FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jenkins, J Blitzer, M Boehm, K Feetham, S Gettig, E Johnson, A Lapham, EV Patenaude, AF Reynolds, PP Guttmacher, AE AF Jenkins, J Blitzer, M Boehm, K Feetham, S Gettig, E Johnson, A Lapham, EV Patenaude, AF Reynolds, PP Guttmacher, AE TI Recommendations of core competencies in genetics essential for all health professionals SO GENETICS IN MEDICINE LA English DT Editorial Material ID NEED C1 NIDCR, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NHGRI, NIH, Bethesda, MD USA. NR 15 TC 43 Z9 43 U1 0 U2 4 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 2001 VL 3 IS 2 BP 155 EP 159 DI 10.1097/00125817-200103000-00011 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 472WH UT WOS:000171007600009 ER PT J AU Wolf, YI Rogozin, IB Kondrashov, AS Koonin, EV AF Wolf, YI Rogozin, IB Kondrashov, AS Koonin, EV TI Genome alignment, evolution of prokaryotic genome organization, and prediction of gene function using genomic context SO GENOME RESEARCH LA English DT Article ID COMPLETE MICROBIAL GENOMES; ESCHERICHIA-COLI; SEQUENCE ALIGNMENT; BACTERIAL GENOMES; PSI-BLAST; PROTEINS; DATABASE; CLUSTERS; OPERONS; TOOL AB Gene order in prokaryotes is conserved to a much lesser extent than protein sequences. Only several operons, primarily those that code for physically interacting proteins, are conserved in all or most of the bacterial and archaeal genomes. Nevertheless, even the limited conservation of operon organization that is observed call provide valuable evolutionary and functional clues through multiple genome comparisons. A program for constructing gapped local alignments of conserved gene strings in two genomes was developed. The statistical significance of the local alignments was assessed using Monte Carlo simulations. Sets of local alignments were generated for all pairs of completely sequenced bacterial and archaeal genomes, and for each genome a template-anchored multiple alignment was constructed. In most pairwise genome comparisons, <10% of the genes in each genome belonged to conserved gene strings. When closely related pairs of species (i.e., two mycoplasmas) are excluded, the total coverage of genomes by conserved gene strings ranged from <5% for the cyanobacterium Synechocystis sp to 24% for the minimal genome of Mycoplasma genitalium, and 23% in Thermotoga maritime. The coverage of the archaeal genomes was only slightly lower than that of bacterial genomes. The majority of the conserved gene strings are known operons, with the ribosomal superoperon being the top-scoring string in most genome comparisons. However, in some of the bacterial-archaeal pairs, the superoperon is rearranged to the extent that other operons, primarily those subject to horizontal transfer, show the greatest level of conservation, such as the archaeal-type H+-ATPase operon or ABC-type transport cassettes. The level of gene order conservation among prokaryotic genomes was compared to the cooccurrence of genomes in clusters of orthologous genes (COGs) and to the conservation of protein sequences themselves. Only limited correlation was observed between these evolutionary variables. Gene order conservation shows a much lower variance than the cooccurrence of genomes in COGs, which indicates that intragenome homogenization via recombination occurs in evolution much faster than intergenome homogenization via horizontal gene transfer and lineage-specific gene loss. The potential of using template-anchored multiple-genome alignments for predicting functions of uncharacterized genes was quantitatively assessed. Functions were predicted or significantly clarified for similar to 90 COGs (similar to4% of the total of 2414 analyzed COGs). The most significant predictions were obtained for the poorly characterized archaeal genomes; these include a previously uncharacterized restriction-modification system, a nuclease-helicase combination implicated in DNA repair, and the probable archaeal counterpart of the eukaryotic exosome. Multiple genome alignments are a resource for studies on operon rearrangement and disruption, which is central to our understanding of the evolution of prokaryotic genomes. Because of the rapid evolution of the gene order, the potential of genome alignment for prediction of gene functions is limited, but nevertheless, such predictions information significantly complements the results obtained through protein sequence and structure analysis. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 44 TC 215 Z9 226 U1 2 U2 18 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAR PY 2001 VL 11 IS 3 BP 356 EP 372 DI 10.1101/gr.GR-1619R PG 17 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 407DG UT WOS:000167255700006 PM 11230160 ER PT J AU Sugimoto, J Matsuura, N Kinjo, Y Takasu, N Oda, T Jinno, Y AF Sugimoto, J Matsuura, N Kinjo, Y Takasu, N Oda, T Jinno, Y TI Transcriptionally active HERV-K genes: Identification, isolation, and chromosomal mapping SO GENOMICS LA English DT Article ID DEPENDENT DIABETES-MELLITUS; ENDOGENOUS-RETROVIRUS-K; LONG TERMINAL REPEAT; SUSCEPTIBILITY GENES; MESSENGER-RNA; EXPRESSION; GENOME; IDDMK(1,2)22; ELEMENTS; PROTEIN AB Preceding the isolation of transcriptionally active HERV-K genes, expression status was examined by RT-PCR and sequence analysis of mRNA from various tissues. In addition to the detection of IDDMK(1,2)22/HERV-K18 expression in peripheral leukocytes, three novel members of the family, which are expressed in multiple tissues, were identified. The novel HERV-K genes (HGMW-approved symbols ERVK4 and ERVK5) were isolated from a BAC library using oligonucleotide probes and assigned by RH mapping to chromosomal regions 3q21-q25.2, 3cen-q13, and 1q21-q23, Although their expression could not be confirmed in any normal tissues by Northern blot analysis, substantial promoter activity of their 5' LTRs was demonstrated in luciferase assays using teratocarcinoma cell lines. Thus, they seem to have the potential to be actively transcribed. The results, combined with those of the expression analysis by RT-PCR and subsequent sequencing of cloned products, also suggest that LTR sequences with subtle base changes might play a role in gene regulation, such as tissue specificity of HERV-K expression, (C) 2001 Academic Press. C1 Ryukyu Univ, Sch Med, Dept Mol Biol, Okinawa 9030215, Japan. Ryukyu Univ, Sch Med, Dept Internal Med 2, Okinawa 9030215, Japan. Kitasato Univ, Sch Med, Dept Pediat, Sagamihara, Kanagawa 2288555, Japan. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Jinno, Y (reprint author), Ryukyu Univ, Sch Med, Dept Mol Biol, Uehara 207, Okinawa 9030215, Japan. NR 38 TC 34 Z9 40 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAR 1 PY 2001 VL 72 IS 2 BP 137 EP 144 DI 10.1006/geno.2001.6473 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 417TK UT WOS:000167850100003 PM 11401426 ER PT J AU Gowda, DC Glushka, J van Halbeek, H Thotakura, RN Bredehorst, R Vogel, CW AF Gowda, DC Glushka, J van Halbeek, H Thotakura, RN Bredehorst, R Vogel, CW TI N-linked oligosaccharides of cobra venom factor contain novel alpha(1-3)galactosylated Le(x) structures SO GLYCOBIOLOGY LA English DT Article DE cobra venom factor; complement-activating glycoprotein; N-linked oligosaccharides; structure determination; alpha-galactosylated Lewis X antigens ID MAGNETIC-RESONANCE SPECTROSCOPY; HUMAN NEUROBLASTOMA-CELLS; NATURAL ANTI-GAL; H-1-NMR SPECTROSCOPY; CARBOHYDRATE CHAINS; GALACTOSYL RESIDUES; MONOCLONAL-ANTIBODY; HIGH-RESOLUTION; ROTATING-FRAME; GLYCOPROTEINS AB Cobra venom factor (CVF), a nontoxic, complement-activating glycoprotein in cobra venom, is a functional analog of mammalian complement component C3b. The carbohydrate moiety of CVF consists exclusively of N-linked oligosaccharides with terminal alpha1-3-linked galactosyl residues, which are antigenic in human. CVF has potential for several medical applications, including targeted cell killing and complement depletion. Here, we report a detailed structural analysis of the oligosaccharides of CVF. The structures of the oligosaccharides were determined by lectin affinity chromatography, antibody affinity blotting, compositional and methylation analyses, and high-resolution H-1-NMR spectroscopy. Approximately 80% of the oligosaccharides are diantennary complex-type, similar to 12% are tri- and tetra-antennary complex-type, and similar to8% are oligomannose type structures. The majority of the complex-type oligosaccharides terminate in Gal alpha1-3Gal beta1-4(Fuc alpha1-3)GlcNAc beta1, a unique carbohydrate structural feature abundantly present in the glycoproteins of cobra venom. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. NIDDK, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Gowda, DC (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NCI NIH HHS [CA01039, CA61210]; NHLBI NIH HHS [HL29523]; NIAID NIH HHS [AI26821] NR 50 TC 16 Z9 19 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAR PY 2001 VL 11 IS 3 BP 195 EP 208 DI 10.1093/glycob/11.3.195 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429DR UT WOS:000168501200005 PM 11320058 ER PT J AU Chuaqui, R Silva, M Emmert-Buck, M AF Chuaqui, R Silva, M Emmert-Buck, M TI Allelic deletion mapping on chromosome 6q and X chromosome inactivation clonality patterns in cervical intraepithelial neoplasia and invasive carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 91st Annual Meeting of the American-Association-for-Cancer-Research CY APR 01-05, 2000 CL SAN FRANCISCO, CALIFORNIA SP Amer Assoc Canc Res DE cervical cancer; cervical intraepithelial neoplasia; laser capture microdissection; deletions; clonality ID GENETIC ALTERATIONS; UTERINE CERVIX; SHORT ARM; OVARIAN-CANCER; BRCA2 GENE; HETEROZYGOSITY; PROGRESSION; FREQUENT; TUMORS; PCR AB Objective. Loss of heterozygosity (LOH) profiles and X chromosome inactivation patterns are analyzed in 42 patients with cervical intraepithelial neoplasias (CIN), including low-grade (CIN1) and high-grade (CIN2, CIN3) lesions, and 22 patients with invasive cervical carcinomas. Method. Laser capture microdissection was utilized to procure pure matched normal and lesional cells from each case. Sixteen microsatellite markers on four chromosomal arms, 6q21-q25.1, 8p21, 13q12.3-q13, and 17q12-q21, were amplified for LOH, as well as the HUMARA locus for X chromosome inactivation analysis. Eight additional markers spanning the long arm of chromosome 6 were utilized in all cases showing LOH on this arm and in which further tissue material was available for microdissection. Results. Fifty-five percent of carcinomas showed deletions on chromosome bands 6q21-q25.1, 43% on 13q12.3-q13, and 40% on 17q12-q21. Deletions on 6q were identified in CIN3 (40%), CIN2 (37%), and CIN1 (10%), on 13q in CIN3 (33%) and CIN2 (33%), and rarely on chromosomal arm 17q. Finer 6q mapping revealed that marker D6S310 (q22) represented the centromeric and marker D6S255 (q25-q16) the telomeric boundary of deletion. A second, telomeric area of deletion at marker D6S281 (q27) was also identified. Monoclonal X chromosome inactivation patterns were identified in 12/13 cancers, 13/14 CIN3, 5/10 CIN2, and 0/6 CIN1. Conclusions. Two areas of deletion on chromosome 6q were identified in cervical tumors, suggesting the presence of tumor suppressor gene(s) inactivated in this neoplasia. LOH on this arm were identified early during cervical tumor progression. LOH on 13q and 17q also occur in cervical cancers. X chromosome inactivation patterns suggest that CIN develops into a monoclonal lesion during progression from CIN1 to CIN3. (C) 2001 Academic Press. C1 Catholic Univ, Dept Pathol, Santiago, Chile. NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. RP Chuaqui, R (reprint author), Catholic Univ, Dept Pathol, Marcoleta 367, Santiago, Chile. NR 46 TC 22 Z9 24 U1 0 U2 0 PU ACADEMIC PRESS INC 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 2001 VL 80 IS 3 BP 364 EP 371 DI 10.1006/gyno.2000.6087 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 410CM UT WOS:000167422500007 PM 11263933 ER PT J AU Santini, G Nati, S Spriano, M Gallamini, A Pierluigi, D Congiu, AM Truini, M Rubagotti, A Chisesi, T Vimercati, R Rossi, E Sertoli, MR Mattei, D Marino, G Gobbi, M AF Santini, G Nati, S Spriano, M Gallamini, A Pierluigi, D Congiu, AM Truini, M Rubagotti, A Chisesi, T Vimercati, R Rossi, E Sertoli, MR Mattei, D Marino, G Gobbi, M TI Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-Hodgkin's lymphoma SO HAEMATOLOGICA LA English DT Article DE fludarabine; cyclophosphamide; mitoxantrone; low-grade non-Hodgkin's lymphoma ID PHASE-II TRIAL; MANTLE-CELL LYMPHOMAS; INDOLENT; CHEMOTHERAPY; REGIMEN; MONOPHOSPHATE; DEXAMETHASONE; MULTICENTER AB Background and Objectives. We report the activity of two combinations of fludarabine (FLU), one with cyclophosphamide (FLU/CY) and the second with CY plus mitoxantrone (FLU/CY/MITO). The aim of the study was to evaluate the activity and toxicity of these two schedules in patients with non-Hodgkin's lymphoma (NHL). Design and Methods. Twenty-two patients with recurrent low grade non-Hodgkin's lymphoma (LGL) received FLU/CY (FLU 25 mg/m(2) days 1 to 3, CY300 mg/m(2) days 1 to 3), and 31 patients received FLU/CY/MITO (FLU 25 mg/m(2) days 1 to 3, CY 300 mg/m(2) days 1 to 3, mitoxantrone 10 mg/m(2) day 1), Patients received antibiotic oral prophylaxis during all treatments and growth factors (G-CSF) when grade III granulocytopenia (WHO scale) occurred. Results. Of the 53 patients, 31 achieved complete remission (CR) (58%) and 16 partial remission (PR) (30%), Response was similar in both arms of the study, After 3 courses, 77% of patients who achieved CR showed a complete disappearance of disease. Seventy-nine per cent of patients experienced granulocytopenia. Few patients had fever, all without infection. One patient died with fever of unknown origin three months after completion of six courses of treatment. Interpretation and Conclusions. Both treatments were seen to be effective in recurrent low-grade NHL. Antibiotic prophylaxis with G-CSF support seems to reduce treatment-related infection. (C) 2001, Ferrata Storti Foundation. C1 Osped S Martino, Azienda Osped S Martino, Div Ematol, Dept Hematol, I-16132 Genoa, Italy. S Croce Hosp, Div Hematol, Cuneo, Italy. Univ Genoa, Natl Canc Inst Genoa, Dept Oncol, I-16126 Genoa, Italy. Univ Genoa, Natl Canc Inst Genoa, Biostat Unit, I-16126 Genoa, Italy. S Giovanni Hosp, Div Hematol, Venice, Italy. Natl Canc Inst, Univ Dept Oncol, Genoa, Italy. Univ Genoa, Dept Hematol, Chair Hematol, I-16126 Genoa, Italy. RP Santini, G (reprint author), Osped S Martino, Azienda Osped S Martino, Div Ematol, Dept Hematol, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. OI Mattei, Daniele /0000-0003-3152-4416 NR 20 TC 28 Z9 28 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA STRADA NUOVA 134, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD MAR PY 2001 VL 86 IS 3 BP 282 EP 286 PG 5 WC Hematology SC Hematology GA 412BN UT WOS:000167534300009 PM 11255275 ER PT J AU Knebel, A AF Knebel, A TI Untitled - Reply SO HEART & LUNG LA English DT Letter ID HYPNOSIS; THERAPY C1 NIH, Bethesda, MD 20892 USA. RP Knebel, A (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0147-9563 J9 HEART LUNG JI Heart Lung PD MAR-APR PY 2001 VL 30 IS 2 BP 166 EP 166 DI 10.1067/mhl.2001.111294 PG 1 WC Cardiac & Cardiovascular Systems; Nursing; Respiratory System SC Cardiovascular System & Cardiology; Nursing; Respiratory System GA 413FT UT WOS:000167599800013 ER PT J AU Cizza, G Dorn, LD Lotsikas, A Sereika, S Rotenstein, D Chrousos, GP AF Cizza, G Dorn, LD Lotsikas, A Sereika, S Rotenstein, D Chrousos, GP TI Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: Potential implications of a preliminary study SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE cortisol; stress; depression; IGF-1; IGF-BP1; insulin ID ACANTHOSIS NIGRICANS; INSULIN SENSITIVITY; PUBARCHE; CHILDHOOD; CHILDREN; HISTORY; PUBERTY; STRESS; ONSET; OBESE AB Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m, Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome. C1 NIMH, CNE, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Allegheny Univ Hlth Sci, Pittsburgh, PA USA. RP Cizza, G (reprint author), NIMH, CNE, Clin Neuroendocrinol Branch, NIH, Bldg 10,Rm 10D-47, Bethesda, MD 20892 USA. FU NCRR NIH HHS [M01RR0084]; NIMH NIH HHS [R03MH53296] NR 24 TC 19 Z9 19 U1 0 U2 5 