addition, expression of procaspase-3, and FLIPL, Bcl-X-L and CD25 was normalized. These results suggest that defective MRL T cell activation, in part due to hypo-active IL-2, underlies the impaired apoptosis of this strain. In addition, the hypo-active variant of IL-2 shared among autoimmune strains may, by causing diminished cell activation and cell death, predispose these strains to develop autoimmune disease. C1 Kangwon Natl Univ, Coll Dent, Kangnung 210702, Kangwondo, South Korea. NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Choi, YN (reprint author), Kangwon Natl Univ, Coll Dent, 123 Chibyun Dong, Kangnung 210702, Kangwondo, South Korea. EM youngnim@kangnung.ac.kr; jpuck@nhgi.nih.gov NR 44 TC 6 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2002 VL 32 IS 3 BP 677 EP 685 DI 10.1002/1521-4141(200203)32:3<677::AID-IMMU677>3.0.CO;2-I PG 9 WC Immunology SC Immunology GA 531VY UT WOS:000174439000010 PM 11857342 ER PT J AU Yogeeswari, P Sriram, D Jit, LRJS Kumar, SS Stables, JP AF Yogeeswari, P Sriram, D Jit, LRJS Kumar, SS Stables, JP TI Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE benzothiazolylthiosemicarbazones; electroshock; pentylenetetrazole; neurotoxicity; fully kindled ID ANTIEPILEPTIC DRUG DEVELOPMENT; MAXIMAL ELECTROSHOCK SCREEN; PHARMACOLOGICAL FACTORS; LABORATORY EVALUATION; ARYL SEMICARBAZONES; SEIZURE MODELS; DERIVATIVES; AGENTS; STIMULATION AB Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the rat p.o. MES test at 30 mg kg(-1). Compound I [4-(6-chlorobenzothiazol-2-yl)-1-(3-isatinimino)thiosemicarbazone] emerged as the most promising one with an ED50 of 17.86 and 6.07 mg kg(-1) in mice i.p. and rat p.o., respectively. Compound I showed a weak ability to block the expression of fully kindled seizures. (C) 2002 Published by Editions scientifiques et medicales Elsevier SAS. C1 Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. NIH, Preclin Pharmacol Sect, Epilepsy Branch, Bethesda, MD 20892 USA. RP Yogeeswari, P (reprint author), Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. NR 24 TC 45 Z9 46 U1 0 U2 2 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD MAR PY 2002 VL 37 IS 3 BP 231 EP 236 AR PII S0223-5234(02)01338-7 DI 10.1016/S0223-5234(02)01338-7 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 546PN UT WOS:000175282700005 PM 11900867 ER PT J AU Costa, PT Herbst, JH McCrae, RR Samuels, J Ozer, DJ AF Costa, PT Herbst, JH McCrae, RR Samuels, J Ozer, DJ TI The replicability and utility of three personality types SO EUROPEAN JOURNAL OF PERSONALITY LA English DT Article; Proceedings Paper CT 1st Expert Workshop on Personality Psychology: Personality Structure and Development Across the Life-Span CY OCT 29-NOV 01, 2000 CL GHENT, BELGIUM SP European Assoc Peronal Psychol ID AREA FOLLOW-UP; 5-FACTOR MODEL; CHILDREN; DISORDER; PROTOTYPES; PREDICTION; RESILIENT; CHILDHOOD; BEHAVIOR; TRAITS AB Personality types are construed as constellations of features that uniquely define discrete groups of individuals. Types are conceptually convenient because they summarize many traits in a single label, but until recently most researchers agreed that there was little evidence for the existence of discrete personality types. Several groups of researchers have now proposed replicable, empirical person clusters based on measures of the Five-Factor Model. We consider several methodological artifacts that might be responsible for these types, and conclude that these artifacts may contribute to the replicability of types, but cannot entirely account for it. The present research attempts to replicate these types in four large and diverse adult samples: the Baltimore Longitudinal Study of Aging (N = 1856); the East Baltimore Epidemiologic Catchment Area study (N = 486); the University of North Carolina Alumni Heart Study (N = 2 420); and an HIV risk reduction intervention study (N = 274). A clear replication (kappa = 0.60) of the proposed types vas found in only one sample by one standard of comparison. The failure of the three personality types to replicate in three of the four samples leads to the conclusion that they are not robust empirical entities. Type membership predicted psychosocial functioning and ego resiliency and control, but only because it summarized trait standing; dimensional trait measures were consistently better predictors. Nevertheless, while the types do not refer to distinct, homogeneous classes of persons, they do have utility as convenient labels summarizing combinations of traits that relate to important outcomes. Published in 2002 by John Wiley Sons, Ltd. C1 NIA, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Univ Calif Riverside, Riverside, CA 92521 USA. RP Costa, PT (reprint author), Ctr Gerontol Res, Personal Stress & Coping Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 45 Z9 45 U1 7 U2 15 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0890-2070 J9 EUR J PERSONALITY JI Eur. J. Personal. PD MAR PY 2002 VL 16 SU 1 BP S73 EP S87 DI 10.1002/per.448 PG 15 WC Psychology, Social SC Psychology GA 544UZ UT WOS:000175181200006 ER PT J AU Drevets, W AF Drevets, W TI Neuroimaging correlates of antidepressant drug response in depression SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 NIMH, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2002 VL 12 SU 1 BP S5 EP S6 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 538VF UT WOS:000174835200007 ER PT J AU Raedler, TJ Knable, MB Jones, DW Gorey, JG Lee, KS Sunderland, T Weinberger, DR AF Raedler, TJ Knable, MB Jones, DW Gorey, JG Lee, KS Sunderland, T Weinberger, DR TI Age-related changes in central muscarinic receptor availability in vivo SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Univ Hamburg, Dept Psychiat, Hamburg, Germany. Stanley Res Fdn, Rockville, MD 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 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2002 VL 12 SU 1 BP S14 EP S14 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 538VF UT WOS:000174835200016 ER PT J AU Grande, JP Warner, GM Walker, HJ Yusufi, ANK Cheng, JF Gray, CE Kopp, JB Nath, KA AF Grande, JP Warner, GM Walker, HJ Yusufi, ANK Cheng, JF Gray, CE Kopp, JB Nath, KA TI TGF-beta 1 is an autocrine mediator of renal tubular epithelial cell growth and collagen IV production SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Review DE TGF-beta 1; proliferation; collagen IV; kidney; tubular epithelial cells ID EXPERIMENTAL DIABETIC NEPHROPATHY; HUMAN TUBULOINTERSTITIAL CELLS; BASEMENT-MEMBRANE DISEASE; FACTOR-BETA ISOFORMS; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; MESANGIAL CELLS; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; INTERSTITIAL FIBROSIS AB Recent studies in cultured cells have provided evidence that a variety of pathobiologic stimuli, including high glucose, angiotensin 11, and thromboxane A(2), trigger a signaling pathway leading to autocrine induction of TGF-beta1. TGF-beta1 production through this pathway may profoundly affect cell growth, matrix synthesis, and response to injury. This study examines the role of autocrine versus exogenously added TGF-beta1 in cellular proliferation and collagen IV production, critical targets of TGF-beta1 signaling, using renal cells derived from TGF-beta1 knockout (KO) animals or wild-type (WT) controls. Growth of WT and KO cells was assessed by cell counting and [H-3]thymidine uptake. Basal and TGF-beta1-stimulated collagen production was assessed by Northern and Western blotting; transcriptional activity of the alpha1(IV) collagen gene was assessed by transient transfection analysis. KO cells grew at a faster rate than WT cells carefully matched for plating density and passage number. This increased growth rate was paralleled by increases in [3H]thymidine uptake. KO cells expressed lower levels of the cell cycle inhibitors p2l and p27 than WT cells. KO cells failed to express TGF-beta1, as expected. Basal TGF-beta3 mRNA levels were higher in KO cells than in WT cells. WT cells expressed higher basal levels of TGF-beta2 mRNA than KO cells. Basal alpha1(IV) and alpha2(IV) collagen mRNA and protein expression were significantly lower in KO cells than WT cells. Administration of exogenous TGF-beta1 induced collagen IV production in both KO and WT cells. Although basal transcriptional activity of an alpha1(IV) collagen-CAT construct was lower in KO cells than WT cells, administration of exogenous TGF-beta1 was associated with significant increases in transcriptional activity of this construct in both KO and WT cells. These studies provide evidence that autocrine production of TGF-beta1 may play a critical role in regulation of growth and basal collagen IV production by renal tubular epithellial cells. C1 Mayo Clin, Dept Lab Med & Pathol, Renal Pathophysiol Lab, Rochester, MN 55905 USA. Mayo Clin, Dept Internal Med, Div Nephrol, Rochester, MN 55905 USA. NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Grande, JP (reprint author), Mayo Clin & Mayo Fdn, Dept Lab Med, 200 1st St SW, Rochester, MN 55905 USA. NR 107 TC 25 Z9 27 U1 0 U2 7 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAR PY 2002 VL 227 IS 3 BP 171 EP 181 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 522VM UT WOS:000173917700004 PM 11856815 ER PT J AU Wang, JF Yang, YK Sullivan, MF Min, JY Cai, JB Zeldin, DC Xiao, YF Morgan, JP AF Wang, JF Yang, YK Sullivan, MF Min, JY Cai, JB Zeldin, DC Xiao, YF Morgan, JP TI Induction of cardiac cytochrome P450 in cocaine-treated mice SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE cardiac P450; cocaine; TNF-alpha; mouse ID ARACHIDONIC-ACID EPOXYGENASE; INDUCED LIVER-INJURY; MOLECULAR-CLONING; HEART; EXPRESSION; MYOCYTES; EXPOSURE; CASCADE; DEATH; ALPHA AB Cytochrome P450 (P450) is a ubiquitous family of enzymes responsible for the metabolism of a wide variety of drugs and their metabolites, including cocaine. To investigate the effects of cocaine on myocardial injuries and cardiac P450 expression, BALB/c mice were injected daily intraperitoneally with cocaine (30 mg/kg) or cocaine plus pretreatment of P450 inhibitors for 14 days. Tumor necrosis factor-alpha (TNF-alpha) content and creatine phosphokinase (CPK) activity in mice hearts and serums were significantly increased after long-term treatment with cocaine. Pretreatment with the P450 inhibitor, cimetidine (Cime, 50 mg/kg) or metyrapone (Mety, 40 mg/kg) abolished or significantly attenuated the effects of cocaine on TNF-a and CPK activity. Western blot analysis shows that mouse cardiac tissues express the P450 isoforms CYP1A1, CYP1A2, and CYP2J2. The protein levels normalized with cyclophilin A were 1.20 +/- 0.07, 0.67 +/- 0.03, and 1.48 +/- 0.01 for CYP1A1, CYP1A2, and CYP2J2, respectively. After cocaine administration, CYP2J2 increased by 43.6% and CYP1A1 increased by 108.5%, but CYP1A2 was not significantly altered. However, the cytochrome P450 inhibitors Cime and Mety suppressed the cocaine-induced increase in CYP1A1 and CYP2J2 expression. Moreover, application of Cime or Mety alone did not alter the level of cardiac TNF-a or the expression of P450. Our results demonstrate that long-term exposure to cocaine causes an increase in cardiac CYP1A1 and CYP2J2 concentration. We speculate that induction of P450 isoforms may cause cardiac injury due to cocaine metabolites locally catalyzed by P450 or the increase in P450 expression itself. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. NIEHS, Labs Pulm Pathobiol, Res Triangle Pk, NC 27709 USA. RP Morgan, JP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. FU NIDA NIH HHS [R01 DA11762-01] NR 23 TC 29 Z9 32 U1 0 U2 0 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAR PY 2002 VL 227 IS 3 BP 182 EP 188 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 522VM UT WOS:000173917700005 PM 11856816 ER PT J AU Mujtaba, T Han, SSW Fischer, I Sandgren, EP Rao, MS AF Mujtaba, T Han, SSW Fischer, I Sandgren, EP Rao, MS TI Stable expression of the alkaline phosphatase marker gene by neural cells in culture and after transplantation into the CNS using cells derived from a transgenic rat SO EXPERIMENTAL NEUROLOGY LA English DT Article DE alkaline phosphatase; transgenic rat; transplant; stem cell; neuron; astrocyte; oligodendrocyte; NRP; GRP; O2A ID NEUROEPITHELIAL STEM-CELLS; SPINAL-CORD; RETROVIRAL VECTORS; PROGENITOR CELLS; PRECURSORS; PROGRESS; NEURONS; STRAIN; MICE; TUBE AB Multipotent stem cells and more developmentally restricted precursors have previously been isolated from the developing nervous system and their properties analyzed by culture assays in vitro and by transplantation in vivo. However, the variety of labeling techniques that have been used to identify grafted cells in vivo have been unsatisfactory. In this article we describe the characteristics of cells isolated from a transgenic rat in which the marker gene human placental alkaline phosphatase (hPAP) is linked to the ubiquitously active R26 gene promoter. We show that hPAP is readily detected in embryonic neuroepithelial stem cells, neuronal-restricted precursor cells, and glial-restricted precursor cells. Transgene expression is robust and can be detected by both immunocytochemistry and histochemistry. Furthermore, the levels of hPAP on the cell surface are sufficient for live cell labeling and fluorescence-activated cell sorting. Expression of hPAP is stable in isolated cells in culture and in cells transplanted into the spinal cord for at least 1 month. We submit that cells isolated from this transgenic rat will be valuable for studies of neural development and regeneration. (C) 2002 Elsevier Science (USA). C1 NIA, Neurosci Lab, GRC, Baltimore, MD 21224 USA. Univ Utah, Sch Med, Dept Neurobiol & Anat, Salt Lake City, UT 84132 USA. MCPHU, Sch Med, Dept Neurobiol & Anat, Philadelphia, PA 19129 USA. Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. RP Rao, MS (reprint author), NIA, Neurosci Lab, GRC, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Fischer, Itzhak/0000-0003-3187-8740 NR 31 TC 43 Z9 45 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAR PY 2002 VL 174 IS 1 BP 48 EP 57 DI 10.1006/exnr.2001.7847 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 531FX UT WOS:000174406300006 PM 11869033 ER PT J AU Mozes, MM Bryant, JL Franks, R Chan, CC Kopp, JB AF Mozes, MM Bryant, JL Franks, R Chan, CC Kopp, JB TI Congenital nuclear cataracts and uveitis in HIV-transgenic mice SO EYE LA English DT Article DE envelope protein; gp 120; HIV-1; nuclear cataract; transgenic mouse; uveitis ID HUMAN-IMMUNODEFICIENCY-VIRUS; A-CRYSTALLIN PROMOTER; INFECTION; CYTOMEGALOVIRUS; GENES; AIDS AB Purpose Patients infected with HIV-1 develop ocular manifestations, some due to opportunistic infections and others attributed to the virus itself. Among the latter are retinal microvasculopathy and uveitis. We have analysed the ocular phenotype in HIV-transgenic mice. Methods We have studied T26 transgenic mice which bear a gag-pol deleted HIV-1 genome. Transgene RNA was detected by Northern analysis. Ocular pathology was assessed by conventional histology, immunostaining for gp120 envelope protein, and in situ apoptosis detection with end-labelling. Results Abnormalities of lens epithelial cell development were detected as early as embryonic day 14.5. Histological changes included the malformation of an embryonal lens nucleus and poor closure of the lens suture lines. This resulted in congenital nuclear cataracts, as occur in congenital viral infections in human patients. In the adult animals, lenses were notable for extensive vacuolation, liquefaction, and degeneration of the cortex. Mild iridocyclitis and vitritis were also noted in adult transgenic mice. Immunostaining demonstrated the expression of gp 120 envelope protein within the lens epithelial and fibre cells. End-labelling with terminal deoxyribonucleotidyl transferase showed increased numbers of apoptotic cells in the adult lens. Conclusions These findings suggest that one or more HIV-1 proteins are associated with congenital nuclear cataract formation and uveitis in HIV-transgenic mice. C1 NIDDKD, Kidney Dis Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Sch Med, Inst Pathophysiol, Budapest, Hungary. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Univ Illinois, Coll Med, Dept Mol Genet, Chicago, IL USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDKD, Kidney Dis Sect, Metab Dis Branch, NIH, Bldg 10,Room 3N116, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X NR 28 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD MAR PY 2002 VL 16 IS 2 BP 177 EP 184 PG 8 WC Ophthalmology SC Ophthalmology GA 558JQ UT WOS:000175962900013 PM 11988819 ER PT J AU Gafni, RI McCarthy, EF Hatcher, T Meyers, JL Inoue, N Reddy, C Weise, M Barnes, KM Abad, V Baron, J AF Gafni, RI McCarthy, EF Hatcher, T Meyers, JL Inoue, N Reddy, C Weise, M Barnes, KM Abad, V Baron, J TI Recovery from osteoporosis through skeletal growth: early bone mass acquisition has little effect on adult bone density SO FASEB JOURNAL LA English DT Article DE child; glucocorticoids; dexamethasone; adolescence; bone density ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MINERAL DENSITY; DIETARY CALCIUM; CHILDREN; MECHANISMS; CHILDHOOD; RABBIT; GLUCOCORTICOIDS; DETERMINANTS; DEFICIENCY AB It is often assumed that bone mineral accretion should be optimized throughout childhood to maximize peak bone mass. In contrast, we hypothesized that bone mineral acquisition early in life would have little or no effect on adult bone mass because many areas of the juvenile skeleton are replaced in toto through skeletal growth. To test this hypothesis, we induced osteoporosis by administering dexamethasone to 5-week-old rabbits for 5 weeks and then allowed them to recover for 16 weeks. Tibial bone mineral density (ash weight/volume) was decreased in the dexamethasone-treated animals at the end of treatment but recovered completely. Bone structure in the femur was assessed by histomorphometry. Trabecular and cortical bone in the distal metaphysis was made osteoporotic by dexamethasone, but was then replaced through endochondral bone formation and recovered. Periosteal bone formation rate in the diaphysis was decreased during dexamethasone treatment but afterwards rebounded above controls and normalized cortical width. Our data suggest that bone mineral acquisition early in life has little effect on adult bone density because the juvenile bone is largely replaced through growth. If this concept generalizes, then interventions to maximize peak bone mass should be directed at adolescents rather than young children. C1 NICHHD, Unit Growth & Dev, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bone Histomorphometry Lab, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Orthopaed Biomech Lab, Dept Orthopaed Surg, Baltimore, MD USA. RP Gafni, RI (reprint author), NICHHD, Unit Growth & Dev, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. EM gafnir@mail.nih.gov NR 34 TC 40 Z9 43 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2002 VL 16 IS 3 BP 736 EP + DI 10.1096/fj.01-0640fje PG 16 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 537JV UT WOS:000174755900003 PM 11923218 ER PT J AU Cristillo, AD Highbarger, HC Dewar, RL Dimitrov, DS Golding, H Bierer, BE AF Cristillo, AD Highbarger, HC Dewar, RL Dimitrov, DS Golding, H Bierer, BE TI Up-regulation of HIV coreceptor CXCR4 expression in human T lymphocytes is mediated in part by a cAMP-responsive element SO FASEB JOURNAL LA English DT Article DE CXCR4; HIV; cyclic AMP; CREB; chemokine receptors; AIDS ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOKINE RECEPTOR CXCR4; HEMATOPOIETIC PROGENITOR CELLS; DOWN-MODULATION; SURFACE EXPRESSION; CUTTING EDGE; CYCLIC-AMP; INFECTION; ENTRY; REPLICATION AB The chemokine and HIV receptor CXCR4 has been shown to play a role in chemotaxis and HIV-1 entry into T cells. Dibutyryl cAMP (DcAMP), an analog of cAMP, has been shown to increase CXCR4 cell surface expression and HIV-1 infectivity, but the molecular mechanism(s) responsible is unknown. Here we show that DcAMP treatment of purified human T lymphocytes increased transcription of CXCR4 mRNA as well as cell surface and intracellular CXCR4 protein expression. DcAMP-mediated stimulation of human PBL increased T-trophic HIV-1 (X4) fusion and viral replication as measured by syncytia formation and p24 levels, respectively. To determine the region( s) of the CXCR4 promoter required for cAMP responsiveness, truncations and point mutations of the CXCR4 promoter (nucleotides -1098 to +59) fused to luciferase were constructed and transiently transfected into human PBL. Deletional analysis demonstrated that the -1098 to -93 region of the CXCR4 promoter construct could be eliminated; the residual (-93 to +59) promoter retained cAMP responsiveness. Site-directed mutagenesis of a putative cAMP-responsive element (CRE) in the 5' UTR (+41 to +49) significantly and specifically attenuated the ability of DcAMP to drive the minimal CXCR4 promoter. Electrophoretic mobility shift assays demonstrated the formation of a complex between the CREB transcription factor and the putative CXCR4 CRE site. Our findings demonstrate a CRE element within the CXCR4 promoter that regulates CXCR4 transcription in response to changes in cAMP signaling. The cAMP-dependent up-regulation of CXCR4 mRNA results in increased CXCR4 intracellular and cell surface protein expression as well as increased HIV infectivity. C1 NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. NIAID, SAIC AIDS Monitoring Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Bierer, BE (reprint author), NHLBI, Lab Lymphocyte Biol, NIH, Bldg 10,Room 6C208,10 Ctr Dr, Bethesda, MD 20892 USA. EM biererb@nih.gov NR 56 TC 31 Z9 32 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2002 VL 16 IS 3 AR UNSP 0892-6638/02/0016-0354 DI 10.1096/fj.01-0744com PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 537JV UT WOS:000174755900027 PM 11874984 ER PT J AU Arraztoa, JA Rocha, A Varela-Nallar, L Velasquez, L Toro, V Cardenas, H Imarai, M AF Arraztoa, JA Rocha, A Varela-Nallar, L Velasquez, L Toro, V Cardenas, H Imarai, M TI IgA in the lumen of the human oviduct is not related to the menstrual cycle but increases during local inflammation SO FERTILITY AND STERILITY LA English DT Editorial Material ID IMMUNE-SYSTEM; IMMUNOGLOBULINS C1 Univ Santiago Chile, Fac Quim & Biol, Dept Biol, Lab Immunol Reprod, Santiago, Chile. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. Univ Andes, Dept Obstet & Ginecol, Fac Med, Merida, Venezuela. Univ Santiago Chile, Fac Quim & Biol, Santiago, Chile. Hosp San Jose, Serv Ant Patol, Santiago, Chile. RP Imarai, M (reprint author), Univ Santiago Chile, Fac Quim & Biol, Dept Biol, Lab Immunol Reprod, 40 Correo 33, Santiago, Chile. NR 12 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAR PY 2002 VL 77 IS 3 BP 633 EP 634 AR PII S0015-0282(01)03214-9 DI 10.1016/S0015-0282(01)03214-9 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 531AT UT WOS:000174393000038 PM 11872227 ER PT J AU Pennington, JAT Hernandez, TB AF Pennington, JAT Hernandez, TB TI Core foods of the US food supply SO FOOD ADDITIVES AND CONTAMINANTS LA English DT Article; Proceedings Paper CT 24th National Nutrient Databank Conference CY JUL 27-29, 2000 CL ST PAUL, MINNESOTA SP Univ Minnesota, Nutrit Coordinating Ctr DE core foods; dietary exposure models; dietary intake; dietary assessment; total diet studies ID TOTAL DIET; REVISION; HISTORY AB The core food dietary intake/exposure model may be used to assess the average intake of nutrients, contaminants and other food components by a population group and various subgroups of the population. The core food model is a mechanism that allows for the selection of the most important foods in a population's food supply so that these foods can be obtained and analysed in the laboratory. The core foods for a population change over time as food consumption patterns are altered by changes in the food supply and/or changes in the demographics of the population. Core foods of the US diet were selected using food consumption data from the 1994-96 US Department of Agriculture (USDA) Continuing Survey of the Food Intake of Individuals (CSFII). The 304 core foods were identified by placing the 5722 foods consumed by survey participants into about 300 groups. The groupings were based on food type, food use and similarity of nutrient composition. The foods within each grouping were ranked in terms of frequency of use and weight of intake, and one food item within each group was selected to become a core food and represent its group. In the model, each core food assumes the full dietary intake (by weight) for all the foods in its group. Daily mean intakes of the 304 selected core foods are presented for women and men of 19-30 years of age. If the food components of interest to investigators using this model are found in selected foods or food types, then only these foods need be analysed. The list of 304 core foods may be shortened by further aggregation to match the needs of different investigators. For example, limited data on food composition may warrant use of a shorter core food list. A shortened food list with average daily intakes of 78 core foods for women and men of 19-30 years of age is provided as an example. C1 NIH, DNRC, Bethesda, MD 20892 USA. Hlth Technom Inc, Annandale, VA 22003 USA. RP Pennington, JAT (reprint author), NIH, DNRC, 6707 Democracy Blvd,Room 629, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 3 U1 0 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK,, ABINGDON OX14 4RN, OXON, ENGLAND SN 0265-203X J9 FOOD ADDIT CONTAM JI Food Addit. Contam. PD MAR PY 2002 VL 19 IS 3 BP 246 EP 271 DI 10.1080/02652030110081164 PG 26 WC Chemistry, Applied; Food Science & Technology; Toxicology SC Chemistry; Food Science & Technology; Toxicology GA 514PX UT WOS:000173451200005 PM 11837242 ER PT J AU Gill, B Chang, J Palmer, S AF Gill, B Chang, J Palmer, S TI China's HIV crisis SO FOREIGN AFFAIRS LA English DT Article AB In a stunning announcement last June, the Chinese government revealed that the country could have as many as 600,000 HIV cases, Outside organizations estimate that the number could be two or three times larger, Once dismissed by Chinese officialdom as a Western problem, the spread of HIV is only now getting serious attention from Beijing. But it may be too late: China already faces a major epidemic. C1 Brookings Inst, Foreign Policy Studies Program, Washington, DC 20036 USA. NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 18 Z9 18 U1 1 U2 1 PU COUNC FOREIGN RELAT INC PI NEW YORK PA 58 E 68TH ST, NEW YORK, NY 10021 USA SN 0015-7120 J9 FOREIGN AFF JI Foreign Aff. PD MAR-APR PY 2002 VL 81 IS 2 BP 96 EP + DI 10.2307/20033087 PG 16 WC International Relations SC International Relations GA 525QA UT WOS:000174081400009 ER PT J AU Le Provost, F Riedlinger, G Yim, SH Benedict, J Gonzalez, FJ Flaws, J Hennighausen, L AF Le Provost, F Riedlinger, G Yim, SH Benedict, J Gonzalez, FJ Flaws, J Hennighausen, L TI The aryl hydrocarbon receptor (AhR) and its nuclear translocator (Arnt) are dispensable for normal mammary gland development but are required for fertility SO GENESIS LA English DT Article DE mammary glands; ovary; mouse; cre; loxP; aryl hydrocarbone receptor ID MICE LACKING; GENE; EXPRESSION; MOUSE; DIFFERENTIATION; DISRUPTION; DELETION AB The aryl hydrocarbon receptor (AhR) and its nuclear translocator (Arnt) are transcription factors that play a role in the detection of and adaptation to environmental signals. AhR-null mice are viable but show impaired lactation. Deletion of the Arnt gene from the mouse genome results in embryonic lethality. To determine the role of Arnt in mammary development and function, we inactivated the Arnt gene in mammary epithelium using Cre-loxP recombination. Inactivation of the Arnt gene during pregnancy did not disrupt alveolar development or the ability of dams to nurse their litters. In contrast, dams in which the Arnt gene had been inactivated during puberty and in ovaries were subfertile, exhibited retarded mammary development, and impaired mammary function. To distinguish defects autonomous to mammary epithelium from indirect effects controlled by ovarian hormones, we transplanted Arnt-null and AhR-null mammary epithelium into wild-type mice and evaluated development after one pregnancy. Normal mammary structures were observed in the absence of Arnt and AhR, demonstrating that neither transcription factor is necessary for mammary development. genesis 32:231-239, 2002. (C) 2002 Wiley-Liss, Inc. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. INRA, Lab Genet Biochim & Cytogenet, Jouy En Josas, France. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101, Bethesda, MD 20892 USA. NR 23 TC 19 Z9 19 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD MAR PY 2002 VL 32 IS 3 BP 231 EP 239 DI 10.1039/gene.10037 PG 9 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 533PB UT WOS:000174538100006 PM 11892012 ER PT J AU Morrison, AC Ballantyne, CM Bray, M Chambless, LE Sharrett, AR Boerwinkle, E AF Morrison, AC Ballantyne, CM Bray, M Chambless, LE Sharrett, AR Boerwinkle, E TI LPL polymorphism predicts stroke risk in men SO GENETIC EPIDEMIOLOGY LA English DT Article DE genetics; risk factors; cerebral infarction; stroke; ischemic ID CORONARY-ARTERY DISEASE; LIPOPROTEIN-LIPASE GENE; EUROPEAN ATHEROSCLEROSIS RESEARCH; ISCHEMIC CEREBROVASCULAR-DISEASE; IMPROVED LIPOLYTIC EFFICIENCY; RECEPTOR-RELATED PROTEIN; HDL-CHOLESTEROL; PLASMA-LIPIDS; ENZYMATIC DETERMINATION; CARDIOVASCULAR HEALTH AB Variation in lipid levels has been associated with atherosclerotic vascular disease, including stroke. Genes contributing to interindividual variation in lipid levels may play a role in the etiology of stroke, either through their effects on lipid synthesis and metabolism or through separate pathways. For this reason, we sought to examine the association between polymorphisms in the lipoprotein lipase (LPL) and apolipoprotein E (APOE) genes and subclinical and clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study. Subclinical stroke was determined by cerebral magnetic resonance imaging (MRI). Subclinical cerebral infarct cases (n = 197) were compared to a stratified random sample identified from individuals participating in the MRI examination (n = 200). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for an average of 7.5 years for potential cerebrovascular events; 218 validated clinical ischemic strokes were identified. A stratified random sample of the ARIC cohort (CRS, n = 964) was used as the comparison group for clinical cases. The LPL S291-carrying genotypes and APOE epsilon2- and epsilon4-carrying genotypes were not significantly associated with subclinical or clinical stroke. The LPL X447-containing genotypes were significantly associated with subclinical (odds ratio [OR], 4.32; 95% confidence interval [CI], 1.23-15.15; P = 0.020) and clinical stroke (hazard rate ratio [HRR], 2.57; 95% CI, 1.24-5.34; P = 0.01) in men, both by themselves and after adjustment for multiple stroke risk factors. The LPL S447X polymorphism is significantly associated with subclinical cerebral infarction and incident clinical ischemic stroke in men from a middle-aged American population. This association does not appear to be mediated by triglyceride, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol levels, or additional stroke risk factors. Genet. Epidemiol. 22:233-242, 2002. (C) 2002 Wiley-Liss, Inc. C1 Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77030 USA. Inst Mol Med, Houston, TX USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Boerwinkle, E (reprint author), Univ Texas, Hlth Sci Ctr, Ctr Human Genet, 1200 Herman Pressler,Suite 453E, Houston, TX 77030 USA. RI Ballantyne, Christie/A-6599-2008 FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 37 TC 33 Z9 37 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAR PY 2002 VL 22 IS 3 BP 233 EP 242 DI 10.1002/gepi.0191 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 534EW UT WOS:000174572500003 PM 11921083 ER PT J AU Tishler, PV Carey, VJ Reed, T Fabsitz, RR AF Tishler, PV Carey, VJ Reed, T Fabsitz, RR TI The role of genotype in determining the effects of cigarette smoking on pulmonary function SO GENETIC EPIDEMIOLOGY LA English DT Article DE smoking; cigarettes; pulmonary function; twins ID IDENTICAL-TWINS; DISEASE; SUSCEPTIBILITY; POLYMORPHISM; OBSTRUCTION; MECHANISMS; RISK AB The effect of cigarette smoking on pulmonary function is highly variable. Some heavy smokers retain normal pulmonary function and others experience profound pulmonary function loss. The role of genotype in this process is unknown. We tested for gene by environment interaction (GxE) in smoking-associated loss of forced expiratory volume in one second (FEVI) using repeated pulmonary function and smoke-exposure measures from 352 twin pairs enrolled in the NHLBI Male Veteran Twin Study. Inferences using global [Jinks and Fulk-er, 1970] and dichotomous [Ramakrishnan et al., 1992] procedures were supplemented with a new model for repeatedly observed twinships. The model facilitates testing of standard heritability hypotheses and families of hypotheses regarding the dependence of quantitative twin-twin phenotypic similarity on continuously varying twin-twin exposure concordance. The global and dichotomous procedures were suggestive of GxE in smoke-associated loss of FEVI (p < 0.01, p = 0.08, respectively). With the new model, overall twin-twin correlation of FEVI for concordant-smoking MZ and DZ twin pairs was estimated at 0.71 and 0.34, respectively. For twins with little or no difference in cigarette use, the intra-pair correlations of FEVI did not differ according to cigarette exposure over a wide range of exposures (0 - > 200 pack years). Even great twin-twin discordance in cigarette smoking (>10 pack years) had little effect of correlations. We conclude that a constant factor, such as genotype, appears to be interposed between the environmental toxin (cigarette smoke) and phenotype (FEVI). Genet. Epidemiol. 22:272282,2002. (C) 2002 Wiley-Liss, Inc. C1 VA Bost Hlth Care Syst, Boston, MA 02132 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. RP Tishler, PV (reprint author), VA Bost Hlth Care Syst, 1400 VFW Pkwy, Boston, MA 02132 USA. FU NHLBI NIH HHS [HL40619] NR 26 TC 10 Z9 10 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAR PY 2002 VL 22 IS 3 BP 272 EP 282 DI 10.1002/gepi.0186 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 534EW UT WOS:000174572500007 PM 11921087 ER PT J AU Robin, NH Biesecker, LG AF Robin, NH Biesecker, LG TI Use of a multiaxial diagnostic system in clinical genetics - Reply SO GENETICS IN MEDICINE LA English DT Letter C1 Case Western Reserve Univ, Univ Hosp Cleveland, Sch Med, Ctr Human Genet, Cleveland, OH 44106 USA. NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Robin, NH (reprint author), Case Western Reserve Univ, Univ Hosp Cleveland, Sch Med, Ctr Human Genet, Cleveland, OH 44106 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD MAR-APR PY 2002 VL 4 IS 2 BP 96 EP 96 DI 10.1097/00125817-200203000-00010 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 530RY UT WOS:000174373800010 ER PT J AU Driscoll, CA Menotti-Raymond, M Nelson, G Goldstein, D O'Brien, SJ AF Driscoll, CA Menotti-Raymond, M Nelson, G Goldstein, D O'Brien, SJ TI Genomic Microsatellites as evolutionary chronometers: A test in wild cats SO GENOME RESEARCH LA English DT Article ID CHEETAH ACINONYX-JUBATUS; TANDEM REPEAT LOCI; GENETIC-VARIATION; MUTATION-RATES; Y-CHROMOSOME; ALLELE FREQUENCIES; GERMLINE MUTATIONS; FLORIDA PANTHER; POPULATION; AFRICAN AB Nuclear microsatellite loci (2- to S-bp tandem repeats) would seem to be ideal markers for population genetic monitoring because of their abundant polymorphism, wide dispersal in vertebrate genomes, near selective neutrality, and ease of assessment; however, questions about their mode of generation, mutation rates and ascertainment bias have limited interpretation considerably. We have assessed the patterns of genomic diversity for ninety feline microsatellite loci among previously characterized populations of cheetahs, lions and Pumas in recapitulating demographic history. The results imply that the microsatellite diversity measures (heterozygosity, allele reconstitution and microsatellite allele variance) offer proportionate indicators, albeit with large variance, of historic population bottlenecks and founder effects. The observed rate of reconstruction of new alleles Plus the growth in the breadth of microsatellite allele size (variance) was used here to develop genomic estimates of time intervals following historic founder events in cheetahs (12,000 yr ago), in North American Pumas (10,000-17,000 yr ago), and in Asiatic lions of the Gir Forest (1000-4000 yr ago). C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Hood Coll, Dept Biol, Frederick, MD 21701 USA. UCL, Galton Lab, Dept Biol, London NW1 2HE, England. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov OI Driscoll, Carlos/0000-0003-2392-505X NR 69 TC 57 Z9 59 U1 5 U2 33 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAR PY 2002 VL 12 IS 3 BP 414 EP 423 DI 10.1101/gr.185702 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 527DP UT WOS:000174171300007 PM 11875029 ER PT J AU Barber, TD Barber, MC Tomescu, O Barr, FG Ruben, S Friedman, TB AF Barber, TD Barber, MC Tomescu, O Barr, FG Ruben, S Friedman, TB TI Identification of target genes regulated by PAX3 and PAX3-FKHR in embryogenesis and alveolar rhabdomyosarcoma SO GENOMICS LA English DT Article DE CASTing; PAX3; Waardenburg; cancer; ARMS; FKHR; EN2; TGFA; VEGF; Itm2A; and BVES ID GROWTH-FACTOR-ALPHA; TRANSCRIPTION FACTOR; PAIRED BOX; IN-VIVO; CHROMOSOMAL TRANSLOCATIONS; WAARDENBURG-SYNDROME; MUSCLE DEVELOPMENT; FUSION PROTEIN; MUTANT MOUSE; EXPRESSION AB PAX3 is a transcription factor important for neural, muscle, and facial development in vertebrates. To identify genes regulated by PAX3, we used a cyclic amplification and selection of targets (CASTing) strategy to isolate cis-regulatory elements bound by PAX3. CASTing libraries were constructed with mouse DNA fragments bound by mouse PAX3, and human genomic DNA fragments bound by human PAX3 and the fusion protein PAX3-FKHR. Approximately 1000 clones were sequenced from each of these three libraries. Numerous putative targets of PAX3 and PAX3-FKHR were identified and six genes, Itm2A, Fath, FLT1, TGFA, BVES, and EN2, were examined closely. The genomic DNA fragments near these genes contain PAX3 binding sites and confer PAX3-dependent regulation. The expression levels of these genes correlate with the PAX3 expression levels in mouse embryos or with PAX3-FKHR expression levels in rhabdomyosarcoma cell lines, and indicate they may be part of the PAX3 regulatory circuitry during embryogenesis and tumor formation. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Human Genome Sci Inc, Dept Preclin Discovery, Rockville, MD 20850 USA. Michigan State Univ, Grad Program Genet, E Lansing, MI 48824 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. RP Friedman, TB (reprint author), Johns Hopkins Med Inst, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. FU NCI NIH HHS [R01-CA64202, R01-CA71838]; NIDCD NIH HHS [1Z01-DC00040-04] NR 49 TC 41 Z9 45 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 0888-7543 J9 GENOMICS JI Genomics PD MAR PY 2002 VL 79 IS 3 BP 278 EP 284 DI 10.1006/geno.2002.6703 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 528BR UT WOS:000174224200003 PM 11863357 ER PT J AU Bramblett, DE Copeland, NG Jenkins, NA Tsai, MJ AF Bramblett, DE Copeland, NG Jenkins, NA Tsai, MJ TI BHLHB4 is a bHLH transcriptional regulator in pancreas and brain that marks the dimesencephalic boundary SO GENOMICS LA English DT Article DE transcription factor; basic helix-loop-helix protein; phylogeny; diencephalon; pancreatic beta-cells; development; physical chromosome mapping ID CENTRAL-NERVOUS-SYSTEM; LOOP-HELIX PROTEIN; MOUSE-BRAIN; DNA-BINDING; GENE; EXPRESSION; INSULIN; IDENTIFICATION; LINKAGE; NEUROD AB We have cloned a basic helix-loop-helix (bHLH) factor gene, Bhlhb4, from a mouse P-cell line. Fluorescence in situ hybridization (FISH) and genetic mapping place Bhlhb4 at the telomeric end of mouse chromosome 2 (H3-H4), syntenic to human chromosome 20q13. Based on phylogenetic analysis, BHLHB4 belongs to a new subgroup of bHLH factors including at least four previously identified mouse bHLH factors: BHLHB5, MIST1, OLIG1, OLIG2, and OLIG3. In the developing nervous system, Bhlhb4 was found to mark the dimesencephalic boundary, suggesting that Bhlhb4 may have a role in diencephalic regionalization. In the pancreas, Bhlhb4 is expressed in a transient fashion that suggests a role in the pancreatic endocrine cell lineage. Transfection experiments show that BHLHB4 can repress transcriptional activation mediated through the pancreatic p-cell specific insulin promoter enhancer RIPE3. Together, these data suggest that BHLHB4 may modulate the expression of genes required for the differentiation and/or maintenance of pancreatic and neuronal cell types. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Bramblett, DE (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. NR 50 TC 25 Z9 28 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAR PY 2002 VL 79 IS 3 BP 402 EP 412 DI 10.1006/geno.2002.6708 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 528BR UT WOS:000174224200016 PM 11863370 ER PT J AU Makrigiannis, AP Pau, AT Schwartzberg, PL McVicar, DW Beck, TW Anderson, SK AF Makrigiannis, AP Pau, AT Schwartzberg, PL McVicar, DW Beck, TW Anderson, SK TI A BAC contig map of the Ly49 gene cluster in 129 mice reveals extensive differences in gene content relative to C57BL/6 mice SO GENOMICS LA English DT Article DE mouse; NK cells; MHC receptor; Ly49 ID LY-49; EXPRESSION; SEQUENCE; COMPLEX; STRAINS; CELLS AB The murine Ly49 gene family is functionally analogous to the human killer cell Ig-like receptor (KIR) family of class I major histocompatibility complex (MHC) receptors. The number of KIR genes varies dramatically between individuals; however, the organization of the Ly49 genes has only been determined for the C57BL/6 (136) mouse. The organization of the 129 Ly49 loci was determined from a BAC contig map by, PCR and Southern blot analysis. In addition to the 10 Ly49 genes known from previous studies of the 129/J strain, 8 new genes were localized to the 129 Ly49 cluster. A gene order of Ly49q(1), e, (nu, q(2)), e/c(2), Vr, s, t, e/c(1), r, u, u/i, i(1), g, p/d, (i(2), p), and o was determined. The 129 Ly49 gene cluster is predicted to span similar to 600 kb. These results indicate that Ly49 gene numbers can be significantly different between inbred mouse strains, analogous to the haplotype differences observed in the human KIR genes. C1 NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21702 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Anderson, SK (reprint author), NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21702 USA. RI Anderson, Stephen/B-1727-2012; McVicar, Daniel/G-1970-2015 OI Anderson, Stephen/0000-0002-7856-4266; FU PHS HHS [N01-C0-12400] NR 27 TC 65 Z9 65 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAR PY 2002 VL 79 IS 3 BP 437 EP 444 DI 10.1006/geno.2002.6724 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 528BR UT WOS:000174224200020 PM 11863373 ER PT J AU Black, A Lane, MA AF Black, A Lane, MA TI Nonhuman primate models of skeletal and reproductive aging SO GERONTOLOGY LA English DT Review DE nonhuman primates; bone; reproduction; animal models; osteoarthritis ID FEMALE RHESUS-MONKEYS; HORMONE-REPLACEMENT THERAPY; MACACA-FASCICULARIS; CYNOMOLGUS MONKEYS; BONE MASS; SEXUAL-BEHAVIOR; MUSCULOSKELETAL SYSTEM; PIGTAILED MACAQUES; JAPANESE MACAQUES; SUBCHONDRAL BONE AB Background. Bone loss, osteoarthritis (OA) and age-related changes in reproduction are some of the most apparent and troubling results of advancing age in the human population. The significance of these changes underscores the need for developing appropriate animal models to study aging of bone and the reproductive system. Objective:This review surveys the literature regarding the current state of nonhuman primates (NHP) as models for skeletal and reproductive aging in humans. Results: Several species of NHP exhibit age-related bone loss as well as changes in the mineral content and architecture of bone that are similar to those reported in humans. In addition, since aged females of some species of NHP exhibit cessation of menses and serum hormone profiles consistent with those described in peri- and premenopausal women, they provide useful models of postmenopausal bone loss. Sensitivity to surgical estrogen depletion and hormone replacement has also been demonstrated in female NHP. Spontaneous development of degenerative arthritis, analogous to humans in age at onset, joint involvement and histologic changes, suggest that NHP are suitable for the study of human OA. Many similarities exist between female NHPs and women in age-related changes in reproductive function including hormone concentrations, menstrual cycling, fertility and the development of endometriosis. Changes in male sexual behavior and fertility with age are also comparable in men and male NHP. Conclusions: Genetic similarity, long lives and similar reproductive endocrinology suggest that NHPs are likely candidates as models of skeletal and reproductive aging in humans. Current data confirm that several species of NHP exhibit changes in bone and reproduction that are comparable to those known to occur in humans. Copyright (C) 2002 S. Karger AG, Basel. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Nutr & Mol Physiol Unit,NIH, Baltimore, MD 21224 USA. RP Black, A (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, Nutr & Mol Physiol Unit,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM black@vax.grc.nia.nih.gov NR 108 TC 22 Z9 26 U1 1 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0304-324X EI 1423-0003 J9 GERONTOLOGY JI Gerontology PD MAR-APR PY 2002 VL 48 IS 2 BP 72 EP 80 DI 10.1159/000048930 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 529HL UT WOS:000174293900003 PM 11867928 ER PT J AU Richardson, MA AF Richardson, MA TI Complementary and alternative therapy use in gynecologic oncology: Implications for clinical practice SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID BREAST-CANCER; MEDICINE USE; UNITED-STATES; WOMEN; ANTIOXIDANTS; CHEMOTHERAPY; PREVALENCE; HERBS C1 Natl Ctr Complementary & Alternat Med, NIH, Bethesda, MD 20892 USA. RP Richardson, MA (reprint author), Natl Ctr Complementary & Alternat Med, NIH, 6707 Democracy Blvd Suite 401, Bethesda, MD 20892 USA. NR 29 TC 5 Z9 5 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2002 VL 84 IS 3 BP 360 EP 362 DI 10.1006/gyno.2002.6612 PG 3 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 530RE UT WOS:000174372100002 PM 11855869 ER PT J AU Cervenakova, L Brown, P Hammond, DJ Lee, CA Saenko, EL AF Cervenakova, L Brown, P Hammond, DJ Lee, CA Saenko, EL TI Factor VIII and transmissible spongiform encephalopathy: the case for safety SO HAEMOPHILIA LA English DT Review DE blood; factor VIII; prion disease; safety; transmissible spongiform encephalopathy; variant Creutzfeldt-Jakob disease ID CREUTZFELDT-JAKOB-DISEASE; FLUORESCENT-LABELED PEPTIDES; ABNORMAL PRION PROTEIN; VON-WILLEBRAND-FACTOR; BLOOD-TRANSFUSION; RISK-FACTORS; CAPILLARY-ELECTROPHORESIS; TONSIL BIOPSY; VARIANT CJD; FACTOR XASE AB Haemophilia A is the most common inherited bleeding disorder, caused by a deficiency in coagulation factor VIII (FVIII). Current treatment of haemophilia A is based on repeated infusions of plasma-derived FVIII concentrate or of recombinant FVIII, which may be exposed to plasma-derived material of human or animal origin used in its tissue culture production process. We review epidemiological and experimental studies relevant to blood infectivity in the transmissible spongiform encephalopathies (TSEs, or `prion' diseases), and evaluate the hypothetical risk of TSE transmission through treatment with plasma-derived or recombinant FVIII. C1 Amer Red Cross, Jerome H Holland Lab, Plasma Derivat Dept, Rockville, MD 20855 USA. NINCDS, NIH, Bethesda, MD 20892 USA. Royal Free Hosp, Haemophilia Ctr, London NW3 2QG, England. Royal Free Hosp, Haemostasis Unit, London NW3 2QG, England. RP Cervenakova, L (reprint author), Amer Red Cross, Jerome H Holland Lab, Plasma Derivat Dept, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. NR 108 TC 18 Z9 19 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2002 VL 8 IS 2 BP 63 EP 75 DI 10.1046/j.1365-2516.2002.00617.x PG 13 WC Hematology SC Hematology GA 541WQ UT WOS:000175009200001 PM 11952840 ER PT J AU Emanuel, E AF Emanuel, E TI Health care reform: Still possible SO HASTINGS CENTER REPORT LA English DT Article C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Emanuel, E (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2002 VL 32 IS 2 BP 32 EP 34 DI 10.2307/3528520 PG 3 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 544BM UT WOS:000175138400015 PM 11998767 ER PT J AU Gooding, HC Wilfond, B Boehm, K Biesecker, BB AF Gooding, HC Wilfond, B Boehm, K Biesecker, BB TI Unintended messages: The ethics of teaching genetic dilemmas SO HASTINGS CENTER REPORT LA English DT Article C1 Johns Hopkins Univ, NHGRI, Genet Counseling Training Program, Baltimore, MD 21218 USA. NR 19 TC 2 Z9 2 U1 0 U2 1 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2002 VL 32 IS 2 BP 37 EP 39 DI 10.2307/3528522 PG 3 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 544BM UT WOS:000175138400017 PM 11998769 ER PT J AU Sigmon, HD Grady, PA AF Sigmon, HD Grady, PA TI Increasing nursing research in cystic fibrosis SO HEART & LUNG LA English DT Article AB A pressing need exists for more research on the clinical, psychosocial, and genetic dimensions of cystic fibrosis (CF) (a broad spectrum of issues to which nursing research is well suited). The National Institute of Nursing Research (NINR) is therefore seeking ways both to bring new nurse researchers into ongoing CF research and also to encourage those already engaged in nursing research in other areas to widen their focus to include CF. These goals were the focus of the NINR Spring Science Workgroup held on May 1-2, 2001, in Bethesda, Maryland. The NINR brought together in interdisciplinary workgroup of clinical scientists and practitioners in the fields of pediatric and adult cystic fibrosis as well as investigators with research expertise in telehealth, genetics, child development. and family interactions, and ethics. The workgroup, chaired by Dr Patricia Grady and Dr Hilary Sigmon, was charged with identifying gaps in current knowledge and suggesting ways to increase the number of nurse researchers engaged in nursing research on CF. C1 NINR, Bethesda, MD 20892 USA. RP Sigmon, HD (reprint author), NINR, 45 Ctr Dr,MCS 6300, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0147-9563 J9 HEART LUNG JI Heart Lung PD MAR-APR PY 2002 VL 31 IS 2 BP 81 EP 84 DI 10.1067/mhl.2002.122808 PG 4 WC Cardiac & Cardiovascular Systems; Nursing; Respiratory System SC Cardiovascular System & Cardiology; Nursing; Respiratory System GA 539JG UT WOS:000174866300001 PM 11910382 ER PT J AU Golenhofen, N Ness, W Wawrousek, EF Drenckhahn, D AF Golenhofen, N Ness, W Wawrousek, EF Drenckhahn, D TI Expression and induction of the stress protein alpha-B-crystallin in vascular endothelial cells SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE alpha B-crystallin; endothelium; stress proteins; stress tolerance ID HEAT-SHOCK PROTEINS; ISCHEMIC-INJURY; HSP27; PROTECTION; FILAMENTS; INVOLVEMENT; MYOFIBRILS; RESISTANCE; CHAPERONE; RECOVERY AB Stress-induced development of enhanced tolerance against various kinds of stresses has been observed in vascular endothelial cells as well as in several other cell types. Stress proteins are thought to play a key role in the development of stress tolerance. In this study we show that endothelial cells of various sources contain the major stress protein of the eye lens, alphaB-crystallin. In the mouse myocardial microvascular cell line, MyEnd, alphaB-crystallin as well as the heat shock proteins HSP 70i and HSP 25 display a low constitutive expression but can be significantly upregulated by sodium arsenite stress. Osmotic stress also resulted in strong upregulation of alphaB-crystallin and HSP 70i but not of HSP 25. Both osmotic and arsenite stress resulted in significant stress tolerance of MyEnd cells against glucose deprivation as assayed by lactate dehydrogenase release and overall cellular morphology. Development of stress tolerance without induction of HSP 25 indicates that HSP 25 is not essential for the protective effect. MyEnd cells from alphaB-crystallin-/- mice displayed a similar degree of stress tolerance showing that alphaB-crystallin is dispensable for protection of cells against energy depletion. The functional role of alphaB-crystallin in endothelial cells needs to be further elucidated. In our experiments HSP 70i turned out to be the only potential candidate of the stress proteins assayed to be involved in the development of tolerance against energy depletion. C1 Univ Wurzburg, Inst Anat & Cell Biol, D-97070 Wurzburg, Germany. NEI, NIH, Bethesda, MD 20892 USA. RP Golenhofen, N (reprint author), Univ Wurzburg, Inst Anat & Cell Biol, Koellikerstr 6, D-97070 Wurzburg, Germany. RI Wawrousek, Eric/A-4547-2008 NR 49 TC 49 Z9 50 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD MAR PY 2002 VL 117 IS 3 BP 203 EP 209 DI 10.1007/s00418-001-0378-7 PG 7 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 539JD UT WOS:000174866000002 PM 11914917 ER PT J AU Cooper, DN Nussbaum, RL Krawczak, M AF Cooper, DN Nussbaum, RL Krawczak, M TI Proposed guidelines for papers describing DNA polymorphism-disease associations SO HUMAN GENETICS LA English DT Editorial Material C1 Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. RP Cooper, DN (reprint author), Univ Wales Coll Cardiff, Coll Med, Inst Med Genet, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. RI Cooper, David/H-4384-2011; Krawczak, Michael/A-8964-2010 OI Cooper, David/0000-0002-8943-8484; Krawczak, Michael/0000-0003-2603-1502 NR 5 TC 80 Z9 82 U1 0 U2 3 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 MAR PY 2002 VL 110 IS 3 BP 207 EP 208 DI 10.1007/s00439-001-0672-4 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 538QH UT WOS:000174826200001 PM 11935332 ER PT J AU Jankovic, D Kullberg, MC Hieny, S Caspar, P Collazo, CM Sher, A AF Jankovic, D Kullberg, MC Hieny, S Caspar, P Collazo, CM Sher, A TI In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(-/-) setting SO IMMUNITY LA English DT Article ID IFN-GAMMA PRODUCTION; LEISHMANIA-MAJOR INFECTION; TOXOPLASMA-GONDII; CUTANEOUS LEISHMANIASIS; INTERFERON-GAMMA; IN-VIVO; IL-12-DEFICIENT MICE; DENDRITIC CELLS; MURINE LEISHMANIASIS; SCHISTOSOMA-MANSONI AB IL-12-deficient mice exposed to nonlethal infections with intracellular pathogens or repeatedly immunized with a pathogen extract developed lowered but nevertheless substantial numbers of IFN-gamma(+) CD4(+) T cells compared to those observed in wild-type animals. Moreover, the CD4(+) responses in these knockout animals failed to default to a Th2 pattern. The protective efficacy of the Th1 cells developing in an IL-12-deficient setting was found to be limited by IL-10 since mice doubly deficient in IL-10 and IL-12 survived, while animals deficient in IL-12 alone succumbed to pathogen challenge. In contrast to IL-12 knockout mice, MyD88-deficient animals exposed to a Th1 microbial stimulus developed a pure Th2 response, arguing that this signaling element plays a more critical function than IL-12 in determining pathogen-induced CD4 polarization. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Jankovic, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM djankovic@niaid.nih.gov NR 79 TC 195 Z9 203 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR PY 2002 VL 16 IS 3 BP 429 EP 439 DI 10.1016/S1074-7613(02)00278-9 PG 11 WC Immunology SC Immunology GA 534EZ UT WOS:000174572800011 PM 11911827 ER PT J AU Hensley, LE Young, HA Jahrling, PB Geisbert, TW AF Hensley, LE Young, HA Jahrling, PB Geisbert, TW TI Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily SO IMMUNOLOGY LETTERS LA English DT Article DE cytokines; chemokines; TRAIL; apoptosis; macrophages; dendritic cells; Ebola virus ID ELECTRON-MICROSCOPY; INTERFERON-ALPHA; NITRIC-OXIDE; APOPTOSIS; MACROPHAGES; MARBURG; CELLS; CYTOTOXICITY; MECHANISMS; MONKEYS AB Ebola virus (EBOV) infections are characterized by dysregulation of normal host immune responses. Insight into the mechanism came from recent studies in nonhuman primates, which showed that EBOV infects cells of the mononuclear phagocyte system (MPS), resulting in apoptosis of bystander lymphocytes. In this study, we evaluated serum levels of cytokines/chemokines in EBOV-infected nonhuman primates, as possible correlates of this bystander apoptosis. Increased levels of interferon (IFN)-alpha, IFN-beta, interleukin (IL)-6, IL-18, MIP-1alpha, and MIP-1beta were observed in all EBOV-infected monkeys, indicating the occurrence of a strong proinflammatory response. To investigate the mechanism(s) involved in lymphoid apoptosis, soluble Fas (sFas) and nitrate accumulation were measured. sFas was detected in 4/9 animals, while, elevations of nitrate accumulation occurred in 3/3 animals. To further evaluate the potential role of these factors in the observed bystander apoptosis and intact animals, in vitro cultures were prepared of adherent human monocytes/macrophages (PHM), and monocytes. differentiated into immature dendritic cells (DC). These cultures were infected with EBOV and analyzed for cytokine/chemokine induction and expression of apoptosis-related genes. In addition, the in vitro EBOV infection of peripheral blood mononuclear cells (PBMC) resulted in strong cytokine/chemokine induction, a marked increase in lactate dehydrogenase (LDH) activity, and an increase in the number of apoptotic lymphocytes examined by electron microscopy. Increased levels of sFAS were detected in PHM cultures, although, <10% of the cells were positive by immunohistochemistry. In contrast, >90% of EBOV-infected PHM were positive for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) by immunohistochemistry, RNA analysis, and flow cytometry. Inactivated EBOV also effected increased TRAIL expression in PHM, suggesting that the TNF receptor superfamily may be involved in apoptosis of the host lymphoid cells, and that induction may occur independent of viral replication. In further studies with infected PHM, expression of MHC II was remarkably suppressed after 6 days, an additional correlate of immunological dysregulation. In conclusion, our findings suggest that infection of mononuclear phagocytes is critical, triggering a cascade of events involving cytokines/chemokines and oxygen free radicals. It is the consequence of these events rather than direct viral infection that results in much of the observed pathology. Identification of cytokine/chemokine, nitric oxide, and reactive oxygen species involvement in the observed filoviral pathogenesis may lend insight into the rational design of therapeutic countermeasures of filoviral pathogenesis. (C) 2002 Elsevier Science B.V. All rights reserved. C1 USA, Med Res Inst Infect Dis, Div Pathol, Ft Detrick, MD 21702 USA. NCI, FCRDD, Expt Immunol Lab, Cellular & Mol Immunol Sect, Frederick, MD 21702 USA. RP Hensley, LE (reprint author), USA, Med Res Inst Infect Dis, Div Pathol, Attn MCMR UIP D,1425 Porter St, Ft Detrick, MD 21702 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 NR 35 TC 137 Z9 149 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD MAR 1 PY 2002 VL 80 IS 3 BP 169 EP 179 AR PII S0165-2478(01)00327-3 DI 10.1016/S0165-2478(01)00327-3 PG 11 WC Immunology SC Immunology GA 529AY UT WOS:000174278900005 PM 11803049 ER PT J AU Khanna, C Jaboin, JJ Drakos, E Tsokos, M Thiele, CJ AF Khanna, C Jaboin, JJ Drakos, E Tsokos, M Thiele, CJ TI Biologically relevant orthotopic neuroblastoma xenograft models: Primary adrenal tumor growth and spontaneous distant metastasis SO IN VIVO LA English DT Article DE neuroblastoma; cancer; murine; xenograft; orthotopic; metastasis; angiogenesis ID MURINE NEUROBLASTOMA; SCID MICE; NUDE; HOST; THERAPY; DISEASE; MOUSE; CELLS AB To provide investigative tools for the study of neuroblastorna (NB) biology and therapy, we have characterized five orthotopic (adrenal) human xenograft models of NB. Initial experiments compared subcutaneous (heterotopic) with adrenal (orthotopic) injections of two NB cell lines (SK-N-AS and SMS-KCNR) in Beige-SCID mice, These studies demonstrated more relevant tumor biology, including angiogenic phenotype, and enhanced spontaneous distant metastasis for orthotopic versus heterotopic tumors. RNase protection assay demonstrated differences in the expression of angiogenesis associated genes flt1, TIE1, angiopoietin, and endoglin) between adrenal and subcutaneous xenografts. Orthotopic models were used to define and characterize the three remaining NB cell lines (SH-SY5Y, LA-1-15N, and IMR32). The pattern of angiogenesis was distinctive for each xenograft model and included a variety of vascular structures. The sites for metastases were distinct for each cell line and included lymph nodes, liver, ovaries, lungs, bone marrow and local bone extension. These well characterized, relevant, highly angiogenic, and metastatic orthotopic models of NB will be a valuable resource to improve our understanding of the biology and treatment of NB. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Pediat Oncol Branch, NIH, 10-13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 47 Z9 49 U1 0 U2 6 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0258-851X J9 IN VIVO JI In Vivo PD MAR-APR PY 2002 VL 16 IS 2 BP 77 EP 85 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 561HR UT WOS:000176134600001 PM 12073775 ER PT J AU Shaw, J Grund, V Durling, L Crane, D Caldwell, HD AF Shaw, J Grund, V Durling, L Crane, D Caldwell, HD TI Dendritic cells pulsed with a recombinant chlamydial major outer membrane protein antigen elicit a CD4(+) type 2 rather than type 1 immune response that is not protective SO INFECTION AND IMMUNITY LA English DT Article ID GENITAL-TRACT INFECTION; GENE KNOCKOUT MICE; T-HELPER; TRACHOMATIS INFECTION; DEFICIENT MICE; IFN-GAMMA; IMMUNOGENICITY; VACCINATION; EPITOPES; LIPOPOLYSACCHARIDE AB Chlamydia trachomatis is an obligate intracellular bacterium that infects the oculogenital mucosae. C trachomatis infection of the eye causes trachoma, the leading cause of preventable blindness. Infections of the genital mucosae are a leading cause of sexually transmitted diseases. A vaccine to prevent chlamydial infection is needed but has proven difficult to produce by using conventional vaccination approaches. Potent immunity to vaginal rechallenge in a murine model of chlamydial genital infection has been achieved only by infection or by immunization with dendritic cells (DC) pulsed ex vivo with whole inactivated organisms. Immunity generated by infection or ex vivo antigen-pulsed DC correlates with a chlamydia-specific interleukin 12 (IL-12)-dependent CD4(+) Th1 immune response. Because of the potent antichlamydial immunizing properties of DC, we hypothesized that DC could be a powerful vehicle for the delivery of individual chlamydial antigens that are thought to be targets for more conventional vaccine approaches. Here, we investigated the recombinant chlamydial major outer membrane protein (rMOMP) as a target antigen. The results demonstrate that DC pulsed with rMOMP secrete IL-12 and stimulate infection-sensitized CD4(+) T cells to proliferate and secrete gamma interferon. These immunological properties implied that rMOMP-pulsed DC would be potent inducers of MOMP-specific CD4(+) Th1 immunity in vivo; however, we observed the opposite result. DC pulsed ex vivo with rMOMP and adoptively transferred to naive mice generated a Th2 rather than a Th1 anti-MOMP immune response, and immunized mice were not protected following infectious challenge. We conclude from these studies that the immunological properties of ex vivo pulsed DC are not necessarily predictive of the immune response generated in vivo following adoptive transfer. These findings suggest that the nature of the antigen used to pulse DC ex vivo influences the Th1-Th2 balance of the immune response in vivo. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. Univ Montana, Dept Pharmaceut Sci, Missoula, MT 59801 USA. RP Caldwell, HD (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, 903 S 3rd St, Hamilton, MT 59840 USA. NR 49 TC 51 Z9 58 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2002 VL 70 IS 3 BP 1097 EP 1105 DI 10.1128/IAI.70.3.1097-1105-2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 522EQ UT WOS:000173883100009 PM 11854188 ER PT J AU Takahashi, Y Konishi, K Cisar, JO Yoshikawa, M AF Takahashi, Y Konishi, K Cisar, JO Yoshikawa, M TI Identification and characterization of hsa, the gene encoding the sialic acid-binding adhesin of Streptococcus gordonii DL1 SO INFECTION AND IMMUNITY LA English DT Article ID SALIVARY-BACTERIAL INTERACTIONS; GRAM-POSITIVE BACTERIA; EXPERIMENTAL ENDOCARDITIS; ACTINOMYCES-NAESLUNDII; CELL-SURFACE; SANGUIS C5; RECEPTORS; SPECIFICITY; PELLICLES; SEQUENCE AB Oral colonization by Streptococcus gordonii, an important cause of subacute bacterial endocarditis, involves bacterial recognition of sialic acid-containing host receptors. The sialic acid-binding activity of this microorganism was previously detected by bacterium-mediated hemagglutination and associated with a streptococcal surface component identified as the Hs antigen. The gene for this antigen (hsa) has now been cloned in Escherichia coli, and its expression has been detected by colony immunoblotting with anti-Hs serum. Mutants of S. gordonii containing hsa inactivated by the insertion of an erythromycin resistance gene or deletion from the chromosome were negative for Hs-immunoreactivity, bacterium-mediated hemagglutinating activity, and adhesion to alpha2-3-linked sialoglycoconjugates. The deletion in the latter mutants was complemented by plasmid-borne hsa, resulting in Hs antigen production and the restoration of cell surface sialic acid-binding activity. The hsa gene encodes a 203-kDa protein with two serine-rich repetitive regions in its 2,178-amino-acid sequence. The first serine-rich region occurs within the amino-terminal region of the molecule, between different nonrepetitive sequences that may be associated with sialic acid binding. The second serine-rich region, which is much longer than the first, is highly repetitive, containing 113 dodecapeptide repeats with a consensus sequence of SASTSASVSASE. This long repetitive region is followed by a typical gram-positive cell wall anchoring region at the carboxyl-terminal end. Thus, the predicted properties of Hsa, which suggest an amino-terminal receptor-binding domain attached to the cell surface by a molecular stalk, are consistent with the identification of this protein as the sialic acid-binding adhesin of S. gordonii DL1. C1 Nippon Dent Univ, Sch Dent Tokyo, Dept Microbiol, Chiyoda Ku, Tokyo 1028159, Japan. Natl Inst Dent Craniofacial Res, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. RP Takahashi, Y (reprint author), Nippon Dent Univ, Sch Dent Tokyo, Dept Microbiol, Chiyoda Ku, 1-9-20 Fujimi, Tokyo 1028159, Japan. NR 36 TC 92 Z9 92 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2002 VL 70 IS 3 BP 1209 EP 1218 DI 10.1128/IAI.70.3.1209-1218.2002 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 522EQ UT WOS:000173883100023 PM 11854202 ER PT J AU Jeevan, A Yoshimura, T Foster, G McMurray, DN AF Jeevan, A Yoshimura, T Foster, G McMurray, DN TI Effect of Mycobacterium bovis BCG vaccination on interleukin-1 beta and RANTES mRNA expression in guinea pig cells exposed attenuated and virulent mycobacteria SO INFECTION AND IMMUNITY LA English DT Article ID TUMOR-NECROSIS-FACTOR; GROWTH-FACTOR-BETA; FACTOR-ALPHA; CYTOKINE PRODUCTION; IFN-GAMMA; PULMONARY TUBERCULOSIS; MURINE MACROPHAGES; ENDOTHELIAL-CELLS; PROTEIN-DEFICIENT; AVIUM INFECTION AB The effect of Mycobacterium bovis BCG vaccination on interleukin-1beta (IL-1beta) or regulated-upon-activation, normally T-cell-expressed and -secreted chemokine (RANTES) mRNA expression in guinea pig spleen cells stimulated with concanavalin A, lipopolysaccharide (LPS), phorbol myristate acetate (PMA) plus ionomycin, or purified protein derivative (PPD) was studied in vitro. Similarly, peritoneal exudate cell-derived macrophages from naive and BCG-vaccinated guinea pigs were infected with M. bovis BCG, Mycobacterium avium, the attenuated Mycobacterium tuberculosis H37Ra strain, or virulent strains H37Rv and Erdman of M. tuberculosis. Total RNA was subjected to Northern blot analysis using probes generated from guinea pig IL-1beta or RANTES cDNA. Although IL-1beta and RANTES mRNA could be detected in the spleen cells from naive animals stimulated with LPS or PMA plus ionomycin, the levels were significantly enhanced after BCG vaccination. mRNA expression was also elevated in macrophages infected with live mycobacteria after BCG vaccination. However, macrophages infected with the virulent H37Rv strain of M. tuberculosis showed 75 to 90% reductions in IL-1beta expression and 25 to 60% reductions in RANTES mRNA expression compared with macrophages infected with the attenuated H37Ra strain. The IL-1beta mRNA levels peaked as soon as 1 h after PPD stimulation and 4 h after M. tuberculosis H37Rv infection of macrophages. In contrast, RANTES mRNA expression was delayed until 48 h after infection. These results indicate that molecular mediators produced in response to various stimuli associated with protective immunity against mycobacteria are upregulated after BCG vaccination; however, a significantly weaker response was observed with virulent M. tuberculosis. These initial studies indicate that BCG vaccination has a positive effect on IL-1beta and RANTES mRNA expression by host cells in a highly relevant animal tuberculosis model. C1 Texas A&M Univ Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Jeevan, A (reprint author), Texas A&M Univ Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, 407 Reynolds Med Bldg, College Stn, TX 77843 USA. FU NIAID NIH HHS [R01 AI 15495, R01 AI015495] NR 49 TC 27 Z9 27 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2002 VL 70 IS 3 BP 1245 EP 1253 DI 10.1128/IAI.70.3.1245-1253.2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 522EQ UT WOS:000173883100028 PM 11854207 ER PT J AU Lee, EAM Palmer, DR Flanagan, KL Reece, WHH Odhiambo, K Marsh, K Pinder, M Gravenor, MB Keitel, WA Kester, KE Diggs, C Kaslow, D Apostolopoulos, V Ballou, WR Hill, AVS Krzych, U Plebanski, M AF Lee, EAM Palmer, DR Flanagan, KL Reece, WHH Odhiambo, K Marsh, K Pinder, M Gravenor, MB Keitel, WA Kester, KE Diggs, C Kaslow, D Apostolopoulos, V Ballou, WR Hill, AVS Krzych, U Plebanski, M TI Induction of T helper type 1 and 2 responses to 19-kilodalton merozoite surface protein 1 in vaccinated healthy volunteers and adults naturally exposed to malaria SO INFECTION AND IMMUNITY LA English DT Article ID HUMORAL IMMUNE-RESPONSES; B-CELL EPITOPES; PLASMODIUM-FALCIPARUM; TERMINAL FRAGMENT; DISULFIDE BONDS; BLOOD STAGES; ANTIGEN; ANTIBODIES; AFRICANS; HUMANS AB Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein I (MSP-1(19)), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-119, immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1(19) induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1(19) immune responses in endemic populations can be boosted by vaccination. C1 Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Nuffield Dept Med,Mol Immunol Grp, Oxford OX3 9DU, England. Inst Anim Hlth, Compton RG20 7NN, Berks, England. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. US Agcy Int Dev, Malaria Vaccine Dev Program, Washington, DC 20523 USA. Kilifi Dist Hosp, KEMRI Ctr Geog Med Res Coast, Kilifi, Kenya. MRC Labs, Banjul, Gambia. Baylor Coll Med, Dept Mol Virol & Microbiol & Med, Houston, TX 77030 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lee, EAM (reprint author), Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Nuffield Dept Med,Mol Immunol Grp, Oxford OX3 9DU, England. EM elee@enterprise.molbiol.ox.ac.uk RI HILL, Adrian/C-1306-2008; Kester, Kent/A-2114-2011 OI Kester, Kent/0000-0002-5056-0802 FU NIAID NIH HHS [N01-AI-25135] NR 25 TC 33 Z9 34 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2002 VL 70 IS 3 BP 1417 EP 1421 DI 10.1128/IAI.70.3.1417-1421.2002 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 522EQ UT WOS:000173883100049 PM 11854228 ER PT J AU Guide, SV Holland, SM AF Guide, SV Holland, SM TI Host susceptibility factors in mycobacterial infection - Genetics and body morphotype SO INFECTIOUS DISEASE CLINICS OF NORTH AMERICA LA English DT Review ID MITRAL-VALVE PROLAPSE; INTERFERON-GAMMA-RECEPTOR; AVIUM COMPLEX INFECTION; JOINT HYPERMOBILITY SYNDROME; CALMETTE-GUERIN INFECTION; ANHIDROTIC ECTODERMAL DYSPLASIA; THORACIC SKELETAL ABNORMALITIES; PULMONARY-DISEASE; IFN-GAMMA; PECTUS EXCAVATUM AB Mycobacteria traditionally have been thought of as virulent pathogens that cause disease by respiratory contagion. Recognition of nontuberculosis mycobacterial (NTM) disease in otherwise normal hosts however, has shown that host susceptibility factors play a key role in infection. Identification of multiple defects in the INFgamma and interleukin-12 pathways, including impaired signaling through the transcription factors STAT1 and NFkappaB, has elucidated the pathways involved in disseminated disease better. In patients with pulmonary Mycobacterium avium complex disease, a characteristic body morphotype suggests that subtle immune defects or polymorphisms may underlie susceptibility. Although there are distinct differences between tuberculosis (TB) and NTM, detection of genetic and phenotypic associations with the latter also may provide insight into risk factors for TB. C1 Stanford Univ, Clin Res Training Program, Palo Alto, CA 94304 USA. NIAID, Host Def Lab, NIH, Immunopathogenesis Unit, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), Bldg 10,Room 11N103,10 Ctr Dr MSC 1886, Bethesda, MD 20892 USA. NR 140 TC 43 Z9 44 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0891-5520 J9 INFECT DIS CLIN N AM JI Infect. Dis. Clin. North Am. PD MAR PY 2002 VL 16 IS 1 BP 163 EP + DI 10.1016/S0891-5520(03)00051-5 PG 25 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 540NG UT WOS:000174934600008 PM 11917812 ER PT J AU Housseau, F Langer, DA Oberholtzer, SD Moorthy, A Levitsky, HI Pardoll, DM Topalian, SL AF Housseau, F Langer, DA Oberholtzer, SD Moorthy, A Levitsky, HI Pardoll, DM Topalian, SL TI Tumor-specific CD8+T lymphocytes derived from the peripheral blood of prostate cancer patients by in vitro stimulation with autologous tumor cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; T lymphocytes; tumor antigens; MHC; costimulation ID CLINICAL-TRIAL; MELANOMA-CELLS; IMMUNOTHERAPY; ANTIGEN; VACCINE; GENERATION; GENE; COSTIMULATION AB To identify tumor-associated antigens as putative targets for developing immunotherapies against prostate cancer, we investigated the ability of T cells derived from the peripheral blood lymphocytes of prostate cancer patients to recognize autologous tumor cells. The technical challenge of growing in vitro carcinoma cell lines from small prostate cancer samples was previously addressed by immortalization of early epithelial cell cultures with the HPV16 transforming proteins E6 and E7 and by genetic characterization of the carcinoma and normal prostate cell lines. In our study, peripheral blood lymphocytes were stimulated in vitro using autologous IFNgamma-treated prostate carcinoma cells transduced with the B7.1 molecule as a source of T-cell costimulation. Tumor-specific CD8+ T lymphocytes were obtained from 3 of 6 prostate cancer patients tested and included T cells restricted by classical and nonclassical HLA molecules. In I case, we demonstrated that the prostate cancer-reactive T cells were TCRalpha/beta+ and recognized autologous tumor cells but not autologous normal cells in the context of HLA-B or -C molecules. These results validate the approach of in vitro stimulation of peripheral blood lymphocytes from prostate cancer patients with autologous tumor cell lines to isolate prostate cancer-specific T cells and demonstrate the existence of a functionally diverse immune response against prostate cancer. Published 2002 Wiley-Liss, Inc. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Topalian, SL (reprint author), NCI, Surg Branch, NIH, 10-2B47, Bethesda, MD 20892 USA. NR 19 TC 9 Z9 9 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2002 VL 98 IS 1 BP 57 EP 62 DI 10.1002/ijc.10154 PG 6 WC Oncology SC Oncology GA 517NF UT WOS:000173616200011 PM 11857386 ER PT J AU De Sanjose, S Marshall, V Sola, J Palacio, V Almirall, R Goedert, JJ Bosch, FX Whitby, D AF De Sanjose, S Marshall, V Sola, J Palacio, V Almirall, R Goedert, JJ Bosch, FX Whitby, D TI Prevalence of Kaposi's sarcoma-associated herpesvirus infection in sex workers and women from the general population in Spain SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE KSHV; HHV-8; HPV DNA; epidemiology; prostitution ID DNA-SEQUENCES; HUMAN-HERPESVIRUS-8 INFECTION; NONSEXUAL TRANSMISSION; MEN; ANTIBODIES; SEROPREVALENCE; CHILDREN; SEROEPIDEMIOLOGY; INDIVIDUALS; SECRETIONS AB Transmission routes of Kaposi's sarcoma-associated herpesvirus (KSHV) in the general population are poorly understood. Whereas sexual transmission appears to be common in homosexual men, the evidence for heterosexual transmission is less convincing. In our study, prevalence of KSHV infection was examined among women in the Spanish general population and among sex workers. Subjects consisted of 100 prostitutes and 100 women randomly sampled from the general population and age-matched to the prostitutes. Women had a personal interview and gynecologic examinations in which a blood sample, cervical cells and oral cells were obtained. Peripheral blood mononuclear cells (PBMC), oral and cervical samples were tested for KSHV DNA by quantitative real-time PCR. Sera were tested for antibodies against human immunodeficiency virus (HIV) by ELISA and against KSHV by latent IFA and K8.1 ELISA. Women who were positive in either serologic assay or PCR were considered infected by KSHV. Human papillomavirus (HPV) DNA in cervical scrapes were evaluated using the Hybrid Capture System(TM). The study population had an average age of 30 years and were HIV-negative. Women from the general population were largely of Spanish nationality, and 61% reported lifetime monogamy. The majority of the prostitutes (76%) were Immigrants, primarily from South America. Sex workers were twice as likely to be infected with KSHV than women in the general population (16% vs. 8%, prevalence odds ratio [OR] = 2.2). KSHV was more prevalent among HPV DNA-positive women (OR = 2.5) and among women with an early age at first sexual intercourse (OR = 2.7, p < 0.05). KSHV DNA was detected by PCR in 3% of the oral cavity samples, In 2% of the cervical samples of the prostitutes and in 1% of the cervical samples of women in the general population. All PBMC samples were negative. These results suggest that in low-risk countries for KSHV, oral shedding and heterosexual contacts are potential pathways for KSHV transmission. (C) 2002 Wiley-Liss, Inc. C1 Inst Catala Oncol, Serv Epidemiol & Registre Canc, Barcelona, Spain. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Regio Sanitaria Llobregat Ctr, Ctr Atencio la Dona, Cornella, Spain. Hosp Monte Naranco, Oviedo, Spain. NCI, Viral Epidemiol Sect, AVP, Frederick, MD 21701 USA. RP De Sanjose, S (reprint author), Inst Catala Oncol, Serv Epidemiol & Registre Canc, Av Gran Via Km 2-7, Barcelona, Spain. RI de Sanjose Llongueras, Silvia/H-6339-2014; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012 OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412 FU NCI NIH HHS [N01-CO-56000] NR 31 TC 57 Z9 59 U1 4 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2002 VL 98 IS 1 BP 155 EP 158 DI 10.1002/ijc.10190 PG 4 WC Oncology SC Oncology GA 517NF UT WOS:000173616200025 PM 11857400 ER PT J AU Spengler, RF Anderson, BE Zenick, H AF Spengler, RF Anderson, BE Zenick, H TI Collaboration and importance of federally sponsored Superfund research programs SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Editorial Material DE research; environmental health; Superfund; hazardous substances C1 ATSDR, Atlanta, GA 30333 USA. NIEHS, Div Extramural Res & Training, Durham, NC USA. US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Spengler, RF (reprint author), ATSDR, Mail Stop E-28,1600 Clifton Rd NE, Atlanta, GA 30333 USA. NR 4 TC 5 Z9 5 U1 0 U2 0 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD MAR PY 2002 VL 205 IS 1-2 BP 1 EP 9 DI 10.1078/1438-4639-00124 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 541KM UT WOS:000174983800001 PM 12018001 ER PT J AU Anderson, B Thompson, C Suk, WA AF Anderson, B Thompson, C Suk, WA TI The Superfund Basic Research Program - making a difference: past, present, and future SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE research; environmental health; Superfund; hazardous substances AB Understanding exposure continues to be a paramount challenge and critical element in successfully managing Superfund sites. The Superfund Basic Research Program, administered by the National Institute of Environmental Health Sciences, an institute of the National Institutes of Health, is committed to providing the nation's decision makers with better tools to identify the routes and effects of exposure and develop innovative technologies to reduce exposures. In this article, we demonstrate how the program contributes to understanding the exposure disease link, highlight the cutting-edge and practical nature of this very fundamental research program and discuss its approach to addressing these problems. We also identify several broad themes that are likely to direct the program's future research endeavors. C1 NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Suk, WA (reprint author), NIEHS, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD MAR PY 2002 VL 205 IS 1-2 BP 137 EP 141 DI 10.1078/1438-4639-00139 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 541KM UT WOS:000174983800016 PM 12018007 ER PT J AU Monk, BJ Tewari, KS Puthawala, AA Syed, AMN Haugen, JA Burger, RA AF Monk, BJ Tewari, KS Puthawala, AA Syed, AMN Haugen, JA Burger, RA TI Treatment of recurrent gynecologic malignancies with iodine-125 permanent interstitial irradiation SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE recurrent gynecologic malignancies; permanent I-125 seed brachytherapy ID RADICAL HYSTERECTOMY; CERVICAL-CANCER; RADIOTHERAPEUTIC TREATMENT; PELVIC EXENTERATION; PRIMARY SURGERY; CARCINOMA; I-125; BRACHYTHERAPY; THERAPY; TUMORS AB Purpose: To analyze the outcome of permanent I-125 interstitial radiotherapy for unresectable retroperitoneal recurrences of gynecologic malignancies. Methods and Materials: A retrospective review of 20 patients treated between 1979 and 1993 was performed to evaluate survival and morbidity associated with the interstitial I-125 technique. Results: Nineteen tumors were located on the lateral pelvic wall and one in the para-aortic region. Eight patients, not previously irradiated, received external beam radiotherapy (EBRT) along with I-125 interstitial implants placed at the time of celiotomy. Nineteen (95%) are dead of disease at 1-69 months of follow-up. The median survival was 7.7 months for patients treated with I-125 alone and 25.4 months for those treated with both I-125 and EBRT. One patient is alive without evidence of disease 69 months after I-125 implantation. Fistulas, bowel obstructions, and fatal complications occurred only among patients previously irradiated. Conclusions: When used in a previously irradiated field, I-125 interstitial radiotherapy has major morbidity and is unlikely to be associated with cure or long-term survival. In radiotherapy-naive patients with unresectable isolated recurrent gynecologic malignancies, I-125 implants and EBRT are feasible and occasionally may contribute to long-term disease-free survival. (C) 2002 Elsevier Science Inc. C1 Univ Calif Irvine, Med Ctr, Chao Family NCI Designated Comprehens Canc Ctr, Div Gynecol Oncol, Orange, CA 92868 USA. Womens Hosp Med Ctr, Mem Med Ctr, Dept Radiat Oncol, Long Beach, CA USA. RP Burger, RA (reprint author), Univ Calif Irvine, Med Ctr, Chao Family NCI Designated Comprehens Canc Ctr, Div Gynecol Oncol, 101 City Dr, Orange, CA 92868 USA. NR 45 TC 19 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2002 VL 52 IS 3 BP 806 EP 815 AR PII S0360-3016(01)02728-6 DI 10.1016/S0360-3016(01)02728-6 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 524EL UT WOS:000173999400029 PM 11849805 ER PT J AU Neimark, H Johnsson, KE Rikihisa, Y Tully, JG AF Neimark, H Johnsson, KE Rikihisa, Y Tully, JG TI Revision of haemotrophic Mycoplasma species names SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE Mycoplasma; Eperythrozoon; Candidatus AB The recently proposed transfer of four rickettsias from the genera Haemobartonella and Eperythrozoon to the genus Mycoplasma with the Candidatus status is herein revised. This is because the Candidatus designation is for new, incompletely described taxa, in order to give them a provisional status. Thus, 'Candidatus Mycoplasma haemofelis' is revised to Mycoplasma haemofelis comb. nov., nom. nov., 'Candidatus Mycoplasma haemomuris' is revised to Mycoplasma haemomuris comb. nov., nom. nov., 'Candidatus Mycoplasma haemosuis' is revised to Mycoplasma haemosuis comb. nov., nom. nov. and 'Candidatus Mycoplasma wenyonii' is revised to Mycoplasma, wenyonii comb. nov. C1 SUNY, Coll Med, Dept Microbiol & Immunol, Brooklyn, NY 11203 USA. Natl Vet Inst, Dept Bacteriol, SE-75189 Uppsala, Sweden. Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. NIAID, Frederick Canc Res & Dev Ctr, Mycoplasma Sect, Frederick, MD 21707 USA. RP Neimark, H (reprint author), 16400 Black Rock Rd, Germantown, MD 20874 USA. NR 1 TC 98 Z9 113 U1 1 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAR PY 2002 VL 52 BP 683 EP 683 DI 10.1099/ijs.0.02283-0 PN 2 PG 1 WC Microbiology SC Microbiology GA 533ER UT WOS:000174516900044 PM 11931184 ER PT J AU Dandona, R Dandona, L Srinivas, M Sahare, P Narsaiah, S Munoz, SR Pokharel, GP Ellwein, LB AF Dandona, R Dandona, L Srinivas, M Sahare, P Narsaiah, S Munoz, SR Pokharel, GP Ellwein, LB TI Refractive error in children in a rural population in India SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article AB PURPOSE. To assess the prevalence of refractive error and related visual impairment in school-aged children in the rural population of the Mahabubnagar district in the southern Indian state of Andhra Pradesh. METHODS. Random selection of village-based clusters was used to identify a sample of children 7 to 15 years of age. From April 2000 through February 2001, children in the 25 selected clusters were enumerated in a door-to-door survey and examined at a rural eye center in the district. The examination included visual acuity measurements, ocular motility evaluation, retinoscopy and autorefraction tinder cycloplegia, and examination of the anterior segment, media, and fundus. Myopia was defined as spherical equivalent refractive error of at least -0.50 D and hyperopia as +2.00 D or more. Children with reduced vision and a sample of those with normal vision underwent independent replicate examinations for quality assurance in seven clusters. RESULTS. A total of 4414 children from 4876 households was enumerated, and 4074 (92.3%) were examined. The prevalence of uncorrected, baseline (presenting), and best corrected visual acuity of 20/40 or worse in the better eye was 2.7%, 2.6%, and 0.78%, respectively. Refractive error was the cause in 61% of eyes with vision impairment, amblyopia in 12%, other causes in 15%, and unexplained causes in the remaining 13%. A gradual shift toward Icss-positive values of refractive error occurred with increasing age in both boys and girls. Myopia in one or both eyes was present in 4.1% of the children. Myopia risk was associated with female gender and having a father with a higher level of schooling. Higher risk of myopia in children of older age was of borderline statistical significance (P = 0.069). Hyperopia in at least one eye was present in 0.8% of children, with no significant predictors. CONCLUSIONS. Refractive error was the main cause of visual impairment in children aged between 7 and 15 years in rural India. There was a benefit of spectacles in 70% of those who had Visual acuity of 20/40 or worse in the better eye at baseline examination. Because visual impairment can have a significant impact on a child's life in terms of education and development, it is important that effective strategies be developed to eliminate this easily treated cause of Visual impairment. C1 LV Prasad Eye Inst, Int Ctr Advancement Rural Eye Care, Hyderabad, Andhra Pradesh, India. Adm Staff Coll India, Ctr Social Serv, Hyderabad, Andhra Pradesh, India. Univ La Frontera, Unidad Epidemiol, Temuco, Chile. Fdn Eye Care Himalaya, Kathmandu, Nepal. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM ellweinl@nei.nih.gov FU NEI NIH HHS [N01 EY 2103] NR 19 TC 205 Z9 212 U1 0 U2 12 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 PY 2002 VL 43 IS 3 BP 615 EP 622 PG 8 WC Ophthalmology SC Ophthalmology GA 526TL UT WOS:000174145700006 PM 11867575 ER PT J AU Murthy, GVS Gupta, SK Ellwein, LB Munoz, SR Pokharel, GP Sanga, L Bachani, D AF Murthy, GVS Gupta, SK Ellwein, LB Munoz, SR Pokharel, GP Sanga, L Bachani, D TI Retractive error in children in an urban population New Delhi SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID REFRACTIVE ERROR; MYOPIA; SCHOOLCHILDREN; EPIDEMIOLOGY; PREVALENCE; NEPAL AB PURPOSE. To assess the prevalence of refractive error and related visual impairment in school-aged children in an urban population in New Delhi, India. METHODS. Random selection of geographically defined clusters was used to identify a sample of children 5 to 15 years of age. From December 2000 through March 2001, children in 22 selected clusters were enumerated through a door-to-door survey and examined at a local facility. The examination included visual acuity measurements, ocular motility evaluation, retinoscopy and autorefraction under cycloplegia, and examination of the anterior segment, media, and fundus. Myopia was defined as spherical equivalent refractive error of at least -0.50 D and hyperopia as +2.00 D or more. Children with reduced vision and a sample of those with normal vision underwent independent replicate examinations for quality assurance in four of the clusters. RESULTS. A total of 7008 children from 3426 households were enumerated, and 6447 (92.0%) examined. The prevalence of uncorrected, baseline (presenting), and best corrected visual acuity of 20/40 or worse in the better eye was 6.4%, 4.9%, and 0.81%, respectively. Refractive error was the cause in 81."7% of eyes with vision impairment, amblyopia in 4.4%, retinal disorders in 4.7%, other causes in 3.3%, and unexplained causes in the remaining 5.9%. There was an age-related shift in refractive error from hyperopia in young children (15.6% in 5-year-olds) toward myopia in older children (10.8% in 15-year-olds). Overall, hyperopia was present in 7.7% of children and myopia in 7.4%. Hyperopia was associated with female gender. Myopia was more common in children of fathers with higher levels of education. CONCLUSIONS. Reduced vision because of uncorrected refractive error is a major public health problem in urban school-aged children in India. Cost-effective strategies are needed to eliminate this easily treated cause of vision impairment. C1 NEI, NIH, Bethesda, MD 20892 USA. All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, New Delhi, India. Univ La Frontera, Unidad Epidemiol Clin, Temuco, Chile. Fdn Eye Care Himalaya, Kathmandu, Nepal. Govt India, Minist Hlth, Natl Programme Control Blindness, New Delhi, India. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 199 Z9 206 U1 0 U2 17 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 PY 2002 VL 43 IS 3 BP 623 EP 631 PG 9 WC Ophthalmology SC Ophthalmology GA 526TL UT WOS:000174145700007 PM 11867576 ER PT J AU Christiansen, SP Peterson, D To, T Youle, R McLoon, L AF Christiansen, SP Peterson, D To, T Youle, R McLoon, L TI Long-term effects of ricin-mAb 35 on extraocular muscles of rabbits: Potential treatment for strabismus SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BONE-MARROW; TOXIN; IMMUNOTOXIN; BUPIVACAINE; INJECTION; ESOTROPIA; TENSION AB PURPOSE. The immunotoxin, ricin-mAb 35, composed of ricin conjugated to a monoclonal antibody against the nicotinic acetylcholine receptor of skeletal muscle, has been proposed as a potential new agent for treatment of focal muscle dystonias. It has been demonstrated that direct injection of ricin-mAb 35 into rabbit extraocular muscle (EOM) results in significant muscle loss within 1 week. In this study, the long-term myopathic effects of ricin-mAb 35 on extraocular muscle were investigated. METHODS. Rabbit superior rectus muscles were injected with ricin-mAb 35 at a dose of 0.2 mug/kg, with the contralateral superior rectus muscle serving as the control. After 56 days, 105 days, and 1 year, the superior rectus muscles were removed and prepared for light or electron microscopy. Postinjection changes in muscle fiber morphometry, and ultrastruclure were examined. Immunohistochemical markers were used to identify inflammatory cellular infiltrate and myosin heavy chain (MHC) isoform expression. RESULTS. Despite evidence of ongoing regeneration, treated muscles continued to show a decrease in both myofiber number and in total cross-sectional area 56 and 105 days after injection. Individual myofiber cross-scctional areas were markedly heterogeneous at 56 days. Myofiber number and muscle cross-sectional area returned to normal 1 year after injection, but pronounced heterogeneity of myofiber size remained. The most significant changes in myosin heavy chain (MHC) isoform expression occurred in the orbital layer, where, at 56 and 105 days, there were increased numbers of fast and neonatal myofibers and decreased numbers of slow myofibers. In the global layer, after both 105 days and 1 year, there was a decrease in myofibers that were positive for slow, neonatal, and developmental MHC expression. CONCLUSIONS. EOM injection with ricin-mAb 35 results in a sustained decrease in muscle mass at 105 days after injection, with subtler morphoractric changes persisting even to 1 year. Changes in muscle force development as a result of ricin-mAb 35 injection are currently under investigation. This novel immunotoxin may be useful in the treatment of strabismus if these studies show sustained weakness in treated muscles. C1 Univ Minnesota, Dept Ophthalmol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. NIH, Biochem Sect, Surg Neurol Branch, Bethesda, MD 20892 USA. RP McLoon, L (reprint author), Univ Minnesota, Dept Ophthalmol, Room 374 LRB,2001 6th St SE, Minneapolis, MN 55455 USA. NR 20 TC 15 Z9 16 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 PY 2002 VL 43 IS 3 BP 679 EP 685 PG 7 WC Ophthalmology SC Ophthalmology GA 526TL UT WOS:000174145700015 PM 11867584 ER PT J AU Kim, SJ Zhang, MF Vistica, BP Chan, CC Shen, DF Wawrousek, EF Gery, I AF Kim, SJ Zhang, MF Vistica, BP Chan, CC Shen, DF Wawrousek, EF Gery, I TI Induction of ocular inflammation by T-helper lymphocytes type 2 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; TH2 CELLS; MICE; UVEITIS; DISEASE; ENCEPHALOMYELITIS; THERAPY; PROTEIN; LENS AB PURPOSE. Sight-damaging ocular inflammation is often mediated by T-helper (Th) lymphocytes. The population of Th cells is divided into two major subsets, designated Th1 and Th2, that differ by their cytokine production and biological activities. In the present study, the capacity of Th1 and Th2 cells to induce ocular inflammation was examined. METHODS. Ocular inflammation was induced in transgenic (Tg) mice that express hen egg lysozyme (HEL) in their lens, by adoptively transferring Th cells that transgenically express HEL-specific receptor. Th1 and Th2 populations were polarized in vitro, and their selective cytokine production was determined by conventional methods. Levels of ocular inflammation were monitored by conventional histologic methods. Infiltrating cells were collected from sections of inflamed eyes by microdissection, and their cytokine production was examined by RT-PCR. RESULTS. Th1 cells were highly immunopathogenic, producing disease in naive recipients at numbers as low as 0.12 x 10(6), whereas Th2 cells were inactive in these recipients, even at 30 x 10(6). Th2 cells, however, produced inflammation when transferred into sublethally irradiated recipients. Distinctive histopathologic changes characterized ocular inflammation induced by the two types of Th cells. Cytokine analysis of infiltrating cells in recipient mouse eyes, as well as of splenocytes of these mice demonstrated that the transferred cells retained their type specificity. Coinjecting Th2 and Th1 cells did not alleviate the ocular disease in naive recipients and even exacerbated the immunopathogenic process in irradiated recipients. CONCLUSIONS. Th2 cells are capable of inducing ocular inflammation, but only in immunodeficient mice, and are profoundly inferior to Th1 cells in their immunopathogenic capacity. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20817 USA. RP Gery, I (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. RI Wawrousek, Eric/A-4547-2008 NR 34 TC 38 Z9 39 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 PY 2002 VL 43 IS 3 BP 758 EP 765 PG 8 WC Ophthalmology SC Ophthalmology GA 526TL UT WOS:000174145700026 PM 11867595 ER PT J AU Eckelman, WC Frank, JA Brechbiel, M AF Eckelman, WC Frank, JA Brechbiel, M TI Theory and practice of imaging saturable binding sites SO INVESTIGATIVE RADIOLOGY LA English DT Review DE MRI; contrast agents; radiotracers; receptors; enzymes ID RECEPTOR-MEDIATED ENDOCYTOSIS; IN-VIVO; TRANSFERRIN; TUMOR; ANTIBODY; AGENT; CELLS; LIVER; NMR C1 NCI, Warren Grant Magnuson Clin Ctr, PET Dept, NIH, Bethesda, MD 20892 USA. NCI, LDRR, Ctr Clin, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NCI, Warren Grant Magnuson Clin Ctr, PET Dept, NIH, Bld 10 Rm 1C495,10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. EM eckelman@nih.gov NR 36 TC 19 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD MAR PY 2002 VL 37 IS 3 BP 101 EP 106 DI 10.1097/00004424-200203000-00001 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 534FB UT WOS:000174572900001 PM 11882788 ER PT J AU Sakai, A Sugawara, M Maeshiro, K Sugawara, K Kitamura, T AF Sakai, A Sugawara, M Maeshiro, K Sugawara, K Kitamura, T TI Parent-child relations of mutual trust, trust in one's best friend, and school adjustment: Junior high school students SO JAPANESE JOURNAL OF EDUCATIONAL PSYCHOLOGY LA Japanese DT Article DE school adjustment; parent-child relations; trust relationships; close friend; junior high school students ID SOCIAL SUPPORT; SUBSTANCE USE; ADOLESCENTS; LONELINESS; ACCEPTANCE; ATTACHMENT; LINKS AB The purpose of the present study was to investigate the relations among school adjustment, parent-child relations of mutual trust, and trust in one's best friend. A questionnaire assessing mood in the class (aggression, anxiety, and relaxation), maladjustment tendencies (loneliness and antisocial tendencies), and young people's trust in their parents and best friend was completed by 270 junior high school students. A questionnaire on parent's trust in their child was completed by 279 mothers and 241 fathers. The main results were as follows : (1) Youth who reported a relationship of mutual trust with their parents were well-adjusted to school. On the other hand, children who did not have a fully trusting relationship with their parents tended to be maladjusted at school. (2) For those children who did not have a relation of mutual trust with their parents, the extent to which they trusted their best friend was related to their tendency to be maladjusted in school (the loneliness and antisocial tendency measures). C1 NIMH, Bethesda, MD 20892 USA. Univ Sacred Heart, I-20123 Milan, Italy. Kumamoto Univ, Kumamoto, Japan. RP Sakai, A (reprint author), NIMH, Bethesda, MD 20892 USA. NR 27 TC 12 Z9 12 U1 0 U2 2 PU JAPANESE ASSOC EDUCATIONAL PSYCHOLOGY PI TOKYO PA 5-24-6-7F HONGO, BUMKYO-KU, TOKYO, 113-0033, JAPAN SN 0021-5015 J9 JPN J EDUC PSYCHOL JI Jpn. J. Educ. Psychol. PD MAR PY 2002 VL 50 IS 1 BP 12 EP 22 PG 11 WC Psychology, Educational SC Psychology GA 705TG UT WOS:000184410700002 ER PT J AU Tinkle, MB Cheek, DJ AF Tinkle, MB Cheek, DJ TI Human genomics: Challenges and opportunities SO JOGNN-JOURNAL OF OBSTETRIC GYNECOLOGIC AND NEONATAL NURSING LA English DT Article DE genetic testing; genetics education; human genome; nursing ID GENE POLYMORPHISMS; ALPHA GENE; ASSOCIATION; PROJECT; WOMEN; RISK; MALFORMATIONS; DISEASE; CARE AB The pace of knowledge development related to genetics continues to progress exponentially. Knowledge gained through the Human Genome Project will have a profound impact on the practice of nursing, and the widespread integration of genetics into nursing education, clinical practice, and research will be essential. Many nurses continue to view genetic services as relegated to a specialist in a tertiary center and not relevant to their practice. This is certainly about to change. This article reviews the major implications of Human Genome Project for changing the landscape of health care and nursing, discusses several specific examples of genetic testing, and describes strategies under way to help prepare nurses to meet these new demands. Understanding new DNA-based genetic-testing technologies will be important for nurses as these tests become more available and nurses assist clients in the management of their genetic health. Nurses must become active participants in embracing the challenges and opportunities related to this genetic revolution, which over the next 5 to 10 years will reach nurses in every specialty and in every practice setting. C1 Natl Inst Nursing Res, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Nursing, Chapel Hill, NC 27515 USA. RP Tinkle, MB (reprint author), Natl Inst Nursing Res, NIH, Bethesda, MD 20892 USA. RI Cheek, Dennis/J-8352-2014; OI Cheek, Dennis/0000-0002-3545-8228 NR 31 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-2175 J9 JOGNN JI JOGNN PD MAR-APR PY 2002 VL 31 IS 2 BP 178 EP 187 PG 10 WC Nursing; Obstetrics & Gynecology SC Nursing; Obstetrics & Gynecology GA 606FN UT WOS:000178723800009 PM 11926401 ER PT J AU Abrams, DI Bebchuk, JD Denning, ET Davey, RT Fox, L Lane, HC Sampson, J Verheggen, R Zeh, D Markowitz, NP AF Abrams, DI Bebchuk, JD Denning, ET Davey, RT Fox, L Lane, HC Sampson, J Verheggen, R Zeh, D Markowitz, NP CA Terry Beirn Community Programs Cli TI Randomized, open-label study of the impact of two doses of subcutaneous recombinant interleukin-2 on viral burden in patients with HIV-1 infection and CD4(+) cell counts of >= 300/mm(3): CPCRA 059 SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE interleukin-2; viral load; dose; immune modulator ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; PNEUMOCYSTIS-CARINII PNEUMONIA; PHASE-II TRIAL; HIV-1-INFECTED PATIENTS; OPPORTUNISTIC INFECTIONS; T-CELLS; DISCONTINUATION; PROPHYLAXIS; COMBINATION AB The effect of intermittent courses of recombinant interleukin-2 (rIL-2) on HIV-1 load in patients receiving combination antiretroviral therapy remains uncertain. CPCRA 059 was an open-label, randomized, multicenter trial in which 511 patients with HIV-1 infection and CD4(+) cell counts of greater than or equal to300/mm(3) who were receiving antiretroviral therapy were assigned to receive no rIL-2 (255 patients [controls]) or subcutaneous rIL-2 in dosages of 4.5 MIU (130) or 7.5 MIU (126) twice daily for 5-day courses every 8 weeks to maintain CD4(+) cell counts that were twice the baseline value or greater than or equal to1000/mm(3). The primary objective of this study was to compare the effects of the two doses of rIL-2 and no rIL-2 on viral load and CD4(+) cell counts over 12 months. There was no difference in the following viral load measurements between the rIL-2 treatment groups and the control treatment group: percentage of patients with viral loads of <50 copies/mL at 12 months (p = .55), time to viral load of greater than or equal to50 copies/mL for patients who had baseline viral loads of <50 copies/mL (p = .35), and change in viral load from baseline for patients who had viral loads of greater than or equal to50 copies/mL at baseline (p = .63). At each follow-up visit, the change in CD4(+) cell count from baseline was significantly greater in the rIL-2 treatment groups than in the control treatment group, with a mean difference of 251/mm(3) at month 12 (95% confidence interval, 207-295; p <.0001). No unanticipated adverse experiences were seen in this trial, to our knowledge the largest randomized evaluation of rIL-2 treatment conducted to date. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Minnesota, Coordinating Ctr Biometr Res, Minneapolis, MN USA. NIAID, NIH, Bethesda, MD 20892 USA. NIAID, Div Aids, NIH, Bethesda, MD USA. Res & Educ Grp, Portland, OR USA. AIDS Res Alliance, Chicago, IL USA. Henry Ford Hosp, Detroit, MI 48202 USA. RP Abrams, DI (reprint author), San Francisco Gen Hosp, Community Consortium, UCSF Posit Hlth Program, Ward 84,Blvd 80,995 Potreo Ave, San Francisco, CA 94110 USA. FU NIAID NIH HHS [2UO1 AI42170-08] NR 35 TC 40 Z9 40 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 MAR 1 PY 2002 VL 29 IS 3 BP 221 EP 231 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 529KX UT WOS:000174299600002 PM 11873071 ER PT J AU Sheppard, HW Celum, C Michael, NL O'Brien, S Dean, M Carrington, M Dondero, D Buchbinder, SP AF Sheppard, HW Celum, C Michael, NL O'Brien, S Dean, M Carrington, M Dondero, D Buchbinder, SP TI HIV-1 infection in individuals with the CCR5-Delta 32/Delta 32 genotype: Acquisition of syncytium-inducing virus at seroconversion SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; CCR5-Delta 32/Delta 32; coreceptors; CCR5; CXCR4; SI; NSI; X4-HIV-1; CCR5 genotype; seroconverters; homozygous/Delta 32 ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; DISEASE PROGRESSION; CCR-5 DELTA-32; UNINFECTED INDIVIDUALS; CORECEPTOR USAGE; DELETION ALLELE; NATURAL-HISTORY; CLINICAL COURSE; UNITED-STATES AB Homozygosity for the 32 base-pair deletion (Delta32/Delta32) in the CCR5 coreceptor gene is associated with incomplete HIV-1 resistance. Six HTV-1-infected Delta32/Delta32 patients have been reported. We report 2 additional Delta32/Delta32-infected individuals, among 106 seroconverters in a vaccine preparedness study. Like the previous 6, these individuals experienced rapid CD4 decline. However. taken together, the 8 patients have neither uniformly high virus load nor rapid progression to AIDS. We obtained five virus isolates from 1 patient at 5, 6, 7, 10, and 12 months after the estimated time of infection. The earliest isolate exhibits the syncytium-inducing (SI) phenotype and exclusive use of the CXCR4 coreceptor. suggesting acquisition of HIV-1 through this coreceptor. Of the remaining 104 seroconverters, 8 were CCR5-Delta32/+ and 96 were CCR5-+/+. Three CCR5-(+/+) seroconverters. who showed the uncommon pattern of early SI virus and rapid CD4 decline had uniformly high viral load and more heterogeneous coreceptor usage. These results further support the conclusion that Delta32-mediated resistance is incomplete and is associated with acquisition of exclusively-X4 variants of HIV-1. The pathogenic potential of these viruses may be different from late-stage X4 virus or early X4 virus acquired by individuals with other CCR5 genotypes. C1 Calif State Dept Hlth Serv, Viral & Rickettsial Dis Lab, Richmond, CA 94804 USA. Univ Washington, Sch Med, Seattle, WA USA. Walter Reed Army Inst Res, Rockville, MD USA. Natl Canc Inst, Bethesda, MD USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. RP Sheppard, HW (reprint author), Calif State Dept Hlth Serv, Viral & Rickettsial Dis Lab, 850 Marina Bay Pkwy, Richmond, CA 94804 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NIAID NIH HHS [N01 AI 45202, N01-AI 45200, N01-AI-35176] NR 47 TC 67 Z9 70 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 MAR 1 PY 2002 VL 29 IS 3 BP 307 EP 313 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 529KX UT WOS:000174299600013 PM 11873082 ER PT J AU Battles, HB Wiener, LS AF Battles, HB Wiener, LS TI From adolescence through young adulthood: Psychosocial adjustment associated with long-term survival of HIV SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE adolescent; HIV/AIDS; long-term survival; loss; pediatric; psychosocial; social support ID SOCIAL SUPPORT; CHILDREN; AIDS; DISCLOSURE AB Purpose: To examine the psychosocial factors associated with long-term survival of pediatric human immunodeficiency virus (HIV) infection. Methods: Children infected with HIV enrolled in clinical trials at the National Cancer Institute and their caregivers were interviewed and completed self-report measures 3 times, approximately 12 months apart, using the Child Behavior Checklist, Social Support Scale for Children, Self-Perception Profile for Children and Adolescents, and a structured interview designed by the investigators. Historical data were also extracted from patient medical charts. Average age of participants was 11.8 years at time 1 and 14 years at time 2; 56.3% of the original sample were male, racial composition was 72.2% white, 13.9% African-American, 6.9% Hispanic, and 6.9% "other"; 38.9% of participants contracted HIV perinatally, 34.7% through a hemophilia-related transfusion, and 26.4% through another type of transfusion. Results: Pearson product-moment correlations revealed that disclosure was found to be positively related to social support, self-competence, and decreased problem behavior, except in the case of public disclosure, in which an independent-sample Student's t-test revealed that it was negatively associated with global self-competence. Social support was significantly negatively correlated with problem behavior. Chi-square analyses of the 5-year follow-up data indicated that participants aged 18 years and older were less likely to complete their academic education than their healthy peers (national norms). Adolescents who lost a parent were more likely to have suffered from depression during their lifetime. Conclusions: Social support and open communication about the diagnosis are essential, particularly at an age at which decisions about relationships, sexual activity, drug use, and plans for the future are the focus of adolescent development and individuation. With advances in medical treatment, HIV-infected children are more likely to survive into adolescence and beyond. Accordingly, their psychosocial needs are changing to more closely resemble the needs of the chronically ill individual, rather than the terminally ill. Families of HIV-infected children should seriously consider preparation for independent living. C1 NCI, Bethesda, MD 20892 USA. RP Battles, HB (reprint author), NCI, 10-13N240,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 82 Z9 85 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAR PY 2002 VL 30 IS 3 BP 161 EP 168 AR PII S1054-139X(01)00341-X DI 10.1016/S1054-139X(01)00341-X PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 526AF UT WOS:000174105700008 PM 11869922 ER PT J AU Karpati, AM Rubin, CH Kieszak, SM Marcus, M Troiano, RP AF Karpati, AM Rubin, CH Kieszak, SM Marcus, M Troiano, RP TI Stature and pubertal stage assessment in American boys: The 1988-1994 Third National Health and Nutrition Examination Survey SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Tanner stage; puberty; stature; boys; growth ID PREVALENCE; OVERWEIGHT; CHILDREN; AGE AB Purpose: To describe current stature and pubertal development in North American boys, and to compare these measures with measures observed approximately 30 years ago. Methods: We analyzed data (i.e., height, weight, and Tanner Stage) from the Third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988-1994, and compared it to the National Health Examination Survey, Cycles II and III (HES II/III) conducted from 1963-1965 and 1966-1970. The surveys included physical examination and questionnaire components, employed cross-sectional designs, and are nationally representative. We used logistic regression to calculate median age at onset of pubertal stages. Results: NHANES III included 2481 boys aged 8 to IS years. HES II comprised 3010 boys aged 8-11 years and HES III comprised 3514 boys aged 12-17 years. The mean heights of the oldest boys in both surveys did not differ significantly; however, at younger ages, boys in the more recent survey were taller (average height difference among those aged 8-14 years was 2.0 cm). Boys in NHANES III were also heavier and had higher body mass index than those in HES II/III. The median estimated ages of onset of pubertal stages in NHANES III were 9.9, 12.2, 13.6, and 15.8 years for genital stages 2-5, respectively, and 11.9, 12.6, 13.6, and 15.7 years for pubic hair stages 2-5, respectively. For some stages, the median estimated age of onset of puberty was earlier among boys in NHANES III than among those in HES III. Conclusions: Differences in mean height at young ages, but not at older ages, suggest that the rate of growth among boys in NHANES III was faster than that of boys in the earlier surveys. This finding, coupled with the finding of earlier ages of onset of some pubertal stages, suggests that boys of this generation may be maturing more rapidly than did boys in the past. (C) Society for Adolescent Medicine, 2002. C1 Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Hlth Studies Branch, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA 30333 USA. Emory Univ, Sch Publ Hlth, Atlanta, GA 30322 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Rubin, CH (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Hlth Studies Branch, 1600 CLifton Rd,NE,MS E-23, Atlanta, GA 30333 USA. OI Troiano, Richard/0000-0002-6807-989X NR 25 TC 65 Z9 69 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD MAR PY 2002 VL 30 IS 3 BP 205 EP 212 AR PII S1054-139X(01)00320-2 DI 10.1016/S1054-139X(01)00320-2 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 526AF UT WOS:000174105700014 PM 11869928 ER PT J AU Szefler, SJ Martin, RJ King, TS Boushey, HA Cherniack, RM Chinchilli, VM Craig, TJ Dolovich, M Drazen, JM Fagan, JK Fahy, JV Fish, JE Ford, JG Israel, E Kiley, J Kraft, M Lazarus, SC Lemanske, RF Mauger, E Peters, SP Sorkness, CA AF Szefler, SJ Martin, RJ King, TS Boushey, HA Cherniack, RM Chinchilli, VM Craig, TJ Dolovich, M Drazen, JM Fagan, JK Fahy, JV Fish, JE Ford, JG Israel, E Kiley, J Kraft, M Lazarus, SC Lemanske, RF Mauger, E Peters, SP Sorkness, CA CA Asthma Clinical Res Network Natl H TI Significant variability in response to inhaled corticosteroids for persistent asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE asthma; beclomethasone dipropionate; exhaled nitric oxide; fluticasone propionate; inhaled corticosteroid; methacholine response; pulmonary response ID FLUTICASONE PROPIONATE; RESPONSIVENESS; PREDNISOLONE; INFLAMMATION; BUDESONIDE; CHILDREN; THERAPY; ONSET AB Background: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. Objective: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. Methods: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV1 and PC20; risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 mug/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 mug/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 mug/day. Results: Maximum FEV1 response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC20 improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV1 response, in contrast to poor (<5%) responses was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb) high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV1/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC20, in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). Conclusions: Near-maximal FEV1 and PC20 effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations. C1 Natl Jewish Med & Res Ctr, Dept Pediat, Denver, CO 80206 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Harlem Hosp Med Ctr, New York, NY USA. Columbia Univ, New York, NY USA. Penn State Univ, Hershey, PA USA. Milton S Hershey Med Ctr, Hershey, PA USA. Univ Wisconsin, Madison, WI USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. McMaster Univ, Hamilton, ON L8S 4L8, Canada. NHLBI, Bethesda, MD 20892 USA. RP Szefler, SJ (reprint author), Natl Jewish Med & Res Ctr, Dept Pediat, Room B104A,1400 Jackson St, Denver, CO 80206 USA. FU NCRR NIH HHS [5 M01 RR-00079, M01-RR-00645, M01-RR-03186, M01-RR02635]; NHLBI NIH HHS [U10 HL-51810, U10 HL-51823, U10 HL-51831, U10 HL-51834, U10 HL-51843, U10 HL-51845, U10 HL-56443] NR 24 TC 362 Z9 376 U1 1 U2 10 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2002 VL 109 IS 3 BP 410 EP 418 DI 10.1067/mai.2002.122635 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 534KW UT WOS:000174586400005 PM 11897984 ER PT J AU Blanc, S Colligan, AS Trabulsi, J Harris, T Everhart, JE Bauer, D Schoeller, DA AF Blanc, S Colligan, AS Trabulsi, J Harris, T Everhart, JE Bauer, D Schoeller, DA TI Influence of delayed isotopic equilibration in urine on the accuracy of the H-2(2) O-18 method in the elderly SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE aging; energy requirements; deuterium; oxygen-18 ID DOUBLY LABELED WATER; ENERGY-EXPENDITURE; RESIDUAL URINE; BODY-WATER; HUMANS; WOMEN; REQUIREMENTS; POPULATION; VALIDATION; SAMPLES AB Isotopic determination of total energy expenditure (TEE) by the doubly labeled water (DLW) method may be affected by urine retention in the elderly. The isotopic enrichments in urine and plasma sampled simultaneously 4 h post-DLW dose were compared in a subset of 281 subjects [139 women, 142 men 75+/-3 (SD) yr] of the 3,075 participants in the Health, Aging: and Body Composition study. Based on analytic precisions, a +/-2% urine-plasma difference was set as the cut-off value. Ten percent of the population presented a difference lower than -2%, suggesting a delay in urine isotopic equilibration. This -13+/-10% urine-plasma difference was not linked to analytic errors, illnesses, the sampling time, or the time and quantity of water intake, suggesting that urine retention may be the main factor. The consequences are an 18+/-13 and 21+/-16% overestimation of the total body water and the TEE, respectively, Unexpectedly, 21% of the population presented a urine-plasma difference higher than +/-2% that resulted, however, in a nonsignificant TEE underestimation of -3+/-5%. In conclusion, the delayed isotopic equilibration observed in urine reduces the accuracy of the DLW method in the elderly. It is recommended, when blood sampling is impossible, to adopt the intercept method with urine sampling 24 h postdose. C1 Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. NIDDKD, Bethesda, MD 20892 USA. NIA, Bethesda, MD 20892 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. RP Schoeller, DA (reprint author), Univ Wisconsin, Dept Nutr Sci, 1415 Linden Dr, Madison, WI 53706 USA. FU NIA NIH HHS [N01-AG-6-2106, N01-AG-6-2102, N01-AG-6-2103] NR 27 TC 41 Z9 41 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 MAR PY 2002 VL 92 IS 3 BP 1036 EP 1044 DI 10.1152/japplphysiol.00743.2001 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 523NF UT WOS:000173960100019 PM 11842037 ER PT J AU Christianson, SW Greiner, DL DeLuca, D Leif, J Phillips, NE Hayes, SM Hayashi, S Joliat, MJ Lyons, BL Shultz, LD AF Christianson, SW Greiner, DL DeLuca, D Leif, J Phillips, NE Hayes, SM Hayashi, S Joliat, MJ Lyons, BL Shultz, LD TI T cell developmental defects in 'viable motheaten' mice deficient in SHP-1 protein-tyrosine phosphatase. Developmental defects are corrected in vitro in the presence of normal hematopoietic-origin stromal cells and in vivo by exogenous IL-7 SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE T lymphocytes; cytokines; protein; kinases; phosphatases ID THYMUS ORGAN-CULTURE; TCR SIGNALING THRESHOLDS; EATEN MUTANT MICE; BONE-MARROW; MOTH-EATEN; DENDRITIC CELLS; MURINE THYMOCYTES; ME ME; INTERLEUKIN-7; FETAL AB Defects in the gene that encodes SHP-1 protein tyrosine phosphatase result in multiple hematopoietic abnormalities and generalized autoimmunity in viable motheaten (me(v)) mice. These mice also exhibit early thymic involution and abnormalities in T cell development. Here, we describe the use of fetal thymic organ culture (FTOC) and bone marrow adoptive transfer to study the effects of SHP-1 deficiency on thymocyte development. Chimeric FTOC established with normal bone marrow placed onto deoxyguanosine-treated fetal thymic lobes or onto scid fetal thymic lobes generated T cells. Bone marrow from SH2-1-deficient me(v)/me(v) mice generated decreased numbers of T cells in chimeric FTOC established using deoxyguanosine-treated thymi but generated normal numbers in chimeric FTOC established using scid thymi. However, scid fetal thymi seeded with me(v)/me(v) bone marrow also exhibited morphological abnormalities and contained elevated numbers of macrophages. Addition of IL-7 to me(v)/me(v) bone marrow-seeded scid FTOC led to increased cell numbers, particularly of macrophages. Intrathymic injection of IL-7 partially restored the ability of progenitor cells in me(v)/me(v) bone marrow to populate the thymus of adoptive recipients. We conclude that abnormal T cell development in me(v)/me(v) mice may in part be due to defects in the ability of bone marrow-derived accessory c ells to provide bioavailable IL-7 to developing thymocytes. (C) 2002 Elsevier Science Ltd. C1 Jackson Lab, Bar Harbor, ME 04609 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Univ Arizona, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Tottori Univ, Fac Med, Sch Life Sci, Dept Immunol, Tottori 680, Japan. RP Shultz, LD (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. FU NCI NIH HHS [CA34196, CA20408]; NCRR NIH HHS [RR07068]; NIAID NIH HHS [AI42669]; NIDDK NIH HHS [DK32520, DK53006]; NIGMS NIH HHS [GM35968] NR 53 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD MAR PY 2002 VL 18 IS 2 BP 119 EP 130 DI 10.1006/jaut.2001.0571 PG 12 WC Immunology SC Immunology GA 542NB UT WOS:000175049000004 PM 11908944 ER PT J AU Rosner, JL Dangi, B Gronenborn, AM Martin, RG AF Rosner, JL Dangi, B Gronenborn, AM Martin, RG TI Posttranscriptional activation of the transcriptional activator rob by dipyridyl in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID MULTIPLE ANTIBIOTIC-RESISTANCE; ORGANIC-SOLVENT TOLERANCE; DNA-BINDING; OUTER-MEMBRANE; PROTEIN; REGULON; MAR; EXPRESSION; SUPEROXIDE; GENE AB The transcriptional activator Rob consists of an N-terminal domain (NTD) of 120 amino acids responsible for DNA binding and promoter activation and a C-terminal domain (CTD) of 169 amino acids of unknown function. Although several thousand molecules of Rob are normally present per Escherichia coli cell, they activate promoters of the rob regulon poorly. We report here that in cells treated with either 2,2'- or 4,4'-dipyridyl (the latter is not a metal chelator), Rob-mediated transcription of various rob regulon promoters was increased substantially. A small, growth-phase-dependent effect of dipyridyl on the rob promoter was observed. However, dipyridyl enhanced Rob's activity even when rob was regulated by a heterologous (lac) promoter showing that the action of dipyridyl is mainly posttranscriptional. Mutants lacking from 30 to 166 of the C-terminal amino acids of Rob had basal levels of activity similar to that of wild-type cells, but dipyridyl treatment did not enhance this activity. Thus, the CTD is not an inhibitor of Rob but is required for activation of Rob by dipyridyl. In contrast to its relatively low activity in vivo, Rob binding to cognate DNA and activation of transcription in vitro is similar to that of MarA, which has a homologous NTD but no CTD. In vitro nuclear magnetic resonance studies demonstrated that 2,2'-dipyridyl binds to Rob but not to the CTD-truncated Rob or to MarA, suggesting that the effect of dipyridyl on Rob is direct. Thus, it appears that Rob can be converted from a low activity state to a high-activity state by a CTD-mediated mechanism in vivo or by purification in vitro. C1 Natl Inst Diabetes Digest & Kidney Dis, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. Natl Inst Diabetes Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Rosner, JL (reprint author), Natl Inst Diabetes Digest & Kidney Dis, Lab Mol Biol, NIH, Bldg 5 Rm 333, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 35 TC 48 Z9 48 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2002 VL 184 IS 5 BP 1407 EP 1416 DI 10.1128/JB.184.5.1407-1416.2002 PG 10 WC Microbiology SC Microbiology GA 523BZ UT WOS:000173932600022 PM 11844771 ER PT J AU Somerville, GA Beres, SB Fitzgerald, JR DeLeo, FR Cole, RL Hoff, JS Musser, JM AF Somerville, GA Beres, SB Fitzgerald, JR DeLeo, FR Cole, RL Hoff, JS Musser, JM TI In vitro serial passage of Staphylococcus aureus: Changes in physiology, virulence factor production, and agr nucleotide sequence SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; REGULATOR AGR; RNA-BINDING; ACONITASE; EXPRESSION; APOPTOSIS; IRON; INACTIVATION; INFECTION; PROTEIN AB Recently, we observed that Staphylococcus aureus strains newly isolated from patients had twofold-higher aconitase activity than a strain passaged extensively in vitro, leading us to hypothesize that aconitase specific activity decreases over time during in vitro passage. To test this hypothesis, a strain recovered from a patient with toxic shock syndrome was serially passaged for 6 weeks, and the aconitase activity was measured. Aconitase specific activity decreased 38% (P < 0.001) by the sixth week in culture. During serial passage, S. aureus existed as a heterogeneous population with two colony types that had pronounced (wild type) or negligible zones of beta-hemolytic activity. The cell density-sensing accessory gene regulatory (agr) system regulates beta-hemolytic activity. Surprisingly, the percentage of colonies with a wild-type beta-hemolytic phenotype correlated strongly with aconitase specific activity (p = 0.96), suggesting a common cause of the decreased aconitase specific activity and the variation in percentage of beta-hemolytic colonies. The loss of the beta-hemolytic phenotype also coincided with the occurrence of mutations in the agrC coding region or the intergenic region between agrC and agrA in the derivative strains. Our results demonstrate that in vitro growth is sufficient to result in mutations within the agr operon. Additionally, our results demonstrate that S. aureus undergoes significant phenotypic and genotypic changes during serial passage and suggest that vigilance should be used when extrapolating data obtained from the study of high-passage strains. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jmusser@niaid.nih.gov RI Somerville, Greg/B-1326-2013; OI Somerville, Greg/0000-0002-0991-8737; DeLeo, Frank/0000-0003-3150-2516 NR 33 TC 96 Z9 100 U1 0 U2 8 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 MAR PY 2002 VL 184 IS 5 BP 1430 EP 1437 DI 10.1128/JB.184.5.1430-1437.2002 PG 8 WC Microbiology SC Microbiology GA 523BZ UT WOS:000173932600025 PM 11844774 ER PT J AU Shi, CZ Soldatov, NM AF Shi, CZ Soldatov, NM TI Molecular determinants of voltage-dependent slow inactivation of the Ca2+ channel SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-CHANNEL; ALPHA(1C) SUBUNIT; POTASSIUM CHANNEL; K+ CHANNEL; MECHANISM; BLOCK; SEGMENT; PHENYLALKYLAMINES; CONDUCTANCE; MEGAPRIMER AB Ba2+ current through the L-type Ca2+ channel inactivates essentially by voltage-dependent mechanisms with fast and slow kinetics. Here we found that slow inactivation is mediated by an annular determinant composed of hydrophobic amino acids located near the cytoplasmic ends of transmembrane segments S6 of each repeat of the ale subunit. We have determined the molecular requirements that completely obstruct slow inactivation. Critical interventions include simultaneous substitution of A752T in IIS6, V1165T in IIIS6, and I1475T in IVS6, each preventing in additive manner a considerable fraction of Ba2+ current from inactivation. In addition, it requires the S405I mutation in segment IS6. The fractional inhibition of slow inactivation in tested mutants caused an acceleration of fast inactivation, suggesting that fast and slow inactivation mechanisms are linked. The channel lacking slow inactivation showed similar to45% of the sustained Ba2+ or Ca2+ current with no indication of decay. The remaining fraction of the current was inactivated with a single-exponential decay (tau(f) similar to 10 ms), completely recovered from inactivation within 100 ms and did not exhibit Ca2+-dependent inactivation properties. No voltage-dependent characteristics were significantly changed, consistent with the C-type inactivation model suggesting constriction of the pore as the main mechanism possibly targeted by Ca2+ sensors of inactivation. C1 NIA, NIH, Baltimore, MD 21224 USA. RP Soldatov, NM (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 40 TC 50 Z9 50 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 1 PY 2002 VL 277 IS 9 BP 6813 EP 6821 DI 10.1074/jbc.M110524200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 525ZQ UT WOS:000174104300010 PM 11751866 ER PT J AU Rathore, D Sacci, JB de la Vega, P McCutchan, TF AF Rathore, D Sacci, JB de la Vega, P McCutchan, TF TI Binding and invasion of liver cells by Plasmodium falciparum sporozoites - Essential involvement of the amino terminus of circumsporozoite protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FLAVOBACTERIUM-HEPARINUM; EXTRACELLULAR-MATRIX; MALARIA SPOROZOITES; CRYSTAL-STRUCTURE; HEPARAN-SULFATE; SALIVARY-GLANDS; REGION-I; THROMBOSPONDIN; VACCINE; ADHESION AB Plasmodium sporozoites display circumsporozoite (CS) protein on their surface, which is involved in the attachment of sporozoites to liver cells. CS protein is a member of the thrombospondin type I repeat (TSR) domain family and possess a single copy of TSR domain toward its carboxyl terminus. We show by a direct measurement the correlation between the binding activity of various segments of the CS protein and their ability to inhibit the invasion of liver cells by the sporozoites. We made eight truncated versions of Plasmodium falciparum CS protein to elucidate the role of various regions in the binding and invasion process. Deletion of the TSR domain actually enhanced binding activity by 2-3-fold without the loss of receptor specificity, indicating that TSR may not be the only domain in defining the specificity of binding. These same deletions blocked invasion of live sporozoites more efficiently than proteins that include the TSR domain. Deletion of as little as six amino acids from amino terminus of the protein, however, renders it incapable of binding to liver cells and as an inhibitor of sporozoite invasion. Hence, the binding of CS protein to liver cells and its ability to inhibit the invasion process are affected in a parallel manner, both positively and negatively, by sequence changes in the encoded CS gene. This indicates that both assays are measuring interrelated phenomenon and points to the essential involvement for the amino-terminal portion of the CS protein in these processes. C1 NIAID, Natl Inst Hlth, Lab Malaria & Vector Res, Growth & Dev Sect, Bethesda, MD 20892 USA. USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP McCutchan, TF (reprint author), NIAID, Natl Inst Hlth, Lab Malaria & Vector Res, Growth & Dev Sect, 4 Ctr Dr,MSC 0425,Rm 126,Bldg 4, Bethesda, MD 20892 USA. NR 41 TC 40 Z9 46 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 1 PY 2002 VL 277 IS 9 BP 7092 EP 7098 DI 10.1074/jbc.M106862200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 525ZQ UT WOS:000174104300045 PM 11751898 ER PT J AU Adamson, ED Minchiotti, G Salomon, DS AF Adamson, ED Minchiotti, G Salomon, DS TI Cripto: A tumor growth factor and more SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID MAMMARY EPITHELIAL-CELLS; LEUKEMIA INHIBITORY FACTOR; CERVICAL-CARCINOMA CELLS; EARLY MOUSE DEVELOPMENT; BREAST-CANCER CELLS; ONE-EYED PINHEAD; LOBULOALVEOLAR DEVELOPMENT; TYROSINE PHOSPHORYLATION; VERTEBRATE DEVELOPMENT; SIGNALING PATHWAYS AB Cripto, a growth factor with an EGF-like domain, and the first member of the EGF-CFC family of genes to Lie sequenced and characterized, contributes to deregulated growth of cancer cells. A role for Cripto in tumor development has been described in the human and the mouse. Members of the EGF-CFC family are found only in vertebrates: CFC proteins in zebrafish, Xenopus, chick, mouse and human have been characterized and indicate some common general functions in development. Cripto expression was first found in human and mouse embryonal carcinoma cells and male teratocarcinomas, and was demonstrated to be over-expressed in breast, cervical, ovarian, gastric, lung, colon, and pancreatic carcinomas in contrast to normal tissues where Cripto expression was invariably low or absent. Cripto may play a role in mammary tumorigenesis, since in vitro, Cripto induces mammary cell proliferation, reduces apoptosis, increases cell migration, and inhibits milk protein expression. This prediction is strengthened by observations of Cripto expression in 80% of human and mouse mammary tumors. At least three important roles for Cripto in development have created considerable interest, and each activity may be distinct in its mechanism of receptor signaling. One role is in the patterning of the anterior-posterior axis of the early embryo, a second is a crucial role in the development of the heart, and a third is in potentiating branching morphogenesis and modulating differentiation in the developing mammary gland. Whether these properties are functions of different forms of Cripto, different Cripto receptors or the distinct domains within this 1538 kDa glycoprotein are examined here, but much remains to be revealed about this evolutionarily conserved gene product. Since all Cripto receptors have not yet been determined with certainty, future possible uses as therapeutic targets remain to be developed. Cripto is released or shed from expressing cells and may serve as an accessible marker gene in the early to mid-progressive stages of breast and other cancers. Meanwhile some speculations on possible receptor complexes for Cripto signaling in mammary cells are offered here as a spur to further discoveries. (C) 2002 Wiley-Liss, Inc. C1 Burnham Inst, La Jolla Canc Res Ctr, La Jolla, CA 92037 USA. CNR, Int Inst Genet & Biophys, Naples, Italy. Natl Canc Inst, Basic Res Lab, Tumor Growth Factor Sect, NIH, Bethesda, MD USA. RP Adamson, ED (reprint author), Burnham Inst, La Jolla Canc Res Ctr, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. NR 76 TC 58 Z9 64 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD MAR PY 2002 VL 190 IS 3 BP 267 EP 278 DI 10.1002/jcp.10072 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 520TH UT WOS:000173797100001 PM 11857442 ER PT J AU Mansfield, ML Covell, DG Jernigan, RL AF Mansfield, ML Covell, DG Jernigan, RL TI A new class of molecular shape descriptors. 1. theory and properties SO JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES LA English DT Article ID SURFACE SHAPE; QUANTITATIVE REPRESENTATION; GAUSSIAN DESCRIPTION; DRUG DESIGN AB The integrals V (n(1), n(2), n(3)) = f dr x(n1),y(n2), z(n3), where f dr represents integration over the volume of a body, such as a molecule, where x, y, and z are Cartesian coordinates of a point in the interior of the body relative to an arbitrary reference frame, and where n(1), n(2), and n(3) are integers greater than or equal to zero, constitute moments of the volume distribution of the body. Considering all such quantities for which 0 less than or equal to n(1) + n(2) + n(3) less than or equal to 6 gives a set of 84 independent numbers which characterize the shape of the body and constitute a very useful set of shape descriptors. They also carry information about the absolute orientation and position of the body, and because their behavior under rotations and translations can be calculated quickly, they provide a fast, robust algorithm for the alignment of two similar molecules as well as a qualitative measure of their similarity. This paper reports the performance of the alignment algorithm on a learning set of about 80 different shapes. The algorithm is further tested against a set of small drug-like compounds that have been screened as anticancer agents. In both cases, excellent alignments of "shape-similar" molecules are obtained. Discussions are provided on many basic properties of these moments, e.g., their behavior under translations and rotations of the reference frame and their symmetry properties. C1 NCI, DCTD, Screening Technol Branch, Frederick, MD 21702 USA. NCI, DBS, Lab Expt & Computat Biol, Bethesda, MD 20892 USA. RP Covell, DG (reprint author), NCI, DCTD, Screening Technol Branch, Frederick, MD 21702 USA. RI Jernigan, Robert/A-5421-2012 FU PHS HHS [N01-56000] NR 24 TC 21 Z9 22 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0095-2338 J9 J CHEM INF COMP SCI JI J. Chem. Inf. Comput. Sci. PD MAR-APR PY 2002 VL 42 IS 2 BP 259 EP 273 DI 10.1021/ci000100o PG 15 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 537AF UT WOS:000174733500016 PM 11911695 ER PT J AU Markoglou, N Wainer, IW AF Markoglou, N Wainer, IW TI Biosynthesis in an on-line immobilized-enzyme reactor containing phenylethanolamine N-methyltransferase in single-enzyme and coupled-enzyme formats SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 25th International Symposium on High Performance Liquid Phase Separations and Related Techniques CY JUN 17-22, 2001 CL MAASTRICHT, NETHERLANDS DE enzymes; immobilized enzymes; phenylethanolamine N-methyltransferase; dopamine beta-hydroxylase; epinephrine; dopamine ID ONLINE DETERMINATION; ALPHA-CHYMOTRYPSIN; CHROMATOGRAPHY; TRYPSIN; PHASES; HPLC AB An immobilized-enzyme reactor (IMER) based upon phenylethanolamnie N-methyltransferase (PNMT) has been developed. The activity of the PNMT-IMER and its applicability for on-line N-methylation of normetanephrine was investigated. The reactor was connected through a switching valve to a cyano (CN) and ODS stationary phase connected in series. The substrate was injected onto the PNMT-IMER and the unreacted substrate and product were eluted and transported via a switching valve onto the analytical columns. The results from the PNMT-IMER/CN-ODS chromatographic system demonstrate that the enzyme retained its catalytic activity. Known substrates and inhibitors for PNMT were examined and the chromatographic system was utilized to carry out both quantitative and qualitative determinations. The PNMT-IMER/CN-ODS system proves to be useful in basic biochemical studies, an ideal for the high throughput screening of substances for PNMT substrate-inhibitor properties. The PNMT-INMR was then coupled in series using switching-valve technology with a previously developed dopamine betad-hydroxylase immobilized-enzyme reactor and used to carry out the on-line two-step synthesis of epinephrine from dopamine. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. McGill Univ, Dept Med, Div Expt Med, Montreal, PQ, Canada. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 15 TC 10 Z9 11 U1 1 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 1 PY 2002 VL 948 IS 1-2 BP 249 EP 256 AR PII S0021-9673(01)01474-1 DI 10.1016/S0021-9673(01)01474-1 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 532TT UT WOS:000174491700025 PM 12831201 ER PT J AU Puzianowska-Kuznicka, M Krystyniak, A Madej, A Cheng, SY Nauman, J AF Puzianowska-Kuznicka, M Krystyniak, A Madej, A Cheng, SY Nauman, J TI Functionally impaired TR mutants are present in thyroid papillary cancer SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RETINOIC ACID RECEPTORS; HORMONE NUCLEAR RECEPTORS; NA+/I SYMPORTER GENE; V-ERBA; CELL-LINES; C-MYC; HEPATOCELLULAR-CARCINOMA; THYROTROPIN RECEPTOR; TRANSCRIPTION FACTOR; NEGATIVE REGULATOR AB TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oneogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40-45% of cases. We found that the mean expression levels of TRbeta mRNA and TRalpha mRNA were significantly lower, whereas the protein levels of TRbeta1 and TRalpha1 were higher in cancer tissues than in healthy thyroid. Sequencing of TRbeta1 and TRalpha1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TRbeta1 or TRalpha1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma. C1 Polish Acad Sci, Med Res Ctr, Dept Endocrinol, PL-02097 Warsaw, Poland. Med Ctr Postgrad Educ, Dept Biochem, PL-02097 Warsaw, Poland. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puzianowska-Kuznicka, M (reprint author), Polish Acad Sci, Med Res Ctr, Dept Endocrinol, 1A Banacha St, PL-02097 Warsaw, Poland. EM monika@amwaw.edu.pl NR 52 TC 81 Z9 84 U1 0 U2 4 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 MAR PY 2002 VL 87 IS 3 BP 1120 EP 1128 DI 10.1210/jc.87.3.1120 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 534ZX UT WOS:000174620600030 PM 11889175 ER PT J AU Egan, JM Clocquet, AR Elahi, D AF Egan, JM Clocquet, AR Elahi, D TI The insulinotropic effect of acute exendin-4 administered to humans: Comparison of nondiabetic state to type 2 diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLUCOSE; MICE; MEN AB Exendin-4 is a potent and long-acting agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an insulinotropic gut peptide and is being evaluated for the regulation of plasma glucose in type 2 diabetes. The purpose of the present study was to ascertain whether exendin-4 is insulinotropic and whether it has long-lived biological effects in nondiabetic and type 2 diabetic subjects. Because incretins are glucose dependent with respect to their insulin-releasing capacity, we used the hyperglycemic glucose clamp technique to begin to address these issues in two separate protocols. In one protocol, we infused exendin-4 (0.15 pmol.kg(-1).min(-1)) in seven nondiabetic and seven type 2 diabetic subjects during the second hour of a 5-h hyperglycemic clamp in which fasting plasma glucose was raised by 5.4 mmol/liter. The second protocol was identical to the first except that plasma glucose was allowed to fall to the fasting levels during the fourth hour and again raised by 5.4 mmol/liter during the fifth hour in four nondiabetic and four diabetic subjects. With the initiation of exendin-4 infusion at 60 min, plasma insulin response was potentiated 4- to 5-fold in both groups. Despite termination of exendin-4 at the end of the second hour, the insulin levels remained elevated for several hours and hyperglycemia was maintained. All volunteers ate a meal 5.5 h after inducing hyperglycemia. Postprandial plasma glucose, insulin, and GLP-1 did not rise in any subject, possibly because of delayed gastric emptying by exendin-4 even though its infusion had been terminated 4 h previously. We concluded that exendin-4 is a potent and long-lasting insulinotropic agent in nondiabetic and diabetic subjects. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Geriatr Res Lab, Boston, MA 02114 USA. NIA, Diabet & Metab Sect, Clin Invest Lab, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Elahi, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Geriatr Res Lab, GRBSB-015,55 Fruit St, Boston, MA 02114 USA. EM elahi.dariush@mgh.harvard.edu FU NCRR NIH HHS [M01RR02719] NR 11 TC 178 Z9 185 U1 0 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2002 VL 87 IS 3 BP 1282 EP 1290 DI 10.1210/jc.87.3.1282 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 534ZX UT WOS:000174620600054 PM 11889200 ER PT J AU Waldmann, TA AF Waldmann, TA TI The IL-2/IL-15 receptor systems: Targets for immunotherapy SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article; Proceedings Paper CT Sass-Foundation Research Conference on New Frontiers in Biological Therapy for Hematological Malignancies CY SEP 02-04, 2001 CL GARGONZA, ITALY SP Sass Fdn DE interleukin-2; interleukin 15; receptors; monoclonal antibodies ID T-CELL LEUKEMIA; HUMANIZED ANTI-TAC; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; MULTICHAIN INTERLEUKIN-2 RECEPTOR; ACTIVATED KILLER-CELLS; MONOCLONAL-ANTIBODY; NATURAL-KILLER; BETA-CHAIN; IL-15 RECEPTOR; GAMMA-CHAIN AB Although interleukin-2 (IL-2) and -15 (IL-15) share two receptor subunits and many functions, at times they provide contrasting contributions to T-cell-mediated immune responses. IL-2, through its pivitol role in activation-induced cell death (AICD), is involved in peripheral tolerance through the elimination of self-reactive T cells. In contrast, in general IL-15 manifests antiapoptotic actions and inhibits IL-2-mediated AICD. IL-15 stimulates persistence of memory phenotype CD8(+) T cells, whereas IL-2 inhibits their expression, Humanized monoclonal antibodies that recognize IL-2Ralpha, the private receptor for IL-2, are being employed to inhibit allograft rejection and to treat T-cell leukemia/lymphoma. Therapies directed toward inhibiting the actions of the inflammatory cytokine, IL-15, are proposed for an array of autoimmune disorders as well as diseases associated with the retrovirus human T-cell lymphotrophic virus 1. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH Bldg 10,Room 4N115,NIH 10 Ctr Dr 1374, Bethesda, MD 20892 USA. NR 51 TC 69 Z9 71 U1 1 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAR PY 2002 VL 22 IS 2 BP 51 EP 56 DI 10.1023/A:1014416616687 PG 6 WC Immunology SC Immunology GA 540XK UT WOS:000174956000001 PM 11998892 ER PT J AU Verma, M Negm, R Srivastava, S AF Verma, M Negm, R Srivastava, S TI The NCI EDRN approach to molecular targets for earlier cancer detection and identification of risk SO JOURNAL OF CLINICAL LIGAND ASSAY LA English DT Article; Proceedings Paper CT Conference on Tumor Markers - New Era CY MAR 02-06, 2001 CL SANTA BARBARA, CALIFORNIA DE biomarkers; EDRN; LCM; MALDI; proteinchip; proteomics; SELDI ID MASS-SPECTROMETRY; DIFFERENTIAL DISPLAY; GENE-EXPRESSION; SERIAL ANALYSIS; LUNG-CANCER; PROTEINS; COMPLEX AB The promise of biomarkers to detect and diagnose cancer in its earliest stage has never been greater. Knowledge of molecular events during the early stages of cancer has advanced at a rapid pace. This advancement has been aided by the development of new high-throughput technologies, enabling the detection of molecular changes at genomic and proteomic levels. Applications of biomarker detection in clinical practice has been limited to single entity quantitation or small panels of tests that identify changes in proteins whose presence or absence signifies an important event. As more biomarkers are discovered it has become evident that no single marker will provide the information necessary to make the best decision in detection and diagnosis. With this in mind, the National Cancer Institute's Early Detection Research Network is promoting a mufti-parametric, mufti-markers approach to biomarkers development and validation. High density oligonucleotide and cDNA arrays are generating information to predict and understand the disease state that can be used to develop novel sentinel endpoints for chemopreventive interventions. In contrast, proteomic-based approaches, such as, a surface enhanced laser desorption and ionization time-of-flight (SELDI-TOF) and matrix assisted laser desorption ionization time-of-flight (MALDI-TOF), are enabling rapid ascertainment of disease status directly from human body fluids, serum, and seminal plasma. These potentially new paradigms for diagnostic technologies are rapid (within minutes), require small samples (less than 1 muL), and, most importantly, are sensitive and accurate in predicting the disease state. Some examples of these applications are discussed. C1 NCI, Canc Biomarkers Res Grp, Div Canc Prevent, NIH, Rockville, MD 20852 USA. RP Srivastava, S (reprint author), NCI, Canc Biomarkers Res Grp, Div Canc Prevent, NIH, 6130 Execut Blvd,EPN-3142, Rockville, MD 20852 USA. NR 16 TC 1 Z9 1 U1 0 U2 0 PU CLINICAL LIGAND ASSAY SOC PI WAYNE PA 3139 S WAYNE RD, WAYNE, MI 48184 USA SN 1081-1672 J9 J CLIN LIGAND ASSAY JI J. Clin. Ligand Assay PD SPR PY 2002 VL 25 IS 1 BP 6 EP 10 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 578ZX UT WOS:000177151900002 ER PT J AU Martinez, A Mulshine, JL AF Martinez, A Mulshine, JL TI Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) as a marker of preinvasive lung cancer SO JOURNAL OF CLINICAL LIGAND ASSAY LA English DT Article; Proceedings Paper CT Conference on Tumor Markers - New Era CY MAR 02-06, 2001 CL SANTA BARBARA, CALIFORNIA DE lung cancer; heterogeneous nuclear ribonucleoprotein A2/B1; early detection; early intervention; genetic instability; clonality; prospective clinical trials ID ANTIGEN; CARCINOGENESIS; OVEREXPRESSION; EXPRESSION; PROTEIN; BINDS; CELLS; RNA AB One of the most promising approaches to reducing lung cancer mortality is through implementing early detection protocols and developing early intervention strategies. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) is an oncofetal protein whose overexpression in epithelial sputum cells can be used as a very early marker to detect lung cancer. Three independent prospective validation trials offer clear examples of the robustness of this technique with sensitivities of about 90%. Recent studies show hnRNP A2/B1 as a marker of field carcinogenesis. Microdissection and posterior analysis of areas immunoreactive to hnRNP A2/B1 demonstrate a clear correlation between overexpression of this ribonucleoprotein and genetic instability. Clonality studies also indicate a common origin for hnRNP A2/B1 immunoreactive premalignant lesions and pulmonary tumors in the same patient. The molecular mechanisms linking hnRNP A2/B1 overexpression and cancer remain to be elucidated, but the use of this molecule as an early marker in the biological history of several tumors has been clearly determined. C1 NCI, Dept Cell & Canc Biol, Intervent Sect, NIH, Bethesda, MD 20892 USA. RP Martinez, A (reprint author), NCI, Dept Cell & Canc Biol, Intervent Sect, NIH, Bldg 10,Room 13N262,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 23 TC 1 Z9 1 U1 0 U2 0 PU CLINICAL LIGAND ASSAY SOC PI WAYNE PA 3139 S WAYNE RD, WAYNE, MI 48184 USA SN 1081-1672 J9 J CLIN LIGAND ASSAY JI J. Clin. Ligand Assay PD SPR PY 2002 VL 25 IS 1 BP 100 EP 103 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 578ZX UT WOS:000177151900020 ER PT J AU Gaydos, CA Crotchfelt, KA Shah, N Tennant, M Quinn, TC Gaydos, JC McKee, KT Rompalo, AM AF Gaydos, CA Crotchfelt, KA Shah, N Tennant, M Quinn, TC Gaydos, JC McKee, KT Rompalo, AM TI Evaluation of dry and wet transported intravaginal swabs in detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in female soldiers by PCR SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LIGASE CHAIN-REACTION; SEXUALLY-TRANSMITTED DISEASES; AMPLICOR CT/NG TESTS; VAGINAL SWABS; MULTICENTER EVALUATION; REACTION ASSAY; DIAGNOSIS; URINE; MILITARY; WOMEN AB Screening women for sexually transmitted diseases (STD) in nonclinic settings is highly desirable because many infections are asymptomatic. This is especially true for military women, for whom logistical, social, and other job-related obstacles present barriers to accessing medical care. We assessed the accuracy of intravaginal swabs transported by mail in a wet versus a dry state for PCR (Amplicor CT/NG test) detection of chlamydia and gonorrhea infections in a cross-sectional study of 793 active-duty military women attending an STD clinic. PCR tests of vaginal swabs (wet and dry) were compared to local clinical methods used on cervical swabs. Standard wet vaginal swab PCR testing detected more chlamydia (11.6%) than cervical enzyme immunoassay (9.3%). For detection of chlamydia using wet swabs, the sensitivity and specificity compared with adjudicated true positives were 94.6% (87 of 92) and 99.3% (696 of 701), respectively. Comparing dry swabs to true-positives for chlamydia, the sensitivity was 91.3% (84 of 92) and the specificity was 99.3% (696 of 701). Standard wet vaginal swab PCR detected more gonorrhea (3.3%) than routine cervical culture (2.1%). The sensitivity and specificity of PCR testing of wet swabs compared to true-positives (infected patients) were 96.3% (26 of 27) and 98.2% (752 of 766) for gonorrhea, respectively. For gonorrhea, the sensitivity and specificity of dry swabs compared to true-positives (infected patients) were 88.9% (24 of 27) and 98.3% (753 of 766), respectively. PCR testing of wet and dry transported intravaginal swabs to detect chlamydia and gonorrhea infections was an accurate diagnostic method for military women. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. Womack Army Med Ctr, Ft Bragg, NC USA. NIAID, NIH, Bethesda, MD 20892 USA. US Dept Def, Global Emerging Infect Surveillance & Response Sy, Silver Spring, MD USA. RP Gaydos, CA (reprint author), Johns Hopkins Univ, Sch Med, 1159 Ross,720 Rutland Ave, Baltimore, MD 21205 USA. RI Gaydos, Charlotte/E-9937-2010 NR 24 TC 39 Z9 42 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2002 VL 40 IS 3 BP 758 EP 761 DI 10.1128/JCM.40.3.758-761.2002 PG 4 WC Microbiology SC Microbiology GA 528HP UT WOS:000174238600004 PM 11880389 ER PT J AU Castle, PE Lorincz, AT Mielzynska-Lohnas, I Scott, DR Glass, AG Sherman, ME Schussler, JE Schiffman, M AF Castle, PE Lorincz, AT Mielzynska-Lohnas, I Scott, DR Glass, AG Sherman, ME Schussler, JE Schiffman, M TI Results of human papillomavirus DNA testing with the hybrid capture 2 assay are reproducible SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CERVICAL-CANCER; EPIDEMIOLOGIC EVIDENCE; WORLDWIDE; WOMEN AB Reproducibility of the Hybrid Capture 2 Test (HC 2) for human papillomavirus (HPV) DNA detection was evaluated by assaying frozen cervical specimens in 1997 and again in 2001 from 1,775 women with normal cervical cytology. Using a cutoff point of 1.0 pg of HPV DNA/ml between a negative and a positive test result, the result of the kappa test for agreement was 0.72 (a kappa value of >0.60 is considered good agreement). Using cutoff points of 1.0 and 10.0 pg/ml between negative and low positive and between low positive and high positive, respectively, the kappa was 0.68 and the linear-weighted kappa was 0.76. The results of this study indicate that HC 2 testing is reproducible even among cytologically normal women with low test values. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Digene Corp, Gaithersburg, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Kaiser Fdn Res Inst, Oakland, CA USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Plaza S,Room 7074, Bethesda, MD 20892 USA. NR 11 TC 53 Z9 61 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2002 VL 40 IS 3 BP 1088 EP 1090 DI 10.1128/JCM.40.3.1088-1090.2002 PG 3 WC Microbiology SC Microbiology GA 528HP UT WOS:000174238600063 PM 11880448 ER PT J AU Potosky, AL Harlan, LC Kaplan, RS Johnson, KA Lynch, CF AF Potosky, AL Harlan, LC Kaplan, RS Johnson, KA Lynch, CF TI Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLON-CANCER; BOWEL PROJECT; RECTAL-CARCINOMA; RANDOMIZED TRIAL; DUKES-B; BREAST; CHEMOTHERAPY; FLUOROURACIL; VALIDATION; LEVAMISOLE AB Purpose: Dissemination of efficacious adjuvant therapies for resectable colorectal cancer has not been comprehensively described. Trends, patterns, and outcomes of adjuvant therapy for colorectal cancer, focusing on age, sex, and racial/ethnic differences, are reported. Materials and Methods: Population-based random samples of patients diagnosed with colorectal cancer diagnosed in nine geographic areas were collected annually between 1987 and 1991 and in 1995 (n = 4,706). Data were obtained from medical record reviews. Multiple logistic regression was used to assess the use of standard adjuvant chemotherapy for colon and rectal cancers. The Cox proportional hazards model was used to assess 9-year mortality. Results: From 1987 until 1995, the use of adjuvant therapy increased in all age groups. There was an increase starting in 1989 for colon and in 1988 for rectal cancer. Use of standard therapy was 78% for those younger than 55 years and 24% for those older than 80 years. White patients received standard therapy more frequently than African-Americans (odds ratio, 1.75; 95% confidence interval [Cl], 1.09 to 2.83). All-cause and cancer-specific mortality exceeding 9 years were lower in those who received standard therapy (all-cause risk ratio [RR], 0.73; 95% Cl, 0.61 to 0.88; cancer-specific RR, 0.87; 95% Cl, 0.70 to 1.09). Conclusion: Standard adjuvant therapies for colorectal cancer disseminated into community practices during the 1990s. However, evidence exists of differential use of therapies by older patients and by African-Americans. The use of standard therapies in the general population is associated with lower mortality. improved dissemination of standard adjuvant therapies to all segments of the population could help reduce mortality. (C) 2002 by American Society of Clinical Oncology. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. RP Potosky, AL (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN Room 4005, Bethesda, MD 20892 USA. NR 31 TC 186 Z9 192 U1 0 U2 3 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 1 PY 2002 VL 20 IS 5 BP 1192 EP 1202 DI 10.1200/JCO.20.5.1192 PG 11 WC Oncology SC Oncology GA 528WZ UT WOS:000174268800010 PM 11870160 ER PT J AU McElroy, SL Frye, MA Suppes, T Dhavale, D Keck, PE Leverich, GS Altshuler, L Denicoff, KD Nolen, WA Kupka, R Grunze, H Walden, J Post, RM AF McElroy, SL Frye, MA Suppes, T Dhavale, D Keck, PE Leverich, GS Altshuler, L Denicoff, KD Nolen, WA Kupka, R Grunze, H Walden, J Post, RM TI Correlates of overweight and obesity in 644 patients with bipolar disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; BODY-WEIGHT GAIN; EATING DISORDER; PREVALENCE; LITHIUM; MECHANISMS; MANAGEMENT; ENDOCRINE; WOMEN AB Objective: Overweight and obesity are common clinical problems encountered in the treatment of bipolar disorder. We therefore assessed the prevalence and clinical correlates of overweight, obesity, and extreme obesity in 644 bipolar patients. Method: 644 outpatients with DSM-IV bipolar disorder in the Stanley Foundation Bipolar Treatment Outcomes Network were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar disorder diagnoses, demographic and historical illness characteristics, comorbid Axis I diagnoses, medical histories, health habits, and body mass indices (BMIs). Results: Fifty-eight percent of the patients with bipolar disorder were overweight, 21% were obese, and 5% were extremely obese. American patients had significantly higher mean (p < .0001) BMIs and significantly higher rates of obesity (p < .001) and extreme obesity (p < .001) than European patients. Significant associations (p:.001) were found between over-weight, obesity, and extreme obesity and gender, age, income level, comorbid binge-eating disorder, hypertension, arthritis, diabetes mellitus, exercise habits, and coffee consumption. Current BMI and weight were each correlated with the number of weight gain-associated psycho-tropics to which patients had been exposed. Multinomial logistic regression (adjusted for site and eating disorder diagnosis and corrected for multiple comparisons) showed that (1) overweight was significantly associated with male gender and hypertension (p < .001), (2) obesity was significantly associated with hypertension (p < .001), and (3) extreme obesity was significantly associated with hypertension and arthritis (p < .001). Conclusion: Overweight, obesity, and extreme obesity were common in this group of bipolar patients, although it was unclear that their prevalence rates were truly elevated, because overweight and obesity are increasingly common public health problems among the general population. Correlates of overweight and obesity in bipolar disorder include patient and treatment variables such as gender, geographical location, comorbid binge-eating disorder, age, income level, degree of exposure to weight gain-associated psychotropics, medical disorders associated with obesity, and health habits. C1 Univ Cincinnati, Coll Med, Biol Psychiat Program, Dept Psychiat,Stanley Fdn Bipolar Treatment Outco, Cincinnati, OH 45267 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. W Los Angeles VA Med Ctr, Los Angeles, CA USA. Univ Texas, SW Med Ctr, Dallas, TX USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Utrecht, Netherlands. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. LMU Univ Hosp, Dept Psychiat, Munich, Germany. Univ Hosp, Dept Psychiat, Freiburg, Germany. RP McElroy, SL (reprint author), Univ Cincinnati, Coll Med, Biol Psychiat Program, Dept Psychiat,Stanley Fdn Bipolar Treatment Outco, POB 670559,231 Albert Sabin Way, Cincinnati, OH 45267 USA. RI Nolen, Willem/E-9006-2014 NR 43 TC 213 Z9 217 U1 4 U2 12 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2002 VL 63 IS 3 BP 207 EP 213 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 534WU UT WOS:000174613400006 PM 11926719 ER PT J AU Pitiphat, W Diehl, SR Laskaris, G Cartsos, V Douglass, CW Zavras, AI AF Pitiphat, W Diehl, SR Laskaris, G Cartsos, V Douglass, CW Zavras, AI TI Factors associated with delay in the diagnosis of oral cancer SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE diagnosis; delay; oral cavity; mouth neoplasms ID SQUAMOUS-CELL CARCINOMA; MARITAL-STATUS; MORTALITY; SERVICES; ALCOHOL; CARE AB Early detection and treatment improve the prognosis for oral cancer. Delays from the onset of symptoms to clinical diagnosis are common. Our aim is to identify factors associated with this delay. Between 1995 and 1998, we interviewed 105 consecutive patients with histologically confirmed oral cancer in Greece. If 21 or more days elapsed from the time the patient noticed major symptoms to a definitive diagnosis, we called it a delay (52% of cases). We used logistic and linear regression to estimate odds ratios of delayed diagnosis and to identify correlates of length of delay, respectively. Former smokers had a 4.3 times greater risk of delayed diagnosis compared with current smokers (95% confidence interval: 1.1-17.1). The length of delay was greater among single patients, nonsmokers, or those with stage IV tumors. Clinicians should be advised that delay in the diagnosis of oral cancer occurs frequently, even in individuals who do not smoke heavily. C1 Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Khon Kaen Univ, Fac Dent, Dept Commun Dent, Khon Kaen 40002, Thailand. Natl Inst Dent & Craniofacial Res, Craniofacial Epidemiol & Genet Branch, Bethesda, MD 20892 USA. Univ Athens, Med Sch, A Sygros Hosp, Oral Med Dept, Athens 10676, Greece. RP Zavras, AI (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. FU NIDCR NIH HHS [K23DE00420]; NIMHD NIH HHS [MD 626829, MD 726655] NR 26 TC 42 Z9 42 U1 1 U2 2 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 MAR PY 2002 VL 81 IS 3 BP 192 EP 197 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559JR UT WOS:000176023500010 PM 11876274 ER PT J AU Akintoye, SO Lee, J Feimster, T Brahim, J Booher, S Kingman, A Robey, PG Collins, MT AF Akintoye, SO Lee, J Feimster, T Brahim, J Booher, S Kingman, A Robey, PG Collins, MT TI Dental phenotypic features in fibrous dysplasia and McCune-Albright syndrome. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. Meharry Med Coll, Needham, MA USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 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 MAR PY 2002 VL 81 SI SI MA 3760 BP A461 EP A461 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703727 ER PT J AU Baysac, MS Horowitz, AM AF Baysac, MS Horowitz, AM TI Oral cancer information in health education textbooks SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 MAR PY 2002 VL 81 SI SI MA 2748 BP A344 EP A344 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702721 ER PT J AU Bedi, GS Ten Hagen, KG AF Bedi, GS Ten Hagen, KG TI Multiple members of the family of UDP-GaINAc : polypeptide N-acetylgalactosaminyltransferases are needed for the O-glycosylation of mucin-type glycoproteins SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Rochester, Rochester, NY 14627 USA. NIH, Bethesda, MD 20892 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 MAR PY 2002 VL 81 SI SI MA 0279 BP A62 EP A62 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700278 ER PT J AU Birkedal-Hansen, H Birkedal-Hansen, H AF Birkedal-Hansen, H Birkedal-Hansen, H TI Frontiers of research in dentistry. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2002 VL 81 SI SI MA 3947 BP A482 EP A482 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703913 ER PT J AU Canto, MT Horowitz, AM Drury, TF AF Canto, MT Horowitz, AM Drury, TF TI Use of skin and oral cancer examinations in the US SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 2747 BP A344 EP A344 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702720 ER PT J AU Cardenas, LM Thyagarajan, T Sreenath, T Kulkarni, A Wright, J AF Cardenas, LM Thyagarajan, T Sreenath, T Kulkarni, A Wright, J TI Dentin phenotype in the transgenic TGF-Ya1 mouse. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ N Carolina, Sch Dent, Chapel Hill, NC 27515 USA. NIH, Bethesda, MD 20892 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 MAR PY 2002 VL 81 SI SI MA 3888 BP A476 EP A476 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703854 ER PT J AU Clovis, JB Horowitz, AM Poel, DH AF Clovis, JB Horowitz, AM Poel, DH TI British Columbia and Nova Scotia dentists' knowledge, opinions and practices: Oral cancers SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Dalhousie Univ, Halifax, NS B3H 3J5, Canada. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 2750 BP A344 EP A344 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702723 ER PT J AU Deutsch, WM Thomas, TL AF Deutsch, WM Thomas, TL TI Dental events during periods of isolation in the US Navy submarine force. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 USN, Sch Postgrad Dent, NIH, Monterey, CA USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 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 MAR PY 2002 VL 81 SI SI MA 0564 BP A94 EP A94 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700562 ER PT J AU Dworkin, SF Lavery, J Schafer, A AF Dworkin, SF Lavery, J Schafer, A TI Case studies in international collaborative oral health research: Ethical dilemmas. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Washington, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. Univ Manitoba, Winnipeg, MB R3T 2N2, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2002 VL 81 SI SI MA 2395 BP A303 EP A303 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702372 ER PT J AU Hatakeyama, J Sreenath, T Thyagarajan, T Hatakeyama, Y Shum, L Gibson, CW Wright, JT Kulkarni, AB AF Hatakeyama, J Sreenath, T Thyagarajan, T Hatakeyama, Y Shum, L Gibson, CW Wright, JT Kulkarni, AB TI Cementum defects in amelogenin null mice. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Funct Genom Unit, NIH, Bethesda, MD USA. NIAMS, NIH, Bethesda, MD USA. Univ Penn, Philadelphia, PA 19104 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 MAR PY 2002 VL 81 SI SI MA 0810 BP A123 EP A123 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700803 ER PT J AU Horowitz, AM Drury, TF Canto, MT AF Horowitz, AM Drury, TF Canto, MT TI Oral cancer examinations among tobacco and alcohol users: US, 1998 SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 2746 BP A344 EP A344 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702719 ER PT J AU Jin, BH Paik, DI Horowitz, AM Moon, HS Kim, JB AF Jin, BH Paik, DI Horowitz, AM Moon, HS Kim, JB TI Knowledge and practices regarding caries prevention among Korean pregnant women SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Shingu Coll, Shingu, South Korea. Seoul Natl Univ, Seoul 151, South Korea. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 0118 BP A43 EP A43 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700119 ER PT J AU Kingman, A AF Kingman, A TI Beyond weighted kappa when evaluating examiner agreement for ordinal responses. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, NIH, Bethesda, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 1 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 MAR PY 2002 VL 81 SI SI MA 1653 BP A219 EP A219 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024701638 ER PT J AU Kulkarni, AB Han, I Limaye, A Ambudkar, I Ward, J Sreenath, T Brady, RO Qasba, P AF Kulkarni, AB Han, I Limaye, A Ambudkar, I Ward, J Sreenath, T Brady, RO Qasba, P TI Elevated levels of globotriaosylceramide in salivary glands of Fabry mice. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIDCR, Funct Genom Unit, NIH, Bethesda, MD USA. NINDS, Dev Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. NCI, VTPS, NIH, Frederick, 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 MAR PY 2002 VL 81 SI SI MA 1073 BP A153 EP A153 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024701062 ER PT J AU Leung, KP Kuchenthal, CA Cisar, JO AF Leung, KP Kuchenthal, CA Cisar, JO TI Comparison of Actinomyces naeslundii T14V type 1 and type 2 fimbriae-associated genes. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 NIH, NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2002 VL 81 SI SI MA 1010 BP A146 EP A146 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024701000 ER PT J AU Ma, DS Park, DY Park, JA Horowitz, AM AF Ma, DS Park, DY Park, JA Horowitz, AM TI Early childhood caries among kindergarten children: prevalence and etiology in Kangnung, Korea. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Kangnung Natl Univ, Coll Dent, Kangnung, South Korea. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 0113 BP A43 EP A43 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700114 ER PT J AU Melvin, JE Watson, GE Andrew, D Ann, D Culp, D Yamada, KM AF Melvin, JE Watson, GE Andrew, D Ann, D Culp, D Yamada, KM TI Salivary gland development: A potential source of novel approaches to treating xerostomia. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Rochester, Rochester, NY 14627 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Univ So Calif, Los Angeles, CA 90089 USA. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 3948 BP A483 EP A483 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703914 ER PT J AU Shugars, DC Asesanya, M Diehl, S Redman, R Malley, K Silva, R Farish, S Francis, T Craig, R Buchanan, R Toledo, A Jordan, R Winn, D AF Shugars, DC Asesanya, M Diehl, S Redman, R Malley, K Silva, R Farish, S Francis, T Craig, R Buchanan, R Toledo, A Jordan, R Winn, D TI Awareness of premalignant oral lesions among US veterans. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 UNC, Sch Dent, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 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 MAR PY 2002 VL 81 SI SI MA 2344 BP A297 EP A297 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702321 ER PT J AU Sreenath, T Hall, B Longenecker, G Thyagarajan, T D'Souza, RN Hong, S Wright, JT Macdougall, M Kulkarni, AB AF Sreenath, T Hall, B Longenecker, G Thyagarajan, T D'Souza, RN Hong, S Wright, JT Macdougall, M Kulkarni, AB TI Targeted disruption of the mouse dentin sialophosphoprotein gene. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD USA. Univ Texas, Hlth Sci Ctr, Dent Branch, Houston, TX USA. Univ N Carolina, Sch Dent, Chapel Hill, NC 27515 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 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 MAR PY 2002 VL 81 SI SI MA 3889 BP A476 EP A476 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703855 ER PT J AU Syme, L Sheiham, A Watt, R Treasure, E Moyses, S Nowjack-Raymer, R Cohen, L AF Syme, L Sheiham, A Watt, R Treasure, E Moyses, S Nowjack-Raymer, R Cohen, L TI Reducing oral health disparities - how can social epidemiology and health promotion research move the agenda forward?. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 UCL, London WC1E 6BT, England. Cardiff Univ, Cardiff CF1 3NS, S Glam, Wales. NIDCR, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2002 VL 81 SI SI MA 3798 BP A465 EP A465 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703765 ER PT J AU Tartaix, P Fisher, LW Boskey, AL AF Tartaix, P Fisher, LW Boskey, AL TI Inhibition of in vitro Mineralization by DMP1 SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Hosp Special Surg, New York, NY 10021 USA. Columbia Univ, Sch Dent Med, New York, NY 10027 USA. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 0097 BP A41 EP A41 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700098 ER PT J AU Tung, MS Lin, S Schaeffer, JM AF Tung, MS Lin, S Schaeffer, JM TI Formation and transformation of calcium phosphate from highly concentrated solutions. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Amer Dent Assoc Hlth Fdn, Chicago, IL 60611 USA. New York Med Coll, Valhalla, NY 10595 USA. 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 MAR PY 2002 VL 81 SI SI MA 4012 BP A490 EP A490 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703978 ER PT J AU Viswanathan, H Berry, JE Tokiyasu, Y Gibson, CW Kulkarni, AB Snead, ML Somerman, MJ AF Viswanathan, H Berry, JE Tokiyasu, Y Gibson, CW Kulkarni, AB Snead, ML Somerman, MJ TI Amelogenin: a signaling protein for periodontal development. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor, MI 48109 USA. Meikai Univ, Sakado, Saitama, Japan. Univ Penn, Philadelphia, PA 19104 USA. NIH, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA 90089 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAR PY 2002 VL 81 SI SI MA 2497 BP A315 EP A315 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702473 ER PT J AU Vitolo, JM Zheng, C Baum, BJ AF Vitolo, JM Zheng, C Baum, BJ TI Nuclear protein binding to a novel retroviral sequence SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 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 MAR PY 2002 VL 81 SI SI MA 0037 BP A34 EP A34 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700038 ER PT J AU Wang, J Zheng, C Baum, B AF Wang, J Zheng, C Baum, B TI Efficiency of genomic integration in vitro by a hybrid adenoretroviral vector SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 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 MAR PY 2002 VL 81 SI SI MA 0038 BP A34 EP A34 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024700039 ER PT J AU Zavras, AI Wu, T Douglass, CW Diehl, SR AF Zavras, AI Wu, T Douglass, CW Diehl, SR TI Association of dopamine receptor and alcohol dehydrogenase single nucleotide polymorphisms (SNPs) with tobacco smoking and alcohol drinking behavior SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Harvard Univ, Sch Dent Med, Cambridge, MA 02138 USA. Natl Inst Dent & Craniofacial Res, 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 MAR PY 2002 VL 81 SI SI MA 2743 BP A344 EP A344 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024702716 ER PT J AU Zavrasi, AI Andreopoulos, N Wu, T Cartsos, V Sun, C Douglass, CW Diehl, SR AF Zavrasi, AI Andreopoulos, N Wu, T Cartsos, V Sun, C Douglass, CW Diehl, SR TI A single nucleotide polymorphism (SNP) of the insulin-like growth factor 2 receptor (IGF2R) decreases risk of oral cancer. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract C1 Harvard Univ, Sch Dent Med, Cambridge, MA 02138 USA. Athens Gen Hosp, Athens, Greece. NIDCR, 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 MAR PY 2002 VL 81 SI SI MA 3755 BP A460 EP A460 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 559KE UT WOS:000176024703722 ER PT J AU Pautler, SE Hewitt, SM Linehan, WM Walther, MM AF Pautler, SE Hewitt, SM Linehan, WM Walther, MM TI Specimen morcellation after laparoscopic radical nephrectomy: Confirmation of histologic diagnosis using needle biopsy SO JOURNAL OF ENDOUROLOGY LA English DT Article ID RENAL-CELL CARCINOMA; EXPERIENCE; CANCER AB Background and Purpose: Laparoscopic radical nephrectomy (LRN) is being increasingly offered for the management of renal-cell carcinoma (RCC). Specimen removal may be performed through a small or hand-port incision or by specimen morcellation. Limited studies exist addressing the accuracy of histopathologic diagnosis in morcellated renal tumors. Because of concerns about the lack of a diagnosis secondary to the morcellation process, we performed premorcellation needle biopsies to obtain nondisrupted tissue for pathologic analysis. Herein, we compare the histopathologic diagnosis achieved via needle biopsy prior to morcellation with that of the final specimen. Patients and Methods: Following successful laparoscopic resection, specimens were entrapped in a Lapsac(TM). Needle biopsies were performed manually through the mouth of the Lapsac, and morcellation was then done in some patients using manual and mechanical methods. The histopathologic diagnoses in the needle biopsy specimens and the morcellated material were compared. Results: Laparoscopic radical nephrectomy with specimen morcellation was performed in 15 patients. Nine patients had premorcellation needle biopsies. Eight of these biopsies had sufficient tissue for diagnosis of RCC. This finding correlated with final diagnosis from the morcellated material. Perinephric fat invasion was identified in three morcellated specimens. Conclusions: Needle biopsy prior to specimen morcellation confirmed the histologic diagnosis of the morcellated specimen. This finding suggests that such histopathology material is adequate for diagnosis and may make premorcellation needle biopsy redundant. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, NIH, Bldg 10,Rm 2B47,10 Ctr Dr, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 8 TC 5 Z9 5 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD MAR PY 2002 VL 16 IS 2 BP 89 EP 92 DI 10.1089/089277902753619573 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 536ZL UT WOS:000174731700005 PM 11962561 ER PT J AU Hegyi, A Friebe, A Gorbalenya, AE Ziebuhr, J AF Hegyi, A Friebe, A Gorbalenya, AE Ziebuhr, J TI Mutational analysis of the active centre of coronavirus 3C-like proteases SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID INFECTIOUS-BRONCHITIS VIRUS; MOUSE HEPATITIS-VIRUS; PAPAIN-LIKE PROTEINASE; STRAND RNA VIRUSES; TRANSMISSIBLE GASTROENTERITIS VIRUS; FELINE ENTERIC CORONAVIRUSES; POLYMERASE-CHAIN-REACTION; PUTATIVE CATALYTIC TRIAD; EQUINE ARTERITIS VIRUS; READING FRAME 1A AB Formation of the coronavirus replication-transcription complex involves the synthesis of large polyprotein precursors that are extensively processed by virus-encoded cysteine proteases. In this study, the coding sequence of the feline infectious peritonitis virus (FIPV) main protease, 3CL(pro), was determined. Comparative sequence analyses revealed that FIPV 3CL(pro) and other coronavirus main proteases are related most closely to the 3C-like proteases of potyviruses. The predicted active centre of the coronavirus enzymes has accepted unique replacements that were probed by extensive mutational analysis. The wild-type FIPV 3CL(pro) domain and 25 mutants were expressed in Escherichia coli and tested for proteolytic activity in a peptide-based assay. The data strongly suggest that, first, the FIPV 3CL(pro) catalytic system employs His(41) and Cys(144) as the principal catalytic residues. Second, the amino acids Tyr(160) and His(162), which are part of the conserved sequence signature Tyr(160)-Met(161)-His(162) and are believed to be involved in substrate recognition, were found to be indispensable for proteolytic activity. Third, replacements of Gly(83) and Asn(64), which were candidates to occupy the position spatially equivalent to that of the catalytic Asp residue of chymotrypsin-like proteases, resulted in proteolytically active proteins. Surprisingly, some of the Asn(64) mutants even exhibited strongly increased activities. Similar results were obtained for human coronavirus (HCoV) 3CL(pro) mutants in which the equivalent Asn residue (HCoV 3CL(pro) Asn(64)) was substituted. These data lead us to conclude that both the catalytic systems and substrate-binding pockets of coronavirus main proteases differ from those of other RNA virus 3C and 3C-like proteases. C1 Univ Wurzburg, Inst Virol & Immunol, D-97078 Wurzburg, Germany. NCI, SAIC, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. RP Ziebuhr, J (reprint author), Univ Wurzburg, Inst Virol & Immunol, Versbacher Str 7, D-97078 Wurzburg, Germany. RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-56000] NR 82 TC 40 Z9 50 U1 1 U2 3 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2002 VL 83 BP 581 EP 593 PN 3 PG 13 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 523XP UT WOS:000173983100011 PM 11842253 ER PT J AU Mulatu, MS Schooler, C AF Mulatu, MS Schooler, C TI Causal connections between socio-economic status and health: Reciprocal effects and mediating mechanisms SO JOURNAL OF HEALTH AND SOCIAL BEHAVIOR LA English DT Article ID SELF-RATED HEALTH; SOCIOECONOMIC-STATUS; UNITED-STATES; OLDER WORKERS; ADULT HEALTH; LIFE-STYLE; MORTALITY; INCOME; INEQUALITIES; BEHAVIORS AB Using structural equation modeling techniques on data from a nationally representative longitudinal survey, we first explored the reciprocal relationships between socio-economic status (SES) and health status. Me then estimated the degree to which health-related lifestyles/behaviors and psychosocial distress are mediating mechanisms of these relationships. As predicted, SES positively affects health, and health positively affects SES. Although the causal path from SES to health is stronger than the reverse, these findings confirmed the hypothesis that both social causation and health selection contribute to social inequalities in health. In terms of the mediating mechanisms through which SES and health affect each other, more than a third of the overall SES-health relationship was accounted for by health-related lifestyles/behaviors and psychosocial distress. A notable part of the effect of SES on health is due to differences in psychological distress, with the effects of health-related lifestyles/behaviors being much smaller. On the other hand, in terms of the effects of health on SES, differences in weight and sleeping behavior are more important than psychological distress. C1 NIMH, Sect Socioenvironm Studies, Bethesda, MD 20892 USA. FU NIA NIH HHS [Y02 AG-1-0168] NR 35 TC 75 Z9 76 U1 1 U2 23 PU AMER SOCIOLOGICAL ASSOC PI WASHINGTON PA 1307 NEW YORK AVE NW #700, WASHINGTON, DC 20005-4712 USA SN 0022-1465 J9 J HEALTH SOC BEHAV JI J. Health Soc. Behav. PD MAR PY 2002 VL 43 IS 1 BP 22 EP 41 DI 10.2307/3090243 PG 20 WC Public, Environmental & Occupational Health; Psychology, Social SC Public, Environmental & Occupational Health; Psychology GA 539XX UT WOS:000174899200002 PM 11949195 ER PT J AU Bennouna, J Hildesheim, A Chikamatsu, K Gooding, W Storkus, WJ Whiteside, TL AF Bennouna, J Hildesheim, A Chikamatsu, K Gooding, W Storkus, WJ Whiteside, TL TI Application of IL-5 ELISPOT assays to quantification of antigen-specific T helper responses SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE ELISPOT assay; IL-5; T-cell frequency; helper T cells ID P53 ANTIBODIES; TH2 CELLS; CANCER; GAMMA; INTERLEUKIN-4; MECHANISMS; TYPE-1; CLONE; MICE AB To be able to determine the frequencies of helper-type T lymphocyte (Th) precursors specific for viral or tumor-associated antigens, an ELISPOT assay for IL-5 production was developed. The assay reproducibility was first determined using fresh or cryopreserved peripheral blood mononuclear cells (PBMC) obtained from six normal donors and tested for IL-5 production after 48 h stimulation with phytohemagglutinin (PHA). Both inter-assay (within-subject CV = 1.6%) and intra-assay (within-subject CV = 0.8%) variabilities were found to be acceptable, and the frequencies of IL-5 secreting cells were comparable in cryopreserved and fresh PBMC of the same donors. The presence and frequency of Th precursor cells to viral capsid L I protein (viral-like particles, VLP-L1) of human papillomavirus type 16 (HPV-16) in PBMC obtained from seven non-immunized donors and two volunteers immunized with VLP-L1 were then evaluated. Using autologous dendritic cells as antigen-presenting cells (APC) for VLP-L1 in direct 48-h ELISPOT assays, the mean frequency of IL-5 secreting CD4+ T cells was found to be < 1/10(5) (negative) in normal donors but was 1/2, 436 and 1/3678 in the two volunteers immunized with VLP-L1. The assay is applicable to monitoring of the frequency of antigen-specific T cells in the peripheral circulation of individuals immunized with HPV-derived antigens. To test the assay utility in the assessment of Th tumor-reactive lymphocytes, we also used it to determine the frequency of the wild-type sequence (wt) p53(22-36) peptide-specific, HLA-DR4-restricted T cells in the bulk CD4+ T cell line. This frequency was 1/33. The ELISPOT assay for IL-5 production can be reliably used to measure Th-type responses in a variety of experimental settings. (C) 2002 Elsevier Science B.V. All lights reserved. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. RP Whiteside, TL (reprint author), Univ Pittsburgh, Inst Canc, W1041 BST,211 Lothrop ST, Pittsburgh, PA 15213 USA. RI bennouna, jaafar/K-9350-2015; OI Storkus, Walter/0000-0001-8961-4444 NR 28 TC 20 Z9 20 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAR 1 PY 2002 VL 261 IS 1-2 BP 145 EP 156 AR PII S0022-1759(01)00566-X DI 10.1016/S0022-1759(01)00566-X PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 528TR UT WOS:000174259800012 PM 11861073 ER PT J AU Franchimont, D Galon, J Vacchio, MS Fan, S Visconti, R Frucht, DM Geenen, V Chrousos, GP Ashwell, JD O'Shea, JJ AF Franchimont, D Galon, J Vacchio, MS Fan, S Visconti, R Frucht, DM Geenen, V Chrousos, GP Ashwell, JD O'Shea, JJ TI Positive effects of glucocorticoids on T cell function by up-regulation of IL-7 receptor alpha SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; INTERLEUKIN-7 RECEPTOR; DEFICIENT MICE; IN-VIVO; LYMPHOID DEVELOPMENT; GAMMA-CHAIN; EXPRESSION; SURVIVAL; DEXAMETHASONE; PROLIFERATION AB Despite the effects of glucocorticoids on immune function, relatively little is known about glucocorticoid-inducible genes and how their products may regulate lymphocyte function. Using DNA microarray technology to analyze gene expression in PBMC from healthy donors, we identified IL-7Ralpha as a glucocorticoid-inducible gene. This observation was confirmed at the mRNA and protein levels. Conversely, TCR signaling decreased IL-7Ralpha expression, and the relative strength of signaling between these two receptors determined the final IL-7Ra levels. The up-regulation of IL-7Ralpha by glucocorticoids was associated with enhanced IL-7-mediated signaling and function. Moreover, IL-7-mediated inhibition of apoptosis at increasing concentrations of glucocorticoids is consistent with enhanced cell sensitivity to IL-7 following glucocorticoid exposure. These observations provide a mechanism by which glucocorticoids may have a positive influence on T cell survival and function. C1 NIAMSD, Lymphocyte Cell Biol Sect, Bethesda, MD 20892 USA. NCI, Lab Immune Cell Biol, Bethesda, MD 20892 USA. NICHHD, Pediat Endocrinol Branch, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Galon, J (reprint author), Inst Rech Biomed Cordeliers, Inst Natl Sante & Rech Med, Lab Immunol Cellulaire & Clin, Unite 255, F-75270 Paris 06, France. RI Visconti, Roberta/C-5299-2009 NR 58 TC 89 Z9 94 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 1 PY 2002 VL 168 IS 5 BP 2212 EP 2218 PG 7 WC Immunology SC Immunology GA 524AR UT WOS:000173990200017 PM 11859107 ER PT J AU Schopf, LR Hoffmann, KF Cheever, AW Urban, JF Wynn, TA AF Schopf, LR Hoffmann, KF Cheever, AW Urban, JF Wynn, TA TI IL-10 is critical for host resistance and survival during gastrointestinal helminth infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INTESTINAL NEMATODE INFECTION; CYTOKINE GENE-EXPRESSION; TRICHURIS-MURIS; PROTECTIVE IMMUNITY; SCHISTOSOMA-MANSONI; TNF-ALPHA; EXPERIMENTAL ENDOTOXEMIA; GRANULOMA-FORMATION; TOXOPLASMA-GONDII AB Resistance to many intestinal nematodes is dependent on the induction of polarized type 2 cytokine responses, whereas type 1 responses can exacerbate these infections. The contributions of IL-4 and IL-13 to the development of resistance have been well described for a variety of intestinal parasites; however, the role of IL-10 has not been previously investigated. In this study we infected IL-10-, IL-10/IL-4-, IL-10/IL-12-, IL-4-, and IL-12-deficient mice with Trichuris muris to determine whether IL-10 contributes to the development of immunity. Interestingly, T. muris-infected IL-10-, IL-4-, and IL-10/IL-4-deficient mice failed to expel the parasite, and animals deficient in IL-10 displayed marked morbidity and mortality. In contrast, double IL-10/IL-12-deficient mice were completely resistant and mounted a highly polarized type 2 cytokine response, demonstrating that the increased susceptibility of IL-10-deficient mice was dependent on IL-12. Further study suggested that the susceptibility of IL-10- and IL-10/IL-4-deficient mice was probably attributable to a marked increase in type 1 cytokine production in those animals. The mortality observed in T. muris-infected IL-10- and IL-10/IL-4-deficient mice correlated with increased inflammation, loss of Paneth cells, and absence of mucus in the cecum. Interestingly, survival was enhanced in T. muris-infected IL-10/IL-4-deficient mice if a broad spectrum antibiotic was administered, suggesting that an outgrowth of opportunistic bacteria was contributing to the high degree of morbidity and mortality. Overall, these studies reveal a critical role for IL-10 in the polarization of Th2 responses, development of resistance during T. muris infection, and maintenance of barrier function in the colon. C1 NIAID, Schistosomiasis Immunol & Pathol Unit, Immunobiol Sect, Parasit Dis Lab,NIH, Bethesda, MD 20892 USA. USDA ARS, Immunol Dis Resistance Lab, Anim & Nat Resources Inst, Beltsville, MD 20705 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Urban, JF (reprint author), NIAID, Schistosomiasis Immunol & Pathol Unit, Immunobiol Sect, Parasit Dis Lab,NIH, Bldg 4,Room 126, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011; OI Urban, Joseph/0000-0002-1590-8869 NR 57 TC 139 Z9 143 U1 0 U2 13 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 1 PY 2002 VL 168 IS 5 BP 2383 EP 2392 PG 10 WC Immunology SC Immunology GA 524AR UT WOS:000173990200039 PM 11859129 ER PT J AU Shibagaki, N Udey, MC AF Shibagaki, N Udey, MC TI Dendritic cells transduced with protein antigens induce cytotoxic lymphocytes and elicit antitumor immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BLOCK POLYMER SURFACTANTS; TAT FUSION PROTEINS; CLASS-I PATHWAY; ADJUVANT ACTIVITY; MAMMALIAN-CELLS; BONE-MARROW; VIVO; VACCINATION; GENERATION; PEPTIDE AB Dendritic cell (DC)-based vaccines are being developed for treatment of patients with cancer, in part because DC are potent inducers of CD8(+) CTL. DC MHC class I:antigenic peptide complexes that are required for CTL elicitation are most often generated by incubating DC with peptides or by transfecting (or transducing) DC with cDNAs (or viral vectors) that encode protein Ags. The former approach is feasible when MHC class I Ags and relevant peptides are known. The latter approach may be hampered by inefficient DC transfection (transduction) and/or difficulties associated with preparation and use of viral vectors. Herein we demonstrate that a bacterial recombinant model tumor-associated Ag (OVA) that contains the HIV TAT protein transduction domain (PTD) was readily engineered and purified, efficiently transduced murine lymphocytes and DC, and was processed by proteasomes for MHC class I-restricted presentation to CTL. In addition, PTD-containing rOVA was processed and presented by DC to CD4 T cells as efficiently as native OVA or rOVA lacking the PTD. PTD-OVA-transduced DC induced CTL in vivo in a Th cell-independent fashion and vaccinated against OVA-expressing tumors. In contrast, rOVA lacking the PTD did not enter the DC MHC class I presentation pathway and DC treated with this protein did not prime OVA-specific CTL in vivo. Treatment of mice harboring clinically apparent OVA-expressing tumors with PTD-OVA-transduced DC resulted in tumor regression in some animals. This straightforward vaccination strategy may translate into DC-based treatments for patients with cancer and other serious diseases. . C1 NCI, Dermatol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Canc Res Ctr, NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. NR 33 TC 108 Z9 115 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2002 VL 168 IS 5 BP 2393 EP 2401 PG 9 WC Immunology SC Immunology GA 524AR UT WOS:000173990200040 PM 11859130 ER PT J AU Rosenberg, SA Tong-On, P Li, Y Riley, JP El-Gamil, M Parkhurst, MR Robbins, PF AF Rosenberg, SA Tong-On, P Li, Y Riley, JP El-Gamil, M Parkhurst, MR Robbins, PF TI Identification of BING-4 cancer antigen translated from an alternative open reading frame of a gene in the extended MHC class II region using lymphocytes from a patient with a durable complete regression following immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; METASTATIC MELANOMA; PEPTIDES; CTL; TAPASIN; MART-1; CELLS AB Multiple human cancer Ags have been identified, although little is known concerning which would be most effectively used in cancer immunotherapy. To gain insight into the selection of appropriate Ags, the immunologic reactivity of a patient who had a durable complete regression of melanoma metastases was measured. PBMCs were directly cloned using the monoclonal anti-CD3 Ab OKT3 and IL-2 without any bias introduced by previous culture. A lymphocyte clone recognized a previously unknown shared melanoma Ag that was identified as the BING-4 protein encoded in a gene-rich region of the extended class II MHC. The HLA-A2-restricted BING-4 immunodominant peptide was translated from a 10-aa-long alternative open reading frame. In vitro sensitization against this peptide generated lymphocytes reactive against HLA-A2(+) melanomas. Real-time semi quantitative RTPCR analysis revealed that 8 of 15 melanoma cell lines overexpressed BING-4, and this correlated with recognition by lymphocytes. Overexpression was not found in normal tissues or other tumor types. Thus, BING-4 represents another candidate Ag for possible use in the immunotherapy of patients with melanoma. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Ctr Canc Res, NIH, Bldg 10,Room 2B42, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-33] NR 17 TC 29 Z9 29 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 1 PY 2002 VL 168 IS 5 BP 2402 EP 2407 PG 6 WC Immunology SC Immunology GA 524AR UT WOS:000173990200041 PM 11859131 ER PT J AU Foxman, EF Zhang, MF Hurst, SD Muchamuel, T Shen, DF Wawrousek, EF Chan, CC Gery, I AF Foxman, EF Zhang, MF Hurst, SD Muchamuel, T Shen, DF Wawrousek, EF Chan, CC Gery, I TI Inflammatory mediators in uveitis: Differential induction of cytokines and chemokines in Th1-versus Th2-mediated ocular inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MONOCYTE CHEMOTACTIC PROTEIN-1; PIGMENT EPITHELIAL-CELLS; CENTRAL-NERVOUS-SYSTEM; T-CELLS; RECEPTOR EXPRESSION; GENETIC SUSCEPTIBILITY; EOTAXIN EXPRESSION; DENDRITIC CELLS; B-CELLS AB Ocular inflammation leads to vision loss through the destruction and scarring of delicate tissues along the visual axis. To identify inflammatory mediators involved in this process, we used real time RT-PCR to quantify the expression of mRNA transcripts of 34 cytokines, 26 chemokines, and 14 chemokine receptors at certain time points during T cell-mediated ocular inflammation. We induced disease by adoptive transfer of Ag-specific Th1 or Th2 cells into recipients expressing the target Ag in their eyes. We also compared the mediator expression patterns seen in adoptive transfer-induced inflammation with that seen in mouse eyes developing experimental autoimmune uveoretinitis. In addition, we used laser capture microdissection to examine chemokine mRNA production by both retinal pigment epithelium cells and infiltrating leukocytes in inflamed eyes. Major findings included the following: 1) Three patterns of expression of the inflammation-related molecules were seen in recipients of adoptively transferred Th cells: preferential expression in Th1 recipients, or in Th2 recipients, or similar expression in both recipient groups. 2) In experimental autoimmune uveoretinitis, the inflammatory mediator expression pattern largely paralleled that seen in Th1-induced disease. 3) Both retinal pigment epithelium and infiltrating leukocytes expressed chemokine transcripts in distinct, but overlapping patterns in inflamed eyes. 4) Interestingly, trancripts of multiple cytokines, chemokines, and chemokine receptors were constitutively expressed in high levels in mouse eyes. Seven of these molecules have not been previously associated with the eye. These data underscore the multiplicity of mediators that participate in the pathogenesis of eye inflammation and point to upstream cytokines as potential therapeutic targets. C1 NEI, NIH, Bethesda, MD 20892 USA. DNA Res Inst, Palo Alto, CA 94304 USA. RP Gery, I (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. RI Wawrousek, Eric/A-4547-2008 NR 76 TC 89 Z9 94 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 MAR 1 PY 2002 VL 168 IS 5 BP 2483 EP 2492 PG 10 WC Immunology SC Immunology GA 524AR UT WOS:000173990200052 PM 11859142 ER PT J AU Keilholz, U Weber, J Finke, JH Gabrilovich, DI Kast, WM Disis, ML Kirkwood, JM Scheibenbogen, C Schlom, J Maino, VC Lyerly, HK Lee, PP Storkus, W Marincola, F Worobec, A Atkins, MB AF Keilholz, U Weber, J Finke, JH Gabrilovich, DI Kast, WM Disis, ML Kirkwood, JM Scheibenbogen, C Schlom, J Maino, VC Lyerly, HK Lee, PP Storkus, W Marincola, F Worobec, A Atkins, MB TI Immunologic monitoring of cancer vaccine therapy: Results of a workshop sponsored by the Society for Biological Therapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Review DE cancer vaccines; immunologic monitoring; immunotherapy ID T-CELL RESPONSES; COLONY-STIMULATING FACTOR; ENDOTHELIAL GROWTH-FACTOR; HERPES-SIMPLEX VIRUS; NATURAL-KILLER-CELLS; GAMMA-ELISPOT-ASSAY; KAPPA-B ACTIVATION; PHASE-I TRIAL; SIGNAL-TRANSDUCTION MOLECULES; SENSITIVE FLUOROMETRIC ASSAY AB The Society for Biological Therapy held a Workshop last fall devoted to immune monitoring for cancer immunotherapy trials. Participants included members of the academic and pharmaceutical communities as well as the National Cancer Institute and the Food and Drug Administration. Discussion focused on the relative merits and appropriate use of various immune monitoring tools. Six breakout groups dealt with assays of T-cell function, serologic and proliferation assays to assess B cell and T helper cell activity, and enzyme-linked immunospot assay, tetramer, cytokine flow cytometry, and reverse transcription polymerase chain reaction assays of T-cell immunity. General conclusions included: (1) future vaccine studies should be designed to determine whether T-cell dysfunction (tumor-specific and nonspecific) correlated with clinical outcome; (2) tetramer-based assays yield quantitative but not functional data (3) enzyme-linked immunospot assays have the lowest limit of detection (4) cytokine flow cytometry have a higher limit of detection than enzyme-linked immunospot assay, but offer the advantages of speed and the ability to identify subsets of reactive cells; (5) antibody tests are simple and accurate and should be incorporated to a greater extent in monitoring plans; (6) proliferation assays are imprecise and should not be emphasized in future studies; (7) the reverse transcription polymerase chain reaction assay is a promising research approach that is not ready for widespread application; and (8)there is a critical need to validate these assays as surrogates for vaccine potency and clinical effect. Current data and opinion support the use of a functional assay like the enzyme-linked immunospot assay or cytokine flow cytometry in combination with a quantitative assay like tetramers for immune monitoring. At present, assays appear to be most useful as measures of vaccine potency. Careful immune monitoring in association with larger scale clinical trials ultimately may enable the correlation of monitoring results with clinical benefit. C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. UKBF Free Univ, Berlin, Germany. Norris Canc Ctr, Los Angeles, CA USA. Cleveland Clin Fdn, Cleveland, OH USA. H Lee Moffitt Canc Ctr, Tampa, FL USA. Loyola Univ, Ctr Med, Maywood, IL USA. Washington Univ, Seattle, WA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Natl Canc Inst, Bethesda, MD USA. BD Biosci, San Jose, CA USA. Duke Univ, Ctr Med, Durham, NC USA. Stanford Univ, Stanford, CA 94305 USA. US FDA, Rockville, MD 20857 USA. RP Atkins, MB (reprint author), Beth Israel Deaconess Med Ctr, Kirstein Hall Rm 158 330 Brookline Ave, Boston, MA 02215 USA. RI Lyerly, Herbert/B-6528-2014; OI Lyerly, Herbert/0000-0002-0063-4770; Storkus, Walter/0000-0001-8961-4444 NR 271 TC 223 Z9 231 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAR-APR PY 2002 VL 25 IS 2 BP 97 EP 138 DI 10.1097/00002371-200203000-00001 PG 42 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 535TP UT WOS:000174662700001 PM 12074049 ER PT J AU Weinreich, DM Rosenberg, SA AF Weinreich, DM Rosenberg, SA TI Response rates of patients with metastatic melanoma to high-dose intravenous interleukin-2 after prior exposure to alpha-interferon or low-dose interleukin-2 SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE interleukin-2; metastatic melanoma; prior immunotherapy; alpha-interferon ID PHASE-II TRIAL; DACARBAZINE; CISPLATIN; TAMOXIFEN; BIOCHEMOTHERAPY; CHEMOTHERAPY; COMBINATION AB We evaluated 567 patients with metastatic melanoma who were treated with high-dose intravenous interleukin-2 (IL-2) to determine whether prior treatment with either alpha-interferon or low-dose IL-2 altered the rates of response to subsequent high-dose IL-2. Of the 567 patients treated, 46 patients had received low-dose IL-2 before, and 78 had received alpha-interferon before. The response rate for patients who had received IL-2 before compared with IL-2 naive patients was 15% versus 21% respectively (p = 0.39). The response rate for patients who had received alpha-interferon before compared with patients who had not Was 13% versus 21% (p = 0.084). Therefore, prior low-dose IL-2 therapy does not appear to prevent a subsequent response to high-dose IL-2. There is a trend for patients who received alpha-interferon before to have a lower-response rate to subsequent high-dose IL-2, but the number of patients evaluated in this study is too small to definitively answer this question. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Rm 2B42 10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-33] NR 9 TC 20 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAR-APR PY 2002 VL 25 IS 2 BP 185 EP 187 DI 10.1097/00002371-200203000-00006 PG 3 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 535TP UT WOS:000174662700006 PM 12074048 ER PT J AU Hisaeda, H Saul, A Reece, JJ Kennedy, MC Long, CA Miller, LH Stowers, AW AF Hisaeda, H Saul, A Reece, JJ Kennedy, MC Long, CA Miller, LH Stowers, AW TI Merozoite surface protein 3 and protection against malaria in Aotus nancymai monkeys SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PLASMODIUM-FALCIPARUM MEROZOITES; KNOWLESI MEROZOITES; TERMINAL FRAGMENT; ANTIBODIES; ANTIGEN; STAGE; PARASITES; INDUCTION; RECEPTORS; IMMUNITY AB A blood-stage vaccine based on Plasmodium falciparum merozoite surface protein 3 (MSP3) was tested for efficacy in a primate model. Aotus nancymai monkeys were vaccinated with yeast-expressed MSP3 before a lethal challenge with Plasmodium falciparum parasites. Five of 7 control monkeys had acute infections and required treatment to control parasitemia. Only 1 of 7 monkeys vaccinated with MSP3 required this treatment. The efficacy of the MSP3 vaccination appeared to be comparable to that of MSP1(42), a leading asexual vaccine candidate, in response to which 2 monkeys experienced acute infections. In the MSP3-vaccinated group, protection correlated with prechallenge titers of antibody to MSP3. In the MSP1 and control groups, protection correlated with antibody to MSP3 raised by challenge infection. C1 NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, Rockville, MD 20852 USA. Univ Tokushima, Sch Med, Dept Parasitol & Immunol, Tokushima 770, Japan. RP Stowers, AW (reprint author), NIAID, Malaria Vaccine Dev Unit, Parasit Dis Lab, NIH, Twinbrook I,5640 Fisher Lane, Rockville, MD 20852 USA. RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 36 TC 62 Z9 62 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 MAR 1 PY 2002 VL 185 IS 5 BP 657 EP 664 DI 10.1086/339187 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 521YL UT WOS:000173868900012 PM 11865423 ER PT J AU Welniak, LA Sun, R Murphy, WJ AF Welniak, LA Sun, R Murphy, WJ TI The role of growth hormone in T-cell development and reconstitution SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE neuroendocrine hormones; thymus; dwarf; deficiency ID BONE-MARROW TRANSPLANTATION; BLOOD MONONUCLEAR-CELLS; FACTOR-I-RECEPTOR; PROLACTIN RECEPTOR; LYMPHOCYTE-T; EPITHELIAL-CELLS; NEUROENDOCRINE HORMONES; SALMONELLA-TYPHIMURIUM; SUPEROXIDE ANION; DWARF MICE AB Growth hormone (GH), directly or through GH-induction of insulin-like growth factor (IGF)-1, has been implicated in lymphocyte development and function. Recent studies have questioned the role of GH and IGF-1 in immune responses. This review examines experimental data describing the immunoregulatory function of GH and attempts to reconcile the literature. C1 NCI, SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Immunoregulat Lab, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), NCI, SAIC, Intramural Res Support Program, Bldg 567,Room 210, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 92 TC 62 Z9 64 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2002 VL 71 IS 3 BP 381 EP 387 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 529BG UT WOS:000174279700002 PM 11867675 ER PT J AU Segal, BH Kuhns, DB Ding, L Gallin, JI Holland, SM AF Segal, BH Kuhns, DB Ding, L Gallin, JI Holland, SM TI Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47(phox): complement, leukotrienes, and reactive oxidants in acute inflammation SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE chronic granulomatous disease; LTB4; C5a; zileuton; superoxide ID CHRONIC GRANULOMATOUS-DISEASE; OMEGA-HYDROXYLASE; TARGETED DISRUPTION; LEUKOCYTE ADHESION; B-4; CYTOCHROME-P-450; INACTIVATION; RECEPTOR; CLONING; SYSTEM AB Leukotriene B-4 (LTB4) is an easily diffusible proinflammatory chemotactic factor that has been posited to prime the initial inflammatory response for the action of other mediators, including C5a. 5-Lipoxygenase-deficient (5LX(-/-)) and C5-deficient mice only generated about 50%, as much peritoneal leukocytosis as wild-type mice following intraperitoneal (IP) challenge with the sterile irritant, thioglycollate (P<0.005). Pretreatment of C5- mice with the specific 5-lipoxygenase inhibitor, zileuton, reduced peritoneal leukocytosis to almost unstimulated levels, suggesting that LTB4 can act independently, of C5a. Previously, LTB4 and C5a have been shown in vitro to be inactivated by metabolites of superoxide. In the current study, we examined the fate of LTB4 in the p47(phox-/-) mouse model of chronic granulomatous disease (CGD) in which the phagocyte NADPH oxidase is unable to produce superoxide. p47(phox-/-) mice generated more thioglycollate-elicited peritoneal leukocytosis than wild-type mice. Pretreatment with zileuton caused a 76%, reduction in peritoneal leukocytosis in p47(phox-/-) mice (P<0.005) and a 54% reduction in wild-type mice (P<0.05), whereas pretreatment with dexamethasone or toradol (a cyclooxygenase inhibitor) bad no effect. Following IP LTB4 (1 mug/mouse), total recovered peritoneal LTB4 was similar between p47(phox-/-) and wild-type mice at 10 and 30 min, but was approximately fivefold greater in p47(phox-/-) mice at 180 min. These data suggest that LTB4 and C5a have separate but overlapping roles in thioglycollate-elicited peritonitis, and at least the leukotriene component is, in turn, regulated by reactive oxidants. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Holland, SM (reprint author), NIAID, Host Def Lab, NIH, 10 Ctr Dr,Dr Msc 1886, Bethesda, MD 20892 USA. NR 24 TC 54 Z9 54 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2002 VL 71 IS 3 BP 410 EP 416 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 529BG UT WOS:000174279700005 PM 11867678 ER PT J AU Peterson, J Ayyobi, AF Ma, YH Henderson, H Reina, M Deeb, SS Santamarina-Fojo, S Hayden, MR Brunzell, AD AF Peterson, J Ayyobi, AF Ma, YH Henderson, H Reina, M Deeb, SS Santamarina-Fojo, S Hayden, MR Brunzell, AD TI Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene SO JOURNAL OF LIPID RESEARCH LA English DT Article DE LPL deficiency; triglyceride; heparin; LPL gene; LPL mass ID HEPATIC LIPASE; FAMILIAL CHYLOMICRONEMIA; PANCREATIC LIPASE; HEPARIN-BINDING; CHIMERIC LIPASE; DEFICIENCY; IDENTIFICATION; LOCALIZATION; INACTIVATION AB Missense mutations in exon 5 of the LPL gene are the most common reported cause of LPL deficiency. Exon 5 is also the region with the strongest homology to pancreatic and hepatic lipase, and is conserved in LPL from different species. Mutant LPL proteins from post-heparin plasma from patients homozygous for missense mutations at amino acid positions 176, 188, 194, 205, and 207, and from COS cells transiently transfected with the corresponding cDNAs were quantified and characterized, in an attempt to determine which aspect of enzyme function was affected by each specific mutation. All but one of the mutant proteins were present, mainly as partially denatured LPL monomer, rendering further detailed assessment of their catalytic activity, affinity to heparin, and binding to lipoprotein particles difficult. However, the fresh unstable Gly(188)-->Glu LPL and the stable Ile(194)-->Thr LPL, although in native conformation, did not express lipase activity. It is proposed that many of the exon 5 mutant proteins are unable to achieve or maintain native dimer conformation, and that the Ile194-->Thr substitution interferes with access of lipid substrate to the catalytic pocket. These results stress the importance of conformational evaluation of mutant LPL. Absence of catalytic activity does not necessarily imply that the substituted amino acid plays a specific direct role in catalysis.-Peterson, J., A. F. Ayyobi, Y. Ma, H. Henderson, M. Reina, S. S. Deeb, S. Santamarina-Fojo, M. R. Hayden, and J. D. Brunzell. Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. C1 Univ Washington, Med Ctr, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. NHLBI, Mol Dis Branch, Bethesda, MD 20892 USA. RP Brunzell, AD (reprint author), Univ Washington, Med Ctr, Dept Med, Div Metab Endocrinol & Nutr, Box 356426, Seattle, WA 98195 USA. RI Hayden, Michael/D-8581-2011; Reina, Manuel/D-4655-2014 OI Hayden, Michael/0000-0001-5159-1419; Reina, Manuel/0000-0002-0701-200X NR 25 TC 15 Z9 17 U1 1 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2002 VL 43 IS 3 BP 398 EP 406 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 534ZT UT WOS:000174620200006 PM 11893776 ER PT J AU Shekim, L AF Shekim, L TI Seeking NIH funding: Defining the process SO JOURNAL OF MEDICAL SPEECH-LANGUAGE PATHOLOGY LA English DT Editorial Material C1 Natl Inst Deafness & Other Commun Disoders, Voice & Speech Program, Sci Programs Branch, NIH, Bethesda, MD 20892 USA. RP Shekim, L (reprint author), Natl Inst Deafness & Other Commun Disoders, Voice & Speech Program, Sci Programs Branch, NIH, Bethesda, MD 20892 USA. EM shekiml@nidcd.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU DELMAR LEARNING PI CLIFTON PARK PA EXECUTIVE WOODS, 5 MAXWELL DR, CLIFTON PARK, NY 12065 USA SN 1065-1438 J9 J MED SPEECH-LANG PA JI J. Med. Speech-Lang. Pathol. PD MAR PY 2002 VL 10 IS 1 BP XI EP XV PG 5 WC Audiology & Speech-Language Pathology; Clinical Neurology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology GA 659LT UT WOS:000181778700002 ER PT J AU Zoeteweij, JP Rinderknecht, AS Davis, DA Yarchoan, R Blauvelt, A AF Zoeteweij, JP Rinderknecht, AS Davis, DA Yarchoan, R Blauvelt, A TI Minimal reactivation of Kaposi's sarcoma-associated herpesvirus by corticosteroids in latently infected B cell lines SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE corticosteroids; Kaposi's sarcoma-associated herpesvirus; Kaposi's sarcoma; immunosuppression ID EPSTEIN-BARR-VIRUS; MULTICENTRIC CASTLEMANS-DISEASE; DNA-SEQUENCES; IN-VITRO; HUMAN-HERPESVIRUS-8; REPLICATION; LYMPHOMA; AIDS; TRANSPLANTATION; IDENTIFICATION AB Corticosteroid use in transplant recipients increases the incidence and severity of Kaposi's sarcoma (KS), a disease associated with KS-associated herpesvirus (KSHV) infection. Recently, the prototypic corticosteroid, hydrocortisone, was shown to directly induce lytic cycle reactivation of KSHV in latently-infected BCBL-1 cells. The purpose of this study was to examine this phenomenon in further detail. After incubation with dexamethasone (less than or equal to 30 muM) or hydrocortisone (less than or equal to 30 muM) for 1-4 days, we evaluated KSHV reactivation in latently infected B cell lines (BC-1, BC-3, and BCBL-1) by assessing early-lytic PF-8 and late-lytic gpK8.1 protein expression using flow cytometry. Viral particle production was monitored by quantifying KSHV minor capsid protein levels in cell culture supernatants. A small increase in the percentage of cells expressing viral lytic proteins was observed in BCBL-1, but not in the other cell lines. In combination with 3 nM 12-O-tetradecanoyl-phorbol-13-acetate, a known chemical inducer of KSHV replication, corticosteroids (0.3 muM) enhanced KSHV reactivation twofold in some cell lines, but not in others. In all experiments, lytic viral protein expression by flow cytometry correlated with production of viral particles in culture supernatants. In summary, we found that corticosteroids were limited inducers of KSHV reactivation in latently infected cells. Thus, our findings suggest that corticosteroids do not enhance the incidence and severity of KS in transplant recipients by direct cellular effects on KSHV reactivation. (C) 2002 Wiley-Liss, Inc. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Blauvelt, A (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 31 TC 13 Z9 13 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 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD MAR PY 2002 VL 66 IS 3 BP 378 EP 383 DI 10.1002/jmv.2155 PG 6 WC Virology SC Virology GA 514TU UT WOS:000173457800012 PM 11793390 ER PT J AU Eichelberger, MC Sperber, E Wagner, M Hoshino, Y Dudas, R Hodgins, V Marron, J Nehring, P Casey, R Burns, B Karron, R Clements-Mann, ML Kapikian, AZ AF Eichelberger, MC Sperber, E Wagner, M Hoshino, Y Dudas, R Hodgins, V Marron, J Nehring, P Casey, R Burns, B Karron, R Clements-Mann, ML Kapikian, AZ TI Clinical evaluation of a single oral dose of human-bovine (UK) reassortant rotavirus vaccines Wa x UK (P1A[8],G6) and Wa x (DS-1 x UK) (P1A[8],G2) SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE rotavirus; clinical trials; vaccine ID POLYMERASE CHAIN-REACTION; QUADRIVALENT VACCINE; COMPLEMENT-FIXATION; YOUNG-CHILDREN; INFANTS; IMMUNOGENICITY; TRIAL; LIVE; SEROTYPES; SAFETY AB The safety, infectivity, and immunogenicity of two human-bovine reassortant rotavirus candidate vaccines were evaluated in adults, children, and infants. One of these, Wa x UK, contained a single human rotavirus gene from the Wa strain that encoded VP4 P1A specificity in a background of 10 bovine genes including the VP7 gene that encodes G6 specificity, whereas the other, Wa x (DS-1 x UK), possessed the human rotavirus VP4 gene from the Wa strain as well as the human VP7 gene from strain DS-1 that encoded G2 specificity. Each of these vaccines appeared to be well-tolerated and immunogenic in infants less than 6 months of age following a single oral dose, and therefore should be evaluated further as vaccine candidates. (C) 2002 Wiley-Liss, Inc. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. RP Kapikian, AZ (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM AKAPIKIAN@niaid.nih.gov FU NIAID NIH HHS [AI-15095, 1-AO-62712] NR 33 TC 12 Z9 13 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD MAR PY 2002 VL 66 IS 3 BP 407 EP 416 DI 10.1002/jmv.2160 PG 10 WC Virology SC Virology GA 514TU UT WOS:000173457800017 PM 11793395 ER PT J AU Josephson, IR Guia, A Stern, MD Lakatta, EG AF Josephson, IR Guia, A Stern, MD Lakatta, EG TI Alterations in properties of L-type Ca channels in aging rat heart SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE L-type Ca channels; cardiac myocytes; aging; heart ID AGE-ASSOCIATED CHANGES; CURRENTS; MODULATION; MYOCYTES; FAILURE; CELLS AB I. R. JOSEPHSON, A. GUIA, M. D. STERN AND E. G. LAKATTA. Alterations in Properties of L-Type Ca Channels in Aging Rat Heart. Journal of Molecular and Cellular Cardiology (2002) 34, 297-308. Previous studies of whole-cell L-type Ca currents in aging heart have demonstrated an increase in the peak Ca current magnitude in proportion to the increase in membrane area, and a slowing of the time course for inactivation. However, the single-channel mechanisms underlying this upregulation, and for the slowed inactivation are not known. We have therefore compared the properties of single L-type Ca channel currents recorded from ventricular myocytes obtained from young adult (3 month), adult (6-8 month) and aging (24 month) Wistar rats, using 5 mM Ba ions as the permeant ion. We report that the peak ensemble-averaged single Ca channel currents from aging heart (-280+/-57fA) were enhanced compared to those from young adult (-137+/-16fA), or adult hearts (-144 +/- 38 fA). This surprising result was related, in part, to an apparent increase in the number of active Ca channels per patch in aging (1.90+/-0.23) v young adult (1.33+/-0.19) or adult heart (1.50+/-0.2). Moreover, there was an increase in the time constant for inactivation of the ensemble-averaged Ca currents of aging (471+/-169ms), compared with young adult (198+/-43ms), or adult heart (196+/-32ms). The aging-related changes were also traced to alterations in single Ca channel gating, including an increase in the average probability of being open, and an increase in the availability of single Ca currents in aging heart. In contrast, the unitary Ca current amplitude was unchanged with aging. These novel findings suggest that the compensatory increase in the L-type Ca currents during aging is a consequence of an apparent increase in both the number, and the activity of individual L-type Ca channels. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Josephson, IR (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM JosephsonI@grc.nia.nih.gov NR 13 TC 27 Z9 29 U1 1 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD MAR PY 2002 VL 34 IS 3 BP 297 EP 308 DI 10.1006/jmcc.2001.1512 PG 12 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 545ED UT WOS:000175202600006 PM 11945022 ER PT J AU Stewart, RR Hoge, GJ Zigova, T Luskin, MB AF Stewart, RR Hoge, GJ Zigova, T Luskin, MB TI Neural progenitor cells of the neonatal rat anterior subventricular zone express functional GABA(A) receptors SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE culture; patch clamp; GABA; chloride current; RT-PCR; antibody labeling ID GAMMA-AMINOBUTYRIC-ACID; CENTRAL-NERVOUS-SYSTEM; OLFACTORY-BULB; GRANULE CELLS; GLUTAMATE DECARBOXYLASES; NEURONAL MIGRATION; POLYSIALIC ACID; IN-VITRO; SUBUNIT; FOREBRAIN AB The interneurons of the olfactory bulb arise from precursor cells in the anterior part of the neonatal subventricular zone, the SVZa, and are distinctive in that they possess a neuronal phenotype and yet undergo cell division. To characterize the differentiation of neonatal SVZa progenitor cells, we analyzed the complement of ionotropic neurotransmitter receptors that they express in vitro. For this analysis, we tested the sensitivity of SVZa progenitor cells to gamma-amino-n-butyric acid (GABA), adenosine triphosphate (ATP), kainate, N-methyl-D-aspartate (NMDA), and acetylcholine (ACh) after I day in vitro. SVZa progenitor cells had chloride currents activated by GABA and muscimol, the GABA(A) receptor-specific agonist, but were insensitive to ATP, kainate, NMDA, and ACh. In addition, GABA- or muscimol-activated chloride currents were blocked nearly completely by 30 muM bicuculline, the GABA(A) receptor-specific antagonist, suggesting that GABA(B) and GABA(C) receptors are absent. Measurements of the chloride reversal potential by gramicidin-perforated patch clamp revealed that currents generated by activation of GABA(A) receptors were inward, and thus, depolarizing. A set of complementary experiments was undertaken to determine by reverse transcription and polymerase chain reaction (RT-PCR) whether SVZa progenitor cells express the messenger RNA (mRNA) coding for glutamic acid decarboxylase 67 (GAD67), used in the synthesis of GABA and for GABA(A) receptor subunits. Both postnatal day (P0) SVZa and olfactory bulb possessed detectable mRNA coding for GAD67. In PO SVZa, the GABA(A) receptor subunits detected with RT-PCR included alpha2-4, beta1-3, and gamma2S (short form). By comparison, the PO olfactory bulb expressed all of the subunits detectable in the SVZa and additional subunit mRNAs: alpha1, alpha5, gamma1, gamma2L (long form), gamma3, and delta subunit mRNAs. Antibodies recognizing GABA, GAD, and various GABA(A) receptor subunits were used to label SVZa cells harvested from P0-1 rats and cultured for 1 day. The cells were immunoreactive for GABA, GAD, and the GABA(A) receptor subunits alpha2-5, beta1-3, and gamma2. To relate the characteristics of GABA(A) receptors in cultured SVZa precursor cells to particular combinations of subunits, the open reading frames of the dominant subunits detected by RT-PCR (alpha2-4,beta3, and gamma2S) were cloned into a mammalian cell expression vector and different combinations were transfected into Chinese hamster ovary-K1 (CHO-K1) cells. A comparison of the sensitivity to inhibition by zinc of GABA(A) receptors in SVZa precursor cells and in CHO-K1 cells expressing various combinations of recombinant GABA(A) receptor subunits suggested that the gamma2S subunit was present and functional in the GABA(A) receptor chloride channel complex. Thus, SVZa precursor cells are GABAergic and a subset of the GABA(A) receptor subunits detected in the olfactory bulb was found in the SVZa, as might be expected because SVZa progenitor cells migrate to the bulb as they differentiate. (C) 2002 Wiley Periodicals, Inc. C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ S Florida, Coll Med, Dept Neurosurg, Tampa, FL 33612 USA. Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. RP Stewart, RR (reprint author), NIAAA, Mol & Cellular Neurobiol Lab, NIH, 12420 Parklawn Dr, Bethesda, MD 20892 USA. FU NLM NIH HHS [LMCN-SP-01] NR 62 TC 81 Z9 84 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD MAR PY 2002 VL 50 IS 4 BP 305 EP 322 DI 10.1002/neu.10038 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 527DA UT WOS:000174169800004 PM 11891665 ER PT J AU Lee, HM Wang, C Hu, ZY Greeley, GH Makalowski, W Hellmich, HL Englander, EW AF Lee, HM Wang, C Hu, ZY Greeley, GH Makalowski, W Hellmich, HL Englander, EW TI Hypoxia induces mitochondrial DNA damage and stimulates expression of a DNA repair enzyme, the Escherichia coli MutY DNA glycosylase homolog (MYH), in vivo, in the rat brain SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE blood oxygenation; cloning; DNA repair; hypoxia; MutY DNA glycosylase; rat brain ID FOCAL CEREBRAL-ISCHEMIA; BASE-EXCISION-REPAIR; OXIDATIVE DAMAGE; ERYTHROPOIETIN GENE; MAMMALIAN HOMOLOG; STRAND BREAKS; HMYH; FRAGMENTATION; PROTEIN; IDENTIFICATION AB Hypoxia-associated, acutely reduced blood oxygenation can compromise energy metabolism, alter oxidant/antioxidant balance and damage cellular components, including DNA. We show in vivo, in the rat brain that respiratory hypoxia leads to formation of the oxidative DNA lesion, 8-hydroxy-2'-deoxyguanosine (oh8dG), a biomarker for oxidative DNA damage and to increased expression of a DNA repair enzyme involved in protection of the genome from the mutagenic consequences of oh8dG. The enzyme is a homolog of the Escherichia coli MutY DNA glycosylase (MYH), which excises adenine residues misincorporated opposite the oxidized base, oh8dG. We have cloned a full-length rat MYH (rMYH) cDNA, which encodes 516 amino acids, and by in situ hybridization analysis obtained expression patterns of rMYH mRNA in hippocampal, cortical and cerebellar regions. Ensuing hypoxia, mitochondrial DNA damage was induced and rMYH expression strongly elevated. This is the first evidence for a regulated expression of a DNA repair enzyme in the context of respiratory hypoxia. Our findings support the premise that oxidative DNA damage is repaired in neurons and the possibility that the hypoxia-induced expression of a DNA repair enzyme in the brain represents an adaptive mechanism for protection of neuronal DNA from injurious consequences of disrupted energy metabolism and oxidant/antioxidant homeostasis. C1 Univ Texas, Med Branch, Dept Surg, Shriners Hosp Children, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Surg, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Pharmacol, Galveston, TX 77550 USA. Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD USA. Univ Texas, Med Branch, Dept Anesthesiol, Galveston, TX 77550 USA. RP Englander, EW (reprint author), Univ Texas, Med Branch, Dept Surg, Shriners Hosp Children, 815 Market St, Galveston, TX 77550 USA. RI Makalowski, Wojciech/I-2843-2016 FU NINDS NIH HHS [R01 NS-39449] NR 49 TC 26 Z9 28 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2002 VL 80 IS 5 BP 928 EP 937 DI 10.1046/j.0022-3042.2002.00774.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 527CY UT WOS:000174169500024 PM 11948257 ER PT J AU Anderson, SJ Barker, PE Hadfield, MG AF Anderson, SJ Barker, PE Hadfield, MG TI Cytonectin expression in Alzheimer disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article ID DOWNS-SYNDROME; V-FMS; ANTIBODIES; LEUKEMIA; CELLS AB Cytonectin is a novel 35,000 molecular weight protein that displays remarkable ion-independent adherence properties. This consigns it to a family of well-known adherence molecules essential for cell communication and the development of 3-dimensional tissue structures. Cytonectin is expressed in a variety of organs and tissues, being evolutionarily conserved from human to avian species. It is hypothesized to serve as a key structural component of the body, and as a "do not attack" signal molecule that prevents tissue destruction by cells of monocyte lineage. This paper describes the properties of cytonectin and its proposed role in normal and disease states. The protein is overexpressed in Alzheimer disease entorhinal cortex as compared to normal age-matched controls. It is also detected in tissues from patients with Down syndrome and leukemia. Its presence in all 3 of these related conditions may prove important to their etiopathogenesis. C1 VCU, Med Coll Virginia, Dept Pathol, Div Neuropathol, Richmond, VA 23298 USA. Natl Inst Stand & Technol, NCI, Biomarkers Validat Lab, Div Biotechnol, Gaithersburg, MD 20899 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Legal Med, Div Neuropathol, Richmond, VA 23298 USA. RP Hadfield, MG (reprint author), VCU, Med Coll Virginia, Dept Pathol, Div Neuropathol, Box 980017,MCV Stn,Med Coll Virginia Campus, Richmond, VA 23298 USA. NR 27 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAR PY 2002 VL 61 IS 3 BP 230 EP 236 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 530BK UT WOS:000174335600005 PM 11895037 ER PT J AU Ambalavanar, R Purcell, L Miranda, M Evans, F Ludlow, CL AF Ambalavanar, R Purcell, L Miranda, M Evans, F Ludlow, CL TI Selective suppression of late laryngeal adductor responses by N-methyl-D-aspartate receptor blockade in the cat SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID NUCLEUS TRACTUS SOLITARIUS; NON-NMDA RECEPTORS; SPASMODIC DYSPHONIA; RESPIRATORY NEURONS; NERVE-STIMULATION; BRAIN-STEM; BOTULINUM TOXIN; CHANNEL COMPLEX; AWAKE HUMANS; CHRONIC PAIN AB Laryngeal adductor responses to afferent stimulation play a key role in airway protection. Although vital for protection during cough and swallow, these responses also must be centrally controlled to prevent airway obstruction by laryngospasm during prolonged stimulation. Our purpose was to determine the role of N-methyl-D-aspartate (NMDA) receptors in modulating early R1 responses (at 9 ms) and/or later more prolonged R2 responses (at 36 ms) during electrical stimulation of the laryngeal afferent fibers contained in the internal branch of the superior laryngeal nerve in the cat. The percent occurrence, amplitude, and conditioning of muscle responses to single superior laryngeal nerve (SLN) stimuli presented in pairs at interstimulus intervals of 250 ms were measured in three experiments: 1) animals that had ketamine as anesthetic premedication were compared with those who did not, when both were maintained under alpha-chloralose anesthesia. 2) The effects of administering ketamine in one group of animals were compared with increasing the depth of alpha-chloralose anesthesia without NMDA receptor blockade in another group of animals. 3) The effects of dextromethorphan (without anesthetic effects) were examined in another group of animals. In the first experiment, the occurrence of R2 responses were reduced from 95% in animals without ketamine premedication to 25% in animals with ketamine premedication (P = 0.015). No differences occurred in the occurrence, amplitude, latency, or conditioning effects on R1 responses between these groups. In the second experiment, the occurrence of R2 responses was reduced from 96 to 79% after an increase in the depth of anesthesia with alpha-chloralose in contrast with reductions in R2 occurrence from 98 to 19% following the administration of ketamine to induce NMDA receptor blockade along with increased anesthesia (P = 0.025). In the third experiment, R2 occurrence was reduced from 89 to 27% (P = 0.017) with administration of dextromethorphan while R1 response occurrence and amplitude did not change. In each of these experiments, NMDA receptor blockade did not have significant effects on cardiac or respiratory rates in any of the animals. The results demonstrate that NMDA receptors play an essential role in long latency R2 laryngeal responses to laryngeal afferent stimulation. On the other hand, early R1 laryngeal adductor responses are likely to involve non-NMDA receptor activation. C1 NINCDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NINCDS, Laryngeal & Speech Sect, NIH, Bldg 10,Rm 5D38,10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 63 TC 12 Z9 12 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR PY 2002 VL 87 IS 3 BP 1252 EP 1262 DI 10.1152/jn.00595.2001 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 537BA UT WOS:000174735700009 PM 11877499 ER PT J AU Kerr, JND Plenz, D AF Kerr, JND Plenz, D TI Dendritic calcium encodes striatal neuron output during up-states SO JOURNAL OF NEUROSCIENCE LA English DT Article DE action potential backpropagation; forward propagation; calcium; Fura-2; organotypic culture; spiny projection neuron; dendritic processing; up-state; down-state; cortex; striatum; substantia nigra; electrophysiology; imaging ID CA1 PYRAMIDAL NEURONS; MEMBRANE-POTENTIAL FLUCTUATIONS; RAT NEOSTRIATAL NEURONS; BACKPROPAGATING ACTION-POTENTIALS; PROPAGATING ACTION-POTENTIALS; MEDIUM SPINY NEURONS; BASAL GANGLIA; IN-VIVO; CELL DENDRITES; HIPPOCAMPAL-NEURONS AB Striatal spiny projection neurons control basal ganglia outputs via action potential bursts conveyed to the globus pallidus and substantia nigra. Accordingly, burst activity in these neurons contributes importantly to basal ganglia function and dysfunction. These bursts are driven by multiple corticostriatal inputs that depolarize spiny projection neurons from their resting potential of approximately -85 mV, which is the down-state, to a subthreshold up-state of -55 mV. To understand dendritic processing of bursts during up-states, changes in intracellular calcium concentration ([Ca2+](i)) were measured in striatal spiny projection neurons from cortex-striatum-substantia nigra organotypic cultures grown for 5-6 weeks using somatic whole-cell patch recording and Fura-2. During up-states, [Ca2+](i) transients at soma and primary, secondary, and tertiary dendrites were highly correlated with burst strength (i.e., the number of spontaneous action potentials). During down-states, the action potentials evoked by somatic current pulses elicited [Ca2+](i) transients in higher-order dendrites that were also correlated with burst strength. Evoked bursts during up-states increased dendritic [Ca2+](i) transients supralinearly by >200% compared with the down-state. In the presence of tetrodotoxin, burst-like voltage commands failed to elicit [Ca2+](i) transients at higher-order dendrites. Thus, dendritic [Ca2+](i) transients in spiny projection neurons encode somatic bursts supralinearly during up-states through active propagation of action potentials along dendrites. We suggest that this conveys information about the contribution of a spiny projection neuron to a basal ganglia output specifically back to the corticostriatal synapses involved in generating these outputs. C1 NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Unit Neural Network Physiol, Lab Syst Neurosci, Bldg 36,Room 2D026,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 79 TC 56 Z9 56 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 1 PY 2002 VL 22 IS 5 BP 1499 EP 1512 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 527NQ UT WOS:000174192500005 PM 11880480 ER PT J AU Zhang, WL Basile, AS Gomeza, J Volpicelli, LA Levey, AI Wess, J AF Zhang, WL Basile, AS Gomeza, J Volpicelli, LA Levey, AI Wess, J TI Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine release; autoreceptors; knockout; mice; muscarinic receptors; oxotremorine; presynaptic; receptors ID SUBTYPE-SPECIFIC ANTIBODIES; RAT STRIATUM; ALZHEIMERS-DISEASE; IN-VIVO; CEREBRAL-CORTEX; RELEASE; BRAIN; LOCALIZATION; MODULATION; STIMULATION AB Forebrain muscarinic acetylcholine (ACh) receptors (mAChRs; M-1-M-5) are predicted to play important roles in many fundamental central functions, including higher cognitive processes and modulation of extrapyramidal motor activity. Synaptic ACh levels are known to be regulated by the activity of presynaptic muscarinic autoreceptors mediating inhibition of ACh release. Primarily because of the use of ligands with limited receptor subtype selectivity, classical pharmacological studies have led to conflicting results regarding the identity of the mAChR sub-types mediating this activity in different areas of the brain. To investigate the molecular identity of hippocampal, cortical, and striatal inhibitory muscarinic autoreceptors in a more direct manner, we used genetically altered mice lacking functional M-2 and/or M-4 mAChRs [knock-out (KO) mice]. After labeling of cellular ACh pools with [H-3] choline, potassium-stimulated [H-3] ACh release was measured in superfused brain slices, either in the absence or the presence of muscarinic drugs. The nonsubtype-selective muscarinic agonist, oxotremorine (0.1-10 muM), inhibited potassium-stimulated [H-3] ACh release in hippocampal, cortical, and striatal slices prepared from wildtype mice by up to 80%. This activity was totally abolished in tissues prepared from M-2-M-4 receptor double KO mice. Strikingly, release studies with brain slices from M-2 and M-4 receptor single KO mice indicated that autoinhibition of ACh release is mediated primarily by the M-2 receptor in hippocampus and cerebral cortex, but predominantly by the M-4 receptor in the striatum. These results, together with additional receptor localization studies, support the novel concept that autoinhibition of ACh release involves different mAChRs in different regions of the brain. C1 NIDDKD, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP NIDDKD, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Levey, Allan/F-2104-2011 OI Levey, Allan/0000-0002-3153-502X FU NINDS NIH HHS [NS30454] NR 53 TC 168 Z9 177 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 1 PY 2002 VL 22 IS 5 BP 1709 EP 1717 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 527NQ UT WOS:000174192500025 PM 11880500 ER PT J AU Kruman, II Kumaravel, TS Lohani, A Pedersen, WA Cutler, RG Kruman, Y Haughey, N Lee, J Evans, M Mattson, MP AF Kruman, II Kumaravel, TS Lohani, A Pedersen, WA Cutler, RG Kruman, Y Haughey, N Lee, J Evans, M Mattson, MP TI Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE apoptosis; comet assay; glycosylase; oxidative stress; transgenic; uracil ID CELL GEL-ELECTROPHORESIS; FOLATE-DEFICIENCY; CORTICAL-NEURONS; BETA-PEPTIDE; URACIL MISINCORPORATION; PRECURSOR PROTEIN; OXIDATIVE STRESS; TRANSGENIC MICE; PLASMA-LEVELS; IN-VITRO AB Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid beta-peptide (Abeta) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Abeta. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Abeta toxicity as the result of reduced repair of Abeta-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of Abeta were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by Abeta. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 NR 80 TC 401 Z9 419 U1 6 U2 32 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 MAR 1 PY 2002 VL 22 IS 5 BP 1752 EP 1762 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 527NQ UT WOS:000174192500029 PM 11880504 ER PT J AU Basso, MA Wurtz, RH AF Basso, MA Wurtz, RH TI Neuronal activity in substantia nigra pars reticulata during target selection SO JOURNAL OF NEUROSCIENCE LA English DT Article DE saccade; primate; inhibition; disinhibition; competition; vision ID FRONTAL EYE FIELD; GANGLIA MOTOR CONTROL; REFLEX BLINK HYPEREXCITABILITY; MONKEY SUPERIOR COLLICULUS; BASAL GANGLIA; OCULOMOTOR FUNCTIONS; VISUAL-SEARCH; CORTICOSTRIATAL PROJECTIONS; PARKINSONS-DISEASE; NEURAL-NETWORK AB Complex visual scenes require that a target for an impending saccadic eye movement be selected from a number of possible targets. We investigated whether changing the number of stimuli from which a target would be identified altered the activity of substantia nigra pars reticulata (SNr) neurons of the basal ganglia (BG) and how such changes might contribute to changes we observed previously in the superior colliculus (SC). One, two, four, or eight visual stimuli appeared on random trials while monkeys fixated a centrally located spot. After a delay, one of the stimuli in the array changed luminance, indicating that it was the saccade target. We found that SNr neurons that had a pause in tonic activity after target onset and when the saccade was made to the target showed a modulation of activity during the multitarget task. Because the number of stimuli in the array increased from one to eight, the initial pause after the onset of the visual stimulus decreased. Activity during the preselection delay was reduced but was independent of the number of possible targets present. When one of the stimuli was identified as the saccade target, but before the saccade was made, we found a sharp decline in activity. This decline was related to the monkey's selecting the target rather than the luminance change identifying the target, because on error trials, when the luminance changed but a saccade was not made to the target, the activity did not decline. The decline for the preferred target location was also accompanied by a lesser decline for adjacent locations. Our findings indicate that SNr activity changes with target selection as it does with saccade initiation and that the SNr could make substantial, direct contributions to the SC at both times. The pause in SNr activity with target selection is consistent with the hypothesis that BG provide a disinhibition for the selection of desired movements. C1 Univ Wisconsin, Sch Med, Dept Physiol, Madison, WI 53706 USA. NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Basso, MA (reprint author), Univ Wisconsin, Sch Med, Dept Physiol, 1300 Univ Ave,Room 291 MSC, Madison, WI 53706 USA. NR 55 TC 86 Z9 86 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 1 PY 2002 VL 22 IS 5 BP 1883 EP 1894 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 527NQ UT WOS:000174192500043 PM 11880518 ER PT J AU Lanuza, MA Garcia, N Santafe, M Gonzalez, CM Alonso, I Nelson, PG Tomas, J AF Lanuza, MA Garcia, N Santafe, M Gonzalez, CM Alonso, I Nelson, PG Tomas, J TI Pre- and postsynaptic maturation of the neuromuscular junction during neonatal synapse elimination depends on protein kinase C SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE acetylcholine receptors; postnatal development; synaptogenesis; polyneuronal innervation; rat ID NERVE MUSCLE JUNCTIONS; SKELETAL-MUSCLE; ACETYLCHOLINE-RECEPTORS; POLYNEURONAL INNERVATION; POSTNATAL MATURATION; NEURAL INFLUENCE; AXON WITHDRAWAL; PHORBOL ESTER; IN-VITRO; CELLS AB The distribution of acetylcholine receptors (AChRs) within and around the neuromuscular junction changes dramatically during the first postnatal weeks, a period during which polyneuronal innervation is eliminated. We reported previously that protein kinase C (PKC) activation accelerates postnatal synapse loss. Because of the close relationship between axonal retraction and AChR cluster dispersal, we hypothesize that PKC can modulate morphological maturation changes of the AChR clusters in the postsynaptic membrane during neonatal axonal reduction. We applied substances affecting PKC activity to the neonatal rat levator auris longus muscle in vivo. Muscles were then stained immunohistochemically to detect both AChRs and axons. We found that, during the first postnatal days of normal development, substantial axonal loss preceded the formation of areas in synaptic sites that were free of AChRs, implying that axonal loss could occur independently of changes in AChR cluster organization. Nevertheless, there was a close relationship between axonal loss and AChR organization; PKC modulates both, although differently. Block of PKC activity with calphostin C prevented both AChR loss and axonal loss between postnatal days 4 and 6. PKC may act primarily to influence AChR clusters and not axons, insofar as phorbol ester activation of PKC accelerated changes in receptor aggregates but produced relatively little axon loss. (C) 2002 Wiley-Liss, Inc. C1 Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, Reus 43201, Spain. NIH, NICHD, Dev Neurobiol Lab, Bethesda, MD 20892 USA. RP Lanuza, MA (reprint author), Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, Sant Llorenc 21, Reus 43201, Spain. OI Santafe, Manel/0000-0002-5462-5108 NR 46 TC 34 Z9 34 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR 1 PY 2002 VL 67 IS 5 BP 607 EP 617 DI 10.1002/jnr.10122 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 527BV UT WOS:000174166400006 PM 11891773 ER PT J AU Oldfield, EH Bennett, A Chen, MY Doppman, JL AF Oldfield, EH Bennett, A Chen, MY Doppman, JL TI Successful management of spinal dural arteriovenous fistulas undetected by arteriography - Report of three cases SO JOURNAL OF NEUROSURGERY LA English DT Article DE spinal cord; dural arteriovenous fistula; arteriovenous malformation; myelopathy; arteriography ID OCCULT VASCULAR MALFORMATIONS; CLINICAL-FEATURES; SURGICAL-MANAGEMENT; MEDULLARY VEINS; LONG-TERM; CORD; INTERRUPTION; EMBOLIZATION; MYELOPATHY; PROGNOSIS AB Spinal dural arteriovenous fistulas (AVFs) frequently cause progressive myelopathy. When they are localized by imaging studies, surgery can be safely performed by simply interrupting the vein draining the fistula intradurally and the results Will be excellent and lasting. In some patients with clinical features of a spinal dural AVF and in whom magnetic resonance imaging and/or myelography findings are consistent with a diagnosis of a spinal dural AVF, however, spinal arteriography demonstrates no such results. The authors used a simple strategy based on knowledge of the epidemiology. pathophysiology. and anatomy of spinal dural AVFs to manage these cases successfully, In two patient, atherosclerotic occlusion was the primary cause for the failure of arteriography to visualize the dural AVF. The presence of an aortic aneurysm Was an additional contributing factor preventing arteriographic visualization one of these patients. In a third patient. massive obesity and aortic atheroslerosis and tortuosity contributed to the absence of findings on three spinal arteriograms before surgical exploration lead to a more focused arteriographic examination that was successful. C1 NIH, NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. NIH, NINDS, Dept Radiol, Bethesda, MD 20892 USA. RP Oldfield, EH (reprint author), NIH, NINDS, Surg Neurol Branch, Bldg 10,Room 5D37-1414, Bethesda, MD 20892 USA. NR 41 TC 27 Z9 29 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD MAR PY 2002 VL 96 IS 2 SU S BP 220 EP 229 DI 10.3171/spi.2002.96.2.0220 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 527FX UT WOS:000174177000012 PM 12450286 ER PT J AU Newbold, R AF Newbold, R TI Effects of developmental exposure to genistein, a soy phytoestrogen, in an experimental animal model. SO JOURNAL OF NUTRITION LA English DT Meeting Abstract C1 NIEHS, Mol Toxicol Lab, Dev Endocrinol Sect, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 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 MAR PY 2002 VL 132 IS 3 BP 580S EP 580S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 527ML UT WOS:000174189800067 ER PT J AU Landauer, MR Seed, TM Srinivasan, V Shapiro, A Takimoto, CH Wang, PS Smith, CD AF Landauer, MR Seed, TM Srinivasan, V Shapiro, A Takimoto, CH Wang, PS Smith, CD TI Genistein protects mice from ionizing radiation injury. SO JOURNAL OF NUTRITION LA English DT Meeting Abstract C1 Armed Forces Radiobiol Res Inst, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAR PY 2002 VL 132 IS 3 BP 588S EP 588S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 527ML UT WOS:000174189800089 ER PT J AU Barnes, S Grubbs, C Smith, M Kirk, M Lubet, R AF Barnes, S Grubbs, C Smith, M Kirk, M Lubet, R TI Greater renal clearance of daidzein and genistein. Accounts for the accumulation of equol in blood of soy-fed rats. SO JOURNAL OF NUTRITION LA English DT Meeting Abstract C1 Univ Alabama, Div Canc Prevent, NCI, Dept Pharmacol,Comprehens Canc Ctr, Birmingham, AL 35294 USA. Univ Alabama, Div Canc Prevent, NCI, Dept Toxicol,Comprehens Canc Ctr, Birmingham, AL 35294 USA. NR 0 TC 3 Z9 3 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 MAR PY 2002 VL 132 IS 3 BP 619S EP 619S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 527ML UT WOS:000174189800182 ER PT J AU Brown, LM Moradi, T Gridley, G Plato, N Dosemeci, M Fraumeni, JF AF Brown, LM Moradi, T Gridley, G Plato, N Dosemeci, M Fraumeni, JF TI Exposures in the painting trades and paint manufacturing industry and risk of cancer among men and women in Sweden SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OCCUPATIONAL RISKS; LUNG-CANCER; BLADDER-CANCER; MORTALITY; WORKERS; COHORT; SURVEILLANCE; MESOTHELIOMA; REGISTRY AB Using data from the 1960 and 19170 Swedish censuses and the Swedish Cancer Register for 1971 to 1989, this study investigated variations in cancer risk by gender associated with employment in painting trades and paint manufacturing. Among men, standardized incidence ratios were significantly increased for lung cancer among painters and lacquerers; bladder cancer among artists; and pancreas cancer, lung cancer, and nonlymphocytic leukemia among paint and varnish plant workers. Risks for women were elevated for cancers of the esophagus, larynx, and oral cavity among lacquerers and for oral cancer among glazers. These findings are consistent with the report of the International Agency for Research on Cancer that classified painting as an occupationally related cause of cancer and provide farther evidence that the risk of certain cancers is increased by exposures in the paint manufacturing process. C1 NCI, DCEG, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Clin Sci Family Med, Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. Karolinska Inst, Dept Publ Hlth Sci, Div Occupat Med, Stockholm, Sweden. RP Brown, LM (reprint author), NCI, DCEG, NIH, 6120 Execut Blvd,Room 8026,MSC 7244, Bethesda, MD 20892 USA. NR 39 TC 24 Z9 26 U1 1 U2 3 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 MAR PY 2002 VL 44 IS 3 BP 258 EP 264 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 530QQ UT WOS:000174370800012 PM 11911027 ER PT J AU Costantini, M Viterbori, P Flego, G AF Costantini, M Viterbori, P Flego, G CA Ligurian Res Grp Hosp Without Pain TI Prevalence of pain in Italian hospitals: Results of a regional cross-sectional survey SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE pain; pain prevalence; epidemiology ID MEDICAL INPATIENTS; CANCER-PATIENTS; MANAGEMENT; EPIDEMIOLOGY; SATISFACTION; ANALGESICS; RELIEF; SAMPLE AB The aims of this study were to quantify the prevalence of pain among hospitalized Italian patients and to describe the potential determinants of pain in this population. All patients older than 18 years and hospitalized for at least 24 hours in one of the 30 public hospitals of the Liguria region (n = 4709) were eligible for pain assessment. Using the Brief Pain Inventory patients with pain during the last 24 hours were asked to score the intensity of pain at the time of the interview, and the worst pain and average pain during the previous 24 hours on 0-10 rating scales. Overall, 87% (4121/4709) of inpatients were interviewed, and 56.6% suffered pain during the last 24 hours. Among patients with pain, the median (into-quartile range) scare of the worst and of the, average pain during the last 24 hours was 7 (5-9) and 5 (3-6), respectively. At the time of interview, 43.1% evaluated patients suffered pain, with a median (interquartile range) of 5 (3-7). Although significant heterogeneity in the distribution of pain was observed among the hospitals, pain prevalence was unacceptably high in most cases. Age, sex, education, diagnosis, and days from surgery were significantly related to pain prevalence in univariate analyses. In a multivariable ordinal regression logistic analysis, only sex, diagnosis, days from surgery, and hospitals remain significantly associated with increased pain prevalence. J Pain Symptom Manage 2002:23:221-230. (C) U.S. Cancer Pain Relief Committee, 2002. C1 Natl Canc Inst, Unit Clin Epidemiol & Trials, I-16132 Genoa, Italy. Biomed Technol Assessment Beta, Unit Evaluat Epidemiol, Genoa, Italy. RP Costantini, M (reprint author), Natl Canc Inst, Unit Clin Epidemiol & Trials, L R Benzi 10, I-16132 Genoa, Italy. RI costantini, massimo/G-1443-2012; OI VITERBORI, PAOLA/0000-0002-0241-646X; costantini, massimo/0000-0002-5293-7079 NR 32 TC 34 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2002 VL 23 IS 3 BP 221 EP 230 DI 10.1016/S0885-3924(01)00405-5 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 532HF UT WOS:000174467700009 PM 11888720 ER PT J AU Kinnula, VL Lehtonen, S Sormunen, R Kaarteenaho-Wiik, R Kang, SW Rhee, SG Soini, Y AF Kinnula, VL Lehtonen, S Sormunen, R Kaarteenaho-Wiik, R Kang, SW Rhee, SG Soini, Y TI Overexpression of peroxiredoxins I, II, III, V, and VI in malignant mesothelioma SO JOURNAL OF PATHOLOGY LA English DT Article DE peroxiredoxin; mesothelioma; lung; antioxidant; radical; tumour ID ANTIOXIDANT DEFENSE-MECHANISMS; MANGANESE SUPEROXIDE-DISMUTASE; ONE-CONSERVED CYSTEINE; TUMOR-NECROSIS-FACTOR; MAMMALIAN PEROXIREDOXIN; THIOREDOXIN PEROXIDASE; PLEURAL MESOTHELIOMA; HYDROGEN-PEROXIDE; CELL-LINES; APOPTOSIS AB Peroxiredoxins (Prxs) are a recently characterized group of thiol-containing proteins with efficient antioxidant capacity, capable of consuming hydrogen peroxide in living cells. Altogether six distinct Prxs have been characterized in mammalian tissues. Their expression was investigated in histological samples of mesothelioma and in cell lines established from the tumours of mesothelioma patients. Four cases with histopathologically healthy pleura from non-smokers were used as controls. Healthy pleural mesothelium was negative or very weakly positive for all Prxs In mesothelioma, the most prominent reactivity was observed with Prxs I, II, V, and VI. Prx I was highly or moderately expressed in 25/36 cases, the corresponding figures for Prxs II-VI being 27/36 (Prx II), 13/36 (Prx III), 2/36 (Prx IV), 24/36 (Prx V), and 30/36 (Prx VI). Positive staining was observed both in the cytosolic and the nuclear compartment, with the exception of Prx III, which showed no nuclear reactivity. The staining pattern of Prxs III and V was granular. Immunoelectron microscopic localization of Prxs was in accordance with the immunohistochemical findings, showing diffuse cytoplasmic localization for Prxs I, II, IV, and VI and distinct mitochondrial labelling for Prxs III and V. There is-as no significant association between the extent of staining and different Prxs. It appeared that Prxs may not haw prognostic significance, but being prominently expressed in most mesotheliomas these proteins, at least in theory, may play a role in the primary drug resistance of this disease. Copyright (C) 2002 John Wiley Sons, Ltd. C1 Univ Oulu, Dept Internal Med, Div Pulm, SF-90220 Oulu, Finland. Oulu Univ Hosp, Oulu, Finland. Bioctr Oulu, Oulu, Finland. NIH, Lab Cell Signaling, Bethesda, MD 20892 USA. Univ Oulu, Dept Pathol, SF-90220 Oulu, Finland. RP Kinnula, VL (reprint author), Univ Oulu, Dept Internal Med, Div Pulm, Kajaanintie 50A, SF-90220 Oulu, Finland. NR 33 TC 168 Z9 185 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD MAR PY 2002 VL 196 IS 3 BP 316 EP 323 DI 10.1002/path.1042 PG 8 WC Oncology; Pathology SC Oncology; Pathology GA 529BU UT WOS:000174280800010 PM 11857495 ER PT J AU McConahy, KL Smiciklas-Wright, H Birch, LL Mitchell, DC Picciano, MF AF McConahy, KL Smiciklas-Wright, H Birch, LL Mitchell, DC Picciano, MF TI Food portions are positively related to energy intake and body weight in early childhood SO JOURNAL OF PEDIATRICS LA English DT Article ID CALORIC COMPENSATION; SELF-REGULATION; YOUNG-CHILDREN; OBESITY; NUTRITION; INFANTS; GROWTH; LIFE AB Objective: To identify portion sizes (quantity ingested at a meal/snack) of foods commonly consumed in early childhood, temporal stability, and relations to energy intake, weight status, and sociodemographic characteristics. Study, design: Three samples were evaluated: the Continuing Surrey of Food Intakes by Individuals, 1994 to 1996, 1998 (CSFII 94-96, 98) (n = 1039), the Nationwide Food Consumption Survey, 1977 to 1978 (NFCS 77-78) (n = 10=15), and a longitudinal sample (n = 55) studied from 12 to 18 months. The CSFII 94-96,98, and NFCS 77-78 samples were compared to evaluate secular trends. Change from 12 to 18 months was assessed in the longitudinal sample. Relations of portion size to other relevant variables were evaluated in the CSFII 94-96, 98 sample. Results: In recent decades, portions remained remarkably similar for most foods. An exception was for meat portions, which were smaller in recent samples. Portions were longitudinally stable for most foods but increased for mills, bread, cereal, juice, and peanut butter. Body weight was positively related to energy intake and portion size but not number of eating occasions and/or foods. Sociodemographically, portion size was inversely related to number of eating occasions and/or foods. Conclusions: Children regulate energy intake largely through portion size. Sociodemographic patterns may have implications for later weight status. C1 Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Penn State Univ, Dept Human Dev & Family Studies, University Pk, PA 16802 USA. RP Picciano, MF (reprint author), NIH, Off Dietary Supplements, Bldg 31,Room 1B29,31 Ctr Dr,MSC 2086, Bethesda, MD USA. NR 37 TC 79 Z9 80 U1 1 U2 6 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 MAR PY 2002 VL 140 IS 3 BP 340 EP 347 DI 10.1067/mpd.2002.122467 PG 8 WC Pediatrics SC Pediatrics GA 542TZ UT WOS:000175061500014 PM 11953733 ER PT J AU Abernethy, DR Soldatov, NM AF Abernethy, DR Soldatov, NM TI Structure-functional diversity of human L-type Ca2+ channel: Perspectives for new pharmacological targets SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Editorial Material ID ALPHA(1C) SUBUNIT GENE; SENSITIVE CALCIUM-CHANNEL; MOLECULAR DETERMINANT; ALPHA-1 SUBUNIT; INACTIVATION; EXPRESSION; CALMODULIN; MYOCYTES; FIBROBLASTS; TRANSCRIPTS AB The L-type Ca2+ channels mediate depolarization-induced influx of Ca2+ into a wide variety of cells and thus play a central role in triggering cardiac and smooth muscle contraction. Because of this role, clinically important classes of 1,4-dihydropyridine, phenylalkylamine, and benzothiazepine Ca2+ channel blockers were developed as powerful medicines to treat hypertension and angina pectoris. Molecular cloning studies revealed that the channel is subject to extensive structure-functional variability due to alternative splicing. In this review, we will focus on a potentially important role of genetically driven variability of Ca2+ channels in expression regulation and mutations, Ca2+-induced inactivation, and modulation of sensitivity to Ca2+ channel blockers with the perspective for new pharmacological targets. C1 NIA, Sect Mol & Clin Pharmacol, Clin Invest Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Soldatov, NM (reprint author), 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 41 TC 58 Z9 58 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2002 VL 300 IS 3 BP 724 EP 728 AR UNSP 900063/967377 DI 10.1124/jpet.300.3.724 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525GE UT WOS:000174059900002 PM 11861774 ER PT J AU Van Ess, PJ Mattson, MP Blouin, RA AF Van Ess, PJ Mattson, MP Blouin, RA TI Enhanced induction of cytochrome P450 enzymes and CAR binding in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice following phenobarbital treatment SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NF-KAPPA-B; CULTURED RAT HEPATOCYTES; TUMOR-NECROSIS-FACTOR; P450-MEDIATED DRUG-METABOLISM; MOUSE-LIVER; ACTIVATED RECEPTOR; GENE-EXPRESSION; X RECEPTOR; INTERLEUKIN-6; ENDOTOXIN AB Phenobarbital (PB) is a well characterized inducer of cytochrome P450 (P450) 2B and 3A subfamilies. Several proinflammatory cytokines have been shown to negatively modulate the induction of P450 by PB. In addition, PB is known to elicit an inflammatory mitogenic effect on the liver. To date, no studies have evaluated the PB induction profile of hepatic P450 in the absence of an intact tumor necrosis factor-alpha (TNFalpha) response. To test the hypothesis that endogenous TNFa. signaling modulates hepatic P450 induction by PB in vivo, PB induction was examined in TNF (p55(-/-)/p75(-/-)) double receptor knockout mice (ko-TNF) and wild-type mice (wt-TNF). CYP2B- and, CYP3A-associated activities and protein content were induced to a significantly greater extent (p < 0.05) in ko-TNF mice compared with wt-TNF mice. In parallel with enhanced CYP2B induction, an apparent elevation in the nuclear accumulation of the principal regulatory protein for transcription of CYP2B genes, the constitutively activated receptor (CAR), was detected in ko-TNF nuclear extracts following PB treatment. Additionally, nuclear factor κ-B binding was induced by PB in wt-TNF mice, but not in ko-TNF mice, indicating that the hepatic inflammatory response following PB treatment differed between wt-TNF and ko-TNF mice. These data demonstrate that endogenous TNFα signaling modulates PB induction of hepatic CYP2B and CYP3A isoforms in vivo. Further, the data presented herein suggest that endogenous TNFα signaling influences PB induction of CYP2B through inhibition of CAR nuclear accumulation. C1 Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, Lexington, KY 40536 USA. Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Blouin, RA (reprint author), Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, 907 Rose St, Lexington, KY 40536 USA. RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [AG14554]; NINDS NIH HHS [NS29001, NS35253] NR 40 TC 8 Z9 9 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2002 VL 300 IS 3 BP 824 EP 830 AR UNSP 4483/965633 DI 10.1124/jpet.300.3.824 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525GE UT WOS:000174059900015 PM 11861787 ER PT J AU Perry, T Lahiri, DK Chen, DM Zhou, J Shaw, KTY Egan, JM Greig, NH AF Perry, T Lahiri, DK Chen, DM Zhou, J Shaw, KTY Egan, JM Greig, NH TI A novel neutrotrophic property of glucagon-like peptide 1: A promoter of nerve growth factor-mediated differentiation in PC12 cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PANCREATIC BETA-CELLS; FUNCTIONAL EXPRESSION; DIABETES-MELLITUS; MAP KINASE; RAT-BRAIN; RECEPTOR; EXENDIN-4; MICE; ACTIVATION; PROTEIN AB The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent Insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders. C1 NIA, NIH, Neurosci Lab, Sect Drug Design & Dev, Baltimore, MD 21224 USA. NIA, NIH, Clin Invest Lab, Gerontol Res Ctr,Diabet Sect, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA. RP Perry, T (reprint author), NIA, NIH, Neurosci Lab, Sect Drug Design & Dev, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 41 TC 156 Z9 166 U1 2 U2 9 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 MAR PY 2002 VL 300 IS 3 BP 958 EP 966 DI 10.1124/jpet.300.3.958 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 525GE UT WOS:000174059900032 PM 11861804 ER PT J AU Prat, E Martin, R AF Prat, E Martin, R TI The immunopathogenesis of multiple sclerosis SO JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT LA English DT Review DE autoimmune diseases; experimental allergic encephalomyelitis; multiple sclerosis; pathogenesis; therapy ID MYELIN BASIC-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; T-CELL RECEPTOR; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; VASCULAR ENDOTHELIAL-CELLS; ALTERED PEPTIDE LIGAND; ALPHA-B-CRYSTALLIN; SJL-J-MICE AB Multiple sclerosis (MS) is a T cell-mediated autoimmune disease that is triggered by unknown exogenous agents in subjects with a specific genetic background. Genes of the major histocompatibility complex class II region are the only ones that have been consistently associated with the disease. However, susceptibility is probably mediated by a heterogeneous array of genes, which demonstrate epistatic interactions. Furthermore, an infectious etiology of MS has been suggested, and it is likely that infectious agents shape the immune response against self-antigens. Composition of plaques, response to therapy, and data from animal models indicate that MS is mediated by myelin-specific CD4 T cells that, upon activation, invade the central nervous system and initiate the disease. Different patterns of tissue damage have been shown in active MS lesions, suggesting that the mechanisms of injury are probably distinct in different subgroups of patients. Heterogeneity in clinical characteristics, magnetic resonance imaging, and response to therapies support this notion. The experience gained during several pharmacological studies has improved our understanding of the pathogenesis of MS. New tools, such as gene expression profiling with cDNA microarrays and proteomics, together with advancements in imaging techniques may help us to identify susceptibility genes and disease markers, which may enable its to design more effective' therapies and to tailor them according to different disease forms or stages. C1 NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr DR MSC 1400, Bethesda, MD 20892 USA. NR 131 TC 31 Z9 32 U1 0 U2 0 PU JOURNAL REHAB RES & DEV PI BALTIMORE PA DEPT OF VETERANS AFFAIRS REHABIL RES & DEVELOP CTR 103 SOUTH GAY STREET, BALTIMORE, MD 21202-4051 USA SN 0748-7711 J9 J REHABIL RES DEV JI J. Rehabil. Res. Dev. PD MAR-APR PY 2002 VL 39 IS 2 BP 187 EP 199 PG 13 WC Rehabilitation SC Rehabilitation GA 556RR UT WOS:000175863200005 PM 12051463 ER PT J AU Cardinal, BJ Jacques, KM Levy, SS AF Cardinal, BJ Jacques, KM Levy, SS TI Evaluation of a university course aimed at promoting exercise behavior SO JOURNAL OF SPORTS MEDICINE AND PHYSICAL FITNESS LA English DT Article; Proceedings Paper CT American-Alliance-for-Health-Physical-Education-Recreation-and-Dance Convention CY MAR 21, 2000 CL ORLANDO, FLORIDA SP Amer Alliance Health Phys Educat Recreat Dance DE students; physical education and training; exercise; health promotion; physical activity; psychology; health behavior; transtheoretical model ID PHYSICAL-ACTIVITY; FEMALE-ADULTS; PROJECT GRAD; STAGE; STRATEGIES; VALIDITY; ALUMNI; HEALTH; SCALE; MODEL AB Background. This study assessed a 10-week, university-required lifetime fitness for health (LFH) course on students' leisure-time exercise behavior and advancement through the stages of change for exercise. Methods. Experimental design: a quasi-experimental design was employed. Setting: public university located in the United States. Participants: a total of 540 students who were enrolled in an LFH course or selected psychology courses volunteered to participate in this study. Intervention: a 30-hour LFH course administered over 10 weeks. The course was delivered both in a lecture and lab format. The control condition consisted of psychology courses. Measures: weekly leisure-time exercise behavior and stage of change for exercise behavior were assessed using valid and reliable self-report questionnaires at pre- and post-intervention. Results. Regardless of course, students' showed minimal changes in their exercise levels from pre- to post-intervention. Moreover, students in the LFH course did not improve their stage of change for exercise behavior as much students in the psychology courses. Regardless of course, participants' stage of change for exercise was an important moderator variable associated with exercise behavior change. Conclusions. As was taught, the LFH course did little to change the participants' exercise levels outside of class, and did little to positively influence the participants' stage of change for exercise behavior. C1 Oregon State Univ, Dept Exercise & Sport Sci, Corvallis, OR 97331 USA. NCI, NIH, Bethesda, MD USA. San Diego State Univ, Dept Exercise & Nutr Sci, San Diego, CA 92182 USA. RP Cardinal, BJ (reprint author), Oregon State Univ, Dept Exercise & Sport Sci, 220 Langton Hall, Corvallis, OR 97331 USA. NR 34 TC 19 Z9 19 U1 1 U2 6 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0022-4707 J9 J SPORT MED PHYS FIT JI J. Sports Med. Phys. Fit. PD MAR PY 2002 VL 42 IS 1 BP 113 EP 119 PG 7 WC Sport Sciences SC Sport Sciences GA 541KG UT WOS:000174983300019 PM 11832885 ER PT J AU Boyd, GM Faden, V AF Boyd, GM Faden, V TI College drinking, what it is, and what to do about it: A review of the state of the science - National Advisory Council on Alcohol Abuse and Alcoholism Task Force on College Drinking - National Institute on Alcohol Abuse and Alcoholism - Overview SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Editorial Material ID ADOLESCENT C1 NIAAA, Prevent Res Branch, Bethesda, MD 20892 USA. RP Boyd, GM (reprint author), NIAAA, Prevent Res Branch, Willco Bldg,6000 Execut Blvd,Suite 505, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 1 U2 2 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD MAR PY 2002 SU 14 BP 6 EP 13 PG 8 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 548KN UT WOS:000175387300002 ER PT J AU Kraemer, KH DiGiovanna, JJ AF Kraemer, KH DiGiovanna, JJ TI Topical enzyme therapy for skin diseases? SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material ID XERODERMA PIGMENTOSUM-CELLS; EPIDERMOLYTIC HYPERKERATOSIS; LAMELLAR ICHTHYOSIS; DNA-REPAIR; DENV GENE; MUTATIONS; CANCER; BACTERIOPHAGE-T4; SUNLIGHT; DAMAGE C1 NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Brown Med Sch, Dept Dermatol, Div Dermatopharmacol, Providence, RI USA. RP Kraemer, KH (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Bldg 37,Room 3E24, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 BC004517-31] NR 25 TC 6 Z9 6 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2002 VL 46 IS 3 BP 463 EP 466 DI 10.1067/mjd.2002.119102 PG 4 WC Dermatology SC Dermatology GA 528XC UT WOS:000174269200023 PM 11862191 ER PT J AU Smith, NL Savage, PJ Heckbert, SR Barzilay, JI Bittner, VA Kuller, LH Psaty, BM AF Smith, NL Savage, PJ Heckbert, SR Barzilay, JI Bittner, VA Kuller, LH Psaty, BM TI Glucose, blood pressure, and lipid control in older people with and without diabetes mellitus: The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE older; diabetes mellitus; hypertension; dyslipidemia; risk-factor control ID MYOCARDIAL-INFARCTION; RANDOMIZED TRIAL; HYPERTENSION; EVENTS; ASSOCIATION; ASPIRIN; TRENDS; ADULTS; DEATH AB OBJECTIVES: To determine the prevalence of cardiovascular risk-factor treatment and control in older adults with normal fasting glucose, impaired fasting glucose, and diabetes mellitus and whether those with diabetes Mellitus had better risk factor control than older adults with normal fasting glucose. DESIGN: Secondary analysis of data from population-based, prospective cohort study of risk factors for cardiovascular and cerebrovascular disease in older people (Cardiovascular Health Study). SETTING: Community-based. PARTICIPANTS: Community-dwelling adults aged 65 and older. MEASUREMENTS: Fasting plasma glucose, serum cholesterol and its subfractions, systolic and diastolic blood pressures, and body mass index. RESULTS: There were 579 (18%) cohort members with diabetes mellitus (77% receiving antidiabetic medication, 23% with fasting glucose : 126 mg/dL and no treatment), 213 (6%) with impaired fasting glucose, and 2,582 (77%) with normal fasting glucose. Of diabetic participants, 12% had recommended fasting glucose levels of less than 110 mg/dL. Of participants with hypertension, a larger proportion of diabetic participants than nondiabetic participants (89%. versus 75%, P <.01) was treated with antihypertensive agents, but a smaller proportion of diabetic participants had recommended blood pressure levels of 129/85 mmHg or lower than nondiabetic participants had recommended blood pressure levels of 139/89 mmHg or lower (27% vs 48%, P <.01). Diabetic dyslipidemic participants were treated less often with lipid-lowering therapy (26% versus 55%, P <.01) and achieved recommended low-density lipoprotein goals less often (8% versus 54%, P <.01) than nondiabetic dyslipidemic participants. CONCLUSIONS: Overall, treatment and control of cardiovascular risk factors were suboptimal in this older population, especially among those with diabetes mellitus. Optimizing risk-factor control can improve health outcomes in older adults with and without diabetes mellitus. C1 Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Alabama, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. Kaiser Permanente, Atlanta, GA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Smith, NL (reprint author), Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85082, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HL-15103, N01-HL-35129]; NIA NIH HHS [R01-AG-09556] NR 40 TC 39 Z9 39 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2002 VL 50 IS 3 BP 416 EP 423 DI 10.1046/j.1532-5415.2002.50103.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 528TU UT WOS:000174260000002 PM 11943034 ER PT J AU Ship, JA Pillemer, SR Baum, BJ AF Ship, JA Pillemer, SR Baum, BJ TI Xerostomia and the geriatric patient SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review DE xerostomia; aging; saliva; Sjogren's; cancer; radiotherapy; medications ID PRIMARY SJOGRENS-SYNDROME; SALIVARY FLOW-RATES; RADIATION-INDUCED XEROSTOMIA; NECK-CANCER PATIENTS; 5-YEAR FOLLOW-UP; DRY MOUTH; ORAL PILOCARPINE; DOUBLE-BLIND; POSTIRRADIATION XEROSTOMIA; CURRENT THERAPIES AB Saliva is essential for the preservation of oral-pharyngeal health, and disorders of salivary physiology are associated with numerous oral and pharyngeal problems, particularly in older people. Although salivary function is remarkably intact in healthy aging, medical problems, medications, and head and neck radiotherapy can cause salivary dysfunction and complaints of xerostomia among older people. Sjogren's syndrome, an autoimmune exocrinopathy, is the most common medical disease associated with salivary dysfunction. Medications with anticholinergic side effects will impair salivary output, and head and neck radiotherapy for cancer will cause permanent destruction of salivary glands. Treatments for salivary problems are based upon establishing a diagnosis, protecting oral and pharyngeal health, stimulating remaining glands, and replacing lost salivary fluids. C1 NYU, Coll Dent, Dept Oral Med, New York, NY 10010 USA. NYU, Coll Dent, Bluestone Ctr Clin Res, New York, NY 10010 USA. Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Ship, JA (reprint author), NYU, Coll Dent, Dept Oral Med, 345 E 24th St, New York, NY 10010 USA. NR 137 TC 131 Z9 137 U1 0 U2 9 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2002 VL 50 IS 3 BP 535 EP 543 DI 10.1046/j.1532-5415.2002.50123.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 528TU UT WOS:000174260000021 PM 11943053 ER PT J AU Humphreys, BL Mandl, KD Cahn, MA AF Humphreys, BL Mandl, KD Cahn, MA TI Bridging the gap in medical informatics and health services research: An introduction SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material C1 Natl Lib Med, NICHSR, Bethesda, MD 20894 USA. Harvard Univ, Sch Med, Boston, MA USA. Childrens Hosp, Boston, MA 02115 USA. RP Humphreys, BL (reprint author), Natl Lib Med, NICHSR, 8600 Rockville Pike,Bldg 38,Room 2W06,Mail Stop, Bethesda, MD 20894 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR-APR PY 2002 VL 9 IS 2 BP 125 EP 126 DI 10.1197/jamia.M0972 PG 2 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 541ZW UT WOS:000175018400006 ER PT J AU Corn, M Rudzinski, KA Cahn, MA AF Corn, M Rudzinski, KA Cahn, MA TI Bridging the gap in medical informatics and health services research: Workshop results and next steps SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article AB In January 2000, the Agency for Healthcare Research and Quality (AHRQ) and the National Library of Medicine (NLM) cosponsored an invitational workshop entitled "Medical Informatics and Health Services Research: Bridging the Gap." Planned by a small committee of representatives from NLM and AHRQ institutional training centers, the workshop was designed to address the need for education of researchers interested in working at the intersection of the fields of medical informatics and health services research. More than 100 educators and researchers from AHRQ- and NLM-sponsored training programs in medical informatics and health services research participated in the workshop. Through a series of plenary presentations and breakout sessions, the workshop addressed ways of increasing the pool of persons interested, trained, and experienced in addressing specific areas of synergy between the two fields. This paper reports on the results of the workshop. C1 Natl Lib Med, NICHSR, Bethesda, MD 20894 USA. Agcy Healthcare Res & Qual, Rockville, MD USA. RP Cahn, MA (reprint author), Natl Lib Med, NICHSR, 8600 Rockville Pike,Bldg 38A,Room 4S-410,Mail St, Bethesda, MD 20894 USA. NR 4 TC 8 Z9 8 U1 0 U2 1 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR-APR PY 2002 VL 9 IS 2 BP 140 EP 143 DI 10.1197/jamia.M0971 PG 4 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 541ZW UT WOS:000175018400009 PM 11861629 ER PT J AU Moyer, SC Cotter, RJ Woods, AS AF Moyer, SC Cotter, RJ Woods, AS TI Fragmentation of phosphopeptides by atmospheric pressure MALDI and ESI/ion trap mass spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID ASSISTED-LASER-DESORPTION/IONIZATION; CATION-PI INTERACTIONS; POST-SOURCE DECAY; PHOSPHORYLATION SITES; SELECTIVE DETECTION; PROTEINS; IDENTIFICATION; PEPTIDES AB An investigation of phosphate loss from phosphopeptide ions was conducted, using both atmospheric pressure matrix-assisted laser desorption/ionization (AP MALDI) and electrospray ionization (ESI) coupled to an ion trap mass spectrometer (ITMS). These experiments were carried out on a number of phosphorylated peptides in order to investigate gas phase dephosphorylation patterns associated with phosphoserine, phosphothreonine, and phosphotyrosine residues. In particular, we explored the fragmentation patterns of phosphotyrosine containing peptides, which experience a loss of 98 Da under collision induced dissociation (CID) conditions in the ITMS. The loss of 98 Da is unexpected for phosphotyrosine, given the structure of its side chain. The fragmentation of phosphoserine and phosphothreonine containing peptides was also investigated. While phosphoserine and phosphothreonine residues undergo a loss of 98 Da under CID conditions regardless of peptide amino acid composition, phosphate loss from phosphotyrosine residues seems to be dependent on the presence of arginine or lysine residues in the peptide sequence. (C) 2002 American Society for Mass Spectrometry. C1 NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 29 TC 69 Z9 70 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD MAR PY 2002 VL 13 IS 3 BP 274 EP 283 AR PII S1044-0305(01)00361-0 DI 10.1016/S1044-0305(01)00361-0 PG 10 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 528TV UT WOS:000174260100010 PM 11908807 ER PT J AU Camarano, G Jones, M Freidlin, RZ Panza, JA AF Camarano, G Jones, M Freidlin, RZ Panza, JA TI Quantitative assessment of left ventricular perfusion defects using real-time three-dimensional myocardial contrast echocardiography SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID INFARCT SIZE; RISK AREA; 3-DIMENSIONAL ECHOCARDIOGRAPHY; CORONARY-OCCLUSION; REPERFUSION; CANINE; INVIVO; MASS; IDENTIFICATION; QUANTIFICATION AB Quantitative assessment of perfusion defects with myocardial contrast echocardiography can be a valuable tool in the evaluation of patients with coronary artery disease. However, the use of 2-dimensional echocardiography for this purpose is limited to a restricted number of imaging planes. Real-time 3-dimensional echocardiography (RT3D) is a novel technique that provides instantaneous volumetric images. The aim of this study was to validate the use of RT3D for the quantitative assessment of myocardial perfusion defects in a model of acute coronary occlusion. To this end, 20 sheep underwent acute ligation of the left anterior descending (n = 14) or the posterior branch of the circumflex (n = 6) artery under general anesthesia. The RT3D images were obtained after left atrial injection of the contrast agent EchoGen (perflenapent emulsion; 0.8-1 mL). Evans blue dye was injected into the occluded coronary artery for subsequent anatomic identification of underperfused myocardium. The mass of the entire left ventricle and of the underperfused myocardial region were measured after death. Blinded off-line calculation of left ventricular (LV) mass and perfusion-defect mass from RT3D images were performed using an interactive aided-manual tracing technique. Total LV mass ranged from 68 to 141 g (mean +/- SD: 92 +/- 24 g). The mass of the perfusion defect ranged from 0 to 43 g (mean SD: 16 +/- 9 g) or 0 to 36% of total LV mass (meant +/- SD: 18% +/- 9%). The RT3D estimation of total LV mass strongly correlated with the anatomic measurement (r = 0.91; y = -2.54 + 1.04x; standard error of the estimate [SEE] = 11.9 g). The RT3D calculation of the mass of underperfused myocardium also strongly correlated with the anatomic measurement, both in absolute terms (r = 0.96; y = 2.01 + 0.87x; SEE = 2.2 g) and when expressed as percentage of total LV mass (r - 0.96; y = 0.11 + 1.02x; SEE = 2.8%). Hence, RT3D with myocardial contrast opacification accurately predicts the amount of underperfused myocardium in an animal model of acute coronary occlusion. This technique may therefore be useful for the quantitative assessment of myocardial perfusion defects in patients with coronary artery disease. C1 NHLBI, NIH, Cardiol Branch, Bethesda, MD USA. NHLBI, NIH, Lab Anim Med & Surg, Bethesda, MD USA. RP Panza, JA (reprint author), Washington Hosp Ctr, 110 Irving St,NW,Suite 2A-74, Washington, DC 20010 USA. NR 23 TC 27 Z9 42 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAR PY 2002 VL 15 IS 3 BP 206 EP 213 DI 10.1067/mje.2002.117338 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 531UZ UT WOS:000174436800003 PM 11875382 ER PT J AU Vannan, M McCreery, T Li, P Han, ZG Unger, E Kuersten, B Nabel, E Rajagopalan, S AF Vannan, M McCreery, T Li, P Han, ZG Unger, E Kuersten, B Nabel, E Rajagopalan, S TI Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID GENE DELIVERY; EXPRESSION; DESTRUCTION; THERAPY; TISSUE; ANGIOGENESIS; DISEASE; CELLS AB We tested the hypothesis that targeted disruption of cationic microbubble-linked plasmid DNA, using diagnostic ultrasound, may aid transfection of large animal myocardium. Plasinid DNA encoding for CAT (pCAT, chloramphenicol acetyltransferase) was bound to a novel cationic microbubble containing MRX-225 for intravenous administration, and 16 dogs in 4 groups variously received this conjugate or plasmid only, or were exposed to ultrasound. Histochemical staining and enzyme-linked immuno-sorbent assay analysis showed CAT activity in the myocardium of only those animals that received microbubble-linked DNA and were exposed to ultrasound. Thus, disruption of cationic-linked, low-dose plasmid systems by diagnostic ultrasound may facilitate transfection of large animal hearts. C1 Univ Michigan, Dept Internal Med, Div Cardiol, Hlth Syst, Ann Arbor, MI 48109 USA. Univ Arizona, Dept Radiol, Tucson, AZ 85724 USA. ImaRx Therapeut Inc, Tucson, AZ USA. NIH, Bethesda, MD 20892 USA. RP Vannan, M (reprint author), Med Coll Penn & Hahnemann Univ, 245 N 15th St,MS-470, Philadelphia, PA 19102 USA. NR 14 TC 81 Z9 87 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAR PY 2002 VL 15 IS 3 BP 214 EP 218 DI 10.1067/mje.2002.119913 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 531UZ UT WOS:000174436800004 PM 11875383 ER PT J AU Abdi, R Huong, TTB Sahagun-Ruiz, A Murphy, PM Brenner, BM Milford, EL McDermott, DH AF Abdi, R Huong, TTB Sahagun-Ruiz, A Murphy, PM Brenner, BM Milford, EL McDermott, DH TI Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ALLOGRAFT-REJECTION; DISEASE PROGRESSION; HIV-1 INFECTION; CCR5 PROMOTER; EXPRESSION; AIDS; RESISTANCE; CX(3)CR1; VARIANT AB Chemokines regulate the trafficking of leukocytes in immunity and inflammation and have been implicated in mouse models in acute cardiac and renal allograft rejection; however, their significance to human transplantation is not yet defined. The association of human chemokine receptor genetic variants, CCR5-Delta32, CCR5-59029-A/G, CCR2-V64I, CX3CR1-V249I, and CX3CR1-T280M, with outcome in 163 renal transplant recipients was examined here. Significant reductions were found in risk of acute renal transplant rejection in recipients who possessed the CCR2-64I allele (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.12 to 0.78; P = 0.014) or who were homozygous for the 59029-A allcle (OR, 0.37; 95% CI, 0.16 to 0.85; P = 0.016). There were no significant differences in the incidence of rejection among patients stratified as with or without CCR5-Delta32 or by the CX3CR1-V249I or CX3CR1-T280M genotypes. Adjustment for known risk factors for transplant rejection confirmed the univariate findings for possession of the CCR2-641 allele (OR, 0.20; P = 0.032) and homozygosity for the 59029-A allele (OR, 0.26; P = 0.027). It was concluded that the risk of acute rejection in renal transplantation is associated with genetic variation in the chemokine receptors CCR2 and CCR5. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. RP McDermott, DH (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N111,9000 Rockville Pike, Bethesda, MD 20892 USA. OI McDermott, David/0000-0001-6978-0867 NR 25 TC 117 Z9 128 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2002 VL 13 IS 3 AR UNSP 1046-6673/1303-0754 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 523PJ UT WOS:000173964000022 PM 11856781 ER PT J AU Muntner, P He, J Hamm, L Loria, C Whelton, PK AF Muntner, P He, J Hamm, L Loria, C Whelton, PK TI Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID VITAL STATUS; RISK-FACTORS; FOLLOW-UP; INDEX; MORTALITY AB Several epidemiologic studies reported that persons with renal insufficiency might have increased cardiovascular disease-related mortality rates in select populations. The association between renal insufficiency and increased cardiovascular disease-related and all-cause mortality rates during 16 yr of follow-up monitoring was examined among participants who were 30 to 74 yr of age at the baseline examinations in 1976 to 1980, with urinary protein dipstick measurements (n = 8786) or serum creatinine levels of less than or equal to3.0 mg/dl (n = 6354), from the Second National Health and Nutrition Examination Survey Mortality Study. GFR were estimated by adjusting serum creatinine levels for age, race, and gender, using the Modification of Diet in Renal Disease formula. Cardiovascular disease-related mortality rates were 6.2, 17.9, and 37.2 deaths/1000 person-yr among subjects with urinary protein levels of <30, 30 to 299, and 300 mg/dl and were 4.1, 8.6, and 20.5 deaths/1000 person-yr among participants with estimated GFR of 90, 70 to 89, and <70 ml/min, respectively. After adjustment for potential confounders, the relative hazards (and 95% confidence intervals) for cardiovascular disease-related death were 1.57 (0.99 to 2.48) and 1.77 (0.97 to 3.21) among subjects with urinary protein levels of 30 to 299 and greater than or equal to300 mg/dl, respectively, compared with <30 mg/dl (P trend = 0.02). The corresponding relative hazards for all-cause-related death were 1.64 (1.23 to 2.18) and 2.00 (1.13 to 3.55; P trend < 0.001). Compared with subjects with estimated GFR of :90 ml/min, those with estimated GFR of <70 ml/min exhibited higher relative risks of death from cardiovascular disease and all causes [1.68 (1.33 to 2.13) and 1.51 (1.19 to 1.91), respectively]. This study indicates that, in a representative sample of the United States general population, renal insufficiency is independently associated with increased cardiovascular disease-related and all-cause mortality rates. C1 Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. NHLBI, Bethesda, MD 20892 USA. RP Muntner, P (reprint author), Tulane Univ SPHTM, Dept Epidemiol, 1430 Tulane Ave,SL-18, New Orleans, LA 70112 USA. NR 27 TC 498 Z9 527 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2002 VL 13 IS 3 AR UNSP 1046-6673/1303-0745 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 523PJ UT WOS:000173964000021 PM 11856780 ER PT J AU Ray, P Acheson, D Chitrakar, R Cnaan, A Gibbs, K Hirschman, GH Christen, E Trachtman, H AF Ray, P Acheson, D Chitrakar, R Cnaan, A Gibbs, K Hirschman, GH Christen, E Trachtman, H TI Basic fibroblast growth factor among children with diarrhea-associated hemolytic uremic syndrome SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CELLS; BFGF; INTERLEUKIN-8; PATHOGENESIS; CHILDHOOD; CYTOKINES; APOPTOSIS; ARGENTINA; RELEASE AB Diarrhea-associated hemolytic uremic syndrome (D+HUS) is characterized by endothelial injury and activation of inflammatory cytokines. Basic fibroblast growth factor (bFGF) is an angiogenic peptide released in response to vascular damage. The plasma concentrations and urinary excretion of bFGF during the course of D+HUS were determined, in comparison with the levels of various inflammatory cytokines, and changes were correlated with clinical and laboratory features of the disease. Serial plasma and urine samples were collected from 31 children with D+HUS, during the acute (days 1 to 7 of hospitalization) and recovery (through day 60 after discharge from the hospital) phases of the disease. The patients were enrolled in the multicenter trial of SYNSORB Pk (SYNSORB Biotech, Calgary, Alberta, Canada) treatment for D+HUS. bFGF, interleukin-1alpha (IL-1alpha), IL-8, and tumor necrosis factor-alpha levels were determined with enzyme-linked immunosorbent assays. bFGF was detected in urine and plasma samples more frequently than were IL-1alpha, IL-8, and tumor necrosis factor-alpha. There was an acute increase in urinary bFGF excretion, which returned to normal during convalescence. Urinary excretion of bFGF during the acute phase was higher among patients who required dialysis, compared with those who did not (48.9 +/- 15.0 and 28.9 +/- 9.0 pg/ml, respectively; P < 0.05). Plasma bFGF concentrations were persistently elevated throughout the period of hospitalization and the follow-up period among patients with D + HUS. Urinary excretion and plasma levels of bFGF were comparable for the SYNSORB Pk-treated (n = 19) and placebo-treated (n = 12) groups. Measurements of urinary and plasma concentrations of bFGF among patients with D+HUS may be useful indices for assessment of the severity of acute renal disease and the timing and adequacy of the systemic angiogenic process during early convalescence. C1 Schneider Childrens Hosp N Shore Long Isl Jewish, Div Nephrol, Dept Pediat, New Hyde Pk, NY 11040 USA. Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. Tufts Univ, New England Med Ctr, Div Geog Med & Infect Dis, Boston, MA 02111 USA. Childrens Hosp Philadelphia, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. NIDDKD, Chron Renal Dis Program, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. RP Trachtman, H (reprint author), Schneider Childrens Hosp N Shore Long Isl Jewish, Div Nephrol, Dept Pediat, Room SCh 365,269-01 76th Ave, New Hyde Pk, NY 11040 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NHLBI NIH HHS [2R01-HL55605]; NIDDK NIH HHS [DK52147, 2R01-DK49419] NR 30 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2002 VL 13 IS 3 AR UNSP 1046-6673/1303-0699 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 523PJ UT WOS:000173964000015 PM 11856774 ER PT J AU Takahashi, N Brooks, HL Wade, JB Liu, W Kondo, Y Ito, S Knepper, MA Smithies, O AF Takahashi, N Brooks, HL Wade, JB Liu, W Kondo, Y Ito, S Knepper, MA Smithies, O TI Posttranscriptional compensation for heterozygous disruption of the kidney-specific NaK2Cl cotransporter gene SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID THICK ASCENDING LIMB; NA-K-2CL COTRANSPORTER; MICE LACKING; BARTTERS-SYNDROME; CL COTRANSPORTER; DESCENDING-LIMB; HENLES LOOP; RAT-KIDNEY; VASOPRESSIN; EXPRESSION AB Mice homozygous for a loss of function mutation of the kidney-specific NaK2Cl cotransporter, BSC1/NKCC2, do not survive. Here the effects of loss of one copy of the gene are studied. NKCC2 mRNA of NKCC2 +/- kidney was 55 +/- 6% of +/+, yet no differences were found between NKCC2 +/+ and +/- mice in BP, blood gas, electrolytes, creatinine, plasma renin concentration, urine volume and osmolality, ability to concentrate and dilute urine, and response to furosemide. When mice were challenged with 180 mM NH4Cl, plasma ammonia and urinary ammonia excretion were increased twofold and fivefold, respectively, but there was still no difference between the two genotypes. NKCC2 +/- mice had a near-normal level of NKCC2 protein and no clear change in the distribution of NKCC2 in the thick ascending limb (TAL) cells. In vitro microperfusion of isolated TAL showed no significant difference between the two genotypes in the basal and vasopressin-stimulated capacity to reabsorb NaCl. There was no difference in the mRNA expressions of thiazide-sensitive NaCl cotransporter, epithelial Na channel (ENaC), aquaporin-2, ROMK, and NaKATPase. Halving the mRNA expression of NKCC2 does not affect BP or fluid balance because of compensatory factors that restore the protein level to near normal. One possible factor is a regulated increase in the movement of cytoplasmic protein to the luminal membrane leading, to a restoration of functional transporter to an essentially wild type level. C1 Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Physiol, Baltimore, MD 21201 USA. Tohoku Univ, Grad Sch Med, Dept Pediat, Sendai, Miyagi 980, Japan. Tohoku Univ, Grad Sch Med, Dept Nephrol Hypertens & Endocrinol, Sendai, Miyagi 980, Japan. RP Smithies, O (reprint author), Univ N Carolina, Dept Pathol & Lab Med, 701 Brinkhous Bullitt Bldg, Chapel Hill, NC 27599 USA. RI Ito, Sadayoshi/A-3933-2015 FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [HL49277]; NIDDK NIH HHS [DK32839]; NIGMS NIH HHS [GM20069] NR 37 TC 28 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2002 VL 13 IS 3 AR UNSP 1046-6673/1303-0604 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 523PJ UT WOS:000173964000004 PM 11856763 ER PT J AU Lutgendorf, SK Kreder, KJ Rothrock, NE Hoffman, A Kirschbaum, C Sternberg, EM Zimmerman, MB Ratliff, TL AF Lutgendorf, SK Kreder, KJ Rothrock, NE Hoffman, A Kirschbaum, C Sternberg, EM Zimmerman, MB Ratliff, TL TI Diurnal cortisol variations and symptoms in patients with interstitial cystitis SO JOURNAL OF UROLOGY LA English DT Article DE bladder; cystitis, interstitial; hydrocortisone; pituitary-adrenal system ID PITUITARY-ADRENAL AXIS; SALIVARY CORTISOL; DATA-BASE; STRESS; DISEASE; IMMUNE; SYMPTOMATOLOGY; ASSOCIATIONS; ACTIVATION; ARTHRITIS AB Purpose: Little attention has focused on systemic factors that may allow a state of chronic bladder inflammation to be established and maintained in interstitial cystitis cases. Abnormalities of the hypothalamic-pituitary-adrenal feedback system result in poorer regulation of the inflammatory response and are present in many chronic inflammatory and pain conditions, of which some have high co-morbidity with interstitial cystitis. Materials and Methods: A total of 48 patients with interstitial cystitis and 35 healthy, age matched controls collected 24-hour urine samples and 3 days of salivary samples at 7 to 8 a.m., 4 to 5 p.m. and 8 to 9 p.m. for cortisol analysis. In addition, they completed a concurrent symptom questionnaire. Prospective symptom diaries also were completed in the month before sampling. Results: Mean urinary or salivary cortisol did not differ in patients and controls. However, patients with interstitial cystitis and higher morning cortisol had significantly less pain and urgency, while those with higher urinary free cortisol reported less overall symptomatology (p <0.05). Relationships with morning cortisol were also observed when controlling for co-morbid conditions known to be affected by the hypothalamic-pituitary-adrenal axis, such as fibromyalgia, chronic fatigue and rheumatoid arthritis. Patients with morning cortisol less than 12.5 nmol./l. were 12.8 times more likely to report high urinary urgency than those with values above this cutoff. Conclusions: These findings imply that regulation of the hypothalamic-pituitary-adrenal axis may be associated with interstitial cystitis symptomatology and there may be different diurnal hypothalamic-pituitary-adrenal patterns in patients with interstitial cystitis who do and do not have co-morbid conditions. These findings may have treatment implications for patients with interstitial cystitis who have early morning cortisol deficiencies. C1 Univ Iowa, Sch Publ Hlth, Dept Psychol, Iowa City, IA 52242 USA. Univ Iowa, Sch Publ Hlth, Dept Urol, Iowa City, IA USA. Univ Iowa, Sch Publ Hlth, Dept Biostat, Iowa City, IA USA. Univ Iowa, Microbiol & Interdisciplinary Grad Program Immuno, Iowa City, IA USA. Univ Dusseldorf, Inst Physiol Psychol 2, D-4000 Dusseldorf, Germany. NIMH, Bethesda, MD 20892 USA. RP Lutgendorf, SK (reprint author), Univ Iowa, Sch Publ Hlth, Dept Psychol, Iowa City, IA 52242 USA. FU NCRR NIH HHS [RR00059]; NIDDK NIH HHS [DK54014] NR 26 TC 32 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2002 VL 167 IS 3 BP 1338 EP 1343 DI 10.1016/S0022-5347(05)65295-0 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 519YK UT WOS:000173752900030 PM 11832727 ER PT J AU Nishimura, Y Igarashi, T Haigwood, N Sadjadpour, R Plishka, RJ Buckler-White, A Shibata, R Martin, MA AF Nishimura, Y Igarashi, T Haigwood, N Sadjadpour, R Plishka, RJ Buckler-White, A Shibata, R Martin, MA TI Determination of a statistically valid neutralization titer in plasma that confers protection against simian-human immunodeficiency virus challenge following passive transfer of high-titered neutralizing antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; HIV-1/SIV CHIMERIC VIRUS; PBL-SCID MICE; T-LYMPHOCYTE; TYPE-1 INFECTION; RESPONSES; MACAQUES; VIREMIA; CELLS; IMMUNIZATION AB We previously reported that high-titered neutralizing antibodies directed against the human immunodeficiency virus type 1 (HIV-1) envelope can block the establishment of a simian immunodeficiency virus (SIV)/HIV chimeric virus (SHIV) infection in two monkeys following passive transfer (R. Shibata et al., Nat. Med. 5:204-210, 1999). In the present study, increasing amounts of neutralizing immunoglobulin G (IgG) were administered to 15 pig-tailed macaques in order to obtain a statistically valid protective neutralization endpoint titer in plasma. Using an in vitro assay which measures complete neutralization of the challenge SHIV, we correlated the titers of neutralizing antibodies in plasma at the time of virus inoculation (which ranged from 1:3 to 1:123) with the establishment of infection in virus-challenged animals. Ten of 15 monkeys in the present experiment were virus free as a result of neutralizing IgG administration as monitored by DNA PCR (peripheral blood mononuclear cells and lymph node cells), RNA PCR (plasma), virus isolation, and the transfer of lymph node cell suspensions (10(8) cells) plus 8 ml of whole blood from protected animals to naive macaques. The titer of neutralizing antibodies in the plasma calculated to protect 99% of virus-challenged monkeys was 1:38. C1 NIAID, Lab Mol Microbiol, NIH, Bethesda, MD 20892 USA. Gilead Sci Inc, Foster City, CA 94404 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. RP Martin, MA (reprint author), NIAID, Lab Mol Microbiol, NIH, 9000 Rockville Pike Bldg 4 Rm 315, Bethesda, MD 20892 USA. NR 36 TC 132 Z9 134 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 MAR PY 2002 VL 76 IS 5 BP 2123 EP 2130 DI 10.1128/JVI.76.5.2123.2130.2002 PG 8 WC Virology SC Virology GA 519ZX UT WOS:000173756300010 PM 11836389 ER PT J AU Dirks, C Duh, FM Rai, SK Lerman, MI Miller, AD AF Dirks, C Duh, FM Rai, SK Lerman, MI Miller, AD TI Mechanism of cell entry and transformation by enzootic nasal tumor virus SO JOURNAL OF VIROLOGY LA English DT Article ID JAAGSIEKTE SHEEP RETROVIRUS; MURINE LEUKEMIA-VIRUS; PULMONARY ADENOMATOSIS; LYSOSOMAL HYALURONIDASE; INTRANASAL TUMORS; EPITHELIAL-CELLS; SARCOMA-VIRUS; LUNG-CANCER; GENE; RECEPTOR AB Enzootic nasal tumor virus (ENTV) induces nasal epithelial cancer in infected sheep, but it is a simple retrovirus lacking a known oncogene. ENTV is closely related to jaagsiekte sheep retrovirus (JSRV), which also causes cancer in sheep but in the epithelial cells of the lower airways and alveoli. Here we show that as with JSRV, the envelope (Env) protein of ENTV can transform cultured cells and thus is likely to be responsible for oncogenesis in animals, In addition, the ENTV Env protein mediates virus entry using the same receptor as does JSRV Env, the candidate tumor suppressor Hya12. However, ENTV Env mediates entry into cells from a more restricted range of species than does JSRV, and based on this finding we have identified amino acid regions in the Env proteins that are important for virus entry. Also, because ENTV does not efficiently use human Hya12 as a receptor, we cloned the ovine Hya12 cDNA and show that the encoded protein functions as an efficient receptor for both ENTV and JSRV. In summary, although ENTV and JSRV use the same cell surface receptor for cell entry and apparently transform cells by the same mechanism, they induce cancer in different tissues of infected sheep, indicating that oncogenesis is regulated at some other level. The transcriptional regulatory elements in these viruses are quite different, indicating that tissue-specific oncogenesis is likely regulated at the level of viral gene expression. C1 Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Cellular Biol Program, Seattle, WA 98109 USA. Intramural Res Support Program, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. Ctr Canc Res, Lab Immunobiol, NCI, Ft Detrick, MD 21702 USA. RP Miller, AD (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, Rm C2-105 1100 Fairview Ave N, Seattle, WA 98109 USA. OI Miller, Dusty/0000-0002-3736-3660 FU NCI NIH HHS [CO 56000, N01CO12400, CO 12400]; NHLBI NIH HHS [P50 HL054881, HL 54881]; NIDDK NIH HHS [DK 47754, P30 DK047754] NR 44 TC 63 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 MAR PY 2002 VL 76 IS 5 BP 2141 EP 2149 DI 10.1128/JVI.76.5.2141-2149.2002 PG 9 WC Virology SC Virology GA 519ZX UT WOS:000173756300012 PM 11836391 ER PT J AU Stromnes, IM Dittmer, U Schumacher, TNM Schepers, K Messer, RJ Evans, LH Peterson, KE Race, B Hasenkrug, KJ AF Stromnes, IM Dittmer, U Schumacher, TNM Schepers, K Messer, RJ Evans, LH Peterson, KE Race, B Hasenkrug, KJ TI Temporal effects of gamma interferon deficiency on the course of friend retrovirus infection in mice SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; NATURAL-KILLER-CELLS; HEPATITIS-B VIRUS; INDUCED ERYTHROLEUKEMIA; IFN-GAMMA; CYTOMEGALOVIRUS-INFECTION; ERYTHROPOIETIN RECEPTORS; MONOCLONAL-ANTIBODIES; ANTIVIRAL DEFENSE; VIRAL-INFECTIONS AB The current studies demonstrate complex and seemingly contradictory effects by gamma interferon (IFN-gamma) on Friend virus (FV) infection. Both temporal and tissue-specific effects were observed. During the first week of infection, IFN-gamma-deficiency caused increased levels of FV infection in multiple tissues. Surprisingly, however, by 2 weeks postinfection, IFN-gamma-deficient mice had significantly lower levels of infection in both the spleen and bone marrow compared to wild-type mice. The rapid reduction of virus in the IFN-gamma-deficient mice correlated with a more rapid virus-neutralizing antibody response than was observed in the wild-type mice. Furthermore, the virus-neutralizing antibody response in wild-type mice could be accelerated by ablation of their IFN-gamma response. Although the IFN-gamma-deficient mice developed an accelerated virus-neutralizing antibody response, they did not class-switch to immunoglobulin G class immunoglobulins nor could they maintain long-term virus-neutralizing antibody titers. Eventually, all of the IFN-gamma-deficient mice failed to keep persistent virus in check and developed fatal FV-induced erythroleukemia. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Univ Wurzburg, Inst Virol, D-97070 Wurzburg, Germany. Netherlands Canc Inst, Dept Immunol, NL-1066 CX Amsterdam, Netherlands. RP Hasenkrug, KJ (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RI Schepers, Koen/H-7108-2013; Peterson, Karin/D-1492-2016 OI Schepers, Koen/0000-0003-2442-242X; Peterson, Karin/0000-0003-4177-7249 NR 53 TC 29 Z9 29 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 MAR PY 2002 VL 76 IS 5 BP 2225 EP 2232 DI 10.1128/JVI.76.5.2225-2232.2002 PG 8 WC Virology SC Virology GA 519ZX UT WOS:000173756300021 PM 11836400 ER PT J AU Wu, TY Lee, CG Buckler-White, A Kozak, CA AF Wu, TY Lee, CG Buckler-White, A Kozak, CA TI Genetic control of a mouse serum lipoprotein factor that inactivates murine leukemia viruses: Evaluation of apolipoprotein F as a candidate SO JOURNAL OF VIROLOGY LA English DT Article ID NON-IMMUNOGLOBULIN FACTOR; MOLECULAR-CLONING; NEUTRALIZATION; ONCORNAVIRUS; MICE AB Mice contain a serum factor capable of inactivating some subgroups of murine leukemia viruses. This leukemia virus-inactivating factor (LVIF) is distinct from immunoglobulin and complement; it has been associated with lipoprotein serum fractions and may be an apolipoprotein. The present study demonstrates that some Swiss-derived inbred strains are LVIF negative. Genetic crosses show this factor to be under control of a single gene that maps to distal chromosome 10 at or near the gene encoding a minor serum apolipoprotein, apolipoprotein F (ApoF). To evaluate this gene as a potential candidate for LVIF, the mouse ApoF gene was cloned and sequenced and its expression was assessed in LVIF-positive and -negative mice; no obvious differences were detected, suggesting that LVIF is under the control of a distinct linked gene. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, LMM, NIH, Bldg 4,Room 329,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. NR 27 TC 7 Z9 8 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 MAR PY 2002 VL 76 IS 5 BP 2279 EP 2286 DI 10.1128/JVI.76.5.2279-2286.2002 PG 8 WC Virology SC Virology GA 519ZX UT WOS:000173756300027 PM 11836406 ER PT J AU Mohan, KVK Som, I Atreya, CD AF Mohan, KVK Som, I Atreya, CD TI Identification of a type 1 peroxisomal targeting signal in a viral protein and demonstration of its targeting to the organelle SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN ROTAVIRUS SA11; FATTY-ACIDS; ENHANCEMENT; INFECTIVITY; MEMBRANE; SEQUENCE; IMPORT; CELLS; VP4 AB Peroxisomes are unimembrane, respiratory organelles of the cell. Transport of cellular proteins to the peroxisomal matrix requires a type 1 peroxisomal targeting signal (PTS1) which essentially constitutes a tripeptide from the consensus sequence S/T/A/G/C/N-K/R/H-L/I/V/M/A/F/Y. Although PTS-containing proteins have been identified in eukaryotes, prokaryotes, and parasites, viral proteins with such signals have not been identified so far. We report here the first instance of a virus, the rotavirus, which causes infantile diarrhea worldwide, containing a functional C-terminal PTS1 in one of its proteins (VP4). Analysis of 153 rotavirus VP4-deduced amino acid sequences identified five groups of conserved C-terminal PTS1 tripeptide sequences (SKL, CKL, GKL, CRL, and CRI), of which CRL is represented in approximately 62% of the sequences. Infection of cells by a CRL-containing representative rotavirus (SA11 strain) and confocal immunofluorescence analysis revealed colocalization of VP4 with peroxisomal markers and morphological changes of peroxisomes. Further, transient cellular expression of green fluorescent protein (GFP)-fused VP4CRL resulted in transport of VP4 to peroxisomes, whereas the chimera lacking the PTS1 signal, GFP-VP4DeltaCRL, resulted in diffuse cytoplasmic staining, suggesting a CRL-dependent targeting of the protein. The present study therefore demonstrates hitherto unreported organelle involvement, specifically of the peroxisomes, in rotaviral infections as demonstrated by using the SA11 strain of rotavirus and opens a new line of investigation toward understanding viral pathogenesis and disease mechanisms. C1 US FDA, Ctr Biol Evaluat & Res, Sect Viral pathogenesis & Vaccine Adverse React, Lab Pediat & Resp Viral Dis,Div Viral Prod, Bethesda, MD 20892 USA. RP Atreya, CD (reprint author), US FDA, Ctr Biol Evaluat & Res, Sect Viral pathogenesis & Vaccine Adverse React, Lab Pediat & Resp Viral Dis,Div Viral Prod, Bldg 29A,Room 2C-11,HFM-460,NIH Campus,8800 Rock, Bethesda, MD 20892 USA. NR 30 TC 27 Z9 27 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 MAR PY 2002 VL 76 IS 5 BP 2543 EP 2547 DI 10.1128/JVI.76.5.2543-2547.2002 PG 5 WC Virology SC Virology GA 519ZX UT WOS:000173756300053 PM 11836432 ER PT J AU Nymark-McMahon, MH Beliakova-Bethell, NS Darlix, JL Le Grice, SFJ Sandmeyer, SB AF Nymark-McMahon, MH Beliakova-Bethell, NS Darlix, JL Le Grice, SFJ Sandmeyer, SB TI Ty3 integrase is required for initiation of reverse transcription SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRIMER-BINDING-SITE; NUCLEOCAPSID PROTEIN; IN-VITRO; AMINO-ACID; NUCLEOPROTEIN COMPLEXES; RETROTRANSPOSON TY3; DIMERIC RNA; ALPHA-BETA; YEAST AB The integrase (IN) encoded by the Saccharomyces cerevisiae retroviruslike element T Q has features found in retrovirus IN proteins including the catalytic triad, an amino-terminal zinc-binding motif, and a nuclear localization sequence. Mutations in the amino- and carboxyl-terminal domains of Ty3 IN cause reduced accumulation of full-length cDNA in the viruslike particles. We show that the reduction in cDNA is accompanied by reduced amounts of early intermediates such as minus-strand, strong-stop DNA. Expression of a capsid (CA)-IN fusion protein (CA-IN) complemented catalytic site and nuclear localization mutants, but not DNA mutants. However, expression of a fusion of CA, reverse transcriptase (RT), and IN (CA-RT-IN) complemented transposition of catalytic site and nuclear localization signal mutants, increased the amount of cDNA in some of the mutants, and complemented transposition of several mutants to low frequencies. Expression of a CA-RT-IN protein with a Ty3 IN catalytic site mutation did not complement transposition of either a Ty3 catalytic site mutant or a nuclear localization mutant but did increase the amount of cDNA in several mutants and complement at least one of the cDNA mutants for transposition. These in vivo data support a model in which independent IN domains can contribute to reverse transcription and integration. We conclude that during reverse transcription, the Ty3 IN domain interacts closely with the polymerase domain and may even constitute a domain within a heterodimeric RT. These studies also suggest that during integration the IN catalytic site and at least portions of the IN carboxyl-terminal domain act in cis. C1 Univ Calif Irvine, Coll Med, Dept Biol Chem, Irvine, CA 92697 USA. Ecole Normale Super Lyon, INSERM U412, LaboRetro, Unite Virol Humaine, F-69364 Lyon, France. NCI, Div Basic Sci, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Sandmeyer, SB (reprint author), Univ Calif Irvine, Coll Med, Dept Biol Chem, Irvine, CA 92697 USA. FU NIGMS NIH HHS [GM33281, R01 GM033281] NR 59 TC 28 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 MAR PY 2002 VL 76 IS 6 BP 2804 EP 2816 DI 10.1128/JVI.76.6.2804-2816.2002 PG 13 WC Virology SC Virology GA 524YA UT WOS:000174039400025 PM 11861848 ER PT J AU Pekrun, K Shibata, R Igarashi, T Reed, M Sheppard, L Patten, PA Stemmer, WPC Martin, MA Soong, NW AF Pekrun, K Shibata, R Igarashi, T Reed, M Sheppard, L Patten, PA Stemmer, WPC Martin, MA Soong, NW TI Evolution of a human immunodeficiency virus type 1 variant with enhanced replication in pig-tailed macaque cells by DNA shuffling SO JOURNAL OF VIROLOGY LA English DT Article ID NUCLEOTIDE-SEQUENCE ANALYSIS; IN-VIVO PASSAGE; MACACA-NEMESTRINA; HIV-1 INFECTION; AIDS VIRUS; PRIMATE MODELS; MOLECULAR CHARACTERIZATION; PIGTAILED MACAQUES; RHESUS MACAQUES; ENVELOPE GENE AB DNA shuffling facilitated the evolution of a human immunodeficiency virus type I (HIV-1) variant with enhanced replication in pig-tailed macaque peripheral blood mononuclear cells (pt mPBMC). This variant consists exclusively of HIV-1-derived sequences with the exception of simian immunodeficiency virus (SIV) nef. Sequences spanning the gag-protease-reverse transcriptase (gag-pro-RT) region from several HIV-1 isolates were shuffled and cloned into a parental HIV-1 backbone containing SIV nef. Neither this full-length parent nor any of the unshuffled HIV-1 isolates replicated appreciably or sustainably in pt mPBMC. Upon selection of the shuffled viral libraries by serial passaging in pt mPBMC, a species emerged which replicated at substantially higher levels (50 to 100 ng/ml p24) than any of the HIV-1 parents and most importantly, could be continuously passaged in pt mPBMC. The parental HIV-1 isolates, when selected similarly, became extinct. Analyses of full-length improved proviral clones indicate that multiple recombination events in the shuffled region and adaptive changes in the rest of the genome contributed synergistically to the improved phenotype. This improved variant may prove useful in establishing a pig-tailed macaque model of HIV-1 infection. C1 Maxygen Inc, Redwood City, CA 94063 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Soong, NW (reprint author), Maxygen Inc, 515 Galveston Dr, Redwood City, CA 94063 USA. NR 48 TC 17 Z9 18 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 MAR PY 2002 VL 76 IS 6 BP 2924 EP 2935 DI 10.1128/JVI.76.6.2924-2935.2002 PG 12 WC Virology SC Virology GA 524YA UT WOS:000174039400036 PM 11861859 ER PT J AU Frank, I Piatak, M Stoessel, H Romani, N Bonnyay, D Lifson, JD Pope, M AF Frank, I Piatak, M Stoessel, H Romani, N Bonnyay, D Lifson, JD Pope, M TI Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): Differential intracellular fate of virions in mature and immature DCs SO JOURNAL OF VIROLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; T-CELLS; HIV-1 INFECTION; IN-VITRO; PRODUCTIVE INFECTION; LANGERHANS CELLS; GP120 RECEPTORS; LYMPHOID-TISSUE; SIV; ANTIGEN AB As potential targets for human immunodeficiency virus type I and simian immunodeficiency virus (HIV-1 and SIV), dendritic cells (DCs) likely play a significant role in the onset and spread of infection as well as in the induction of antiviral immunity. Using the SIV-macaque system to study the very early events in DC-virus interactions, we compared chemically inactivated SIV having conformationally and functionally intact envelope glycoproteins (2,2'-dithiodipyridine [AT-2] SIV) to infectious and heat-treated SIV. Both human and macaque DCs interact similarly with SIV without detectable effects on DC viability, phenotype, or endocytic function. As assessed by measuring cell-associated viral RNA, considerable amounts of virus are captured by the DCs and this is reduced when the virus is heat treated or derived from a strain that expresses low levels of envelope glycoprotein. Immunostaining for SIV proteins and electron microscopy indicated that few intact virus particles are retained at the periphery of the endocytically active, immature DCs. This contrasts with a perinuclear localization of numerous virions in large vesicular compartments deeper within mature DCs (in which macropinocytosis is down-regulated). Both immature and mature DCs are capable of clathrin-coated pit-mediated uptake of SIV, supporting the notion that the receptor-mediated uptake of virus can occur readily in mature DCs. While large numbers of whole viruses were preferentially found in mature DCs, both immature and mature DCs contained similar amounts of viral RNA, suggesting that different uptake/virus entry mechanisms are active in immature and mature DCs. These findings have significant implications for cell-to-cell transmission of HIV-1 and SIV and support the use of AT-2 SIV, an authentic but noninfectious form of virus, as a useful tool for studies of processing and presentation of AT-2 SIV antigens by DCs. C1 Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. Univ Innsbruck, Dept Dermatol & Venerol, A-6020 Innsbruck, Austria. RP Pope, M (reprint author), Populat Council, Biomed Res Ctr, 1230 York Ave, New York, NY 10021 USA. EM mpope@popcbr.rockefeller.edu FU NCI NIH HHS [N01-CO-56000]; NIAID NIH HHS [AI47681] NR 57 TC 109 Z9 109 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2002 VL 76 IS 6 BP 2936 EP 2951 DI 10.1128/JVI.76.6.2936-2951.2002 PG 16 WC Virology SC Virology GA 524YA UT WOS:000174039400037 PM 11861860 ER PT J AU Ott, DE Coren, LV Sowder, RC Adams, J Nagashima, K Schubert, U AF Ott, DE Coren, LV Sowder, RC Adams, J Nagashima, K Schubert, U TI Equine infectious anemia virus and the ubiquitin-proteasome system SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; LATE ASSEMBLY DOMAIN; PROLINE-RICH MOTIF; CELLULAR PROTEINS; GAG POLYPROTEIN; MN STRAIN; TYPE-1; DEGRADATION; RELEASE AB Some retroviruses contain monoubiquitinated Gag and do not bud efficiently from cells treated with proteasome inhibitors, suggesting an interaction between the ubiquitin-proteasome system and retrovirus assembly. We examined equine infectious anemia virus (EIAV) particles and found that approximately 2% of the p9(Gag) proteins are monoubiquitinated, demonstrating that this Gag protein interacts with an ubiquitinating activity. Different types of proteasome inhibitors were used to determine if proteasome Inactivation affects EIAV release from chronically infected cells. Pulse-chase immunoprecipitation and time course immunoblot analyses showed that proteasome inactivation slightly decreased virus release (at most a twofold effect), while it did not affect Gag processing. These results contrast with those obtained with other viruses which are sensitive to these inhibitors. This suggests that, although its Gag is monoubiquitinated, the requirements for EIAV release are somewhat different from those for retroviruses that are sensitive to proteasome inhibitors. C1 Natl Canc Inst Frederick, SAIC Frederick, AIDS Vaccine Program, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, SAIC Frederick, Res Technol Program, Ft Detrick, MD 21702 USA. Millennium Pharmaceut, Cambridge, MA 02139 USA. NIAID, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. Heinrich Pette Inst, D-20251 Hamburg, Germany. RP Ott, DE (reprint author), Natl Canc Inst Frederick, SAIC Frederick, AIDS Vaccine Program, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 55 TC 48 Z9 49 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 MAR PY 2002 VL 76 IS 6 BP 3038 EP 3044 DI 10.1128/JVI.76.6.3038-3044.2002 PG 7 WC Virology SC Virology GA 524YA UT WOS:000174039400047 PM 11861870 ER PT J AU Andejeski, Y Breslau, ES Hart, E Lythcott, N Alexander, L Rich, I Bisceglio, I Smith, HS Visco, FM AF Andejeski, Y Breslau, ES Hart, E Lythcott, N Alexander, L Rich, I Bisceglio, I Smith, HS Visco, FM CA US Army Medical Res Material Comma TI Benefits and drawbacks of including consumer reviewers in the scientific merit review of breast cancer research SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Review ID CARE; ADVOCACY AB Background: This study assessed participant opinions about inclusion of breast cancer survivors as lay representatives in a scientific and technical merit review of proposals for the 1995 Department of Defense Breast Cancer Research Program (DOD BCRP). Methods: The evaluation employed a prepanel and postpanel survey design, which was intended to elicit feedback about attitudes, perceptions, and beliefs toward collaborative consumer and scientist participation in scientific merit review. Qualitative methods were used to describe the consumers' and scientists' responses, to explore the significance of this interaction, and to gain an understanding of the benefits and disadvantages of bringing these participants together. Results: Both groups were initially troubled about the consumers' lack of scientific background and questioned their qualifications and preparation for participation in a scientific panel. In particular, consumers were concerned that their judgments would not be taken seriously by scientists, a concern somewhat lessened by participation. After the meeting, scientists viewed the consumers as hard-working, dedicated survivors and advocates and endorsed the presence of carefully chosen lay panel members. Scientists were troubled that consumers potentially would have an impact on voting and on the subsequent scoring of proposals, a concern that was not validated by quantitative findings. Conclusions: As a result of these data, the DOD BCRP continues to embrace clarify the nature of collaborative participation in scientific merit review. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21201 USA. NCI, Off Commun, Bethesda, MD 20892 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. Amer Social Hlth Assoc, Res Triangle Pk, NC USA. US Dept Def, Congress Directed Med Res Program Off, Springfield, VA USA. Sci Applicat Int Corp, Biomed Technol Div, Frederick, MD USA. Geraldine Brush Canc Res Inst, San Francisco, CA USA. Natl Breast Canc Coalit, Washington, DC USA. RP Breslau, ES (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 15 W Lee St, Baltimore, MD 21201 USA. NR 34 TC 14 Z9 14 U1 0 U2 3 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 MAR PY 2002 VL 11 IS 2 BP 119 EP 136 DI 10.1089/152460902753645263 PG 18 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 537FJ UT WOS:000174748000005 PM 11975860 ER PT J AU Bar-Gal, GK Smith, P Tchernov, E Greenblatt, C Ducos, P Gardeisen, A Horwitz, LK AF Bar-Gal, GK Smith, P Tchernov, E Greenblatt, C Ducos, P Gardeisen, A Horwitz, LK TI Genetic evidence for the origin of the agrimi goat (Capra aegagrus cretica) SO JOURNAL OF ZOOLOGY LA English DT Article DE agrimi; Capra aegagrus cretica; bezoar goat; Capra aegagrus aegagrus; Crete; aDNA; cytochrome b ID GENUS CAPRA; DNA AB The agrimi goat Capra aegagrus cretica is unique to Crete and its offshore islands. It has been identified as a sub-species of the wild bezoar goat Capra areagrus aegagrus Erxleben, 1777, which it closely resembles in horn shape, body form and coloration. This classification has been disputed by some researchers who claim that the agrimi are feral goats, derived from early domestic stock brought to the island by the first Neolithic settlers. In order to clarify this issue, DNA analyses (cytochrome b and D loop sequences) were carried out on tissue of live and skeletonized agrimi and compared to sequences of wild and domestic caprines. Results conclusively show the agrimi to be a feral animal, that clades with domestic goats (Capra hircus) rather than with wild Asiatic bezoar. This study demonstrates that morphometric criteria do not necessarily reflect genetic affinities, and that the taxonomic classification of agrimi should be revised. C1 Hebrew Univ Jerusalem, Dept Anat & Embryol, Lab Bioanthropol & Ancient DNA, IL-91904 Jerusalem, Israel. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Hebrew Univ Jerusalem, Fac Life Sci, Dept Evolut Syst & Ecol, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Kuvin Ctr Study Infect & Trop Dis, IL-91120 Jerusalem, Israel. CDAR, CNRS UMR 154, F-34970 Lattes, France. RP Horwitz, LK (reprint author), Hebrew Univ Jerusalem, Dept Anat & Embryol, Lab Bioanthropol & Ancient DNA, POB 12272, IL-91904 Jerusalem, Israel. NR 40 TC 9 Z9 11 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0952-8369 J9 J ZOOL JI J. Zool. PD MAR PY 2002 VL 256 BP 369 EP 377 DI 10.1017/S0952836902000407 PN 3 PG 9 WC Zoology SC Zoology GA 539NA UT WOS:000174876000009 ER PT J AU Bissler, JJ Tsoras, M Goring, HHH Hug, P Chuck, G Tombragel, E McGraw, C Schlotman, J Ralston, MA Hug, G AF Bissler, JJ Tsoras, M Goring, HHH Hug, P Chuck, G Tombragel, E McGraw, C Schlotman, J Ralston, MA Hug, G TI Infantile dilated X-linked cardiomyopathy, G4.5 mutations, altered lipids, and ultrastructural malformations of mitochondria in heart, liver, and skeletal muscle SO LABORATORY INVESTIGATION LA English DT Article ID BARTH-SYNDROME; 3-METHYLGLUTACONIC ACIDURIA; CARDIOSKELETAL MYOPATHY; ABNORMAL MITOCHONDRIA; GENE; NEUTROPENIA AB Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose. C1 Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. Childrens Med Ctr, Dayton, OH USA. SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. NCI, Sect Membrane Struct & Funct, Lab Expt & Computat Biol, FCRDC, Frederick, MD 21701 USA. RP Bissler, JJ (reprint author), Childrens Hosp Res Fdn 5, 3333 Burnet Ave, Cincinnati, OH 45229 USA. FU NCRR NIH HHS [M01 RR8084]; NIDDK NIH HHS [DK0241801] NR 24 TC 31 Z9 32 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD MAR PY 2002 VL 82 IS 3 BP 335 EP 344 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 534ZK UT WOS:000174619500011 PM 11896212 ER PT J AU Epstein, FH London, JF Peters, DC Goncalves, LM Agyeman, K Taylor, J Balaban, RS Arai, AE AF Epstein, FH London, JF Peters, DC Goncalves, LM Agyeman, K Taylor, J Balaban, RS Arai, AE TI Multislice first-pass cardiac perfusion MRI: Validation in a model of myocardial infarction SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article; Proceedings Paper CT 72nd Annual Scientific Session of the American-Heart-Association CY NOV 07-10, 1999 CL ATLANTA, GEORGIA SP Amer Heart Assoc DE magnetic resonance imaging; echo-planar imaging; heart; myocardial perfusion; canine ID ECHO-TRAIN READOUT; BOLUS; QUANTIFICATION; MULTISECTION; SEQUENCE; TRANSIT; DISEASE; RESERVE; VOLUME; HUMANS AB The purpose of this study was to validate a first-pass MRI method for imaging myocardial perfusion with multislice coverage and relatively small analyzable regions of interest (ROIs). A fast gradient-echo (FGRE) sequence with an echo-train (ET) readout was used to achieve multislice coverage, and a high dose of a contrast agent (CA) was used to achieve a high signal-to-noise ratio (SNR). Dogs (N = 6) were studied 1 day after reperfused myocardial infarction, and fluorescent microspheres were used as a standard for perfusion. First-pass MRI correlated well vs. microsphere flow, achieving mean R values of 0.87 (range = 0.82-0.93), 0.71 (range = 0.46-0.85), and 0.72 (range = 0.49-0.95) for subendocardial ROIs, transmural ROIs, and the endocardial-epicardial ratio, respectively. Additionally, analysis of myocardial time-intensity curves (TICs) indicated that 15.8 +/- 6.6degrees sectors, corresponding to 260 mul of endocardium, can be analyzed (R-2 > 0.95). Published 2002 Wiley-Liss, Inc.(dagger) C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Epstein, FH (reprint author), Univ Virginia, Dept Radiol, Box 800170, Charlottesville, VA 22904 USA. RI Balaban, Robert/A-7459-2009; OI Balaban, Robert/0000-0003-4086-0948; Goncalves, Lino/0000-0001-9255-3064 NR 29 TC 54 Z9 54 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2002 VL 47 IS 3 BP 482 EP 491 DI 10.1002/mrm.10085 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 526JP UT WOS:000174127500009 PM 11870835 ER PT J AU Shapiro, EM Borthakur, A Shapiro, MJ Reddy, R Leigh, JS AF Shapiro, EM Borthakur, A Shapiro, MJ Reddy, R Leigh, JS TI Fast MRI of RF heating via phase difference mapping SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; temperature; radiofrequency heating; paramagnetic; RF coil ID PROTON CHEMICAL-SHIFT; MAGNETIC-RESONANCE; IN-VIVO; HUMAN HEAD; LANTHANIDE COMPLEX; TISSUE; SAR; INHOMOGENEITY; DISTRIBUTIONS; SPECTROSCOPY AB A method is presented for the rapid acquisition of temperature maps derived from phase difference maps. The temperature-dependent chemical shift coefficients (TDCSCs) of various concentrations of aqueous cobalt and dysprosium-based compounds were measured. The largest TDCSC calculated was for 100 mM DyEDTA, which had a TDCSC of -0.09 PPM/K; 160 mM CoCl2 had a TDCSC of -0.04 PPM/K. These temperature-dependent chemical shifts (TDCSs) result in phase changes in the MR signal with changing temperature. Agarose phantoms were constructed with each paramagnetic metal. A fast gradient-echo (FGRE) MR image was acquired to serve as the baseline image. A "test" MRI procedure was then performed on the phantom. Immediately afterwards, a second FGRE MR image was acquired, serving as the probing image. Proper image processing as a phase difference map between the probing image and the baseline image resulted in an image which quantitatively described the temperature increase of the phantom in response to a particular "test" imaging experiment. Applications of this technique in assessing the safety of pulse sequences and MR coils are discussed. (C) 2002 Wiley-Liss, Inc. C1 Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Novartis Inst Biomed Res, Summit, NJ USA. RP Shapiro, EM (reprint author), NINCDS, NIH, Lab Funct & Mol Imaging, 10 Ctr Dr,Bldg 10 B1D118, Bethesda, MD 20892 USA. EM ShapiroE@ninds.nih.gov OI Reddy, Ravinder/0000-0003-4580-2392 FU NCRR NIH HHS [P41 RR002305, P41 RR002305-236875, P41 RR002305-236874, RR02305] NR 32 TC 15 Z9 16 U1 3 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2002 VL 47 IS 3 BP 492 EP 498 DI 10.1002/mrm.10067 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 526JP UT WOS:000174127500010 PM 11870836 ER PT J AU Thompson, RB McVeigh, ER AF Thompson, RB McVeigh, ER TI High temporal resolution phase contrast MRI with multiecho acquisitions SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; phase contrast; temporal resolution; flow; cardiac ID ECHO-PLANAR; MAGNETIC-RESONANCE; BREATH-HOLD; BLOOD-FLOW; HEART; SEQUENCE; ECHOCARDIOGRAPHY; QUANTIFICATION; REGURGITATION; QUANTITATION AB Velocity imaging with phase contrast (PC) MRI is a noninvasive tool for quantitative blood flow measurement in vivo. A shortcoming of conventional PC imaging is the reduction in temporal resolution as compared to the corresponding magnitude imaging. For the measurement of velocity in a single direction, the temporal resolution is halved because one must acquire two differentially flow-encoded images for every PC image frame to subtract out non-velocity-related image phase information. In this study, a high temporal resolution PC technique which retains both the spatial resolution and breath-hold length of conventional magnitude imaging is presented. Improvement by a factor of 2 in the temporal resolution was achieved by acquiring the differentially flow-encoded images in separate breath-holds rather than interleave within a single breath-hold. Additionally, a multiecho readout was incorporated into the PC experiment to acquire more views per unit time than is possible with the single gradient-echo technique A total improvement in temporal resolution by similar to5 times over conventional PC imaging was achieved. A complete set of images containing velocity data in all three directions was acquired in four breath-holds, with a temporal resolution of 11.2 ms and an in-plane spatial resolution of 2 mm x 2 mm. Published 2002 Wiley-Liss, Inc.(dagger) C1 NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Thompson, RB (reprint author), NIH, Cardiac Energet Lab, Room B1D 416,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. RI Thompson, Richard/E-9821-2011 FU Intramural NIH HHS [Z01 HL004608-08] NR 40 TC 18 Z9 18 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2002 VL 47 IS 3 BP 499 EP 512 DI 10.1002/mrm.10079 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 526JP UT WOS:000174127500011 PM 11870837 ER PT J AU Cavagna, P Stone, G Stanyon, R AF Cavagna, P Stone, G Stanyon, R TI Black rat (Rattus rattus) genomic variability characterized by chromosome painting SO MAMMALIAN GENOME LA English DT Article ID CYTOGENETIC ANALYSIS; DNA; MOUSE; CATS; HYBRIDIZATION; EVOLUTION; SEGMENTS; ANCIENT; MAMMALS; HUMANS AB Black rats are Of Outstanding interest in parasitology and infective disease analysis, We used chromosome paints from both the mouse (Mus musculus) and the Norway rat (Rattus norvegicus) to characterize the genome of two Black rat subspecies from Italy. Both subspecies have two large metacentrics (n. 1. 4) not present in the Norway rat (2n = 42). Rattus rattus rattus has a diploid number of 2n = 38. while Rattus rattus frugivorous has two small metacentric or B chromosomes for a diploid number of 2n 38 + 2B, T e 21 mouse paints gave 38 signals on the R. r. rattus karyotype and 39 signals in the R. r. frugivorous karyotype. The two metacentrics, not present in R, norvegicus, were hybridized by mouse 16/1/17 and mouse 4/10/15. These chromosomes are homologous to: RRA I = RNO 5/7. and RRA4 = RNO 9/11 and not "4/7" and "11/12" as previously reported. Furthermore, the synteny of Chr 13 of the R. r. frugivorous with R. norvegicus Chr 16 and mouse Chrs 8/14 is not complete. because there is a small pericentromeric insertion of RNO Chr 18 (mouse Chr 18). If we consider only the two metacentrics, RRA1 and RRA4. the principal differences between R. norvegicus and R, rattus, then we can propose the derived synteny of 124 genes in the black rat. A comparison of the Z index between rats and mice shows an acceleration of genomic evolution among genus, species, and subspecies. The chromosomal differences between R. r. rattus x R. r. frugivorous suggest that they may be classified as different species because hybrids would produce 50% unbalanced gametes. C1 NCI, Canc Res Ctr, Genet Branch, Comparat Mol Cytogenet Sect, Frederick, MD 21702 USA. Univ Genoa, Dept Expt BIol, I-16132 Genoa, Italy. RP Stanyon, R (reprint author), NCI, Canc Res Ctr, Genet Branch, Comparat Mol Cytogenet Sect, Bldg 560,Room 11-74A, Frederick, MD 21702 USA. OI Stanyon, Roscoe/0000-0002-7229-1092 NR 40 TC 25 Z9 27 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD MAR PY 2002 VL 13 IS 3 BP 157 EP 163 DI 10.1007/s0033501-1020-7 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 526CL UT WOS:000174110800007 PM 11919687 ER PT J AU Bi, L Okabe, I Bernard, DJ Nussbaum, RL AF Bi, L Okabe, I Bernard, DJ Nussbaum, RL TI Early embryonic lethality in mice deficient in the p110 beta catalytic subunit of PI 3-kinase SO MAMMALIAN GENOME LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; P110-ALPHA; P85-ALPHA-P110-BETA; REQUIREMENT; MITOGENESIS; DISRUPTION; INHIBITOR; P85-ALPHA; KINASES C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,4A72, Bethesda, MD 20892 USA. NR 22 TC 216 Z9 223 U1 0 U2 6 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD MAR PY 2002 VL 13 IS 3 BP 169 EP 172 DI 10.1007/s00335-001-2123-x PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 526CL UT WOS:000174110800009 PM 11919689 ER PT J AU Duncan, MK Cui, WW Oh, DJ Tomarev, SI AF Duncan, MK Cui, WW Oh, DJ Tomarev, SI TI Prox1 is differentially localized during lens development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE lens development; prox1; confocal microscopy; crystallin; transcription; promoter; chromatin; subcellular distribution ID SENSE ORGAN LINEAGE; SIBLING CELL FATE; ASYMMETRIC SEGREGATION; TRANSCRIPTION FACTOR; PROSPERO; DROSOPHILA; GENE; EXPRESSION; NUMB; MAF AB Prox1, the vertebrate cognate of Drosophila Prospero, is a homeodomain protein essential for the development of the lens, liver and lymphatic system. While it is well established that the subcellular distribution of Prospero changes during development, this had not been demonstrated for Prox1. Here, high-resolution confocal microscopy demonstrated that Prox1 protein is predominately cytoplasmic in the lens placode as well as the lens epithelium and germinative zone throughout development. However during fiber cell differentiation, Prox1 protein redistributes to cell nuclei. Finally, as lens fiber cells condense their chromatin in response to lens denucleation, Prox1 remains in the nucleus but does not appear to interact with DNA. Thus, it appears that the function of Prox1, like that of its Drosophila cognate Prospero, is at least partially controlled by changes in its subcellular distribution during development. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. NEI, Mol & Dev Biol Lab, Mol Genet Sect, Bethesda, MD 20892 USA. RP Duncan, MK (reprint author), Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. FU NEI NIH HHS [R01 EY12221] NR 19 TC 61 Z9 64 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD MAR PY 2002 VL 112 IS 1-2 BP 195 EP 198 AR PII S0925-4773(01)00645-1 DI 10.1016/S0925-4773(01)00645-1 PG 4 WC Developmental Biology SC Developmental Biology GA 535XT UT WOS:000174672200021 PM 11850194 ER PT J AU Hong, SK Kim, CH Yoo, KW Kim, HS Kudoh, T Dawid, IB Huh, TL AF Hong, SK Kim, CH Yoo, KW Kim, HS Kudoh, T Dawid, IB Huh, TL TI Isolation and expression of a novel neuron-specific onecut homeobox gene in zebrafish SO MECHANISMS OF DEVELOPMENT LA English DT Article DE zebrafish; onecut; homeodomain; brain; spinal cord; primary neurogenesis; mindbomb; narrowminded ID HEPATOCYTE NUCLEAR FACTOR-6; HOMEODOMAIN; DROSOPHILA; EMBRYOS; BRAIN; CUT AB A complete cDNA of a novel zebrafish gene named onecut has been isolated; this gene encodes a protein of 446 amino acids with a Cut domain (73 amino acid residues) and a homeodomain. The Cut domain of zebrafish Onecut is highly similar to those in mammalian hepatocyte nuclear factor-6 and Drosophila Onecut, sharing 90 and 88% amino acid identity, respectively. The expression of zebrafish onecut is restricted to neuronal cells, being first detected in trigeminal ganglia neurons at the end of gastrulation. By the 1-somite stage, onecut expression has begun in primary neurons of the lateral stripes in the neural plate, and appeared in neuronal cells of the medial stripes at the 2-somite stage. By the 4-somite stage, onecut expression expanded to the intermediate stripes and to subsets of neuronal cells in the midbrain and hindbrain. Subsequently, onecut expression intensified in the lateral region of midbrain and hindbrain, yet no onecut-positive cells were seen in the telencephalon. By 24 hpf, onecut transcripts remained abundant in the spinal cord but were no longer detectable in differentiated Rohon-Beard sensory neurons. The expression of onecut was greatly increased in the neural mutant mindbomb, while being decreased in narrowminded, (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Huh, TL (reprint author), Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. NR 14 TC 25 Z9 25 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD MAR PY 2002 VL 112 IS 1-2 BP 199 EP 202 AR PII S0925-4773(01)00647-5 DI 10.1016/S0925-4773(01)00647-5 PG 4 WC Developmental Biology SC Developmental Biology GA 535XT UT WOS:000174672200022 PM 11850195 ER PT J AU Dagher, R Long, LM Read, EJ Leitman, SF Carter, CS Tsokos, M Goletz, TJ Avila, N Berzofsky, JA Helman, LJ Mackall, CL AF Dagher, R Long, LM Read, EJ Leitman, SF Carter, CS Tsokos, M Goletz, TJ Avila, N Berzofsky, JA Helman, LJ Mackall, CL TI Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: An inter-institute NIH study SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article DE immunotherapy; tumor vaccine; IL-2; translocation; Ewing sarcoma rhabdomyosarcoma ID CYTOTOXIC T-CELLS; DENDRITIC CELLS; PROTEIN; MELANOMA; LEUKEMIA; ANTIGEN; AGE AB Background. Patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma have poor prognoses and limited therapeutic options. We have investigated the use of peptide pulsed vaccination in an attempt to immunologically target the breakpoint region of tumor specific fusion proteins expressed in these tumors. Procedure. Sixteen patients with recurrent, translocation positive, Ewing sarcoma, and alveolar rhabdomyosarcoma underwent apheresis for collection of peripheral blood mononuclear cells. Following countercurrent centrifugal elutriation, an apheresis product comprised predominantly of monocytes but containing small numbers of circulating immature dendritic cells was pulsed with peptides derived from the breakpoint region of the fusion proteins. Vaccines were administered intravenously concomitant with continuous intravenous rhIL-2 at 9 x 10(6) IU/m(2)/day. Results. Toxicity was limited to IL-2 related effects and was generally mild. Following vaccination, all patients showed progressive disease, most in a rapid fashion following the first vaccine. One patient showed evidence of an immunologic response and another showed a mixed clinical response. Patients enrolled on this tumor vaccine trial showed significant immunosuppression and large bulky tumors. Conclusions. Peptide vaccination as administered in this trial did not alter the dismal clinical outcome for patients with recurrent pediatric sarcomas. Future trials of tumor vaccines in this population should target patient populations with improved immune competence and smaller tumor burdens. Furthermore, optimization of the antigen presenting cell populations may be important for inducing immune responses to peptide antigens. Published 2002 Wiley-Liss, Inc.(dagger). C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Dagher, R (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 82 Z9 90 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD MAR PY 2002 VL 38 IS 3 BP 158 EP 164 DI 10.1002/mpo.1303 PG 7 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 523TY UT WOS:000173972700002 PM 11836714 ER PT J AU Dworkin, MS Schwan, TG Anderson, DE AF Dworkin, MS Schwan, TG Anderson, DE TI Tick-borne relapsing fever in North America SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Article ID SPIROCHETE BORRELIA-HERMSII; LYME-DISEASE; ANTIGENIC VARIATION; IDENTIFICATION; INFECTIONS; ANTIBODY; CANADA; GLPQ AB Relapsing fever is characterized by recurring episodes of fever and nonspecific symptoms (e.g., headache, myalgia, arthralgia, shaking chills, and abdominal complaints). The illness is caused by an infection from the Borrelia species (spirochetes) that may be acquired through the bite of an infected tick (Ornithodoros species) or contact with the hemolymph of an infected human body louse (Pediculus humanus). In North America, most cases have been acquired in the western United States, southern British Columbia, and few cases have been reported from Mexico. Most cases have been acquired from exposure to rustic tick-infested cabins and caves. This article reviews relapsing fever, especially tick-borne relapsing fever in North America. C1 Illinois Dept Publ Hlth, Dept Infect Dis, Chicago, IL 60601 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, ON, Canada. Washington State Univ, Coll Pharm, Spokane, WA USA. RP Dworkin, MS (reprint author), Illinois Dept Publ Hlth, Dept Infect Dis, 160 N LaSalle,7 South, Chicago, IL 60601 USA. NR 60 TC 52 Z9 57 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0025-7125 J9 MED CLIN N AM JI Med. Clin. N. Am. PD MAR PY 2002 VL 86 IS 2 BP 417 EP + DI 10.1016/S0025-7125(03)00095-6 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA 545WK UT WOS:000175240400014 PM 11982310 ER PT J AU Arioglu, E Andewelt, A Diabo, C Bell, M Taylor, SI Gorden, P AF Arioglu, E Andewelt, A Diabo, C Bell, M Taylor, SI Gorden, P TI Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance) SO MEDICINE LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; SUCCESSFUL IMMUNOSUPPRESSIVE THERAPY; ACANTHOSIS NIGRICANS; DIABETES-MELLITUS; HODGKINS-DISEASE; MONOCLONAL GAMMOPATHY; SPONTANEOUS REMISSION; ANTIBODIES; HYPOGLYCEMIA; PATIENT C1 NIDDK, NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), NIDDK, NIH, Ctr Clin, MSC 1829,10 Ctr Dr,Room 8S235 A, Bethesda, MD 20892 USA. NR 82 TC 84 Z9 94 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD MAR PY 2002 VL 81 IS 2 BP 87 EP 100 DI 10.1097/00005792-200203000-00001 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 530YT UT WOS:000174387700001 PM 11889410 ER PT J AU Branton, MH Schiffmann, R Sabnis, SG Murray, GJ Quirk, JM Altarescu, G Goldfarb, L Brady, RO Balow, JE Austin, HA Kopp, JB AF Branton, MH Schiffmann, R Sabnis, SG Murray, GJ Quirk, JM Altarescu, G Goldfarb, L Brady, RO Balow, JE Austin, HA Kopp, JB TI Natural history of Fabry renal disease - Influence of alpha-galactosidase A activity and genetic mutations on clinical course SO MEDICINE LA English DT Article ID DIABETIC NEPHROPATHY; A GENE; REPLACEMENT THERAPY; ATYPICAL VARIANT; TRANSPLANTATION; KIDNEY; HETEROZYGOTES; HEMIZYGOTES; PROGRESSION; RECURRENCE C1 NIDDKD, Metab Dis Branch, Bethesda, MD 20892 USA. NINCDS, NIH, Dev & Metab Neurol Branch, Bethesda, MD USA. NINCDS, NIH, Clin Neurogenet Unit, Bethesda, MD USA. Armed Forces Inst Pathol, Washington, DC USA. RP Kopp, JB (reprint author), NIH, 10-3N116, Bethesda, MD 20892 USA. OI Kopp, Jeffrey/0000-0001-9052-186X NR 63 TC 236 Z9 253 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD MAR PY 2002 VL 81 IS 2 BP 122 EP 138 DI 10.1097/00005792-200203000-00003 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA 530YT UT WOS:000174387700003 PM 11889412 ER PT J AU Lawrence, DM Major, EO AF Lawrence, DM Major, EO TI HIV-1 and the brain: connections between HIV-1-associated dementia, neuropathology and neuroimmunology SO MICROBES AND INFECTION LA English DT Review DE AIDS dementia complex; HIV-1 encephalopathy; viral encephalitis ID HUMAN-IMMUNODEFICIENCY-VIRUS; NECROSIS-FACTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; POLYMERASE CHAIN-REACTION; PRIMARY HUMAN ASTROCYTES; HUMAN FETAL ASTROCYTES; CELLULAR RESERVOIRS; CHEMOKINE RECEPTORS; TYPE-1 INFECTION; AIDS DEMENTIA AB AIDS patients frequently exhibit neurological disorders due to the neurotoxic events that result from HIV-1 and/or opportunistic infections in the brain. This review examines recent clinical findings related to HIV-1-associated dementia, and outlines current areas of basic research that may clarify how HIV-1-associated encephalopathy produces clinical symptoms of brain dysfunction. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved. C1 NINCDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Lawrence, DM (reprint author), NINCDS, Lab Mol Med & Neurosci, NIH, Bldg 36,Room 5W21,36 Convent Dr,MSC 4164, Bethesda, MD 20892 USA. NR 44 TC 64 Z9 70 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD MAR PY 2002 VL 4 IS 3 BP 301 EP 308 AR PII S1286-4579(02)01542-3 DI 10.1016/S1286-4579(02)01542-3 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 539JT UT WOS:000174867300006 PM 11909740 ER PT J AU Pikis, A Immel, S Robrish, SA Thompson, J AF Pikis, A Immel, S Robrish, SA Thompson, J TI Metabolism of sucrose and its five isomers by Fusobacterium mortiferum SO MICROBIOLOGY-SGM LA English DT Article DE phospho-alpha-glucosidase; sucrose isomers; sucrose-6-phosphate hydrolase; Klebsiella pneumoniae; Escherichia coli O157 : H7 ID CLOSTRIDIUM-BEIJERINCKII NCIMB-8052; PHOSPHOTRANSFERASE SYSTEM; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; FAMILY 4; SUCROSE-6-PHOSPHATE HYDROLASE; KLEBSIELLA-PNEUMONIAE; NUCLEATUM ATCC-10953; STREPTOCOCCUS-MUTANS; LACTOCOCCUS-LACTIS AB Fusobacterium mortiferum utilizes sucrose [glucose-fructose in alpha(1-->2) linkage] and its five isomeric alpha-D-glucosyl-D-fructoses as energy sources for growth. Sucrose-grown cells are induced for both sucrose-6-phosphate hydrolase (S6PH) and fructokinase (FK), but the two enzymes are not expressed above constitutive levels during growth on the isomeric compounds. Extracts of cells grown previously on the sucrose isomers trehalulose alpha(1-->1), turanose alpha(1-->3), maltulose alpha(1-->4), leucrose alpha(1-->5) and palatinose alpha(1-->6) contained high levels of an NAD(+) plus metal-dependent phospho-alpha-glucosidase (MalH). The latter enzyme was not induced during growth on sucrose. MalH catalysed the hydrolysis of the 6'-phosphorylated derivatives of the five isomers to yield glucose 6-phosphate and fructose, but sucrose 6-phosphate itself was not a substrate. Unexpectedly, MalH hydrolysed both alpha- and beta-linked stereomers of the chromogenic analogue p-nitrophenyl glucoside 6-phosphate. The gene malH is adjacent to malB and malR, which encode an Ell(CB) component of the phosphoenolpyruvate-dependent sugar: phosphotransferase system and a putative regulatory protein, respectively. The authors suggest that for F. mortiferum, the products of malB and malH catalyse the phosphorylative translocation and intracellular hydrolysis of the five isomers of sucrose and of related alpha-linked glucosides. Genes homologous to malB and malH are present in both Klebsiella pneumoniae and the enterohaemorrhagic strain Escherichia coli O157:H7. Both these organisms grew well on sucrose, but only K. pneumoniae exhibited growth on the isomeric compounds. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Microbial Biochem & Genet Unit, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Infect Dis, Washington, DC 20010 USA. Tech Univ Darmstadt, Inst Organ Chem, D-64287 Darmstadt, Germany. RP Thompson, J (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, Microbial Biochem & Genet Unit, NIH, Bethesda, MD 20892 USA. NR 41 TC 19 Z9 22 U1 0 U2 6 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD MAR PY 2002 VL 148 BP 843 EP 852 PN 3 PG 10 WC Microbiology SC Microbiology GA 529YB UT WOS:000174327900026 PM 11882720 ER PT J AU Jaffe, ES AF Jaffe, ES TI Lymphoid lesions of the head and neck: A model of lymphocyte homing and lymphomagenesis SO MODERN PATHOLOGY LA English DT Article DE B-cell; Epstein Barr virus; follicular lymphoma; immunophenotyping; lymphocyte homing; lymphoma; lymphomagenesis; MALT lymphoma; NK-cell lymphoma; T-cell ID EPSTEIN-BARR-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; KILLER-CELL LYMPHOMAS; NON-HODGKINS-LYMPHOMA; ANGIOCENTRIC IMMUNOPROLIFERATIVE LESIONS; COMPARATIVE GENOMIC HYBRIDIZATION; T-CELL; B-CELL; MALIGNANT-LYMPHOMA; NATURAL-KILLER AB Lymphoid lesions of the head and neck mainly affect the nasopharynx, nasal and paranasal sinuses, and salivary glands. These three compartments each are affected by a different spectrum of lymphoid malignancies and can serve as model for mechanisms of lymphomagenesis. The type of lymphoma seen reflects the underlying biology and function of the particular site involved. The nasopharynx and Waldeyer's ring are functionally similar to the mucosal associated lymphoid tissue (MALT) of the gastrointestinal tract and are most commonly affected by B-cell lymphomas, with mantle cell lymphoma being a relatively frequent subtype. The most prevalent lymphoid lesion of the salivary gland is lymphoepithelial sialadenitis, associated with Sjogrens syndrome. Lymphoepithelial sialadenitis is a condition in which MALT is acquired in a site not normally containing lymphoid tissue. Patients with Sjogren's syndrome are at increased risk to develop B-cell lymphomas, most commonly MALT lymphomas. The nasal and paranasal sinuses are the prototypical site for the development of extranodal natural killer (NK) /T-cell lymphoma, nasal type. This condition must be distinguished from other conditions causing the clinical picture of lethal midline granuloma, including Wegener's granulomatosis and infectious disorders. Lymphomatoid granulomatosis is common in the lung but is rarely seen in the midline facial structures. C1 NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), Bldg 10,Room 2N202,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. NR 78 TC 34 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD MAR PY 2002 VL 15 IS 3 BP 255 EP 263 DI 10.1038/modpathol.3880521 PG 9 WC Pathology SC Pathology GA 537CM UT WOS:000174740200008 PM 11904341 ER PT J AU Joshi, PB Kelly, BL Kamhawi, S Sacks, DL McMaster, WR AF Joshi, PB Kelly, BL Kamhawi, S Sacks, DL McMaster, WR TI Targeted gene deletion in Leishmania major identifies leishmanolysin (GP63) as a virulence factor SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE parasitic protozoan; leishmanolysin; complement; transgenic knockout ID SURFACE PROTEASE; NULL MUTANTS; LIPOPHOSPHOGLYCAN; MEXICANA; PROMASTIGOTES; DISTINCT; GLYCOPROTEIN; MACROPHAGES; RESISTANCE; EXPRESSION AB Leishmanolysin, the Leishmania surface metalloproteinase of 63 kDa (GP63) has been described as a parasite virulence factor and is involved in the direct interaction of promastigotes and host macrophage receptors and interaction with the complement cascade. To study the role of leishmanolysin in the pathogenesis and virulence of Leishmania major, targeted gene replacement was used to delete the entire 20 kb region containing all seven leishmanolysin genes (gp63 genes 1-7). The resulting L. major leishmanolysin deficient mutants showed normal development inside the sand fly vector, however, promastigotes recovered from sand flies or from culture showed an increase in sensitivity to complement-mediated lysis and a delay in lesion formation in BALB/c animals. The phenotypic differences could be significantly improved by expression of a cloned leishmanolysin gene. These results demonstrate that leishmanolysin is a vital virulence factor in Leishmania pathogenesis. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ British Columbia, Jack Bell Res Ctr, Dept Med Genet, Vancouver, BC V6H 3Z6, Canada. Vancouver Hosp, Immun & Infect Res Ctr, Vancouver, BC V6H 3Z6, Canada. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP McMaster, WR (reprint author), Univ British Columbia, Jack Bell Res Ctr, Dept Med Genet, 2660 Oak St, Vancouver, BC V6H 3Z6, Canada. NR 31 TC 130 Z9 137 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD MAR PY 2002 VL 120 IS 1 BP 33 EP 40 DI 10.1016/S0166-6851(01)00432-7 PG 8 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 529RL UT WOS:000174312300003 PM 11849703 ER PT J AU Kim, BC Mamura, M Choi, KS Calabretta, B Kim, SJ AF Kim, BC Mamura, M Choi, KS Calabretta, B Kim, SJ TI Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BCL-X-L; TGF-BETA; SMAD PROTEINS; CYTOCHROME-C; BH3 DOMAIN; B-CELLS; CASPASE; DEATH; GROWTH-FACTOR-BETA-1; PHOSPHORYLATION AB Transforming growth factor beta (TGF-beta) induces apoptosis in a variety of cells. We have previously shown that TGF-beta1 rapidly induces apoptosis in the FaO rat hepatoma cell line. We have now studied the effect of TGF-beta1 on the expression of different members of the Bcl-2 family in these cells. We observed no detectable changes in the steady-state levels of Bcl-2, Bcl-X-L, and Bax. However, TGF-beta1 induced caspase-dependent cleavage of BAD at its N terminus to generate a 15-kDa truncated protein. Overexpression of the 15-kDa truncated BAD protein enhanced TGF-beta1-induced apoptosis, whereas a mutant BAD resistant to caspase 3 cleavage blocked TGF-beta1-induced apoptosis. Overexpression of Smad3 dramatically enhanced TGF-beta1-induced cleavage of BAD and apoptosis, whereas antisense Smad3 blocked TGF-beta1-induced apoptosis and BAD cleavage. These results suggest that TGF-beta1 induces apoptosis through the cleavage of BAD in a Smad3-dependent mechanism. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Ajou Univ, Sch Med, Lab Endocrinol, Inst Med Sci,Paldal Gu, Suwon 441749, South Korea. Ajou Univ, Sch Med, Med Genet Lab, Inst Med Sci,Paldal Gu, Suwon 441749, South Korea. Thomas Jefferson Univ, Kimmel Canc Inst, Dept Microbiol Immunol, Philadelphia, PA 19107 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room B1106, Bethesda, MD 20892 USA. OI Mamura, Mizuko/0000-0003-4531-0144 FU NCI NIH HHS [P01 CA078890, P01 CA78890] NR 49 TC 86 Z9 93 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2002 VL 22 IS 5 BP 1369 EP 1378 DI 10.1128/MCB.22.5.1369-1378.2002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521JN UT WOS:000173837000010 PM 11839804 ER PT J AU Korotkov, KV Novoselov, SV Hatfield, DL Gladyshev, VN AF Korotkov, KV Novoselov, SV Hatfield, DL Gladyshev, VN TI Mammalian selenoprotein in which selenocysteine (Sec) incorporation is supported by a new form of Sec insertion sequence element SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA STRUCTURAL MOTIF; ENDOPLASMIC-RETICULUM; 15-KDA SELENOPROTEIN; MESSENGER-RNAS; PROTEIN; THIOREDOXIN; TRANSLATION; EUKARYOTES; EXPRESSION; APPARATUS AB Selenocysteine (Sec), the 21st amino acid in protein, is encoded by UGA. The Sec insertion sequence (SECIS) element, which is the stem-loop structure present in 3' untranslated regions (UTRs) of eukaryotic selenoprotein-encoding genes, is essential for recognition of UGA as a codon for See rather than as a stop signal. We now report the identification of a new eukaryotic selenoprotein, designated selenoprotein M (SelM). The 3-kb human SelM-encoding gene has five exons and is located on chromosome 22 but has not been correctly identified by either Celera or the public Human Genome Project. We characterized human and mouse SelM cDNA sequences and expressed the selenoprotein in various mammalian cell lines. The 3' UTR of the human, mouse, and rat SelM-encoding genes lacks a canonical SECIS element. Instead, See is incorporated in response to a conserved mRNA structure, in which cytidines are present in place of the adenosines previously considered invariant. Substitution of adenosines for cytidines did not alter See incorporation; however, other mutant structures did not support selenoprotein synthesis, demonstrating that this new form of SECIS element is functional. SelM is expressed in a variety of tissues, with increased levels in the brain. It is localized to the perinuclear structures, and its N-terminal signal peptide is necessary for protein translocation. C1 Univ Nebraska, Dept Biochem, Beadle Ctr N151, Lincoln, NE 68588 USA. NCI, Sect Mol Biol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Beadle Ctr N151, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU NCI NIH HHS [CA80946, R01 CA080946]; NIGMS NIH HHS [R01 GM061603, GM61603] NR 24 TC 98 Z9 106 U1 1 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 MAR PY 2002 VL 22 IS 5 BP 1402 EP 1411 DI 10.1128/MCB.22.5.1402-1411.2002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521JN UT WOS:000173837000013 PM 11839807 ER PT J AU Lefebvre, B Brand, C Lefebvre, P Ozato, K AF Lefebvre, B Brand, C Lefebvre, P Ozato, K TI Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EMBRYONAL CARCINOMA-CELLS; TUMOR VIRUS PROMOTER; HISTONE DEACETYLASE; IN-VIVO; CHROMATIN STRUCTURE; BETA-2 PROMOTER; MMTV PROMOTER; CANCER CELLS; N-COR; EXPRESSION AB All-trans-retinoic acid receptors (RAR) and 9-cis-retinoic acid receptors (RXR) are nuclear receptors known to cooperatively activate transcription from retinoid-regulated promoters. By comparing the transactivating properties of RAR and RXR in P19 cells using either plasmid or chromosomal reporter genes containing the mRARbeta2 gene promoter, we found contrasting patterns of transcriptional regulation in each setting. Cooperativity between RXR and RAR occurred at all times with transiently introduced promoters, but was restricted to a very early stage (<3 h) for chromosomal promoters. This time-dependent loss of cooperativity was specific for chromosomal templates containing two copies of a retinoid-responsive element (RARE) and was not influenced by the spacing between the two RAREs. This loss of cooperativity suggested a delayed acquisition of RAR full transcriptional competence because (i) cooperativity was maintained at RAR ligand subsaturating concentrations, (ii) overexpression of SRC-1 led to loss of cooperativity and even to strong repression of chromosomal templates activity, and (iii) loss of cooperativity was observed when additional cis-acting response elements were activated. Surprisingly, histone deacetylase inhibitors counteracted this loss of cooperativity by repressing partially RAR-mediated activation of chromosomal promoters. Loss of cooperativity was not correlated to local histone hyperacetylation or to alteration of constitutive RNA polymerase II (RNAP) loading at the promoter region. Unexpectedly, RNAP binding to transcribed regions was correlated to the RAR activation state as well as to acetylation levels of histones H3 and H4, suggesting that RAR acts at the mRARbeta promoter by triggering the switch from an RNA elongation-incompetent RNAP form towards an RNA elongation-competent RNAP. C1 Fac Med Henri Warembourg, INSERM, U 459, F-59045 Lille, France. Fac Med Henri Warembourg, Ligue Natl Contre Canc, F-59045 Lille, France. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Lefebvre, P (reprint author), Fac Med Henri Warembourg, INSERM, U 459, 1 Pl Verdun, F-59045 Lille, France. RI Lefebvre, Philippe/F-2685-2010 OI Lefebvre, Philippe/0000-0002-9366-5129 NR 64 TC 23 Z9 23 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 MAR PY 2002 VL 22 IS 5 BP 1446 EP 1459 DI 10.1128/MCB.22.5.1446-1459.2002 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 521JN UT WOS:000173837000017 PM 11839811 ER PT J AU Salnikow, K Kluz, T Costa, M Piquemal, D Demidenko, ZN Xie, KP Blagosklonny, MV AF Salnikow, K Kluz, T Costa, M Piquemal, D Demidenko, ZN Xie, KP Blagosklonny, MV TI The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; WILD-TYPE P53; FACTOR EXPRESSION; FACTOR 1-ALPHA; MESSENGER-RNA; CELLS; STABILIZATION; ACTIVATION; KINASE; TRANSCRIPTION AB Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca2+) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca2+ neither induced the HIF-1alpha protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca2+ induced NDRG-1/Cap43 mRNA in HIF-1alpha-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca2+ ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca2+-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca2+-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca2+ activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia. C1 NYU, Dept Environm Med, NIEHS Ctr, Sch Med, New York, NY 10016 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. Univ Montpellier 2, F-34095 Montpellier, France. NIH, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. RP Salnikow, K (reprint author), NYU, Dept Environm Med, NIEHS Ctr, Sch Med, 550 1St Ave, New York, NY 10016 USA. RI costa, max/H-1754-2012; OI Piquemal, David/0000-0002-5870-4276 FU NCI NIH HHS [CA 16087, P30 CA016087]; NIEHS NIH HHS [R01 ES005512, ES 00260, ES 05512, ES 10344, P30 ES000260, P42 ES010344] NR 35 TC 141 Z9 153 U1 0 U2 6 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 MAR PY 2002 VL 22 IS 6 BP 1734 EP 1741 DI 10.1128/MCB.22.6.1734-1741.2002 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524WH UT WOS:000174035500012 PM 11865053 ER PT J AU Hodge, DL Martinez, A Julias, JG Taylor, LS Young, HA AF Hodge, DL Martinez, A Julias, JG Taylor, LS Young, HA TI Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of posttranscriptional control SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; CELL STIMULATORY FACTOR; NATURAL-KILLER-CELLS; IFN-GAMMA; TRANSCRIPTION FACTOR; T-CELLS; GROWTH-FACTORS; HUMAN NK; PROMOTER; ACTIVATION AB Posttranscriptional control of gamma interferon (IFN-gamma) gene expression has not been extensively studied and is poorly understood. Our work describes a posttranscriptional mechanism that modulates IFN-gamma mRNA expression in stimulated natural killer (NK) cells through nuclear retention of the IFN-gamma mRNA. This is evidenced by the elevated and sustained nuclear accumulation of both precursor and processed IFN-gamma mRNAs in NK cells stimulated with interleukin-12 (IL-12). The elevated nuclear mRNA accumulation persists long after transcriptional activity has subsided and the rate of cytoplasmic IFN-gamma mRNA accumulation has dropped. The IL-12-induced nuclear retention of the IFN-gamma mRNA prevails until a secondary cytokine stimulus is received. The secondary stimulus, which is initiated by IL-2, mediates transcription-independent movement of the nuclear IFN-gamma mRNA. Concurrent with the nucleocytoplasmic movement of the IFN-gamma mRNA, we have observed increases in the amount of processed nuclear IFN-gamma mRNA that are greater than that seen for the unprocessed IFN-gamma mRNA. The increase in processed IFN-gamma mRNA appears to be due to increased mRNA stability which then promotes increased nucleocytoplasmic shuttling of the mature IFN-gamma mRNA. These data support a model whereby mobilization of nuclear IFN-gamma mRNA stores allows NK cells to rapidly and robustly respond to secondary cytokine activators in a transcription-independent manner, thus shortening the time for overall cellular response to inflammatory signals. C1 NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. RP Young, HA (reprint author), NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 NR 61 TC 39 Z9 40 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 MAR PY 2002 VL 22 IS 6 BP 1742 EP 1753 DI 10.1128/MCB.22.6.1742-1753.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524WH UT WOS:000174035500013 PM 11865054 ER PT J AU Chen, HW Marinissen, MJ Oh, SW Chen, X Melnick, M Perrimon, N Gutkind, JS Hou, SX AF Chen, HW Marinissen, MJ Oh, SW Chen, X Melnick, M Perrimon, N Gutkind, JS Hou, SX TI CKA, a novel multidomain protein, regulates the JUN N-terminal kinase signal transduction pathway in Drosophila SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MATERNAL EFFECT PHENOTYPES; CELL SHEET MOVEMENT; DORSAL CLOSURE; LARVAL CUTICLE; ZYGOTIC LOCI; CALMODULIN-BINDING; PLASMA-MEMBRANE; X-CHROMOSOME; WD REPEAT; JNK AB The Drosophila melanogaster JUN N-terminal kinase (DJNK) and DPP (decapentaplegic) signal transduction pathways coordinately regulate epithelial cell sheet movement during the process of dorsal closure in the embryo. By a genetic screen of mutations affecting dorsal closure in Drosophila, we have now identified a multidomain protein, connector of kinase to AP-1 (cka), that functions in the DJNK pathway and controls the localized expression of dpp in the leading-edge cells. We have also investigated how CKA acts. This unique molecule forms a complex with HEP (DJNKK), BSK (DJNK), DJUN, and DFOS. Complex formation activates BSK kinase, which in turn phosphorylates and activates DJUN and DFOS. These data suggest that CKA represents a novel molecule regulating AP-1 activity by organizing a molecular complex of kinases and transcription factors, thus coordinating the spatial-temporal expression of AP-1-regulated genes. C1 NCI, FCRDC, Immunol Lab, NIH, Frederick, MD 21702 USA. New England Biolabs Inc, Lab Cell Signaling, Beverly, MA 01915 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. RP Hou, SX (reprint author), NCI, FCRDC, Immunol Lab, NIH, Bldg 560,Room 12-70, Frederick, MD 21702 USA. RI Gutkind, J. Silvio/A-1053-2009; Chen, Hua-Wei/A-8018-2011; Perrimon, Norbert/F-9766-2011 NR 44 TC 41 Z9 42 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2002 VL 22 IS 6 BP 1792 EP 1803 DI 10.1128/MCB.22.6.1792-1803.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524WH UT WOS:000174035500017 PM 11865058 ER PT J AU El-Osta, A Kantharidis, P Zalcberg, JR Wolffe, AP AF El-Osta, A Kantharidis, P Zalcberg, JR Wolffe, AP TI Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SWI-SNF COMPLEX; DNA METHYLATION; TRANSCRIPTIONAL REPRESSION; CHROMOSOMAL PROTEIN; REPLICATION FOCI; X-CHROMOSOME; MECP2; ACETYLATION; EXPRESSION; CHROMATIN AB Overexpression of the human multidrug resistance gene I (MDR1) is a negative prognostic factor in leukemia. Despite intense efforts to characterize the gene at the molecular level, little is known about the genetic events that switch on gene expression in P-glyco protein-negative cells. Recent studies have shown that the transcriptional competence of MDR1 is often closely associated with DNA methylation. Chromatin remodeling and modification targeted by the recognition of methylated DNA provide a dominant mechanism for transcriptional repression. Consistent with this epigenetic model, interference with DNA methyltransferase and histone deacetylase activity alone or in combination can reactivate silent genes. In the present study, we used chromatin immunoprecipitation to monitor the molecular events involved in the activation and repression of MDR1. Inhibitors of DNA methyltransferase (5-azacytidine [5aC]) and histone deacetylase (trichostatin A [TSA]) were used to examine gene transcription, promoter methylation status, and the chromatin determinants associated with the MDR1 promoter. We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones 113 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression. MDR1 expression was significantly increased following combined 5aC and TSA treatments. Inhibition of histone deacetylase is not an overriding mechanism in the reactivation of methylated MDR1. Our results provide us with a clearer understanding of the molecular mechanism necessary for repression of MDR1. C1 Peter MacCallum Canc Inst, Sir Donald & Lady Trescowthick Res Labs, Melbourne, Vic 3002, Australia. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Sangamo BioSci Inc, Point Richmond Tech Ctr, Richmond, CA 94804 USA. RP El-Osta, A (reprint author), Peter MacCallum Canc Inst, Sir Donald & Lady Trescowthick Res Labs, St Andrews Pl, Melbourne, Vic 3002, Australia. NR 66 TC 140 Z9 151 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 MAR PY 2002 VL 22 IS 6 BP 1844 EP 1857 DI 10.1128/MCB.22.6.1844-1857.2002 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 524WH UT WOS:000174035500021 PM 11865062 ER PT J AU DeGiorgis, JA Reese, TS Bearer, EL AF DeGiorgis, JA Reese, TS Bearer, EL TI Association of a nonmuscle myosin II with axoplasmic organelles SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID AXONAL-TRANSPORT; PHYLOGENETIC ANALYSIS; ACTIN-FILAMENTS; SQUID AXOPLASM; HEAVY-CHAIN; MOTOR; SUPERFAMILY; ISOFORMS; MOVEMENT; KINESIN AB Association of motor proteins with organelles is required for the motors to mediate transport. Because axoplasmic organelles move on actin filaments, they must have associated actin-based motors, most likely members of the myosin superfamily. To gain a better understanding of the roles of myosins in the axon we used the giant axon of the squid, a powerful model for studies of axonal physiology. First, a similar to220 kDa protein was purified from squid optic lobe, using a biochemical protocol designed to isolate myosins. Peptide sequence analysis, followed by cloning and sequencing of the full-length cDNA, identified this similar to220 kDa protein as a nonmuscle myosin II. This myosin is also present in axoplasm, as determined by two independent criteria. First, RT-PCR using sequence-specific primers detected the transcript in the stellate ganglion, which contains the cell bodies that give rise to the giant axon. Second, Western blot analysis using nonmuscle myosin II isotype-specific antibodies detected a single similar to220 kDa band in axoplasm. Axoplasm was fractionated through a four-step sucrose gradient after 0.6 M KI treatment, which separates organelles from cytoskeletal components. Of the total nonmuscle myosin II in axoplasm, 43.2% copurified with organelles in the 15% sucrose fraction, while the remainder (56.8%) was soluble and found in the supernatant. This myosin decorates the cytoplasmic surface of 21% of the axoplasmic organelles, as demonstrated by immunogold electron-microscopy. Thus, nonmuscle myosin II is synthesized in the cell bodies of the giant axon, is present in the axon, and is associated with isolated axoplasmic organelles. Therefore, in addition to myosin V, this myosin is likely to be an axoplasmic organelle motor. C1 Brown Univ, Mol & Cell Biol & Biochem Program, Providence, RI 02912 USA. Brown Univ, Dept Pathol & Med, Providence, RI 02912 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. NINCDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Bearer, EL (reprint author), Brown Univ, Mol & Cell Biol & Biochem Program, Providence, RI 02912 USA. FU NIGMS NIH HHS [R01 GM047368, GM-07601, GM-47368, T32 GM007601, R01 GM047368-05] NR 41 TC 22 Z9 23 U1 0 U2 1 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 MAR PY 2002 VL 13 IS 3 BP 1046 EP 1057 DI 10.1091/mbc.01-06-0315 PG 12 WC Cell Biology SC Cell Biology GA 534LC UT WOS:000174587000024 PM 11907281 ER PT J AU Caterson, E Nesti, L Danielson, KG Tuan, RS AF Caterson, E Nesti, L Danielson, KG Tuan, RS TI Human marrow-derived mesenchymal progenitor cells - Isolation, culture expansion, and analysis of differentiation SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE mesenchymal progenitor cells; differentiation; fetal bovine serum; tissue engineering ID STEM-CELLS; BONE-MARROW; CHONDROGENIC DIFFERENTIATION; CDNA; REGENERATION; EXPRESSION; SEQUENCE; INVITRO; LIVER; FORMS AB A number of adult mesenchymal tissues contain subpopulations of undifferentiated cells, which retain the capacity to differentiate along multiple lineages. These mesenchymal progenitor cells may be cultured in an undifferentiated state and, when given the appropriate signals, differentiate into an expanding list of several mesenchymal and a few ectodermal derived tissues. The maintenance and propagation of the multipotential nature of these progenitor cell populations are crucially dependent on the isolation protocol, the culture expansion conditions, particularly the properties of the fetal bovine serum supplement in the culture medium. This article describes a method for selection of the appropriate serum lot, and introduces a simplified isolation technique to optimize the yield of progenitor cells that maintain the capability of undergoing multilineage differentiation in response to appropriate cues. Cell populations isolated and culture expanded in this manner, by virtue of their multiple differentiation potential, should serve as ideal candidate cells for tissue engineering applications for the repair and regeneration of tissue damaged by disease and or trauma. C1 NIAMSD, Cartilage Biol & Orthoped Branch, NIH, Bethesda, MD 20992 USA. FU NIAMS NIH HHS [AR 44501, AR 45181, AR 39740]; NIDCR NIH HHS [DE 12864] NR 33 TC 140 Z9 151 U1 0 U2 10 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD MAR PY 2002 VL 20 IS 3 BP 245 EP 256 DI 10.1385/MB:20:3:245 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 532TM UT WOS:000174491200003 PM 11936255 ER PT J AU Wallqvist, A Rabow, AA Shoemaker, RH Sausville, EA Covell, DG AF Wallqvist, A Rabow, AA Shoemaker, RH Sausville, EA Covell, DG TI Establishing connections between microarray expression data and chemotherapeutic cancer pharmacology SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; CELLS IN-VITRO; GENE-EXPRESSION; MOLECULAR CLASSIFICATION; EPITHELIAL-CELLS; DRUG DISCOVERY; PROTEIN-KINASE; BINDING; BREAST; IDENTIFICATION AB We have investigated three different microarray datasets of similar to6 K gene expressions across the National Cancer Institute's panel of 60 tumor cell lines. Initial assessments of reproducibility for gene expressions within each dataset, as derived from sequence analysis of full-length sequences as well as expressed sequence tags (EST), found statistically significant results for no more than 36% of those cases where at least one replicate of a gene appears on the array. Filtering the data based only on pairwise comparisons among these three datasets creates a list of similar to400 significant concordant expression patterns. The expression profiles of these smaller sets of genes were used to locate similar expression profiles of synthetic agents screened against these same 60 tumor cell lines. A correspondence was found between mRNA expression patterns and 50% growth inhibition response patterns of screened agents for 11 cases that were subsequently verifiable from ligand-target crystallographic data. Notable amongst these cases are genes encoding a variety of kinases, which were also found to be targets of small drug-like molecules within the database of protein structures. These 11 cases lend support to the premise that similarities between expression patterns and chemical responses for the National Cancer Institute's tumor panel can be related to known cases of molecular structure and putative cellular function. The details of the 11 verifiable cases and the concordant gene subsets are provided. Discussions about the prospects of using this approach as a data mining tool are included. C1 Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, NIH, Frederick, MD 21702 USA. RP Wallqvist, A (reprint author), Sci Applicat Int Corp, Frederick, MD 21702 USA. OI wallqvist, anders/0000-0002-9775-7469 FU NCI NIH HHS [N01-CO-56000] NR 50 TC 39 Z9 40 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2002 VL 1 IS 5 BP 311 EP 320 PG 10 WC Oncology SC Oncology GA 606MD UT WOS:000178737000003 PM 12489847 ER PT J AU Iavarone, C Wolfgang, C Kumar, V Duray, P Willingham, M Pastan, I Bera, TK AF Iavarone, C Wolfgang, C Kumar, V Duray, P Willingham, M Pastan, I Bera, TK TI PAGE4 is a cytoplasmic protein that is expressed in normal prostate and in prostate cancers SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NUCLEAR-PROTEIN; IDENTIFICATION; DATABASE; TESTIS; CELLS; GENE AB PAGE4 is an X chromosome-linked cancer-testis antigen that was identified by expressed sequence tags database mining and a functional genomic approach. PAGE4 is preferentially expressed in normal male and female reproductive tissues and also in a variety of cancers including prostate. In the present study, we have used in situ hybridization to show that PAGE4 mRNA is expressed only in the epithelial cells of normal and prostate-cancer specimens. Analysis of the protein product encoded by the PAGE4 mRNA reveals that it encodes a M-r 16,000 protein and is detected in tissue extracts from both normal prostate and prostate cancer. Cell fractionation analysis of PAGE4 protein indicates that PAGE4 is localized in the cytoplasm of the cell. Furthermore, cDNA microarray analysis indicates that the expression of lipoprotein lipase, a gene frequently deleted in prostate cancer, is down-regulated in a cell line that expresses PAGE4. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pathol, Winston Salem, NC 27157 USA. RP Bera, TK (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr MSC 4264,Bldg 37,Room 5106, Bethesda, MD 20892 USA. NR 19 TC 13 Z9 14 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2002 VL 1 IS 5 BP 329 EP 335 PG 7 WC Oncology SC Oncology GA 606MD UT WOS:000178737000005 PM 12489849 ER PT J AU Kopelovich, L Fay, JR Glazer, RI Crowell, JA AF Kopelovich, L Fay, JR Glazer, RI Crowell, JA TI Peroxisome proliferator-activated receptor modulators as potential chemopreventive agents SO MOLECULAR CANCER THERAPEUTICS LA English DT Review ID PPAR-GAMMA AGONISTS; HUMAN PROSTATE-CANCER; HUMAN COLON-CANCER; INHIBITS CELL-GROWTH; HUMAN BREAST-CANCER; NF-KAPPA-B; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); KERATINOCYTE DIFFERENTIATION; IN-VITRO; ANTIDIABETIC THIAZOLIDINEDIONE AB Peroxisome proliferator-activated receptors (PPARs), members of the superfamily of nuclear steroid hormone receptors, have traditionally been studied for their role in lipid, glucose, and energy homeostasis. Recent evidence suggests that pharmacological activation of PPARgamma and PPARalpha, and inhibition of PPARdelta, may prevent cancer. PPARgamma agonists induce differentiation, inhibit the growth of established tumor cells in vitro and in vivo, and have chemopreventive effects in animal models. PPARa has anti-inflammatory and differentiating activity and protects against the oxidative damage associated with aging. In contrast, PPARdelta expression may be a factor in colorectal carcinogenesis. PPARdelta is normally repressed by the adenomatous polyposis coli tumor suppressor gene, and impaired adenomatous polyposis coli is strongly associated with human colorectal cancer risk. This review presents a rationale for using PPAR modulators as cancer chemopreventive drugs. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Pharmacol, Washington, DC 20057 USA. RP Kopelovich, L (reprint author), NCI, Div Canc Prevent, Room 2114,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 84 TC 64 Z9 67 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2002 VL 1 IS 5 BP 357 EP 363 PG 7 WC Oncology SC Oncology GA 606MD UT WOS:000178737000008 PM 12489852 ER PT J AU Kireeva, ML Walter, W Tchernajenko, V Bondarenko, V Kashlev, M Studitsky, VM AF Kireeva, ML Walter, W Tchernajenko, V Bondarenko, V Kashlev, M Studitsky, VM TI Nucleosome remodeling induced by RNA polymerase II: Loss of the H2A/H2B dimer during transcription SO MOLECULAR CELL LA English DT Article ID DNA HYBRID; TRANSCRIBING POLYMERASE; HISTONES H2A/H2B; IN-VITRO; ELONGATION; CHROMATIN; TEMPLATES; CORE; PROCESSIVITY; DISPLACEMENT AB RNA polymerase II (Pol II) must transcribe genes in a chromatin environment in vivo. We examined transcription by Pol II through nucleosome cores in vitro. At physiological and lower ionic strengths, a mononucleosome imposes a strong block to elongation, which is relieved at increased ionic strength. Passage of Pol II causes a quantitative loss of one H2A/H2B dimer but does not after the location of the nucleosome. In contrast, bacteriophage SP6 RNA polymerase (RNAP) efficiently transcribes through the same nucleosome under physiological conditions, and the histone octamer is transferred behind SP6 RNAP. Thus, the mechanisms for transcription through the nucleosome by Pol II and SP6 RNAP are clearly different. Moreover, Pol II leaves behind an imprint of disrupted chromatin structure. C1 NCI, Frederick Canc Res & Dev Ctr, Canc Res Ctr, Frederick, MD 21702 USA. Wayne State Univ, Sch Med, Dept Biochem, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Kashlev, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Canc Res Ctr, Frederick, MD 21702 USA. RI Studitsky, Vasily/A-9382-2014 FU NIGMS NIH HHS [GM58650] NR 39 TC 235 Z9 242 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR PY 2002 VL 9 IS 3 BP 541 EP 552 DI 10.1016/S1097-2765(02)00472-0 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 537QA UT WOS:000174769300012 PM 11931762 ER PT J AU Nelson, TJ Backlund, PS Yergey, AL Alkon, DL AF Nelson, TJ Backlund, PS Yergey, AL Alkon, DL TI Isolation of protein subpopulations undergoing protein-protein interactions SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID ATP SYNTHASE; WATER-MAZE; BINDING; RAT; CALMODULIN; REGION; SYSTEM; MUSCLE; FAMILY; PHAGE AB A new method is described for isolating and identifying proteins participating in protein-protein interactions in a complex mixture. The method uses a cyanogen bromide-activated Sepharose matrix to isolate proteins that are non-covalently bound to other proteins. Because the proteins are accessible to chemical manipulation, mass spectrometric identification of the proteins can yield information on specific classes of interacting proteins, such as calcium-dependent or substrate-dependent protein interactions. This permits selection of a subpopulation of proteins from a complex mixture on the basis of specified interaction criteria. The new method has the advantage of screening the entire proteome simultaneously, unlike the two-hybrid system or phage display, which can only detect proteins binding to a single bait protein at a time. The method was tested by selecting rat brain extract for proteins exhibiting calcium-dependent protein interactions. Of 12 proteins identified by mass spectrometry, eight were either known calcium-binding proteins or proteins with known calcium-dependent protein interactions, indicating that the method is capable of enriching a subpopulation of proteins from a complex mixture on the basis of a specific class of protein interactions. Because only naturally occurring interactions of proteins in their native state are observed, this method will have wide applicability to studies of protein interactions in tissue samples and autopsy specimens, for screening for perturbations of protein-protein interactions by signaling molecules, pharmacological agents or toxins, and screening for differences between cancerous and untransformed cells. C1 Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. NICHD, Lab Cellular & Mol Biophys, Sect Metab Anal & Mass Spectrometry, NIH, Bethesda, MD 20892 USA. RP Nelson, TJ (reprint author), Blanchette Rockefeller Neurosci Inst, 9601 Med Ctr Dr, Rockville, MD 20850 USA. NR 36 TC 8 Z9 8 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD MAR PY 2002 VL 1 IS 3 BP 253 EP 259 DI 10.1074/mcp.T100006-MCP200 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 654UV UT WOS:000181515200010 PM 12096125 ER PT J AU Hall, JM McDonnell, DP Korach, KS AF Hall, JM McDonnell, DP Korach, KS TI Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BETA ER-BETA; NUCLEAR RECEPTOR; TRANSCRIPTIONAL COACTIVATOR; PEPTIDE ANTAGONISTS; GLUCOCORTICOID RECEPTOR; ACTIVATION FUNCTION-1; PROMOTER-CONTEXT; ALPHA; BINDING; IDENTIFICATION AB Hormone-activated ERs (ERalpha and ERbeta) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the regulatory regions of target genes. Once considered to function solely as receptor tethers, there is an increasing amount of recent evidence to suggest that the sequence of the ERE can influence receptor activity. In this study, we have performed a systematic analysis of the role of different EREs in ER pharmacology. Specifically, by measuring ER activity on the vitellogenin A2, complement 3 gene, pS2, and lactoferrin EREs, we demonstrate that the activities of E2 and xenoestrogen ligands through ERalpha and ERbeta are significantly influenced by the nature of the response element. Using a series of ERalpha and ERbeta interacting peptides that contain the coactivator-binding motif LXXLL, we show that the type of ERE with which the receptor associates regulates the structure of the coactivator pocket on ER. Furthermore, using a novel ELISA developed to measure ER-coactivator interactions revealed that these different conformational states of ERalpha and ERbeta are functionally relevant, as they dictate receptor coactivator binding preference. Together, these results indicate that the DNA response element is a key regulator of receptor structure and biological activity and suggest the ERE sequence influences the recruitment of coactivators to the ER at target gene promoters. We propose that DNA-induced alteration of protein structure and coregulator recruitment may serve as a universal regulatory component for differential gene expression by other nuclear hormone receptors and unrelated transcription factors. C1 Natl Inst Environm Hlth Sci, Receptor Biol Sect, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. RP Korach, KS (reprint author), Natl Inst Environm Hlth Sci, Receptor Biol Sect, POB 12233,MD B3-02, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NIDDK NIH HHS [DK-48807] NR 56 TC 179 Z9 183 U1 1 U2 5 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 MAR PY 2002 VL 16 IS 3 BP 469 EP 486 DI 10.1210/me.16.3.469 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527CB UT WOS:000174167200005 PM 11875105 ER PT J AU Shillingford, JM Miyoshi, K Robinson, GW Grimm, SL Rosen, JM Neubauer, H Pfeffer, K Hennighausen, L AF Shillingford, JM Miyoshi, K Robinson, GW Grimm, SL Rosen, JM Neubauer, H Pfeffer, K Hennighausen, L TI Jak2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GROWTH-FACTOR-I; PROLACTIN RECEPTOR; GLAND DEVELOPMENT; CELLS; ACTIVATION; STAT5A; PHOSPHORYLATION; MICE; DIFFERENTIATION; PROLIFERATION AB The PRL receptor (PrIR) and the signal transducer and activator of transcription 5a (Stat5a) are essential for the proliferation and differentiation of mammary epithelium during pregnancy. Based on tissue culture cell experiments, Jak2 is the tyrosine kinase responsible for the phosphorylation of both the PrIR and Stat5. We have now used a genetic approach to test the role of Jak2 in the mammary gland, a PrIR-responsive tissue. Because Jak2-null embryos die at E12.5, we transplanted Jak2-null mammary anlagen into cleared fat pads of wildtype mice and investigated epithelial development during pregnancy. In the absence of Jak2, no secretory alveoli were present at parturition, and epithelial cell proliferation was reduced by 95% after an acute hormone treatment. Furthermore, the Na-K-Cl cotransporter, a ductal marker, was maintained in Jak2-null epithelium and the sodium-phosphate cotransporter type Ilb, a secretory cell marker, was absent. Nuclear Stat5a was only observed in a few epithelial cells in Jak2-null glands at pregnancy and parturition compared with most epithelial cells in wild-type glands. Taken together, our results demonstrate that Jak2 is a critical tyrosine kinase that conveys intracellular signals necessary for proliferation and differentiation of mammary epithelium during pregnancy. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany. RP Shillingford, JM (reprint author), NIH, Lab Genet & Physiol, 9000 Rockville Pike,Room 105,Bldg 8, Bethesda, MD 20817 USA. EM jonshi@helix.nih.gov RI Robinson, Gertraud/I-2136-2012; Neubauer, Hans/C-4467-2016 OI Neubauer, Hans/0000-0002-3467-4105 NR 30 TC 61 Z9 63 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2002 VL 16 IS 3 BP 563 EP 570 DI 10.1210/me.16.3.563 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527CB UT WOS:000174167200013 PM 11875116 ER PT J AU Shah, BH Olivares-Reyes, JA Yesilkaya, A Catt, KJ AF Shah, BH Olivares-Reyes, JA Yesilkaya, A Catt, KJ TI Independence of angiotensin II-induced MAP kinase activation from angiotensin type 1 receptor internalization in clone 9 hepatocytes SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR RECEPTOR; AGONIST-INDUCED PHOSPHORYLATION; ADRENAL GLOMERULOSA CELLS; SMOOTH-MUSCLE CELLS; PHENYLARSINE OXIDE; BETA-ARRESTIN; BETA(2)-ADRENERGIC RECEPTOR; TYROSINE PHOSPHORYLATION; MUSCARINIC ACETYLCHOLINE AB The agonist-induced internalization of several G protein-coupled receptors is an obligatory requirement for their activation of MAPKs. Studies on the relationship between endocytosis of the angiotensin 11 (Ang 11) type 1 receptor (AT(1)-R) and Ang II-induced ERK1/2 activation were performed in clone 9 (C9) rat hepatic cells treated with inhibitors of endocytosis [sucrose, phenylarsine oxide (PAO), and concanavalin A]. Although Ang II-induced endocytosis of the AT(1)-R was prevented by sucrose and PAO, and was partially inhibited by concanavalin A, there was no impairment of Ang II-induced ERK activation. However, the specific epidermal growth factor receptor (EGF-R) kinase inhibitor, AG1478, abolished Ang II-induced activation of ERK1/2. Sucrose and PAO also inhibited EGF-induced internalization of the EGF-R in C9 cells, and the inability of these agents to impair EGF-induced ERK activation suggested that the latter is also independent of receptor endocytosis. In COS-7 cells transiently expressing the rat AT(1A)-R, Ang 11 also caused ERK activation through EGF-R transactivation. Furthermore, a mutant AT1A-R with truncated carboxyl terminus and impaired internalization retained full ability to activate ERK1/2 in response to Ang 11 stimulation. These findings demonstrate that Ang If-induced ERK1/2 activation in C9 hepatocytes is independent of both AT(1)-R and EGF-R endocytosis and is mediated by transactivation of the EGF-R. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36, Bethesda, MD 20892 USA. NR 69 TC 24 Z9 25 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 MAR PY 2002 VL 16 IS 3 BP 610 EP 620 DI 10.1210/me.16.3.610 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 527CB UT WOS:000174167200017 PM 11875120 ER PT J AU Topol, IA Nemukhin, AV Burt, SK AF Topol, IA Nemukhin, AV Burt, SK TI Quantum chemical modelling of reactivity and selectivity of 1,2-dithiolanes towards retroviral and cellular zinc fingers SO MOLECULAR PHYSICS LA English DT Article ID HIV-1 NUCLEOCAPSID PROTEIN; INHIBITION; EJECTION AB Interactions of 1,2-dithiolane species with zinc-containing sites, which mimic the zinc finger domains of retroviral and the cellular zinc finger proteins, have been investigated by quantum chemistry tools. According to the calculations, the immediate domains of zinc binding sites in the cellular and retroviral zinc fingers interact differently with such agents of the disulphide family. Thus, when approaching the model cellular-type domains, the molecules of 1,2-dithiolanes experience considerable potential barriers along the reaction path. However, these species react practically barrier-less with the model retroviral-type domains at the correlated DFT level. The results of the quantum chemical modelling provide firm support to the selectivity of 1,2-dithiolanes towards retroviral and cellular zinc fingers. This can be of great practical importance for the design of therapeutics that accomplish functional inactivation of the zinc fingers of the human immunodeficiency virus (HIV-1) retroviral type nucleocapsid protein NCp7. C1 NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick, MD 21702 USA. Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RP Topol, IA (reprint author), NCI, Adv Biomed Comp Ctr, SAIC Frederick, POB B, Frederick, MD 21702 USA. RI Nemukhin, Alexander/P-9662-2015 NR 18 TC 2 Z9 2 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK,, ABINGDON OX14 4RN, OXON, ENGLAND SN 0026-8976 J9 MOL PHYS JI Mol. Phys. PD MAR PY 2002 VL 100 IS 6 BP 791 EP 797 DI 10.1080/00268970110096308 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 528EQ UT WOS:000174231800008 ER PT J AU Mullegger, J Lepperdinger, G AF Mullegger, J Lepperdinger, G TI Hyaluronan is an abundant constituent of the extracellular matrix of Xenopus embryos SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE hyaluronan; extra cellular matrix; embryogenesis; vertebrate development ID NEURAL CREST; MURINE MACROPHAGES; CELL-MIGRATION; DG42 GENE; ANGIOGENESIS; EXPRESSION; FRAGMENTS; SYNTHASE; ACID; EMBRYOGENESIS AB The spatiotemporal distribution of hyaluronan (HA), a major constituent of the vertebrate extracellular matrix, was analyzed during early embryonic development of Xenopus laevis. This polysaccharide is abundantly present in ventricular structures such as the blastocoel, the archenteron as well as later on in the hepatic cavity, the brain ventricles and the developing heart. At the blastula stage, HA was detected in the extracellular matrix of the ecto- and mesodermal primordia. Shortly before gastrulation, it becomes enriched at the basal site of the superficial cell layer of the ectoderm. During gastrulation, enhanced synthesis of HA takes place in the involuting marginal zone, shortly before invagination starts, hence, resulting in a torus-like deposition in the deep layer of the equatorial mesodermal primordium. After gastrulation, HA appears to accumulate within the extracellular matrix demarcating the primary germ layers. During tailbud stages, it is found highly enriched in many mesodermal derivatives, e.g., in mesenchyme, the heart, precordal cartilage and the lung primordia. Furthermore, extracellular matrix of the ventral mesodermal cell layer in the trunk region and the immediate proximity of blood vessels contain high amounts of HA. Mol. Reprod. Dev. 61: 312-316, 2002. (C) 2002 Wiley-Liss, Inc. C1 Dept Biochem, Inst Mol Biol, Salzburg, Austria. RP Lepperdinger, G (reprint author), NICHHD, NIH, LMG, 6 Center Lane,Bldg 6B 4B412, Bethesda, MD 20892 USA. NR 32 TC 15 Z9 15 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD MAR PY 2002 VL 61 IS 3 BP 312 EP 316 DI 10.1002/mrd.10097 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 517HX UT WOS:000173606000004 PM 11835576 ER PT J AU Schechter, AN AF Schechter, AN TI Prematurity in gene therapy SO MOLECULAR THERAPY LA English DT Article ID DNA; TRANSFORMATION; ETHICS C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 17 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2002 VL 5 IS 3 BP 217 EP 219 DI 10.1006/mthe.2002.0554 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 527NT UT WOS:000174192700003 PM 11863409 ER PT J AU Kluge, KA Bonifacino, AC Sellers, S Agricola, BA Donahue, RE Dunbar, CE AF Kluge, KA Bonifacino, AC Sellers, S Agricola, BA Donahue, RE Dunbar, CE TI Retroviral transduction and engraftment ability of primate hematopoietic progenitor and stem cells transduced under serum-free versus serum-containing conditions SO MOLECULAR THERAPY LA English DT Article ID MARROW REPOPULATING CELLS; COLONY-STIMULATING FACTOR; MEDIATED GENE-TRANSFER; EX-VIVO EXPANSION; RHESUS PERIPHERAL-BLOOD; NONHUMAN-PRIMATES; CD34(+) CELLS; IN-VITRO; THERAPY; CULTURES AB The ability to efficiently transduce hematopoietic stem and progenitor cells under serum-free conditions would be desirable for safety and standardization of clinical gene therapy protocols. Using rhesus macaques, we studied the transduction efficiency and engraftment ability of CD34-enriched SCF/G-CSF mobilized progenitor cells (PBSC) transduced with standard amphotropic marking vectors under serum-free and serum-containing conditions. Supernatants were collected from producer cells 16 hours after serum-free medium or medium containing 10% fetal calf serum was added. Vector titers were approximately two- to threefold higher when producer cells were cultured in serum-containing medium. However, retroviral transduction of rhesus CFU-GM was improved using serum-free vector-containing medium. For analysis of engraftment with transduced cells, three macaques had CD34+ peripheral blood stem cells split into two fractions for transduction. One fraction was transduced using serum-free vector-containing medium, and the other fraction was transduced using standard serum-containing medium. The two fractions were re-infused simultaneously following total body irradiation. In all three animals, there was equivalent marking from both vectors for 7-9 months post-transplantation. These data are encouraging regarding the removal of serum-containing medium from clinical hematopoietic cell transduction protocols, given the lack of a detrimental effect on transduction and engraftment with transduced cells. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 37 TC 11 Z9 13 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 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2002 VL 5 IS 3 BP 316 EP 322 DI 10.1006/mthe.2002.0544 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 527NT UT WOS:000174192700016 PM 11863422 ER PT J AU Vreugde, S Ereven, A Kros, CJ Marcotti, W Fuchs, H Kurima, K Wilcox, ER Friedman, TB Griffith, AJ Balling, R de Angelis, MH Avraham, KB Steel, KP AF Vreugde, S Ereven, A Kros, CJ Marcotti, W Fuchs, H Kurima, K Wilcox, ER Friedman, TB Griffith, AJ Balling, R de Angelis, MH Avraham, KB Steel, KP TI Beethoven, a mouse model for dominant, progressive hearing loss DFNA36 SO NATURE GENETICS LA English DT Article ID OUTER HAIR-CELLS; POTASSIUM CURRENT; EXPRESSION; DEAFNESS; INNER; MICE; COCHLEA; MAPS AB Despite recent progress in identifying genes underlying deafness, there are still relatively few mouse models of specific forms of human deafness. Here we describe the phenotype of the Beethoven (Bth) mouse mutant and a missense mutation in Tmc1 (transmembrane cochlear-expressed gene 1). Progressive hearing loss (DFNA36) and profound congenital deafness (DFNB7/B11) are caused by dominant and recessive mutations of the human ortholog, TMC1 (ref. 1), for which Bth and deafness (dn)(1) are mouse models, respectively. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. MRC, Inst Hearing Res, Nottingham NG7 2RD, England. Univ Sussex, Sch Biol Sci, Brighton BN1 9QG, E Sussex, England. GSF, Res Ctr Environm & Hlth, Inst Expt Genet, D-85764 Neuherberg, Germany. Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. RP Avraham, KB (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RI Fuchs, Helmut/M-7347-2014; Hrabe de Angelis, Martin/F-5531-2012 OI Fuchs, Helmut/0000-0002-5143-2677; Hrabe de Angelis, Martin/0000-0002-7898-2353 NR 13 TC 120 Z9 123 U1 1 U2 9 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 MAR PY 2002 VL 30 IS 3 BP 257 EP 258 DI 10.1038/ng848 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 526YP UT WOS:000174157600008 PM 11850623 ER PT J AU Kurima, K Peters, LM Yang, YD Riazuddin, S Ahmed, ZM Naz, S Arnaud, D Drury, S Mo, JH Makishima, T Ghosh, M Menon, PSN Deshmukh, D Oddoux, C Ostrer, H Khan, S Riazuddin, S Deininger, PL Hampton, LL Sullivan, SL Battey, JF Keats, BJB Wilcox, ER Friedman, TB Griffith, AJ AF Kurima, K Peters, LM Yang, YD Riazuddin, S Ahmed, ZM Naz, S Arnaud, D Drury, S Mo, JH Makishima, T Ghosh, M Menon, PSN Deshmukh, D Oddoux, C Ostrer, H Khan, S Riazuddin, S Deininger, PL Hampton, LL Sullivan, SL Battey, JF Keats, BJB Wilcox, ER Friedman, TB Griffith, AJ TI Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function SO NATURE GENETICS LA English DT Article ID INNER-EAR; LOCUS DN; MOUSE; CHROMOSOME-19; SENSITIVITY; DFNB3; MICE AB Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration(1,2). TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells. C1 Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, Mol Genet Lab, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. Univ Punjab, Ctr Excellence Mol Biol, Lahore, Pakistan. Louisiana State Univ, Hlth Sci Ctr, Dept Genet, New Orleans, LA USA. All India Inst Med Sci, Dept Pediat, Genet Unit, New Delhi, India. Rotary Deaf Sch, Ichalkaranji Tilawani, Maharashtra, India. NYU, Sch Med, Dept Pediat, Human Genet Program, New York, NY USA. Tulane Univ, Med Ctr, Dept Environm Hlth Sci, New Orleans, LA USA. NINCDS, G Prot Coupled Receptors Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Mol Neurosci Sect, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Hearing Sect, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct & Funct, Mol Genet Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. RI naz, sadaf/F-4406-2015; OI Naz, Sadaf/0000-0002-1912-0235; Deininger, Prescott/0000-0002-1067-3028 NR 36 TC 177 Z9 190 U1 4 U2 14 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 MAR PY 2002 VL 30 IS 3 BP 277 EP 284 DI 10.1038/ng842 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 526YP UT WOS:000174157600011 PM 11850618 ER PT J AU Yarden, RI Pardo-Reoyo, S Sgagias, M Cowan, KH Brody, LC AF Yarden, RI Pardo-Reoyo, S Sgagias, M Cowan, KH Brody, LC TI BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage SO NATURE GENETICS LA English DT Article ID CELL-CYCLE; PHOSPHORYLATION; PROTEIN; CDC25; SERINE-216; LINKAGE; COMPLEX; LINE; ATM AB The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain-a motif that is found in many proteins that are implicated in DNA damage response and in genome stability(1). Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints(2-5). Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm(6). We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Omaha, NE 68198 USA. RP Brody, LC (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 25 TC 313 Z9 337 U1 3 U2 13 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 MAR PY 2002 VL 30 IS 3 BP 285 EP 289 DI 10.1038/ng837 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 526YP UT WOS:000174157600012 PM 11836499 ER PT J AU Norbury, CC Malide, D Gibbs, JS Bennink, JR Yewdell, JW AF Norbury, CC Malide, D Gibbs, JS Bennink, JR Yewdell, JW TI Visualizing priming of virus-specific CD8(+) T cells by infected dendritic cells in vivo SO NATURE IMMUNOLOGY LA English DT Article ID MHC CLASS-I; ANTIGEN-PRESENTING CELLS; EXOGENOUS ANTIGEN; IMMUNE-RESPONSE; EXPRESSION; MICE; DEGRADATION; MECHANISMS; MOLECULES; MATURATION AB The rational design of vaccines that elicit CD8(+) T cell responses requires knowledge of the identity of the antigen-presenting cell (APC), the location and time of presentation and the nature of the antigen presented by the APC. Here we address these questions for an antigen encoded by a recombinant vaccinia virus. We found that, following local infection, vaccinia virus infected macrophages and dendritic cells in draining lymph nodes. However, only the dendritic cells presented antigen to naive CD8(+) T cells, as determined by direct visualization of sectioned nodes by confocal microscopy. Presentation occurred as rapidly as 6 h after inoculation and quickly declined in parallel with the number of infected cells present in the nodes. These data provide direct evidence that virus-infected APCs prime naive CD8(+) T cells in vivo. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 40 TC 234 Z9 235 U1 1 U2 6 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 MAR PY 2002 VL 3 IS 3 BP 265 EP 271 DI 10.1038/ni762 PG 7 WC Immunology SC Immunology GA 525LV UT WOS:000174074000015 PM 11828323 ER PT J AU Fang, DY Elly, C Gao, BX Fang, N Altman, Y Joazeiro, C Hunter, T Copeland, N Jenkins, N Liu, YC AF Fang, DY Elly, C Gao, BX Fang, N Altman, Y Joazeiro, C Hunter, T Copeland, N Jenkins, N Liu, YC TI Dysregulation of T lymphocyte function in itchy mice: a role for itch in T(H)2 differentiation SO NATURE IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; MOTH-EATEN; UBIQUITIN; EXPRESSION; MUTATIONS; LOCUS; GENE; ACTIVATION; RECEPTORS; LIGASE AB Itch is an E3 ubiquitin ligase that is disrupted in nonagouti-lethal or itchy mice. Itch deficiency leads to severe immune and inflammatory disorders and constant itching of the skin. Here we show that Itch(-/-) T cells show an activated phenotype and enhanced proliferation. Production of the type 2 T helper (T(H)2) cell cytokines interleukin 4 (IL-4) and IL-5 by Itch-/- T cells was augmented upon stimulation, and the T(H)2-dependent serum concentrations of immunoglobulin G1 (IgG1) and IgE in itchy mice were also increased. Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in T(H)2 differentiation. These results provide a molecular link between Itch deficiency and the aberrant activation of immune responses in itchy mice. C1 La Jolla Inst Allergy & Immunol, Div Cell Biol, San Diego, CA 92121 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. NCI, Frederick, MD 21702 USA. RP Liu, YC (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, San Diego, CA 92121 USA. RI Fang, Deyu/I-7245-2013 OI Fang, Deyu/0000-0002-4211-2751 FU NIDDK NIH HHS [R01DK56558] NR 30 TC 221 Z9 233 U1 3 U2 7 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 MAR PY 2002 VL 3 IS 3 BP 281 EP 287 DI 10.1038/ni763 PG 7 WC Immunology SC Immunology GA 525LV UT WOS:000174074000017 PM 11828324 ER PT J AU Colucci, F Schweighoffer, E Tomasello, E Turner, M Ortaldo, JR Vivier, E Tybulewicz, VLJ Di Santo, JP AF Colucci, F Schweighoffer, E Tomasello, E Turner, M Ortaldo, JR Vivier, E Tybulewicz, VLJ Di Santo, JP TI Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases SO NATURE IMMUNOLOGY LA English DT Article ID NK CELL-DIFFERENTIATION; TYROSINE KINASE; KILLER-CELLS; NKG2D RECEPTOR; MICE LACKING; T-CELLS; ACTIVATION; MOUSE; COMPLEX; FAMILY AB The intracellular signals that trigger natural cytotoxicity have not been clearly determined. The Syk and ZAP-70 tyrosine kinases are essential for cellular activation initiated by B and T cell antigen receptors and may drive natural killer (NK) cell cytotoxicity via receptors bearing immunoreceptor tyrosine-based activation motifs (ITAMs). However, we found that, unlike B and T cells, NK cells developed in Syk(-/-)ZAP-70(-/-) mice and, despite their nonfunctional ITAMs, lysed various tumor targets in vitro and eliminated tumor cells in vivo, including those without NKG2D ligands. The simultaneous inhibition of phosphotidyl inositol 3 kinase and Src kinases abrogated the cytolytic activity of Syk(-/-)ZAP-70(-/-) NK cells and strongly reduced that of wild-type NK cells. This suggests that distinct and redundant signaling pathways act synergistically to trigger natural cytotoxicity. C1 Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France. Natl Inst Med Res, London NW7 1AA, England. CNRS Marseille Luminy, INSERM, Ctr Immunol, Marseille, France. Babraham Inst, Cambridge CB2 4AT, England. NCI, Frederick, MD 21702 USA. RP Colucci, F (reprint author), Inst Pasteur, Lab Cytokines & Lymphoid Dev, Paris, France. RI Colucci, Francesco/F-2844-2010; Di Santo, James/M-4298-2014; Turner, Martin/N-9976-2014; OI Colucci, Francesco/0000-0001-5193-6376; Di Santo, James/0000-0002-7146-1862; Turner, Martin/0000-0002-3801-9896; Tomasello, Elena/0000-0002-6839-5219; Tybulewicz, Victor/0000-0003-2439-0798 NR 34 TC 89 Z9 90 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2002 VL 3 IS 3 BP 288 EP 294 DI 10.1038/ni764 PG 7 WC Immunology SC Immunology GA 525LV UT WOS:000174074000018 PM 11836527 ER PT J AU Meyer-Lindenberg, A Miletich, RS Kohn, PD Esposito, G Carson, RE Quarantelli, M Weinberger, DR Berman, KF AF Meyer-Lindenberg, A Miletich, RS Kohn, PD Esposito, G Carson, RE Quarantelli, M Weinberger, DR Berman, KF TI Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia SO NATURE NEUROSCIENCE LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; DOPA DECARBOXYLASE ACTIVITY; VENTRAL TEGMENTAL AREA; CEREBRAL BLOOD-FLOW; CORTICAL REGULATION; WORKING-MEMORY; CORTEX; BRAIN; RECEPTORS; RELEASE AB Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are known to be abnormal in schizophrenia. To test the hypothesis that these phenomena are related, we measured presynaptic dopaminergic function simultaneously with regional cerebral blood flow during the Wisconsin Card Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and matched controls. We show that the dopaminergic uptake constant K-i in the striatum was significantly higher for patients than for controls. Patients had significantly less WCST-related activation in PFC. The two parameters were strongly linked in patients, but not controls. The tight within-patient coupling of these values, with decreased PFC activation predicting exaggerated striatal 6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction may lead to dopaminergic transmission abnormalities. C1 NIMH, Unit Integrat Neuroimaging, NIH, Bethesda, MD 20892 USA. NINCDS, NIH, Bethesda, MD 20832 USA. NIH, PET Dept, Ctr Clin, Bethesda, MD 20832 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20832 USA. RP Meyer-Lindenberg, A (reprint author), NIMH, Unit Integrat Neuroimaging, NIH, 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Quarantelli, Mario/A-6154-2009; Carson, Richard/H-3250-2011; OI Carson, Richard/0000-0002-9338-7966; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Quarantelli, Mario/0000-0001-7836-454X NR 46 TC 382 Z9 393 U1 3 U2 24 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 MAR PY 2002 VL 5 IS 3 BP 267 EP 271 DI 10.1038/nn804 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 526TP UT WOS:000174146000018 PM 11865311 ER EF