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAR PY 2001 VL 33 IS 3 BP 138 EP 143 DI 10.1055/s-2001-14927 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 431NY UT WOS:000168638500004 PM 11355746 ER PT J AU Taaffe, DR Thompson, JL Butterfield, GE Hoffman, AR Marcus, R AF Taaffe, DR Thompson, JL Butterfield, GE Hoffman, AR Marcus, R TI Recombinant human growth hormone, but not insulin-like growth factor-I, enhances central fat loss in postmenopausal women undergoing a diet and exercise program SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE fat loss; hormones; exercise ID X-RAY ABSORPTIOMETRY; CARDIOVASCULAR RISK-FACTORS; GH-DEFICIENT ADULTS; BODY-COMPOSITION; OLDER MEN; ADIPOSE-TISSUE; RESISTANCE EXERCISE; BINDING-PROTEINS; ELDERLY WOMEN; VISCERAL FAT AB We examined the effect of recombinant human growth hormone (rhGH) and/or recombinant human insulin-like growth factor-I (rhIGF-I) on regional fat loss in postmenopausal women undergoing a weight loss regimen of diet plus exercise. Twenty-seven women aged 59-79 years, 20-40% above ideal body weight, completed a 12-week program consisting of resistance training 2 days/week and walking 3 days/week, while consuming a diet that was 500 kcal/day less than that required for weight maintenance, Participants were randomly assigned in a double-blind fashion to receive rhGH (0.025 mg/kg BW/day: n=7), rhIGF-I (0.015 mg/kg BW/day: n=7), rhGH + rhIGF-I (n = 6), or placebo (PL: n = 7). Regional and whole body fat mass were determined by dual X-ray absorptiometry. Body fat distribution was assessed by the ratios of trunk fat-to-limb fat (TrF/LimbF) and trunk fat-to-total fat (TrF/TotF), Limb and trunk fat decreased in all groups (p < 0.01). For both ratios of fat distribution, the rhGH treated group experienced an enhanced loss of truncal compared to peripheral fat (p less than or equal to 0.01), with no significant change for those administered rhIGF-I or FL. There was no association between change in fat distribution and indices of cardiovascular disease risk as determined by serum lipid/lipoprotein levels and maximal aerobic capacity. These results suggest that administration of rhGH facilitates a decrease in central compared to peripheral fat in older women undertaking a weight loss program that combines exercise and moderate caloric restriction, although no beneficial effects are conferred to lipid/lipoprotein profiles, Further, the effect of rhGH is not enhanced by combining rhCH with rhIGF-I administration. In addition, rhIGF-I does not augment the loss of trunk fat when administered alone. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Dept Pediat, Ctr Hlth Promot & Dis Prevent, Albuquerque, NM 87131 USA. Vet Affairs Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Palo Alto, CA USA. Vet Affairs Hlth Care Syst, Med Serv, Palo Alto, CA USA. Stanford Univ, Dept Med, Stanford, CA 94305 USA. RP Taaffe, DR (reprint author), Univ Queensland, Sch Human Movement Studies, Fac Hlth Sci, Connell Bldg, St Lucia, Qld 4072, Australia. RI Biguzzi, Felipe/E-4724-2015 FU NIA NIH HHS [AG-10999] NR 47 TC 13 Z9 13 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAR PY 2001 VL 33 IS 3 BP 156 EP 162 DI 10.1055/s-2001-14930 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 431NY UT WOS:000168638500007 PM 11355749 ER PT J AU Roberts, RL Jenkins, KT Lawler, T Wegner, FH Newman, JD AF Roberts, RL Jenkins, KT Lawler, T Wegner, FH Newman, JD TI Bromocriptine administration lowers serum prolactin and disrupts parental responsiveness in common marmosets (Callithrix j. jacchus) SO HORMONES AND BEHAVIOR LA English DT Article DE alloparental; behavior; prolactin; bromocriptine; common marmoset; Callithrix ID NEW-WORLD PRIMATE; MATERNAL-BEHAVIOR; HELPING-BEHAVIOR; MESSENGER-RNA; LONG-FORM; FEMALE RATS; RECEPTOR; EXPRESSION; CONTACT; BRAIN AB The influence of prolactin on parental responsiveness was investigated in eight unpaired, parentally inexperienced common marmosets (Callithrix jacchus; 6 female, 2 male). The marmosets were prescreened with infants (1-10 days of age) and required to exhibit short latency retrieval and infant carrying in at least three consecutive pretests as criterion for inclusion in this study. The marmosets were then administered the dopamine agonist bromocriptine (0.5 mg/0.5ml vehicle subcutaneously) and the vehicle alone (0.5 mi 10% ethanol solution) twice daily for 3 consecutive days in random order. Bromocriptine treatment reduced circulating prolactin to nondetectable levels. Bromocriptine treatment eliminated infant retrieval in four of the eight marmosets and was associated with significantly increased retrieval latencies and significantly reduced carrying durations in the four monkeys that continued to retrieve following bromocriptine treatment. When given the vehicle alone, the marmosets retrieved infants significantly faster than during pretests, suggesting a handling effect of the injection series. Bromocriptine treatments were associated with significantly increased movement during the tests. The results of this study indicate that prolactin and/or its regulatory neurotransmitters are involved in the control of the spontaneous display of parental responsiveness in common marmosets. (C) 2001 Academic Press. C1 NICHHD, Comparat Ethol Lab, Unit Dev Neuroethol, Madison, WI USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. RP Roberts, RL (reprint author), NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. NR 19 TC 42 Z9 42 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X J9 HORM BEHAV JI Horm. Behav. PD MAR PY 2001 VL 39 IS 2 BP 106 EP 112 DI 10.1006/hbeh.2000.1639 PG 7 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 410WW UT WOS:000167464900002 PM 11243738 ER PT J AU Chen, L Li, CL Qiao, WH Xu, XL Deng, CX AF Chen, L Li, CL Qiao, WH Xu, XL Deng, CX TI A Ser(365)-> Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia SO HUMAN MOLECULAR GENETICS LA English DT Article ID HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-FORMATION; LETHAL SKELETAL DYSPLASIA; THANATOPHORIC DYSPLASIA; PARATHYROID-HORMONE; INDIAN HEDGEHOG; CHONDROCYTE DIFFERENTIATION; TARGETED DISRUPTION; TRANSGENIC MICE; FGFR3 MUTATIONS AB Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several types of human skeletal dysplasia, including the neonatally lethal dwarfism known as thanatophoric dysplasia. An engineered Ser(365)-->Cys substitution in mouse FGFR3, which is equivalent to a mutation associated with thanatophoric dysplasia-I in humans, has now been shown to cause severe dwarfism but not neonatal death. The mutant mice exhibit shortened limbs as a result of markedly reduced proliferation and impaired differentiation of growth plate chondrocytes. The receptor-activating mutation also resulted in downregulation of expression of the Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) receptor genes, both of which are important for bone growth. Interactions between FGFR3- and PTHrP-receptor-mediated signals during endochondral ossification were examined with embryonic metatarsal bones maintained in culture under defined conditions. Consistent with the in vivo observations, FGF2 inhibited bone growth in culture and induced downregulation of IHH and PTHrP receptor gene expression. Furthermore, PTHrP partially reversed the inhibition of long bone growth caused by activation of FGFR3; however, it impaired the differentiation of chondrocytes in an FGFR3-independent manner. These observations suggest that FGFR3 and IHH-PTHrP signals are transmitted by two interacting parallel pathways that mediate both overlapping and distinct functions during endochondral ossification. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Daping Hosp, Inst Surg Res, Chongqing 400042, Peoples R China. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9N105, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 45 TC 99 Z9 105 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2001 VL 10 IS 5 BP 457 EP 465 DI 10.1093/hmg/10.5.457 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 407FB UT WOS:000167260600003 PM 11181569 ER PT J AU Balemans, W Ebeling, M Patel, N Van Hul, E Olson, P Dioszegi, M Lacza, C Wuyts, W Van den Ende, J Willems, P Paes-Alves, AF Hill, S Bueno, M Ramos, FJ Tacconi, P Dikkers, FG Stratakis, C Lindpaintner, K Vickery, B Foernzler, D Van Hul, W AF Balemans, W Ebeling, M Patel, N Van Hul, E Olson, P Dioszegi, M Lacza, C Wuyts, W Van den Ende, J Willems, P Paes-Alves, AF Hill, S Bueno, M Ramos, FJ Tacconi, P Dikkers, FG Stratakis, C Lindpaintner, K Vickery, B Foernzler, D Van Hul, W TI Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST) SO HUMAN MOLECULAR GENETICS LA English DT Article ID TISSUE GROWTH-FACTOR; CHROMOSOME 17Q12-Q21; PHYSICAL MAP; DISEASE; REGION; SEQUENCE; FAMILY; GENE; LOCALIZATION; BRCA1 AB Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance, Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated oy nana malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to similar to1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis. C1 Univ Antwerp, Dept Med Genet, B-2610 Wilrijk, Belgium. F Hoffmann La Roche & Co Ltd, Div Pharmaceut, CH-4002 Basel, Switzerland. Roche Biosci, Inflammatory Dis Unit, Palo Alto, CA USA. Erasmus Univ, Dept Clin Genet, NL-3000 DR Rotterdam, Netherlands. Univ Fed Bahia, Dept Ginecol Obstet & Reprod Humana, Salvador, BA, Brazil. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. Univ Zaragoza, Dept Pediat Radiol & Med Fis, Zaragoza, Spain. Univ Cagliari, Ist Neurol, Cagliari, Italy. Univ Groningen Hosp, Dept Otorhinolaryngol, Groningen, Netherlands. NICHHD, Unit Genet Endocrinol, Bethesda, MD 20892 USA. F Hoffmann La Roche & Co Ltd, Roche Genet, CH-4002 Basel, Switzerland. RP Van Hul, W (reprint author), Univ Antwerp, Dept Med Genet, Univ Pl 1, B-2610 Wilrijk, Belgium. RI wuyts, wim/B-1346-2012; Dikkers, Frederik/M-1212-2013; OI wuyts, wim/0000-0002-4349-9038; Ramos Fuentes, Feliciano Jesus/0000-0002-5732-2209 NR 40 TC 551 Z9 584 U1 2 U2 20 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 1 PY 2001 VL 10 IS 5 BP 537 EP 543 DI 10.1093/hmg/10.5.537 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 407FB UT WOS:000167260600012 PM 11181578 ER PT J AU Watabe, H Channing, MA Riddell, C Jousse, F Libutti, SK Carrasquillo, JA Bacharach, SL Carson, RE AF Watabe, H Channing, MA Riddell, C Jousse, F Libutti, SK Carrasquillo, JA Bacharach, SL Carson, RE TI Noninvasive estimation of the aorta input function for measurement of tumor blood flow with [O-15]water SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE aorta; input function; tumor blood flow; [O-15]water ID POSITRON EMISSION TOMOGRAPHY; TIME-ACTIVITY CURVE; GLUCOSE-UTILIZATION; PET SCANNER; FDG PET; OXYGEN-15-WATER; VALIDATION; ALGORITHM; CAMERA AB Quantitative measurement of tumor blood flow with [O-15]water can be used to evaluate the effects of tumor treatment over time, Since quantitative flow measurements require an input function, we developed the profile fitting method (PFM) to measure the input function from positron emission tomography images of the aorta. First, a [C-11]CO scan was acquired and the aorta region was analyzed, The aorta diameter was determined by fitting the image data with a model that includes scanner resolution, the measured venous blood radioactivity concentration, and the spillover of counts from the background, The diameter was used in subsequent fitting of [O-15]water dynamic images to estimate the aorta and background radioactivity concentrations. Phantom experiments were performed to test the model. Image quantification biases (up to 15%) were found for small objects, particularly for those in a large elliptical phantom, However, the bias in the PFM concentration estimates was much smaller (2%-6%), A simulation study showed that PFM had less bias and/or variability in flow parameter estimates than an ROI method, PFM was applied to human [C-11]CO and [O-15]water dynamic studies with left ventricle input functions used as the gold standard. PFM parameter estimates had higher variability than found in the simulation but with minimal bias, These studies suggest that PFM is a promising technique for the noninvasive measurement of the aorta [O-15]water input function. C1 NIH, PET Dept, WG Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. Natl Cardiovasc Ctr, Res Inst, Dept Investigat Radiol, Suita, Osaka 5658565, Japan. Natl Cardiovasc Ctr, Res Inst, Dept Invest Radiol, Osaka 5658565, Japan. RP Carson, RE (reprint author), NIH, PET Dept, WG Magnuson Clin Ctr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; Carson, Richard/H-3250-2011; OI Carson, Richard/0000-0002-9338-7966; Carrasquillo, Jorge/0000-0002-8513-5734 NR 25 TC 24 Z9 24 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD MAR PY 2001 VL 20 IS 3 BP 164 EP 174 DI 10.1109/42.918468 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 425WV UT WOS:000168315400003 PM 11341707 ER PT J AU Bunnell, SC Kapoor, V Trible, RP Zhang, WG Samelson, LE AF Bunnell, SC Kapoor, V Trible, RP Zhang, WG Samelson, LE TI Dynamic actin polymerization drives T cell receptor-induced spreading: A role for the signal transduction adaptor LAT SO IMMUNITY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; MICROTUBULE-ORGANIZING CENTER; CYTOSKELETAL REORGANIZATION; PHOSPHOLIPASE C-GAMMA-1; IMMUNOLOGICAL SYNAPSE; TYROSINE KINASES; SYNDROME PROTEIN; B-CELLS; ACTIVATION; ANTIGEN AB T cell activation induces functional changes in cell shape and cytoskeletal architecture. To facilitate the collection of dynamic, high-resolution images of activated T cells, we plated T cells on coverslips coated with antibodies to the T cell receptor (TCR). Using these images, we were able to quantitate the morphological responses of individual cells over time. Here, we show that TCR engagement triggers the formation and expansion of contacts bounded by continuously remodeled actin-rich rings, These processes are associated with the extension of lamellipodia and require actin polymerization, tyrosine kinase activation, cytoplasmic calcium increases, and LAT, an important hematopoietic adaptor. In addition, the maintenance of the resulting contact requires sustained calcium influxes, an intact microtubule cytoskeleton, and functional LAT. C1 NCI, Div Basic Sci, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP Samelson, LE (reprint author), NCI, Div Basic Sci, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NR 51 TC 257 Z9 260 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR PY 2001 VL 14 IS 3 BP 315 EP 329 DI 10.1016/S1074-7613(01)00112-1 PG 15 WC Immunology SC Immunology GA 419QE UT WOS:000167959500010 PM 11290340 ER PT J AU Passwell, JH Harlev, E Ashkenazi, S Chu, CY Miron, D Ramon, R Farzan, N Shiloach, J Bryla, DA Majadly, F Roberson, R Robbins, JB Schneerson, R AF Passwell, JH Harlev, E Ashkenazi, S Chu, CY Miron, D Ramon, R Farzan, N Shiloach, J Bryla, DA Majadly, F Roberson, R Robbins, JB Schneerson, R TI Safety and immunogenicity of improved Shigella O-specific polysaccharide-protein conjugate vaccines in adults in Israel SO INFECTION AND IMMUNITY LA English DT Article ID INFLUENZAE TYPE-B; ENTEROINVASIVE ESCHERICHIA-COLI; LIPOPOLYSACCHARIDE ANTIBODIES; IMMUNOLOGICAL PROPERTIES; DYSENTERIAE TYPE-1; RURAL BANGLADESH; SERUM ANTIBODIES; PUBLIC-HEALTH; INFECTIONS; TOXIN AB Data suggest that the O-specific polysaccharide (O-SP) domain of the lipopolysaccharide (LPS) of Shigella species is both an essential virulence factor and a protective antigen and that a critical level of serum immunoglobulin G (IgG) to this antigen will confer immunity to shigellosis. Because covalent attachment of polysaccharides to proteins increases their immunogenicity, especially in infants and in young children, the O-SP of Shigella species were bound to medically useful proteins, and the safety and immunogenicity of the resultant conjugates were confirmed in adults and 4- to 7-year-old children. Succinylation of the carrier protein improved the immunogenicity of Shigella conjugates in mice and increased their yield. Based on these results, a clinical trial of O-SP conjugates of Shigella sonnei and Shigella flexneri 2a bound to succinylated mutant Pseudomonas aeruginosa exotoxin A (rEPA(succ)) or native or succinylated Corynebacterium diphtheriae toxin mutant (CRM9 or CRM9(succ)) was conducted in healthy adults. The conjugates were safe and immunogenic. S. sonnei-CRM9, S. sonnei-CRM9(succ), and S. sonnei-rEPA(succ), elicited significant rises of geometric mean (GM) IgG anti-LPS within 1 week of injection (P < 0.001). At 26 weeks, the GM anti-LPS levels elicited by these three conjugates were similar and higher than their prevaccination levels IP < 0.0001). GM IgG anti-LPS levels elicited by S. flexneri 2a-rEPA(succ) were significantly higher than those elicited by S.flexneri 2a-rCRM9(succ) at all intervals after injection. At 26 weeks, the levels of IgG anti-LPS in vaccinees were higher than their prevaccination levels (P < 0.0001). The serum antibody responses were specific, as there was no significant rise of anti-LPS to the heterologous O-SP in any vaccinee. Both conjugates elicited statistically significant rises of serum antibodies to the injected carrier protein. At 6 months, these five Shigella conjugates elicited higher fold rises than similar conjugates (D. N. Taylor et al., Infect. Immun. 61:3678-3687, 1993). Based on these data, we chose S, sonnei-CRM9 and S. flexneri 2a-rEPA(succ) for evaluation in children. C1 Chaim Sheba Med Ctr, Samuel Jared Pediat Immunol Lab, IL-5261 Tel Hashomer, Israel. Schneider Childrens Hosp, Tel Aviv, Israel. NICHHD, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Passwell, JH (reprint author), Chaim Sheba Med Ctr, Samuel Jared Pediat Immunol Lab, IL-5261 Tel Hashomer, Israel. NR 57 TC 70 Z9 76 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 2001 VL 69 IS 3 BP 1351 EP 1357 DI 10.1128/IAI.69.3.1351-1357.2001 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200015 PM 11179298 ER PT J AU Hu, WG Chen, J McMichael, JC Gu, XX AF Hu, WG Chen, J McMichael, JC Gu, XX TI Functional characteristics of a protective monoclonal antibody against serotype A and C lipooligosaccharides from Moraxella catarrhalis SO INFECTION AND IMMUNITY LA English DT Article ID NONTYPABLE HAEMOPHILUS-INFLUENZAE; BRANHAMELLA-CATARRHALIS; EPITHELIAL-CELLS; NEISSERIA-MENINGITIDIS; PULMONARY CLEARANCE; LIPOPOLYSACCHARIDE ANTIGENS; BORDETELLA-PERTUSSIS; OTITIS-MEDIA; ANIMAL-MODEL; GONORRHOEAE AB A monoclonal antibody (MAb), designated MAb 8E7 (immunoglobulin G3), specific for Moraxella catarrhalis lipooligosaccharide (LOS) was evaluated for its functional activity in vitro and in a mouse model of colonization. Enzyme-linked immunosorbent assay (ELISA) demonstrated that the MAb 8E7 could be prepared to a high titer against LOS of the homologous strain 035E, and that it had bactericidal activity, MAb 8E7 reacted with M. catarrhalis serotype A and C LOSs but not serotype B LOS, as measured by ELISA and Western blotting. On the basis of published structures of LOSs, this suggests that the epitope recognized by MAb 8E7 is directed to a common sequence of either alpha -GlcNAc-(1-->2)-beta -Glc-(1--> at the branch substituting position 4 of the trisubstituted Glc residue or a terminal tetrasaccharide alpha -Gal-(1-->4)-beta -Gal-(1-->4)-alpha -Glc-(1-->2)-beta -Glc-(1--> at the branch substituting position 6 of the trisubstituted Glc residue. In a whole-cell ELISA, MAb 8E7 reacted with 70% of the 30 wild-type strains and clinical isolates tested. Immune-electron microscopy demonstrated that MAb 8E7 reacted with a cell surface-exposed epitope of LOS on strain O35E, MAb 8E7 inhibited the adherence of strain 035E to Chang conjunctival epithelial cells by 90%. Passive immunization with MAb 8E7 could significantly enhance the clearance of strain O35E from mouse lungs in an aerosol challenge mouse model. This enhanced bacterial clearance was inhibited when MAb 8E7 was absorbed by ill. catarrhalis serotype A LOS, indicating that the M, catarrhalis LOS-directed antibody may play a major role in the enhancement of M. catarrhalis clearance from lungs. These data suggest that MAb 8E7, which recognizes surface-exposed LOS of M. catarrhalis, is a protective antibody against M, catarrhalis. C1 Natl Inst Deafness & Other Commun Disorders, Immunol Lab, Rockville, MD 20850 USA. Wyeth Lederle Vaccines & Pediat, W Henrietta, NY 14586 USA. RP Gu, XX (reprint author), 5 Res Ct, Rockville, MD 20850 USA. NR 36 TC 33 Z9 34 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 2001 VL 69 IS 3 BP 1358 EP 1363 DI 10.1128/IAI.69.3.1358-1363.2001 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200016 PM 11179299 ER PT J AU Dorward, DW Larson, RS AF Dorward, DW Larson, RS TI Murine model for lymphocytic tropism by Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN LYME-DISEASE; B-CELL LYMPHOMA; MICE; HISTOPATHOLOGY; SPIROCHETE; INFECTION; PATHOLOGY; ANTIGENS; LESIONS; OSPA AB In vitro studies have demonstrated direct interactions between Borrelia burgdorferi and human B and T cells. However, largely because disseminated infections typically occur at very low density, little is known about associations between spirochetes and mammalian host cells in vivo. To assess whether spirochetes interact directly with lymphocytes in mammals, we developed a mouse model for lymphotropism. By repeatedly coincubating spirochetes with primary mouse lymphocytes that were immobilized by adherence to immunomagnetic beads, we were able to preferentially enrich cultures for or against bacteria with constitutive affinity for murine B and T cells. Populations of lymphotropically enriched, stock infectious, and lymphotropically depleted spirochetes were injected intradermally into mice. Lymphocytes were then purified from the blood and spleens of challenged mice and placed into spirochetal culture medium. Cultures of B. burgdorferi were obtained from primary lymphocyte preparations from mice challenged with each of the three populations of spirochetes. Recovery of lymphocyte-associated bacteria occurred within 1 h of challenge with enriched bacteria. Lymphocyte preparations from mice challenged with stock infectious and lymphotropically depleted bacteria produced cultures after 1 day postchallenge. All lymphocyte preparations were culture negative after I week These results demonstrate that lymphotropic B. burgdorferi is infectious in mice and suggest that associations between spirochetes and lymphocytes occur in vivo. The results also suggest that factors involved in lymphocytic binding may be inducible in vivo. Thus, this system provides a model for studying the role of such interactions in mammalian infections. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Dorward, DW (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 36 TC 1 Z9 1 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 2001 VL 69 IS 3 BP 1428 EP 1432 DI 10.1128/IAI.69.3.1428-1432.2001 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200025 PM 11179308 ER PT J AU Stowers, AW Cioce, V Shimp, RL Lawson, M Hui, G Muratova, O Kaslow, DC Robinson, R Long, CA Miller, LH AF Stowers, AW Cioce, V Shimp, RL Lawson, M Hui, G Muratova, O Kaslow, DC Robinson, R Long, CA Miller, LH TI Efficacy of two alternate vaccines based on Plasmodium falciparum merozoite surface protein 1 in an Aotus challenge trial SO INFECTION AND IMMUNITY LA English DT Article ID B-CELL EPITOPES; CARBOXYL-TERMINAL FRAGMENT; HUMAN MALARIA PARASITE; CD4(+) T-CELLS; SACCHAROMYCES-CEREVISIAE; C-TERMINUS; PROTECTIVE IMMUNITY; MONKEYS; ANTIBODIES; ANTIGEN AB In an attempt to produce a more defined, clinical-grade version of a vaccine based on Plasmodium falciparum merozoite surface protein 1 (MSP1), we evaluated the efficacy of two recombinant forms of MSP1 in an Aotus nancymai challenge model system. One recombinant vaccine, bvMSP1(42), based on the 42-kDa C-terminal portion of MSP1, was expressed as a secreted protein in baculovirus-infected insect cells. A highly pure baculovirus product could be reproducibly expressed and purified at yields in excess of 8 mg of pure protein per liter of culture. This protein, when tested for efficacy in the Aotus challenge model, gave significant protection,,vith only one of seven monkeys requiring treatment for uncontrolled parasitemia after challenge with P. falciparum, The second recombinant protein, P30P2MSP1(19), has been used in previous studies and is based on the smaller, C-terminal 19-kDa portion of MSP1 expressed in Saccharomyces cerevisiae. Substantial changes were made in its production process to optimize expression. The optimum form of this vaccine antigen las judged by in vitro and in vivo indicators) was then evaluated, along with bvMSP1(42), for efficacy in the A. nancymai system. The new formulation of P30P3MSP1(19) performed significantly worse than bvMSP1(42) and appeared to be less efficacious than we have found in the past, with four of seven monkeys in the vaccinated group requiring treatment for uncontrolled parasitemia. With both antigens, protection was seen only when high antibody levels were obtained by formulation of the vaccines in Freund's adjuvant, Vaccine formulation in an alternate adjuvant, MF59, resulted in significantly lower antibody titers and no protection. C1 NIAID, Malaria Vaccine Dev Unit, LPD, NIH, Rockville, MD 20852 USA. Novavax Inc, Rockville, MD USA. Univ Hawaii, Dept Trop Med & Med Microbiol, Honolulu, HI 96822 USA. RP Stowers, AW (reprint author), NIAID, Malaria Vaccine Dev Unit, LPD, NIH, Twinbrook 2,Room 103,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 37 TC 103 Z9 109 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 2001 VL 69 IS 3 BP 1536 EP 1546 DI 10.1128/IAI.69.3.1536-1546.2001 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200041 PM 11179324 ER PT J AU Cooper, PJ Chico, M Sandoval, C Espinel, I Guevara, A Levine, MM Griffin, GE Nutman, TB AF Cooper, PJ Chico, M Sandoval, C Espinel, I Guevara, A Levine, MM Griffin, GE Nutman, TB TI Human infection with Ascaris lumbricoides is associated with suppression of the interleukin-2 response to recombinant cholera toxin B subunit following vaccination with the live oral cholera vaccine CVD 103-HgR SO INFECTION AND IMMUNITY LA English DT Article ID T-CELL; HUMAN ONCHOCERCIASIS; SCHISTOSOMA-MANSONI; CYTOKINE RESPONSES; ANTIBODY-RESPONSES; IMMUNE-RESPONSES; IMMUNIZATION; IMMUNOGENICITY; ADJUVANT; IVERMECTIN AB To investigate the potential immunomodulatory effects of concurrent ascariasis on the cytokine response to a live oral vaccine, we measured cytokine responses to cholera toxin B subunit (CT-B) following vaccination with the live oral cholera vaccine CVD 103-HgR in Ascaris lumbricoides-infected subjects randomized in a double-blind study to receive two doses of either albendazole or placebo prior to vaccination and in a group of healthy U.S. controls. Postvaccination cytokine responses to CT-B were characterized by transient increases in the production of interleukin-2 (IL-2; P = 0.02) and gamma interferon (IFN-gamma; P = 0.001) in the three study groups combined; however, postvaccination increases in IFN-gamma were significant only in the albendazole-treated A, lumbricoides infection group (P = 0.008). Postvaccination levels of IL-2 were significantly greater in the albendazole-treated group compared with the placebo group (P = 0.03), No changes in levels of Th1 and Th2 cytokines in response to control ascaris antigens were observed over the same period, These findings indicate that vaccination with CVD 103-HgR is associated with a Th1 cytokine response (IL-2 and IFN-gamma) to CT-B, that infection with A, lumbricoides diminishes the magnitude of this response, and that albendazole treatment prior to vaccination was able to partially reverse the deficit in IL-2, The potential modulation of the immune response to oral vaccines by geohelminth parasites has important implications for the design of vaccination campaigns in geohelminth-endemic areas. C1 St George Hosp, Sch Med, Div Infect Dis, London SW17 0RE, England. Univ Maryland, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Hosp Vozandes, Dept Clin Invest, Quito, Ecuador. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Cooper, PJ (reprint author), St George Hosp, Sch Med, Div Infect Dis, Cranmer Terrace, London SW17 0RE, England. EM pc102d@hotmail.com NR 38 TC 145 Z9 146 U1 0 U2 4 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 2001 VL 69 IS 3 BP 1574 EP 1580 DI 10.1128/IAI.69.3.1574-1580.2001 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200046 PM 11179329 ER PT J AU Lukomski, S Nakashima, K Abdi, I Cipriano, VJ Shelvin, BJ Graviss, EA Musser, JM AF Lukomski, S Nakashima, K Abdi, I Cipriano, VJ Shelvin, BJ Graviss, EA Musser, JM TI Identification and characterization of a second extracellular collagen-like protein made by group A Streptococcus: Control of production at the level of translation SO INFECTION AND IMMUNITY LA English DT Article ID GROUP-A STREPTOCOCCI; FIBRONECTIN-BINDING PROTEIN; SHOCK-LIKE SYNDROME; PHASE VARIATION; INFLUENZAE LIPOPOLYSACCHARIDE; HAEMOPHILUS-INFLUENZAE; VIRULENCE DETERMINANT; NEISSERIA-GONORRHOEAE; ALKALINE-PHOSPHATASE; ANTIGENIC VARIATION AB A recent study found that group A Streptococcus (GAS) expresses a cell surface protein with similarity to human collagen (S, Lukomski, K. Nakashima, I. Abdi, V, J, Cipriano, R. M, Ireland, S. R, Reid, G, G, Adams, and J, M. Musser, Infect. Immun, 68:6542-6553, 2000), This streptococcal collagen-like protein (Scl) contains a long region of Gly-X-X motifs and was produced by serotype M1 GAS strains. In the present study, a second member of the scl gene family was identified and designated scl2. The Scl2 protein also has a collagen-like region, which in M1 strains is composed of 38 contiguous Gly X-X triplet motifs, The scl2 gene was present in all 50 genetically diverse GAS strains studied. The Scl2 protein is highly polymorphic, and the number of Gly-X-X motifs in the 50 strains studied ranged from 31 in one serotype M1 strain to 79 in serotype M28 and M77 isolates. The scl1 and scl2 genes were simultaneously transcribed in the exponential phase, and the Sd proteins were also produced. Scl1 and Scl2 were identified in a cell-associated form and free in culture supernatants, Production of Scl1 is regulated by Mga, a positive transcriptional regulator that controls expression of several GAS virulence factors. In contrast, production of Scl2 is controlled at the level of translation by variation in the number of short-sequence pentanucleotide repeats (CAAAA) located immediately downstream of the GTG (Val) start codon. Control of protein production by this molecular mechanism has not been identified previously in GAS. Together, the data indicate that GAS simultaneously produces two extracellular human collagen-like proteins in a regulated fashion. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. FU NIAID NIH HHS [AI-33119, AI38406] NR 44 TC 71 Z9 72 U1 1 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 2001 VL 69 IS 3 BP 1729 EP 1738 DI 10.1128/IAI.69.3.1729-1738.2001 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200067 PM 11179350 ER PT J AU Igietseme, JU Portis, JL Perry, LL AF Igietseme, JU Portis, JL Perry, LL TI Inflammation and clearance of Chlamydia trachomatis in enteric and nonenteric mucosae SO INFECTION AND IMMUNITY LA English DT Article ID CELL-ADHESION MOLECULE-1; ALTERNATIVELY SPLICED TRANSCRIPTS; GENITAL-TRACT INFECTION; HERPES-SIMPLEX VIRUS; GENE KNOCKOUT MICE; IMMUNE-RESPONSES; VASCULAR ADDRESSIN; INTESTINAL-MUCOSA; ORAL IMMUNIZATION; LYMPHOID-TISSUE AB Immunization(s) fostering the induction of genital mucosa-targeted immune effecters is the goal of vaccines against sexually transmitted diseases. However, it is uncertain whether vaccine administration should be based on the current assumptions about the common mucosal immune system. We investigated the relationship between mucosal sites of infection, infection-induced inflammation, and immune-mediated bacterial clearance in mice using the epitheliotropic pathogen Chlamydia trachomatis, Chlamydial infection of the conjunctival, pulmonary, or genital mucosae stimulated significant changes in tissue architecture with dramatic up-regulation of the vascular addressin, VCAM, a vigorous mixed-cell inflammatory response with an influx of alpha4 beta1(+) T cells, and clearance of bacteria within 30 days. Conversely, intestinal mucosa infection was physiologically inapparent, with no change in expression of the local MAdCAM addressin, no VCAM induction, no histologically detectable inflammation, and no tissue pathology. Microbial clearance was complete within 60 days in the small intestine but bacterial titers remained at high levels for at least 8 months in the large intestine. These findings are compatible with the notion that VCAM plays a functional role in recruiting cells to inflammatory foci, and its absence from the intestinal mucosa contributes to immunologic homeostasis at that site, Also, expression of type 1 T cell-mediated immunity to intracellular Chlamydia may exhibit tissue-specific variation, with the rate and possibly the mechanism(s) of clearance differing between enteric and nonenteric mucosae. The implications of these data for the common mucosal immune system and the delivery of vaccines against mucosal pathogens are discussed. C1 Morehouse Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30310 USA. NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Igietseme, JU (reprint author), Morehouse Sch Med, Dept Microbiol & Immunol, 720 Westview Dr SW, Atlanta, GA 30310 USA. FU NCRR NIH HHS [G12 RR003034, RR03034]; NIAID NIH HHS [AI41231, R01 AI041231] NR 53 TC 20 Z9 20 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 2001 VL 69 IS 3 BP 1832 EP 1840 DI 10.1128/IAI.69.3.1832-1840.2001 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200078 PM 11179361 ER PT J AU Nash, TE Lujan, HT Mowatt, MR Conrad, JT AF Nash, TE Lujan, HT Mowatt, MR Conrad, JT TI Variant-specific surface protein switching in Giardia lamblia SO INFECTION AND IMMUNITY LA English DT Article ID ANTIGENIC VARIATION; TRYPANOSOMA-BRUCEI; TRANSFORMATION; IDENTIFICATION AB Surface antigen switching in Giardia lamblia was analyzed using monoclonal antibodies specific for two variant-specific surface proteins (VSPs). Two VSPs were detected on the surface of single trophozoites. Dual expression persisted for 13 h but disappeared at 36 h, as in other parasites that undergo surface antigenic variation. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike,Bldg 4,Rm B1-06, Bethesda, MD 20892 USA. NR 15 TC 30 Z9 31 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 2001 VL 69 IS 3 BP 1922 EP 1923 DI 10.1128/IAI.69.3.1922-1923.2001 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 404GZ UT WOS:000167090200092 PM 11179375 ER PT J AU Shahabuddin, M Costero, A AF Shahabuddin, M Costero, A TI Spatial distribution of factors that determine sporogonic development of malaria parasites in mosquitoes SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE immunity; insect; vector; disease-transmission; midgut; transmission-blocking; Plasmodium ID AEDES-AEGYPTI MIDGUT; TRANSMISSION-BLOCKING IMMUNITY; PLASMODIUM-FALCIPARUM MALARIA; VECTOR ANOPHELES-GAMBIAE; SALIVARY-GLANDS; PERITROPHIC MEMBRANE; INNATE IMMUNITY; IN-VITRO; CIRCUMSPOROZOITE PROTEIN; POPULATION-DYNAMICS AB Mosquitoes transmit malaria, but only a few species permit the complete development and transmission of the parasite., Also, only a fraction of the ingested parasites develop in the vector. The attrition occurs in different compartments during the parasite's complex developmental scheme in the insect. A number of factors, both physical and biochemical, that affect the development have been proposed or demonstrated. Each of these factors is located within a specific space in the insect. We have divided this space into six compartments, which are distinct in their biochemical and biophysical nature: Endoperitrophic space, Peritrophic matrix, Ectopretrophic space, Midgut epithelium, Haemocoel and Salivary gland. Because factors that influence a particular stage of parasite development share the same microenvironment within these compartments, they must be considered collectively to exploit them for designing effective transmission blocking strategies. In this article we discuss these factors according to their spatial location in the mosquito. Published by Elsevier Science Ltd. C1 NIAID, Dept Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Shahabuddin, M (reprint author), NIAID, Dept Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 106 TC 25 Z9 31 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD MAR 1 PY 2001 VL 31 IS 3 SI SI BP 231 EP 240 DI 10.1016/S0965-1748(00)00142-9 PG 10 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 410DA UT WOS:000167423700003 PM 11167092 ER PT J AU Egan, CA Meadows, KP Van Orman, CB Vanderhooft, SL AF Egan, CA Meadows, KP Van Orman, CB Vanderhooft, SL TI Neurologic variant of epidermal nevus syndrome with a facial lipoma SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Article ID PHAKOMATOSIS AB A 1-year-old girl presented for evaluation of a linear plaque on her forehead. She was born at 36 weeks' gestation following an uncomplicated pregnancy and delivery. At birth, she was noted to have an enlarged right cheek. She had no seizure history, but developed grand mal seizures 1 year later. On examination, she had a yellow plaque on her forehead which extended onto her nose. Under her right jaw. extending onto her anterior neck, there was a cafe-au-lait macule within which there was a yellow plaque which followed the lines of Blaschko. Her right cheek was enlarged and was erythematous (Fig. 1). Magnetic resonance imaging (MRI) of her face showed a mass in the right cheek deep to the subcutaneous fat tissue layer. The signal from the mass was identical to that from the fat. indicating that the mass represented a lipoma. This was later excised surgically and was histologically a lipoma. MRI of the brain demonstrated enlargement of the right lateral ventricle in addition to enlargement of the right cerebral hemisphere. There was also evidence of abnormal gyral architecture. Computerized tomography (CT) three-dimensional reconstruction of the skull demonstrated overgrowth of the right maxilla, right mandible, and right orbit (Fig. 2). C1 Univ Utah, Hlth Sci Ctr, Dept Dermatol, Salt Lake City, UT USA. Univ Utah, Hlth Sci Ctr, Dept Pediat Neurol, Salt Lake City, UT USA. RP Egan, CA (reprint author), NIH, Dermatol Branch, NCI, Bldg 10,Rm 12N236,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 8 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0011-9059 J9 INT J DERMATOL JI Int. J. Dermatol. PD MAR PY 2001 VL 40 IS 3 BP 189 EP 190 DI 10.1046/j.1365-4362.2001.00774.x PG 2 WC Dermatology SC Dermatology GA 446CY UT WOS:000169496400008 PM 11422522 ER PT J AU Chen, G Huang, LD Zeng, WZ Manji, HK AF Chen, G Huang, LD Zeng, WZ Manji, HK TI Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE bcl-2; neurogenesis; neurotrophic; lithium; valproate; AU-rich; Rho; N-acetyl aspartate (NAA) ID MESSENGER-RNA STABILITY; SIGNAL-TRANSDUCTION PATHWAYS; ENOYL-COA HYDRATASE; NEUROBLASTOMA SH-SY5Y CELLS; MANIC-DEPRESSIVE ILLNESS; NITRIC-OXIDE SYNTHASE; DISPLAY PCR REVEALS; KINASE ROK-ALPHA; CNS IN-VIVO; GENE-EXPRESSION AB Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT-PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers - the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and/or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses. C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Bldg 49,Room B1EE16,49 Convent Dr MSC 4405, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 NR 114 TC 27 Z9 30 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-4930 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAR PY 2001 VL 4 IS 1 BP 47 EP 64 PG 18 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 428CK UT WOS:000168443400007 PM 11343630 ER PT J AU D'Agostini, F Balansky, RM Bennicelli, C Lubet, RA Kelloff, GJ De Flora, S AF D'Agostini, F Balansky, RM Bennicelli, C Lubet, RA Kelloff, GJ De Flora, S TI Pilot studies evaluating the lung tumor yield in cigarette smoke-exposed mice SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE cigarette smoke; lung tumors; animal models ID ENVIRONMENTAL TOBACCO-SMOKE; HALOGEN LAMPS; INDUCED CLASTOGENICITY; CHRONIC INHALATION; N-ACETYLCYSTEINE; A/J MICE; CARCINOGENICITY; CANCER; INHIBITION; INDUCTION AB In spite of the major role played by cigarette smoking in the epidemiology of lung cancer, it is very difficult to reproduce the carcinogenicity of this complex mixture in animal models. We implemented a series of pilot experiments in three mouse strains, exposed either to environmental cigarette smoke (ECS) or mainstream cigarette smoke (MCS) or its condensate (MCSC). The whole-body exposure of Aroclor-treated A/J mice to ECS resulted in a rapid and potent induction of micronuclei in peripheral blood erythrocytes. After 6 months of exposure, 6 h a day, followed by 4 months of recovery in filtered air, both lung tumor incidence and multiplicity were significantly increased as compared to sham-exposed mice (77.8% vs. 22.2%, and 1.11 +/- 0.26 vs. 0.22 +/- 0.15, means +/- SE). Multiple i.p. injections of butylated hydroxytoluene did not significantly enhance the tumor yield. Another experiment confirmed the responsiveness of A/J mice exposed to ECS for 5 months, followed by 4 months of recovery in air (75.0% vs. 25.0%, and 1.05 +/- 0.17 vs. 0.25 +/- 0.10). In contrast, the increase in lung tumor yield after exposure to ECS for 2 months, followed by recovery in air for 7 months, was not significant, and the continuous exposure to ECS for 9 months was totally ineffective. These data, in agreement with previous results of others, show that exposure of A/J mice to ECS for 5-6 months, followed by recovery in air for 4 months, is successful in inducing a weak but significant and reproducible increase in lung tumor yield. Furthermore, the simultaneous exposure to the light emitted by halogen quartz bulbs for 9 months and to ECS for 5 months, followed by 4 months in air, was again weakly tumorigenic (incidence of 55.0% and multiplicity of 0.75 +/- 0.19), whereas exposure to both ECS and light for 9 months was devoid of effect. The whole-body exposure of A/J mice to MCS, 1 h a day for 5 months, or weekly i.p. injections of MCSC for 5 months, followed in both cases by 4 months of recovery in air, failed to enhance the lung tumor yield. The whole-body exposure of SKH-1 hairless mice to ECS for 6 months, followed by exposure to halogen light for 8 months, resulted in the formation of multiple skin tumors but failed to produce lung tumors. The whole-body exposure of C57BL/6 mice to ECS for 6 months failed to induce any lung tumor but caused alopecia, gray hair, and hair bulb cell apoptosis, which were prevented by the oral administration of N-acetylcysteine. C1 Univ Genoa, Dept Hlth Sci, Sect Hyg & Prevent Med, I-16132 Genoa, Italy. Natl Canc Inst, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Sect Hyg & Prevent Med, Via A Pastore 1, I-16132 Genoa, Italy. FU NCI NIH HHS [N01-CN-75008] NR 43 TC 38 Z9 38 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD MAR PY 2001 VL 18 IS 3 BP 607 EP 615 PG 9 WC Oncology SC Oncology GA 402YY UT WOS:000167016800024 PM 11179494 ER PT J AU Coleman, CN Cumberlin, R AF Coleman, CN Cumberlin, R TI We're from the government and we're here to help you SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 NCI, Radiat Res Program, EPN, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Res Program, EPN, NIH, Suite 6000,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2001 VL 49 IS 3 BP 617 EP 618 DI 10.1016/S0360-3016(00)01404-8 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 400XK UT WOS:000166897800001 PM 11172940 ER PT J AU Brown, DR Talkington, DF Thacker, WL Brown, MB Dillehay, DL Tully, JG AF Brown, DR Talkington, DF Thacker, WL Brown, MB Dillehay, DL Tully, JG TI Mycoplasma microti sp nov., isolated from the respiratory tract of prairie voles (Microtus ochrogaster) SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE mycoplasma; rodent; prairie vole; respiratory tract AB Mycoplasmas were isolated from the respiratory tracts of prairie voles (Microtus ochrogaster). This paper presents biochemical, serological and molecular genetic characterizations of those organisms and proposes a new species, Mycoplasma microti sp. nov. The type strain of Mycoplasma microti is strain IL371(T) (ATCC 700935(T)). C1 Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32610 USA. Ctr Dis Control & Prevent, Div Bacterial & Mycot Dis, Atlanta, GA 30333 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Div Anim Resources, Atlanta, GA 30322 USA. NIAID, Mycoplasma Sect, Frederick, MD 21702 USA. RP Brown, DR (reprint author), Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32610 USA. NR 13 TC 3 Z9 3 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAR PY 2001 VL 51 BP 409 EP 412 PN 2 PG 4 WC Microbiology SC Microbiology GA 413QD UT WOS:000167622500016 PM 11321086 ER PT J AU Brown, MB Brown, DR Klein, PA McLaughlin, GS Schumacher, IM Jacobson, ER Adams, HP Tully, JG AF Brown, MB Brown, DR Klein, PA McLaughlin, GS Schumacher, IM Jacobson, ER Adams, HP Tully, JG TI Mycoplasma agassizii sp nov., isolated from the upper respiratory tract of the desert tortoise (Gopherus agassizii and the gopher tortoise (Gopherus polyphemus) SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE mycoplasma; tortoise; upper respiratory tract disease ID DISEASE; TESTUDINIS; ANTIBODIES AB Biochemical, serological and molecular genetic studies were performed on seven mycoplasma isolates that were recovered from the upper respiratory tract of clinically ill desert tortoises. The isolates were serologically related to each other but serologically distinct from previously described species. Unique mycoplasma species-specific 16S rRNA nucleotide sequences were found in the proposed type strain. The name Mycoplasma agassizii is proposed for these isolates. The type strain is PS6(T)(= ATCC 700616(T)) which caused upper respiratory tract disease (URTD) in experimentally infected tortoises. C1 Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32610 USA. Univ Florida, Coll Vet Med, Dept Small Anim Clin Sci, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Pathol & Lab Med, Gainesville, FL 32610 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. NIAID, Myocplasma Sect, Frederick, MD 21702 USA. RP Brown, MB (reprint author), Univ Florida, Coll Vet Med, Dept Pathobiol, Gainesville, FL 32610 USA. NR 26 TC 23 Z9 24 U1 3 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAR PY 2001 VL 51 BP 413 EP 418 PN 2 PG 6 WC Microbiology SC Microbiology GA 413QD UT WOS:000167622500017 PM 11321087 ER PT J AU Brown, DR Farley, JM Zacher, LA Carlton, JMR Clippinger, TL Tully, JG Brown, MB AF Brown, DR Farley, JM Zacher, LA Carlton, JMR Clippinger, TL Tully, JG Brown, MB TI Mycoplasma alligatoris sp nov., from American alligators SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE mycoplasma; alligator; crocodilian; reptile AB Mycoplasmas were isolated from multiple tissues of diseased American alligators (Alligator mississippiensis). This paper presents biochemical, serological and molecular genetic characterizations of a lethal pathogen of alligators for which the name Mycoplasma alligatoris sp, nov. is proposed. The type strain is A21JP2(T) (ATCC 700619(T)). C1 Univ Florida, Coll Vet Med, Dept Pathol, Gainesville, FL 32610 USA. Univ Florida, Coll Vet Med, Dept Small Anim Clin Sci, Gainesville, FL 32610 USA. NIAID, Mycoplasma Sect, Frederick, MD 21702 USA. RP Brown, DR (reprint author), Univ Florida, Coll Vet Med, Dept Pathol, Gainesville, FL 32610 USA. NR 22 TC 27 Z9 27 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAR PY 2001 VL 51 BP 419 EP 424 PN 2 PG 6 WC Microbiology SC Microbiology GA 413QD UT WOS:000167622500018 PM 11321088 ER PT J AU Pettersson, B Tully, JG Bolske, G Johansson, KE AF Pettersson, B Tully, JG Bolske, G Johansson, KE TI Re-evaluation of the classical Mycoplasma lipophilum cluster (Weisburg et al. 1989) and description of two new clusters in the hominis group based on 16S rDNA sequences SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE 16S rRNA; hominis group; Mollicutes; Mycoplasma lipophilum cluster; phylogeny ID RIBOSOMAL-RNA GENE; PHYLOGENY; SPERMATOPHILUM; CLASSIFICATION; DEFINITION AB The Mycoplasma lipophilum cluster (Weisburg ef al. 1989) in the hominis group of the mollicutes is re-evaluated in this work to update the phylogenetic framework for classification of species within the genus Mycoplasma. Therefore, sequences of the 16S rRNA gene were determined from previously described species, and 11 were found to be closely related to the M. lipophilum cluster, A selection of members of the other hitherto defined clusters of the hominis group was included for phylogenetic analysis, revealing that the classical M. lipophilum cluster could be re-organized into two clusters, namely the M. lipophilum cluster and the Mycoplasma bovis cluster. The former was found to contain two species, while the latter contained 20 species. The two clusters were closely related, sharing an ancestral branch with the Mycoplasma synoviae cluster. Furthermore, the M. bovis cluster could be divided into subclusters. Interestingly, two species, Mycoplasma equigenitalium and Mycoplasma elephantis, formed a distinct and early branch of the M, lipophilum, M. bovis and M, synoviae clusters. This entity was termed the M. equigenitalium cluster. The clusters and subclusters could be verified by using neighbour-joining and maximum-likelihood analyses on a variety of data sets, bootstrap calculations, secondary structure analysis and signature nucleotides. Therefore, the new 16S rDNA data presented in this work were used to reevaluate the M. lipophilum cluster, leading to the definition of two additional clusters, At present, the mollicutes belonging to the hominis group can be classified into ten evolutionary lineages. C1 Royal Inst Technol, Dept Biotechnol, S-10044 Stockholm, Sweden. NIAID, Frederick Canc Res & Dev Ctr, Mycoplasma Sect, Frederick, MD 21702 USA. Natl Vet Inst, Dept Bacteriol, S-75189 Uppsala, Sweden. RP Pettersson, B (reprint author), Royal Inst Technol, Dept Biotechnol, S-10044 Stockholm, Sweden. NR 37 TC 18 Z9 18 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAR PY 2001 VL 51 BP 633 EP 643 PN 2 PG 11 WC Microbiology SC Microbiology GA 413QD UT WOS:000167622500040 PM 11321109 ER PT J AU Bukh, J Forns, X Emerson, SU Purcell, RH AF Bukh, J Forns, X Emerson, SU Purcell, RH TI Studies of hepatitis C virus in chimpanzees and their importance for vaccine development SO INTERVIROLOGY LA English DT Article DE hepatitis C virus; acute hepatitis C; chronic hepatitis C; flaviviridae; chimpanzee; immunity; neutralizing antibodies; virus pools; vaccine ID NON-B-HEPATITIS; HYPERVARIABLE REGION-1; IMMUNE GLOBULIN; NON-A; INOCULATED CHIMPANZEES; SEQUENCE STABILITY; HYPERIMMUNE SERUM; DNA IMMUNIZATION; GLYCOPROTEIN E2; CELL-SURFACE AB Persistent infection with hepatitis C virus (HCV) is an important cause of chronic liver disease worldwide. Therefore, the development of vaccines to prevent HCV infection, or at least to prevent progression to chronicity, is a major goal. Potential HCV vaccine candidates include recombinant proteins, recombinant viruses, DNA constructs, synthetic peptides and virus-like particles. Various vaccine candidates have been shown to generate humoral and cellular immune responses in animals, primarily in mice. However, the efficacy of most vaccine candidates in protecting against HCV has not been tested because the chimpanzee, the only animal other than humans that is susceptible to HCV, is not readily available, requires special facilities, and is very expensive. The course of infection in chimpanzees is similar in its diversity to that in humans and detailed studies in this model are beginning to define the immune responses that can terminate HCV infection. Of relevance for vaccine evaluation was the titration in chimpanzees of different HCV variants to provide well-characterized challenge pools. In addition, monoclonal virus pools generated from chimpanzees infected with cloned viruses make it possible now to examine immunity to HCV without the confounding factor of antigenic diversity of the challenge virus (quasispecies). The vaccine trials performed in chimpanzees to date all have tested the efficacy of immunizations with various forms of the envelope proteins of HCV. Copyright (C) 2001 S. Karger AG, Basel. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 7,Room 201,7 Ctr Dr, Bethesda, MD 20892 USA. NR 71 TC 43 Z9 47 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0300-5526 J9 INTERVIROLOGY JI Intervirology PD MAR-JUN PY 2001 VL 44 IS 2-3 BP 132 EP 142 DI 10.1159/000050040 PG 11 WC Virology SC Virology GA 464JU UT WOS:000170530100008 PM 11509874 ER PT J AU Eberhard, J Trilling, D Barr, RA Dellinger, A Wagner, E Foley, DJ AF Eberhard, J Trilling, D Barr, RA Dellinger, A Wagner, E Foley, DJ TI Older drivers SO ISSUES IN SCIENCE AND TECHNOLOGY LA English DT Editorial Material C1 Natl Highway Traff Safety Adm US, Off Res & Traffic Records, Washington, DC 20590 USA. US Dept Transportat, Off Secretary, Washington, DC USA. NIA, Off Extramural Act, Bethesda, MD 20892 USA. Ctr Dis Control, Atlanta, GA 30333 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Eberhard, J (reprint author), Natl Highway Traff Safety Adm US, Off Res & Traffic Records, Washington, DC 20590 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0748-5492 J9 ISSUES SCI TECHNOL JI Issues Sci. Technol. PD SPR PY 2001 VL 17 IS 3 BP 16 EP 17 PG 2 WC Engineering, Multidisciplinary; Engineering, Industrial; Multidisciplinary Sciences; Social Issues SC Engineering; Science & Technology - Other Topics; Social Issues GA 492MK UT WOS:000172172000015 ER PT J AU Leshner, AI AF Leshner, AI TI Addiction is a brain disease SO ISSUES IN SCIENCE AND TECHNOLOGY LA English DT Article ID DRUG C1 NIDA, NIH, Bethesda, MD 20892 USA. RP Leshner, AI (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. NR 9 TC 9 Z9 9 U1 2 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0748-5492 J9 ISSUES SCI TECHNOL JI Issues Sci. Technol. PD SPR PY 2001 VL 17 IS 3 BP 75 EP 80 PG 6 WC Engineering, Multidisciplinary; Engineering, Industrial; Multidisciplinary Sciences; Social Issues SC Engineering; Science & Technology - Other Topics; Social Issues GA 492MK UT WOS:000172172000035 ER PT J AU Read, JS Tuomala, R Kpamegan, E Zorrilla, C Landesman, S Brown, G Vajaranant, M Hammill, H Thompson, B AF Read, JS Tuomala, R Kpamegan, E Zorrilla, C Landesman, S Brown, G Vajaranant, M Hammill, H Thompson, B CA Women Infants Transmission Study TI Mode of delivery and postpartum morbidity among HIV-infected women: The Women and Infants Transmission Study SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 6th Conference on Retroviruses and Opportunistic Infections CY JAN 31-FEB 04, 1999 CL CHICAGO, ILLINOIS DE postpartum morbidity; HIV infection; AIDS; mode of delivery ID CESAREAN-SECTION; ANTIRETROVIRAL TREATMENT; MATERNAL COMPLICATIONS; PLACENTAL REMOVAL; POSITIVE WOMEN; RISK-FACTORS; ENDOMETRITIS; PROPHYLAXIS; AIDS AB Cesarean delivery before onset of labor and rupture of membranes (i.e., scheduled cesarean delivery) is associated with a lower risk of vertical transmission of HIV. The following a priori hypotheses were tested: among HIV-infected women, scheduled cesarean delivery is associated with a higher risk of postpartum morbidity, longer hospitalization, and a higher risk of rehospitalization than spontaneous vaginal delivery. Postpartum morbidity occurred following 178 of 1,186 (15%) of deliveries during 1990 to 1998 in The Women and Infants Transmission Study. The most commonly reported postpartum morbidity events were: fever without infection, hemorrhage or severe anemia, endometritis, urinary tract infection, and cesarean wound complications. Several time trends were observed: the median duration of ruptured membranes decreased (p < .001), intrapartum antibiotic use increased (p < .001), the median antepartum plasma HIV RNA concentration decreased (p < .001). and the incidence of any postpartum morbidity decreased (p = .02). With spontaneous vaginal delivery as the reference category, both scheduled (odds ratio [OR] = 4.69: 95% confidence interval [95% CI], 2.03-10.84), and nonscheduled (OR, 2.50; 95% CI, 1.24-5.04) cesarean deliveries were associated with fever without infection; with urinary tract infection (OR, 3.79; 95% CI 1.04-13.85; OR, 3.86; 95% CI, 1.55-9.60, respectively), and with any postpartum morbidity (OR, 3.19: 95% CI 1.69-6.00; OR, 4.10; 95% CI, 2.71-6.19, respectively). Nonscheduled cesarean deliveries were more likely to be complicated by endometritis (OR, 6.98: 95% CI, 3.53-13.78). Adjusted ORs relating mode of delivery and each of the outcomes (fever without infection, urinary tract infection, endometritis, and any postpartum morbidity) were similar to unadjusted ORs. Results of this analysis indicate scheduled cesarean delivery is associated with an increased risk of any postpartum morbidity and, specifically, postpartum fever without infection. The potential for postpartum morbidity with scheduled cesarean delivery should be considered in light of possible adverse events associated with other interventions to decrease the risk of vertical transmission of HIV. Counseling of HIV-infected pregnant women regarding scheduled cesarean delivery as a possible intervention to decrease maternal-infant transmission of HIV should include discussion of these results, as well as new data as they become available, regarding the incidence and severity of postpartum morbidity events among HIV-infected women according to mode of delivery. C1 NICHD, Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. CTASC, Baltimore, MD USA. Univ Puerto Rico, San Juan, PR 00936 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Columbia Univ, New York, NY USA. Univ Illinois, Chicago, IL USA. Baylor Coll Med, Houston, TX 77030 USA. RP Read, JS (reprint author), NICHD, Adolescent & Maternal AIDS Branch, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd MSC 7510, Bethesda, MD 20892 USA. FU NIAID NIH HHS [U01 AI 34842, N01 AI 85339, U01 AI 34840, U01 AI 34854, U01 AI 34856, U01 AI 34841]; NICHD NIH HHS [HD-8-2913, R0-1-HD-25714] NR 33 TC 47 Z9 50 U1 0 U2 4 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 2001 VL 26 IS 3 BP 236 EP 245 DI 10.1097/00126334-200103010-00005 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 411EL UT WOS:000167485100005 PM 11242196 ER PT J AU Gomez-Cordoves, C Bartolome, B Vieira, W Virador, VM AF Gomez-Cordoves, C Bartolome, B Vieira, W Virador, VM TI Effects of wine phenolics and sorghum tannins on tyrosinase activity and growth of melanoma cells SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE wine phenolics; sorghum tannins; melanogenesis; melanocyte; melanoma ID PHOTODIODE-ARRAY DETECTION; GREEN TEA; IN-VITRO; RED WINE; (-)-EPIGALLOCATECHIN GALLATE; ANTIOXIDANT ACTIVITY; HUMAN MELANOCYTES; CARCINOMA-CELLS; TUMOR PROMOTER; MELANOGENESIS AB In this study, three different phenolic (anthocyanin, other flavonoid, and phenolic acid) fractions from wine and a condensed tannin preparation from sorghum were tested for their effects on melanogenesis of normal cells and growth of human melanoma cells. The wine phenolic fractions decreased melanogenic activity (tyrosinase activity) at concentrations that resulted in a slight variation in melanocyte viability. Sorghum tannins, however, increased melanogenic activity, although no increase was found in total melanin at the concentrations that least affect melanocyte viability. Incubation of human melanoma cells with the wine fractions and sorghum tannins resulted in a decrease in colony formation, although the effect was not dose dependent in all cases. These results suggest that all of these phenolic fractions have potential as therapeutic agents in the treatments of human melanoma, although the mechanisms by which cellular toxicity is effected seem to be different among the fractions. C1 CSIC, Inst Fermentac Ind, E-28006 Madrid, Spain. NIH, Bethesda, MD 20892 USA. RP Gomez-Cordoves, C (reprint author), CSIC, Inst Fermentac Ind, Juan Cierva 3, E-28006 Madrid, Spain. RI Bartolome, Begona/H-4857-2012 OI Bartolome, Begona/0000-0002-4470-251X NR 41 TC 54 Z9 57 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD MAR PY 2001 VL 49 IS 3 BP 1620 EP 1624 DI 10.1021/jf001116h PG 5 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 437AE UT WOS:000168967400091 PM 11312905 ER PT J AU Flynn, KM Delclos, KB Newbold, RR Ferguson, SA AF Flynn, KM Delclos, KB Newbold, RR Ferguson, SA TI Behavioral responses of rats exposed to long-term dietary vinclozolin SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE fungicide; endocrine disrupter; androgen ID SEX-DIFFERENCES; TESTOSTERONE PROPIONATE; SACCHARIN PREFERENCE; GONADAL-HORMONES; PLAY; FUNGICIDE; DIFFERENTIATION; DEFEMINIZATION; ANTIANDROGEN; METABOLITES AB Vinclozolin is a fungicide used on food crops with human exposure estimated at similar to2 mug/kg/day from ingestion; occupational exposure, however, may be greater. The metabolites of vinclozolin have been reported to act as antiandrogens and have adverse effects on reproductive physiology and behavior in animals. Here, pregnant rats were fed soy-free diets containing 0, 10, 150, or 750 ppm of vinclozolin (approximately 0, 0.8, 12, and 60 mg/kg/day for an adult) beginning on gestational day 7, and offspring were continued on these diets through sacrifice at postnatal day 77. Male and female offspring were assessed for changes in several nonreproductive sexually dimorphic behaviors: open field and running wheel locomotor activity, play behavior, and consumption of saccharin- and sodium chloride-flavored solutions. There was a significant interaction of sex with vinclozolin exposure on running wheel activity, which indicated that females in the high-dose exposure group were hypoactive compared to same-sex controls. There was a significant overall effect of vinclozolin exposure on fluid consumption, and high-dose animals showed increased intake of the saccharin solution and decreased intake of plain water while saccharin was available. Effects were more pronounced in females, which drank 40.8% more saccharin than control females, whereas males drank 6.2% more than control males. There were no effects of vinclozolin treatment on play behavior or sodium solution intake. Gestational duration, total and live pups per litter, litter sex ratios, and birth weight were also not significantly affected, nor were body weight and food intake for dams and offspring. These results indicate that long-term dietary exposure to vinclozolin does not have severe toxicological consequences on the nonreproductive behaviors measured here. However, exposure may cause subtle alterations in locomotor activity and consumption of saccharin-flavored solution. C1 US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. Natl Inst Environm Hlth Sci, Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Ferguson, SA (reprint author), US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, 3900 NCTR Rd,HFT-132, Jefferson, AR 72079 USA. NR 32 TC 21 Z9 21 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD MAR PY 2001 VL 49 IS 3 BP 1658 EP 1665 DI 10.1021/jf0008893 PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 437AE UT WOS:000168967400097 PM 11312911 ER PT J AU Hickel, KW AF Hickel, KW TI War, region, and social welfare: Federal aid to servicemen's dependents in the South, 1917-1921 SO JOURNAL OF AMERICAN HISTORY LA English DT Review ID UNITED-STATES C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Hickel, KW (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 106 TC 12 Z9 12 U1 0 U2 0 PU ORGANIZATION AMER HISTORIANS PI BLOOMINGTON PA 112 N BRYAN ST, BLOOMINGTON, IN 47408 USA SN 0021-8723 J9 J AM HIST JI J. Am. Hist. PD MAR PY 2001 VL 87 IS 4 BP 1362 EP 1391 DI 10.2307/2674732 PG 30 WC History SC History GA 416RK UT WOS:000167793800005 ER PT J AU Guesbeck, NR Hickey, MS MacDonald, KG Pories, WJ Harper, I Ravussin, E Dohm, GL Houmard, JA AF Guesbeck, NR Hickey, MS MacDonald, KG Pories, WJ Harper, I Ravussin, E Dohm, GL Houmard, JA TI Substrate utilization during exercise in formerly morbidly obese women SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE fat; lipid; obesity ID ENERGY-EXPENDITURE; POST-OBESE; FAT OXIDATION; WEIGHT-GAIN; METABOLISM; INDIVIDUALS; NONOBESE; DIET AB The purpose of this study was to compare substrate utilization during fasting and submaximal exercise in morbidly obese women after weight loss (WL) with that in weight-matched controls (C). WL were studied in the weight-stable condition similar to 24 mo after gastric bypass surgery. Energy intake (self-reported) and expenditure ((H2O)-H-2-O-18) were also compared. The respiratory exchange ratio during exercise at the same absolute (15 W) workload was significantly (P less than or equal to 0.05) elevated in WL vs. C (0.90 +/- 0.02 vs. 0.83 +/- 0.03); this was reflected as lower fat utilization in WL (29.7 +/- 4.8 vs. 53.2 +/- 9.7% of energy from fat). Respiratory exchange ratio during exercise at the same relative (65% of maximal O-2 uptake) intensity was also significantly (P < 0.05) elevated in WL (0.96 +/- 0.01 vs. 0.89 +/- 0.02), and fat use was concomitantly depressed (12.4 +/- 3.0 vs. 34.3 +/- 9.9% of energy from fat). Resting substrate utilization, daily energy expenditure, and self-reported relative macronutrient intake did not differ between groups. These data suggest that lipid oxidation is depressed during physical activity in WL. This defect may, at least in part, contribute to a propensity for the development of morbid obesity. C1 E Carolina Univ, Human Performance Lab, Greenville, NC 27858 USA. E Carolina Univ, Dept Exercise & Sport Sci, Greenville, NC 27858 USA. E Carolina Univ, Dept Biochem, Greenville, NC 27858 USA. E Carolina Univ, Dept Surg, Greenville, NC 27858 USA. NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Houmard, JA (reprint author), E Carolina Univ, Human Performance Lab, Ward Sports Med Bldg, Greenville, NC 27858 USA. FU NIA NIH HHS [AG-10025]; NIDDK NIH HHS [DK-46121, DK-52999] NR 25 TC 22 Z9 25 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD MAR PY 2001 VL 90 IS 3 BP 1007 EP 1012 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 403PJ UT WOS:000167051400033 PM 11181612 ER PT J AU Feigenson, N Park, J Salovey, P AF Feigenson, N Park, J Salovey, P TI The role of emotions in comparative negligence judgments SO JOURNAL OF APPLIED SOCIAL PSYCHOLOGY LA English DT Article ID COUNTERFACTUAL THINKING; ATTRIBUTIONAL ANALYSIS; SOCIAL-PERCEPTION; OUTCOME SEVERITY; INJURY SEVERITY; DAMAGE AWARDS; MOCK JURORS; RESPONSIBILITY; LIABILITY; ANGER AB This experiment studied the role of emotional arousal in mediating the impact of plaintiff and defendant blameworthiness and accident severity on comparative negligence judgments. Participants (N = 214) read descriptions and viewed photographs of 2 accident cases varying in outcome severity, victim blameworthiness, and defendant blameworthiness. Participants then rated their emotional responses to the cases, apportioned fault between the parties, and assessed gross and discounted damages. Blameworthiness and outcome severity affected apportionment of fault, and the effects of blameworthiness and severity appeared to be mediated by the arousal of anger toward the parties. Damage awards were determined primarily by the severity of the accident and were not mediated by emotional arousal. C1 Quinnipiac Univ, Sch Law, Hamden, CT 06518 USA. NICHHD, Bethesda, MD 20892 USA. Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Feigenson, N (reprint author), Quinnipiac Univ, Sch Law, Hamden, CT 06518 USA. NR 52 TC 15 Z9 15 U1 0 U2 1 PU V H WINSTON & SON INC PI PALM BEACH PA 360 SOUTH OCEAN BLVD, PH-B, PALM BEACH, FL 33480 USA SN 0021-9029 J9 J APPL SOC PSYCHOL JI J. Appl. Soc. Psychol. PD MAR PY 2001 VL 31 IS 3 BP 576 EP + DI 10.1111/j.1559-1816.2001.tb02057.x PG 28 WC Psychology, Social SC Psychology GA 428XL UT WOS:000168486900008 ER PT J AU Long, CD Hayes, SF van Putten, JPM Harvey, HA Apicella, MA Seifert, HS AF Long, CD Hayes, SF van Putten, JPM Harvey, HA Apicella, MA Seifert, HS TI Modulation of gonococcal piliation by regulatable transcription of pilE SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HUMAN EPITHELIAL-CELLS; NEISSERIA-GONORRHOEAE; ANTIGENIC VARIATION; DNA TRANSFORMATION; PHASE VARIATION; IV PILI; PATHOGENIC NEISSERIA; SHUTTLE MUTAGENESIS; GENE CONVERSION; SEQUENCE AB The gonococcal pilus, a member of the type TV family of pill, is composed of numerous monomers of the pilin protein and plays an important role in the initiation of disease by providing the primary attachment of the bacterial cell to human mucosal tissues. Piliation also correlates with efficient DNA transformation. To investigate the relationships between these pilus-related functions, the piliation state, and the availability of pilin, we constructed a derivative of MS11-C9 (Delta pitE1) in which the lacIOP regulatory sequences control pilE transcription. In this strain, MS11-C9.10, the steady-state levels of pilin mRNA and protein directly correlate with the concentration of IPTG (isopropyl-beta -D-thiogalactopyranoside) in the growth medium and can reach near-wild-type levels of expression. Transmission electron microscopy (TEM) demonstrated that the number of pill per cell correlated with the steady-state expression levels: at a low level of transcription, single long pill were observed; at a moderate expression level, many singular and bundled pill were expressed; and upon full gene expression, increased lateral association between pill was observed. Analysis of pilus assembly by TEM and epithelial cell adherence over a time course of induction demonstrated that pill were expressed as early as 1 h postinduction. Analysis at different steady-state levels of transcription demonstrated that DNA transformation efficiency and adherence of MS11-C9.10 to transformed and primary epithetial cells also correlated with the level of piliation, These data show that modulation of the level of pilE transcription, without a change in pilE sequence, can alter the number of pill expressed per cell, pilus bundling, DNA transformation competence, and epithelial cell adherence of the gonococcus. C1 Northwestern Univ, Sch Med, Dept Immunol Microbiol, Chicago, IL 60611 USA. NIAID, Rocky Mt Labs, Microscopy Branch, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. Univ Iowa, Dept Microbiol, Iowa City, IA 52242 USA. RP Seifert, HS (reprint author), Northwestern Univ, Sch Med, Dept Immunol Microbiol, 303 E Chicago Ave S213, Chicago, IL 60611 USA. OI van Putten, Jos/0000-0002-4126-8172 FU NIAID NIH HHS [U19 AI031494, R37 AI033493, AI33493, AI18384, AI31494, R01 AI033493, U19 AI038515]; NIGMS NIH HHS [T32 GM008061] NR 61 TC 20 Z9 20 U1 0 U2 2 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 2001 VL 183 IS 5 BP 1600 EP 1609 DI 10.1128/JB.183.5.1600-1609.2001 PG 10 WC Microbiology SC Microbiology GA 401TD UT WOS:000166943600013 PM 11160091 ER PT J AU Sledjeski, DD Whitman, C Zhang, AX AF Sledjeski, DD Whitman, C Zhang, AX TI Hfq is necessary for regulation by the untranslated RNA DsrA SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI K-12; OMPA MESSENGER-RNA; HOST FACTOR-I; GENE-EXPRESSION; SALMONELLA-TYPHIMURIUM; RPOS TRANSLATION; SIGMA-FACTOR; PROTEIN; PROMOTER; BINDING AB DsrA is an 85-nucleotide, untranslated RNA that has multiple regulatory activities at 30 degreesC. These activities include the translational regulation of RpoS and H-NS, global transcriptional regulators in Escherichia coli, Hfq is an E. coli protein necessary for the in vitro and in vivo replication of the RNA phage Q beta, Hfq also plays a role in the degradation of numerous RNA transcripts. Here we show that an hfq mutant strain is defective for DsrA-mediated regulation of both rpoS and hns. The defect in rpoS expression can be partially overcome by overexpression of DsrA, Hfq does not regulate the transcription of DsrA, and DsrA does not alter the accumulation of Hfq. However, in an hfq mutant, chromosome-expressed DsrA was unstable (half-life of 1 min) and truncated at the 3' end. When expressed from a multicopy plasmid, DsrA was stable in both wild-type and hfq mutant strains, but it had only partial activity in the hfq mutant strain. Purified Hfq binds DsrA in vitro. These results suggest that Hfq acts as a protein cofactor for the regulatory activities of DsrA by either altering the structure of DsrA or forming an active RNA-protein complex. C1 Med Coll Ohio, Dept Microbiol & Immunol, Toledo, OH 43614 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Sledjeski, DD (reprint author), Med Coll Ohio, Dept Microbiol & Immunol, 3055 Arlington Ave, Toledo, OH 43614 USA. OI Sledjeski, Darren/0000-0001-9882-6625 FU NIGMS NIH HHS [GM56448] NR 38 TC 198 Z9 203 U1 1 U2 11 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 2001 VL 183 IS 6 BP 1997 EP 2005 DI 10.1128/JB.183.6.1997-2005.2001 PG 9 WC Microbiology SC Microbiology GA 407FJ UT WOS:000167261300019 PM 11222598 ER PT J AU Barrientos, LG Campos-Olivas, R Louis, JM Fiser, A Sali, A Gronenborn, AM AF Barrientos, LG Campos-Olivas, R Louis, JM Fiser, A Sali, A Gronenborn, AM TI Letter to the Editor: H-1, C-13, N-15 resonance assignments and fold verification of a circular permuted variant of the potent HIV-inactivating protein cyanovirin-N* SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE circular permutation; cyanovirin-N; HIV-1; residual dipolar couplings; resonance assignments C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Pels Family Ctr Biochem & Struct Biol, Lab Mol Biophys, New York, NY 10021 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RI Campos-Olivas, Ramon/L-9173-2014 OI Campos-Olivas, Ramon/0000-0002-5743-2221 NR 10 TC 15 Z9 16 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAR PY 2001 VL 19 IS 3 BP 289 EP 290 DI 10.1023/A:1011292919947 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 414ZJ UT WOS:000167695800014 PM 11330821 ER PT J AU Baker, RA Milstien, S Katusic, ZS AF Baker, RA Milstien, S Katusic, ZS TI Effect of vitamin C on the availability of tetrahydrobiopterin in human endothelial cells SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE vitamin C; nitric oxide synthase; peroxynitrite; tetrahydrobiopterin; MnTBAP ID NITRIC-OXIDE SYNTHASE; CORONARY-ARTERY DISEASE; DEPENDENT VASODILATION; VASOMOTOR DYSFUNCTION; SUPEROXIDE; HYPERCHOLESTEROLEMIA; PEROXYNITRITE; HYPERTENSION; ASCORBATE; OXIDATION AB Vitamin C has long been known for its beneficial vascular effects, but its mechanism of action remains unclear. Recent reports suggest that vitamin C may prevent endothelial dysfunction by scavenging free radicals and increasing the bioavailability of nitric oxide. To investigate this area further, we studied the effect of vitamin C (10(-4) M) and Mn(III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP; 10(-5) M), a scavenger of superoxide, hydrogen peroxide, and peroxynitrite, on endothelial nitric oxide synthase (eNOS) enzymatic activity in cultured human umbilical vein endothelial cells, L-Citrulline formation (a measure of eNOS enzymatic activity) was significantly increased in cells treated for 24 h with vitamin C. No effect was observed after MnTBAP treatment. Chronic administration of vitamin C also had no effect on eNOS protein expression. Treatment with vitamin C for 24 h significantly increased levels of the eNOS co-factor tetrahydrobiopterin (BH4), whereas MnTBAP did not affect its levels. Sepiapterin (10(-4) M), a precursor of BH4, significantly increased eNOS activity, whereas addition of vitamin C to cells treated with sepiapterin did not cause any further increase in eNOS activity. Our results suggest that the beneficial effect of vitamin C on endothelial function is best explained by increased intracellular BH4 content and subsequent enhancement of eNOS activity. This effect appears to be independent of the ability of vitamin C to scavenge superoxide anions. C1 Mayo Clin & Mayo Fdn, Dept Anesthesiol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Katusic, ZS (reprint author), Mayo Clin & Mayo Fdn, Dept Anesthesiol, 200 1st St SW, Rochester, MN 55905 USA. NR 32 TC 10 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD MAR PY 2001 VL 37 IS 3 BP 333 EP 338 PG 6 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 404TB UT WOS:000167115800012 ER PT J AU Yewdell, JW Schubert, U Bennink, JR AF Yewdell, JW Schubert, U Bennink, JR TI At the crossroads of cell biology and immunology: DRiPs and other sources of peptide ligands for MHC class I molecules SO JOURNAL OF CELL SCIENCE LA English DT Article DE CD8 cell; T cell; proteasome; defective ribosomal product (DRiP); major histocompatibility complex (MHC); antigen presentation; antigenic peptide; ubiquitin; protein synthesis ID TOXIC LYMPHOCYTES-T; NEWLY SYNTHESIZED PROTEINS; ANTIGEN PRESENTATION; PROTEASOMAL DEGRADATION; 26S PROTEASOME; GENERATION; EPITOPES; RECOGNITION; INHIBITORS; COMPLEX AB CD8(+) T cells are a critical element of vertebrate immune responses to viruses and other intracellular parasites. They roam the body, monitoring cells for the presence of foreign peptides associated with MHC class I molecules of the major histocompatibility complex (MHC), Although it is clear that most of these peptides are generated through the action of proteasomes, the nature of the substrates degraded by proteasomes is an open question. Recent findings indicate that the major pool of substrates consists of a heterogeneous subset of proteins that are degraded within minutes of their synthesis. Evidence suggests that the fraction of newly synthesized proteins targeted for destruction is remarkably high - 30% or more, depending on cell type - possibly because they are defective in some way and cannot reach their intended conformation or location cellular in a time frame deemed appropriate by cells. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 47 TC 63 Z9 65 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 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR PY 2001 VL 114 IS 5 BP 845 EP 851 PG 7 WC Cell Biology SC Cell Biology GA 412RW UT WOS:000167569000003 PM 11181168 ER PT J AU Obermoeller-McCormick, LM Li, YH Osaka, H FitzGerald, DJ Schwartz, AL Bu, GJ AF Obermoeller-McCormick, LM Li, YH Osaka, H FitzGerald, DJ Schwartz, AL Bu, GJ TI Dissection of receptor folding and ligand-binding property with functional minireceptors of LDL receptor-related protein SO JOURNAL OF CELL SCIENCE LA English DT Article DE LRP; RAP; minireceptor; endocytosis; receptor folding ID PSEUDOMONAS EXOTOXIN-A; LIPOPROTEIN-RECEPTOR; ALPHA-2-MACROGLOBULIN RECEPTOR; PLASMINOGEN-ACTIVATOR; GENE FAMILY; SPECIALIZED CHAPERONE; IN-VIVO; LRP; DEGRADATION; EXPRESSION AB The LDL receptor-related protein (LRP) is a large, multifunctional endocytic receptor that binds and endocytoses a variety of structurally and functionally distinct ligands, LRP contains four putative ligand-binding domains. However, only domains II, III and IV, but not domain I, bind the receptor-associated protein (RAP), a molecular chaperone and universal antagonist for LRP, In order to dissect the function of RAP in LRP folding and to examine the ligand-binding properties of LRP, we generated LRP minireceptors that represent each of the four putative ligand-binding domains (termed mLRP1, mLRP2, mLRP3 and mLRP4, respectively), We found that proper folding and trafficking of mLRP2, mLRP3, mLRP4, but not mLRP1, is facilitated by coexpression of RAP, When these mLRPs were stably expressed in Chinese Hamster Ovary cells that lack the endogenous LRP, we found that each of these receptors was processed and traffics through the secretory pathway, Cell surface expression of these minireceptors was quantitatively examined by how cytometric analyses. Using these minireceptor cell lines to map the ligand-binding domains, we found that although the majority of ERP ligands bind to both domain II and domain IV, Pseudomonas exotoxin A utilizes only domain IV for its binding to LRP, We conclude that while domains II and IV of LRP share many ligand-binding properties, each of the putative ligand-binding domains of LRP is unique in its contribution to ligand binding. C1 Washington Univ, Sch Med, St Louis Childrens Hosp, Dept Pediat, St Louis, MO 63110 USA. Washington Univ, Sch Med, St Louis Childrens Hosp, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. Washington Univ, Sch Med, St Louis Childrens Hosp, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Bu, GJ (reprint author), Washington Univ, Sch Med, St Louis Childrens Hosp, Dept Pediat, St Louis, MO 63110 USA. FU NHLBI NIH HHS [HL53280, HL59150]; NIDDK NIH HHS [DK56783] NR 34 TC 79 Z9 80 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR PY 2001 VL 114 IS 5 BP 899 EP 908 PG 10 WC Cell Biology SC Cell Biology GA 412RW UT WOS:000167569000008 PM 11181173 ER PT J AU Abdel-Malek, ZA Scott, MC Furumura, N Lamoreux, ML Ollmann, M Barsh, GS Hearing, VJ AF Abdel-Malek, ZA Scott, MC Furumura, N Lamoreux, ML Ollmann, M Barsh, GS Hearing, VJ TI The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes SO JOURNAL OF CELL SCIENCE LA English DT Article DE melanocortin 1 receptor; agouti signaling protein; alpha-melanocyte stimulating hormone; melanocytes; eumelanin; pheomelanin ID STIMULATING-HORMONE-RECEPTOR; B16 MELANOMA-CELLS; MOLECULAR-CLONING; IN-VITRO; ALPHA-MELANOTROPIN; RED HAIR; GENE; MELANOGENESIS; TYROSINASE; EXPRESSION AB The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-type mouse follicular melanocytes where it induces pheomelanin synthesis. Studies using purified full-length agouti signaling protein has shown that it competes with alpha -melanocyte stimulating hormone for binding to the melanocortin 1 receptor. We have investigated whether ASP binds exclusively to the melanocortin 1 receptor expressed on mouse melanocytes in primary culture, or additionally activates a receptor that has not been identified yet. We have compared the responses of congenic mouse melanocytes derived from C57 BL/6J-E+/E+, e/e, or E-so/E-so mice to alpha -MSH and/or ASP. E+/E+ melanocytes express the wild-type melanocortin 1 receptor, e/e melanocytes express a loss-of-function mutation in the melanocortin 1 receptor that results in a yellow coat color, and E-so/E-so is a mutation that causes constitutive activation of the melanocortin 1 receptor and renders melanocytes unresponsive to a-melanocyte stimulating hormone. Mouse E+/E+ melanocytes, but not e/e or E-so/E-so melanocytes, respond to agouti signaling protein with decreased basal tyrosinase activity, and reduction in levels of tyrosinase and tyrosinase-related proteins 1 and 2, Only in E+/E+ melanocytes does agouti signaling protein abrogate the stimulatory effects of alpha -melanocyte stimulating hormone on cAMP formation and tyrosinase activity. These results indicate that a functional melanocortin 1 receptor is obligatory for the response of mammalian melanocytes to agouti signaling protein. C1 Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH 45221 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Abdel-Malek, ZA (reprint author), Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH 45221 USA. FU NIEHS NIH HHS [R01 ES 06882, R01 ES 09110] NR 34 TC 45 Z9 50 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 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR PY 2001 VL 114 IS 5 BP 1019 EP 1024 PG 6 WC Cell Biology SC Cell Biology GA 412RW UT WOS:000167569000019 PM 11181184 ER PT J AU Wu, XF Rao, K Bowers, MB Copeland, NG Jenkins, NA Hammer, JA AF Wu, XF Rao, K Bowers, MB Copeland, NG Jenkins, NA Hammer, JA TI Rab27a enables myosin Va-dependent melanosome capture by recruiting the myosin to the organelle SO JOURNAL OF CELL SCIENCE LA English DT Article DE Rab; myosin V; Melanosome; Organelle motility; melanocyte ID COAT-COLOR; SECRETORY VESICLES; POLARIZED DELIVERY; DILUTE MELANOCYTES; MOUSE MELANOCYTES; WILD-TYPE; TRANSPORT; ACTIN; PROTEINS; YEAST AB The peripheral accumulation of melanosomes characteristic of wild-type mouse melanocytes is driven by a cooperative process involving long-range, bidirectional, microtubule-dependent movements coupled to capture and local movement in the actin-rich periphery by myosin Va, the product of the dilute locus. Genetic evidence suggests that Rab27a, the product of the ashen locus, functions with myosin Va in this process. Here we show that ashen melanocytes, like dilute melanocytes, exhibit normal dendritic morphology and melanosome biogenesis, an abnormal accumulation of end-stage melanosomes in the cell center, and rapid, bidirectional, microtubule-dependent melanosome movements between the cell center and the periphery. This phenotype suggests that ashen melanocytes, like dilute melanocytes, are defective in peripheral melanosome capture. Consistent with this, introduction into ashen melanocytes of cDNAs encoding wild-type and GTP-bound versions of Rab27a restores the peripheral accumulation of melanosomes in a microtubule-dependent manner. Conversely, introduction into wild-type melanocytes of the GDP-bound version of Rab27a generates an ashen/dilute phenotype, Rab27a colocalizes with endstage melanosomes in wild-type cells, and is most concentrated in melanosome-rich dendritic tips, where it also colocalizes with myosin Va. Finally, neither endogenous myosin Va nor an expressed, GFP-tagged, myosin Va tail domain fusion protein colocalize with melanosomes in ashen melanocytes, in contrast to that seen previously in wild-type cells. These results argue that Rab27a serves to enable the myosinVa-dependent capture of melanosomes delivered to the periphery by bidirectional, microtubule-dependent transport, and that it does so by recruiting the myosin to the melanosome surface. We suggest that Rab27a, in its GTP-bound and melanosome-associated form, predominates in the periphery, and that it is this form that recruits the myosin, enabling capture. These results argue that Rab27a serves as a myosin Va 'receptor', and add to the growing evidence that Rab GTPases regulate vesicle motors as well as SNARE pairing. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 39 TC 157 Z9 161 U1 1 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR PY 2001 VL 114 IS 6 BP 1091 EP 1100 PG 10 WC Cell Biology SC Cell Biology GA 419ME UT WOS:000167952200008 PM 11228153 ER PT J AU Gao, C Negash, S Wang, HS Ledee, D Guo, HT Russell, P Zelenka, P AF Gao, C Negash, S Wang, HS Ledee, D Guo, HT Russell, P Zelenka, P TI Cdk5 mediates changes in morphology and promotes apoptosis of astrocytoma cells in response to heat shock SO JOURNAL OF CELL SCIENCE LA English DT Article DE Cdk5; p35; adhesion; heat stress; cytoskeleton; U373; astroglioma cells ID CYCLIN-DEPENDENT KINASE-5; NEURONAL CDC2-LIKE KINASE; PROTEIN-KINASE; NEURITE OUTGROWTH; RAT-BRAIN; REGULATORY SUBUNIT; SURVIVAL SIGNALS; PHOSPHORYLATION; ACTIVATOR; EXPRESSION AB The cyclin-dependent kinase member, Cdk5, is expressed in a variety of cell types, but neuron-specific expression of its activator, p35, is thought to limit its activity to neurons, Here we demonstrate that both Cdk5 and p35 are expressed in the human astrocytoma cell line, U373, Cdk5 and p35 are present in the detergent-insoluble cytoskeletal fraction of this cell line and Cdk5 localizes to filopodia and vinculin-rich regions of cell-matrix contact in lamellopodia, When exposed to a 46 degreesC heat shock, U373 cells change shape, lose cell-matrix contacts and show increased levels of apoptosis, To test whether Cdk5 activation might play a role in these events, U373 cells were stably transfected with histidine-tagged or green fluorescent protein-tagged constructs of Cdk5 or a dominant negative mutation, Cdk5T33, Under normal growth conditions, growth characteristics of the stably transfected lines were indistinguishable from untransfected U373 cells and Cdk5 localization was not changed, However, when subjected to heat shock, cells stably transfected with Cdk5-T33 remained flattened, showed little loss of cell-matrix adhesion, and exhibited significantly lower levels of apoptosis, In contrast, cells that overexpressed wild-type Cdk5 showed morphological changes similar to those seen in untransfected U373 cells in response to heat shock and had significantly higher levels of apoptosis, Heat-shocked cells showed changes in p35 mobility and stability of the Cdk5/p35 complex consistent with endogenous Cdk5 activity, Together these findings suggest that endogenous Cdk5 activity may play a key role in regulating morphology, attachment, and apoptosis in U373 cells, and raise the possibility that Cdk5 may be a general regulator of cytoskeletal organization and cell adhesion in both neuronal and non-neuronal cells. C1 NEI, NIH, Bethesda, MD 20892 USA. Yang Ming Univ, Taipei, Taiwan. RP Zelenka, P (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 53 TC 34 Z9 36 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR PY 2001 VL 114 IS 6 BP 1145 EP 1153 PG 9 WC Cell Biology SC Cell Biology GA 419ME UT WOS:000167952200013 PM 11228158 ER PT J AU Furuya, K Ginis, I Takeda, H Chen, Y Hallenbeck, JM AF Furuya, K Ginis, I Takeda, H Chen, Y Hallenbeck, JM TI Cell permeable exogenous ceramide reduces infarct size in spontaneously hypertensive rats supporting in vitro studies that have implicated ceramide in induction of tolerance to ischemia SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE ceramides; ischemic tolerance; lipopolysaccharides; middle cerebral artery occlusion; tumor necrosis factor-alpha ID FOCAL CEREBRAL-ISCHEMIA; TUMOR-NECROSIS-FACTOR; IMMUNOHISTOCHEMICAL LOCALIZATION; SPHINGOMYELIN PATHWAY; GERBIL HIPPOCAMPUS; INDUCED APOPTOSIS; BLOOD-FLOW; TNF-ALPHA; DEATH; ACTIVATION AB Previous work in primary cell culture has shown that TNF-alpha: and ceramide are involved in the signaling that induces tolerance to brain ischemia (Ginis et al., 1999; Liu et al., 2000). To validate the in vitro studies, the authors administered cell permeable analogs of ceramides intracisternally or intravenously to examine their effect on neuroprotection after focal cerebral ischemia. Permanent middle cerebral artery occlusion (MCAO) was performed in spontaneously hypertensive rats. Infarct volumes were assessed at 24 hours after surgery. D-erythro-N-acetylsphingosine (C2-ceramide) or its vehicle was infused intracisternally for 1 hour before MCAO. In a second set of studies, D-erythro-N-octanoylsphingosine (C8-ceramide) or its vehicle was injected intravenously 48 or 24 hours before MCAO to mimic preconditioning (PC) and was also injected 5 minutes after MCAO. C2-ceramide infusion significantly reduced infarct volumes by approximately 14% (P < 0.05). C2-ceramide injection reduced infarct volumes approximately 17% compared with controls. This effect was constant and significant compared with controls over the time periods examined (P < 0.01). This work supports findings in primary brain cell cultures that implicate ceramide as a downstream signal that is proximate to development of tolerance to brain ischemia. Because the degree of protection represents approximately 50% of the maximal infarct reduction observed in this model, there are probably additional signaling pathways that subserve tolerance. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, 36 Convet Dr,MSC 4128,Bldg 36,Rm 4A03, Bethesda, MD 20892 USA. NR 45 TC 39 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2001 VL 21 IS 3 BP 226 EP 232 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 408VJ UT WOS:000167347900006 PM 11295877 ER PT J AU Ruetzler, CA Furuya, K Takeda, H Hallenbeck, JM AF Ruetzler, CA Furuya, K Takeda, H Hallenbeck, JM TI Brain vessels normally undergo cyclic activation and inactivation: Evidence from tumor necrosis factor-alpha, heme oxygenase-1, and manganese superoxide dismutase immunostaining of vessels and perivascular brain cells SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE tumor necrosis factor-alpha; heme oxygenase-1; manganese superoxide dismutase immunohistochemistry; blood vessels; brain ID ENDOTHELIAL-CELLS; OXIDATIVE DAMAGE; RAT-BRAIN; PERIPHERAL-CIRCULATION; DEGENERATIVE DISEASES; ISCHEMIC STROKE; RISK-FACTORS; TNF-ALPHA; EXPRESSION; LIPOPOLYSACCHARIDE AB Studies of vascular biology during the past decade have identified an expanding list of agonists and antagonists that regulate local hemostasis, inflammation, and reactivity in blood vessels. Interactions at the blood-endothelial interface are intricate and complex and have been postulated to play a role in the initiation of stroke and the progression of brain injury during early hours of ischemia, particularly in conjunction with reperfusion injury (Hallenbeck, 1996). In the current study of normal and activated vessels in rat brain, immunoreactive tumor necrosis factor-alpha (TNF-alpha); heme oxygenase-1 (HO-1), and manganese superoxide dismutase (MnSOD) exhibit concentric perivascular rings involving vessel wall and surrounding parenchyma that appear to coincide with one another in serial sections. The ring patterns suggest periodic radial expansion of these molecules released through a process of cyclic activation and inactivation of brain vessel segments. In this process, the rings appear randomly scattered instead of affecting all vessels within a high power field (HPF) synchronously. The average number of vessels per HPF (mean rt SD) with perivascular cuffs of immunoreactive MnSOD increased from 51 +/- 28 in Wistar, 72 +/- 46 in Wistar-Kyoto, and 84 +/- 30 in Sprague Dawley rats (no spontaneous strokes) to 184 +/- 72 in spontaneously hypertensive stroke-prone rats (spontaneous strokes). Perivascular immunoreactive cuffs are also increased in spontaneously hypertensive rats by induction of cytokine expression by lipopolysaccharide (64 +/- 15 vs. 131 +/- 32 /HPF). The patterns of TNF-alpha, HO-1, and MnSOD in naive animals are interpreted to indicate that focal hemostatic balance normally fluctuates in brain vessels and influences surrounding parenchymal cells. Perivascular immunoreactive cuffs representing this process are more frequent in animals with polysaccharide-induced endothelial activation or genetic stroke proneness. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128,Bldg 36,Room 4A03, Bethesda, MD 20892 USA. NR 47 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2001 VL 21 IS 3 BP 244 EP 252 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 408VJ UT WOS:000167347900008 PM 11295879 ER PT J AU Munoz, M Martinez, A Cuttitta, F Gonzalez, A AF Munoz, M Martinez, A Cuttitta, F Gonzalez, A TI Distribution of adrenomedullin-like immunoreactivity in the central nervous system of the frog SO JOURNAL OF CHEMICAL NEUROANATOMY LA English DT Review DE adrenomedullin; neuropeptides; immunohistochemistry; neuroanatomy; evolution; amphibia ID GENE-RELATED PEPTIDE; URODELE PLEURODELES-WALTLII; BASAL GANGLIA ORGANIZATION; ADRENAL ZONA GLOMERULOSA; NORTHERN LEOPARD FROG; ANURAN RANA-RIDIBUNDA; CALCITONIN-GENE; SPINAL-CORD; XENOPUS-LAEVIS; NEUROPEPTIDE-Y AB Adrenomedullin (AM) is a recently discovered peptide widely distributed in the mammalian brain. By using an antiserum specific for human AM, we have analyzed the localization of AM-like immunoreactivity in the brain and spinal cord of the anuran amphibian Rana perezi. Cell bodies immunoreactive (AMi) for AM were located in the dorsal, lateral and medial pallial regions, diagonal band of Broca, medial septum, and above and rostral to the anterior commissure. A large population of AMi neurons was located in the anterior preoptic area, suprachiasmatic nucleus and in the infundibular hypothalamus. The processes of these latter cells are part of the hypothalamo-hypophysial pathway to the neural and intermediate lobes. Labeled cells were observed in the pretectal region, posterior tubercle and the mesencephalic anteroventral tegmental nucleus. Strikingly, Purkinje cells in the cerebellum also showed AM immunoreactivity. albeit not all of these cells were equally stained. Additional cells M ere located in the parabrachial region, principal trigeminal sensory nucleus, reticular nuclei medius and inferior, and the intermediolateral gray of the spinal cord. Immunolabeled fibers were widespread throughout the brain and spinal cord of the frog. They were particularly abundant in the medial amygdala, hypothalamus, mesencephalic tectum, periventricular pray and spinal cord. The distribution pattern of AM-like immunoreactivity in the brain of the frog is very selective and does not correspond with the pattern observed for any other transmitter or neuroactive molecule. The wide distribution of this peptide strongly suggests that it may play a significant role in the multiple neuronal functions in the amphibian brain. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Complutense Madrid, Fac Biol, Dept Cell Biol, Madrid 28040, Spain. NCI, Dept Cell & Canc Biol, NIH, Rockville, MD 20850 USA. RP Gonzalez, A (reprint author), Univ Complutense Madrid, Fac Biol, Dept Cell Biol, Madrid 28040, Spain. RI Martinez, Alfredo/A-3077-2013; Gonzalez, Agustin/H-2146-2015 OI Martinez, Alfredo/0000-0003-4882-4044; Gonzalez, Agustin/0000-0002-3052-0694 NR 108 TC 20 Z9 20 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0891-0618 J9 J CHEM NEUROANAT JI J. Chem. Neuroanat. PD MAR PY 2001 VL 21 IS 2 BP 105 EP 123 DI 10.1016/S0891-0618(00)00114-9 PG 19 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 430NC UT WOS:000168579200001 PM 11312053 ER PT J AU Vitiello, B AF Vitiello, B TI Long-term effects of stimulant medications on the brain: Possible relevance to the treatment of attention deficit hyperactivity disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID REPEATED METHYLPHENIDATE TREATMENT; REPEATED D-AMPHETAMINE; PSYCHIATRIC STATUS; MOTOR-ACTIVITY; DEFICIT/HYPERACTIVITY DISORDER; INTRAVENOUS DEXTROAMPHETAMINE; BEHAVIORAL SENSITIZATION; NATURALISTIC ASSESSMENT; MAGNETIC-RESONANCE; NUCLEUS-ACCUMBENS AB In spite of extensive data supporting the short-term efficacy and safety of stimulant medications in the treatment of children with attention deficit hyperactivity disorder (ADHD), only limited information is available on the long-term effects of these drugs. On one hand, it is unclear whether treatment of ADHD with amphetamine-like stimulant medications for extended periods of time during child development can carry negative consequences, as manifested by an increase in use of illicit drugs, higher incidence of mania, psychosis, or other manifestations of psychopathology. On the other hand, it is not known whether the beneficial effects of stimulants extend beyond acute symptomatic relief and affect important outcome variables, such as later psychopathology, educational achievement, antisocial behavior, and social or occupational status. Data from naturalistic follow-up of clinical samples are limited by lack of appropriate controls and self-selection biases that are difficult to determine and control. These studies have reached conflicting conclusions, although most of them found no lasting negative effects of chronic stimulant treatment. Studies in animals, mainly in rodents, indicate that repeated exposure to stimulants leads to behavioral sensitization to the psychomotor effects of these medications. Extrapolation of these data to therapeutic use in humans is difficult given interspecies differences and the relatively high doses and parenteral route of administration usually employed in animals. This report is based on the proceedings of a workshop organized by the National Institute of Mental Health in December 1999 to discuss possible research approaches to studying the long-term effects of stimulants in children with ADHD. Both clinical and basic neuroscience data are reviewed, and opportunities for future research are highlighted. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. NR 68 TC 54 Z9 54 U1 4 U2 17 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD SPR PY 2001 VL 11 IS 1 BP 25 EP 34 DI 10.1089/104454601750143384 PG 10 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 421WR UT WOS:000168087000004 PM 11322742 ER PT J AU Rosner, K Winter, DB Kasmer, C Skovgaard, GL Tarone, RE Bohr, VA Gearhart, PJ AF Rosner, K Winter, DB Kasmer, C Skovgaard, GL Tarone, RE Bohr, VA Gearhart, PJ TI Impact of age on hypermutation of immunoglobulin variable genes in humans SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE immunoglobulin genes; hypermutation; aging; antibody selection; mismatch repair ID MEMORY B-CELLS; MISMATCH REPAIR DEFICIENCY; HUMAN DNA-POLYMERASE; SOMATIC HYPERMUTATION; PERIPHERAL-BLOOD; REGION GENE; MICE DEFICIENT; CDR3 LENGTHS; LYMPHOCYTES; REPERTOIRE AB Chronological aging is associated with an accumulation of DNA mutations that results in cancer formation. The effect of aging on spontaneous mutations in humans is difficult to study because mutations are infrequent in the overall genome and tumors are relatively rare. In contrast, somatic mutations in immunoglobulin variable genes are abundant and can be studied in peripheral blood lymphocytes. To determine if aging alters the frequency and pattern of hypermutation, we sequenced 331 cDNA clones with rearranged V(H)6 genes and compared 452 mutations from young humans to 570 mutations from old humans. There were more mutated clones in the young population compared to the old population. Among the mutated clones, the frequency, location, and types of substitutions were similar between the young and the old groups. However, the ratio of replacement-to-silent mutations was much higher in the complementarity-determining regions of heavy chains from old people, which indicates that their B cells had been selected by antigen. Among individuals, there was variability in the frequency of tandem mutations, which we have observed in mice defective for the PMS2 mismatch repair protein. Microsatellite variability in DNA, which is caused by impaired mismatch repair; was then measured, and there was a strong correlation between the frequency of tandem mutations and microsatellite alterations. The data suggest that individuals vary in their mismatch repair capacity, which can affect the mutational spectra in their antibodies. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Rigshosp, Lab Mol Gerontol & Dermatol, DK-2100 Copenhagen, Denmark. Bispebjerg Hosp, Dept Dermatol, DK-2400 Copenhagen, Denmark. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Gearhart, PJ (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 59 TC 21 Z9 21 U1 0 U2 2 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 2001 VL 21 IS 2 BP 102 EP 115 DI 10.1023/A:1011003821798 PG 14 WC Immunology SC Immunology GA 424PE UT WOS:000168240000005 PM 11332649 ER PT J AU Yang, YF Tomura, M Iwasaki, M Mukai, T Gao, P Ono, S Zou, JP Shearer, GM Fujiwara, H Hamaoka, T AF Yang, YF Tomura, M Iwasaki, M Mukai, T Gao, P Ono, S Zou, JP Shearer, GM Fujiwara, H Hamaoka, T TI IL-12 as well as IL-2 upregulates CCR5 expression on T cell receptor-triggered human CD4(+) and CD8(+) T cells SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE IL-12; IL-2; chemokine receptor; CCR5; T cells ID CHEMOKINE RECEPTORS; TYROSINE PHOSPHORYLATION; TUMOR-REGRESSION; HIV-1 ENTRY; IFN-GAMMA; LYMPHOCYTES; INTERLEUKIN-12; MIP-1-BETA; MIP-1-ALPHA; INDUCTION AB The expression of chemokine receptors on leukocytes is related to their activation state. However, the exact mechanism underlying the induction of each chemokine receptor is poorly understood. Here, we investigated how CCR5, a chemokine receptor implicated in T cell trafficking and HIV infection, is induced in human T cells. CCR5 was marginally detected on a freshly prepared human peripheral blood mononuclear cell (PBMC) population. Long-term (8-day) stimulation of PBMC with IL-2 resulted in high levels of CCR5 expression on T cells. IL-12 failed to induce CCR5 on T cells in such a directly stimulated PBMC population. Stimulation of PBMC T cells with anti-CDS plus anti-CD28 induced detectable albeit very low levels of CCR5 along with the induction of IL-12 receptor. However, these TCR-triggered T cells expressed much higher levels of CCR5 when stimulated with IL-12. Although IL-2 also induced CCR5 expression, CCR5 expression was more potent in IL-12 than IL-2 stimulation. These results indicate that, in addition to IL-2, IL-12 plays an important role in the induction of CCR5 expression on T cells, particularly TCR-triggered T cells. C1 Osaka Univ, Biomed Res Ctr, Dept Oncol C6, Osaka 5650871, Japan. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Fujiwara, H (reprint author), Osaka Univ, Biomed Res Ctr, Dept Oncol C6, 2-2 Yamada Oka, Osaka 5650871, Japan. NR 39 TC 32 Z9 35 U1 0 U2 3 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 2001 VL 21 IS 2 BP 116 EP 125 DI 10.1023/A:1011059906777 PG 10 WC Immunology SC Immunology GA 424PE UT WOS:000168240000006 PM 11332650 ER PT J AU Porcella, SF Schwan, TG AF Porcella, SF Schwan, TG TI Borrelia burgdorferi and Treponema pallidum: a comparison of functional genomics, environmental adaptations and pathogenic mechanisms SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER SURFACE-PROTEIN; LIPOPROTEINS; TEMPERATURE; EXPRESSION; SEQUENCE; CULTIVATION; ANTIBODY; CULTURE; GENE C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 35 TC 31 Z9 36 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2001 VL 107 IS 6 BP 651 EP 656 DI 10.1172/JCI12484 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 413GR UT WOS:000167604400001 PM 11254661 ER PT J AU Strober, W Nakamura, K Kitani, A AF Strober, W Nakamura, K Kitani, A TI The SAMP1/Yit mouse: another step closer to modeling human inflammatory bowel disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CD4(+) T-CELLS; CHRONIC INTESTINAL INFLAMMATION; DEFICIENT MICE; MURINE MODEL; IFN-GAMMA; COLITIS; INTERLEUKIN-10; TOLERANCE; PATHOGENESIS; ANTIBODIES C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bldg 10,Room 11N238, Bethesda, MD 20892 USA. NR 25 TC 26 Z9 28 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2001 VL 107 IS 6 BP 667 EP 669 DI 10.1172/JCI12559 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 413GR UT WOS:000167604400005 PM 11254665 ER PT J AU Koustova, E Sei, Y Fossom, L Wei, ML Usherwood, PNR Keele, NB Rogawski, MA Basile, AS AF Koustova, E Sei, Y Fossom, L Wei, ML Usherwood, PNR Keele, NB Rogawski, MA Basile, AS TI LP-BM5 virus-infected mice produce activating autoantibodies to the AMPA receptor SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CENTRAL-NERVOUS-SYSTEM; RASMUSSENS ENCEPHALITIS; AUTOIMMUNE-DISEASE; PROTEINS; RETROVIRUS; BRAIN; AIDS; MODULATION; AGONIST AB Autoantibodies to alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) receptors may contribute to chronic hyperexcitability syndromes and neurodegeneration, but their origin is unclear We examined LP-BM5 murine leukemia virus-infected mice, which manifest excitotoxic brain lesions and hypergammaglobulinemia, for the presence of AMPA-receptor Ab's. Endogenous IgG accumulated upon neurons in the neocortex and caudate/putamen of infected mice and interacted with native and recombinant AMPA-receptor subunits with the following relative abundance: GluR3 greater than or equal to GluR1 > GluR2 = GluR4, as determined by immunoprecipitation. In a radioligand assay, IgG preparations from infected mice specifically inhibited [H-3]AMPA binding to receptors in brain homogenates, an activity that was lost after preadsorbing the IgG preparation to immobilized LP-BM5 virus. These IgGs also evoked currents when applied to hippocampal pyramidal neurons or to damaged cerebellar granule neurons. These currents could be blocked using any of several AMPA receptor antagonists. Thus, anti-AMPA-receptor Ab's can be produced as the result of a virus infection, in part through molecular mimicry. These Ab's may alter neuronal signaling and contribute to the neurodegeneration observed in these mice, actions that may be curtailed by the use of AMPA-receptor antagonists. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Basile, AS (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Room 121,MSC 0826, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 34 TC 17 Z9 18 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2001 VL 107 IS 6 BP 737 EP 744 DI 10.1172/JCI11500 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 413GR UT WOS:000167604400013 PM 11254673 ER PT J AU Halbur, PG Kasorndorkbua, C Gilbert, C Guenette, D Potters, MB Purcell, RH Emerson, SU Toth, TE Meng, XJ AF Halbur, PG Kasorndorkbua, C Gilbert, C Guenette, D Potters, MB Purcell, RH Emerson, SU Toth, TE Meng, XJ TI Comparative pathogenesis of infection of pigs with hepatitis E viruses recovered from a pig and a human SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID SPORADIC ACUTE HEPATITIS; UNITED-STATES; SWINE; PREVALENCE; IDENTIFICATION; HEV; SEROREACTIVITY; ANTIBODIES; SEQUENCE; VARIANT AB Specific-pathogen-free pigs were inoculated with one of two hepatitis E viruses (KEV) tone recovered from a pig and the other from a human) to study the relative pathogenesis of the two viruses in swine. Fifty-four pigs were randomly assigned to three groups. Seventeen pigs in group 1 served as uninoculated controls, 18 pigs in group 2 were intravenously inoculated with the swine HEV recovered from a pig in the United States, and 19 pigs in group 3 were intravenously inoculated with the US-2 strain of human HEV recovered from a hepatitis patient in the United States. Two to four pigs from each group were necropsied at 3, 7, 14, 20, 27, or 55 days postinoculation (DPI). Evidence of clinical disease or elevation of liver enzymes or bilirubin was not found in pigs from any of the three groups. Enlarged hepatic and mesenteric lymph nodes were observed in both HEV-inoculated groups. Multifocal lymphoplasmacytic hepatitis was observed in 9 of 17, 15 of 18, and 16 of 19 pigs in groups 1 to 3, respectively. Focal hepatocellular necrosis was observed in 5 of 17, 10 of 18, and 13 of 19 pigs in groups 1 to 3, respectively. Hepatitis lesions were very mild in group 1 pigs, mild to moderate in group 2 pigs, and moderate to severe in group 3 pigs. Hepatic inflammation and hepatocellular necrosis peaked in severity at 20 DPI and were still moderately severe at 55 DPI in the group inoculated with human HEV. Hepatitis lesions were absent or nearly resolved by 55 DPI in the swine-HEV-inoculated pigs. All HEV-inoculated pigs seroconverted to anti-HEV immunoglobulin G. HEV RNA was detected by reverse transcriptase FCR in feces, fiver tissue, and bile of pigs in both MEV-inoculated groups from 3 to 27 DPI. Based on evaluation of microscopic lesions, the US-2 strain of human HEV induced more severe and persistent hepatic lesions in pigs than did swine HEV. Pig livers or cells from the livers of HEV-infected pigs may represent a risk for transmission of HEV from pigs to human xenograft recipients. Since HEV was shed in the feces of infected pigs, exposure to feces from infected pigs represents a risk for transmission of HEV, and pigs should be considered a reservoir for HEV. C1 Iowa State Univ, Coll Vet Med, Dept Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA. Virginia Polytech Inst & State Univ, Coll Vet Med, Dept Biomed Sci & Pathobiol, Ctr Mol Med & Infect Dis, Blacksburg, VA 24061 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Halbur, PG (reprint author), Iowa State Univ, Coll Vet Med, Dept Vet Diagnost & Prod Anim Med, Ames, IA 50011 USA. RI Meng, X.J./B-8769-2009 OI Meng, X.J./0000-0002-2739-1334 FU NIAID NIH HHS [AI01653-01, AI46505-01] NR 41 TC 198 Z9 210 U1 3 U2 11 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 2001 VL 39 IS 3 BP 918 EP 923 DI 10.1128/JCM.39.3.918-923.2001 PG 6 WC Microbiology SC Microbiology GA 408FY UT WOS:000167316900014 PM 11230404 ER PT J AU Santos, N Volotao, EM Soares, CC Albuquerque, MCM da Silva, FM de Carvalho, TRB Pereira, CFA Chizhikov, V Hoshino, Y AF Santos, N Volotao, EM Soares, CC Albuquerque, MCM da Silva, FM de Carvalho, TRB Pereira, CFA Chizhikov, V Hoshino, Y TI Rotavirus strains bearing genotype G9 or P[9] recovered from Brazilian children with diarrhea from 1997 to 1999 SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; PORCINE ROTAVIRUS; UNITED-STATES; MOLECULAR CHARACTERIZATION; VP4 GENOTYPES; P-TYPE; SEROTYPE; IDENTIFICATION; PCR; EMERGENCE AB Human rotavirus strains belonging to genotype G9 or P[9] were detected in a collection of stool specimens from children with diarrhea in two cities of the state of Rio de Janeiro, Brazil, between March 1997 and December 1999. G9 strains were first detected in April 1997 and remained prevalent until the end of the study, at a frequency of 15.9% (n = 157). A high percentage of VP7 nucleotide (99.0 to 99.5%) and deduced amino acid identity (98.6 to 99.1%) was found between three randomly selected Brazilian G9 strains and the American G9 strain US1205. A novel G9:P[4] genotype combination was detected in addition to G9:P[8] and G9:P[6], demonstrating that this G genotype may undergo constant genetic reassortment in nature. The P[9] rotavirus strains constituted 10.2%, the majority of which were detected between April and July 1997. The RNA electrophoretic migration pattern of the G3:P[9] strains resembled that of AU-1 virus (G3:P3[9]), suggesting a genetic similarity between the Brazilian G3:P[9] strains and the Japanese virus, which is similar to a feline rotavirus genetically. C1 Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941590 Rio De Janeiro, Brazil. Univ Fed Fluminense, Dept Microbiol, BR-24300000 Niteroi, RJ, Brazil. US FDA, Ctr Biol Evaluat & Res, Kensington, MD 20895 USA. NIH, Infect Dis Lab, Bethesda, MD 20892 USA. RP Santos, N (reprint author), Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, Cidade Univ,CCS-Bl I, BR-21941590 Rio De Janeiro, Brazil. RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 37 TC 76 Z9 78 U1 0 U2 0 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 2001 VL 39 IS 3 BP 1157 EP 1160 DI 10.1128/JCM.39.3.1157-1160.2001 PG 4 WC Microbiology SC Microbiology GA 408FY UT WOS:000167316900058 PM 11230448 ER PT J AU Henry, ME Schmidt, ME Matochik, JA Stoddard, EP Potter, WZ AF Henry, ME Schmidt, ME Matochik, JA Stoddard, EP Potter, WZ TI The effects of ECT on brain glucose: A pilot FDG PET study SO JOURNAL OF ECT LA English DT Article DE electroconvulsive therapy; brain glucose; [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; ELECTROCONVULSIVE-THERAPY; MOOD DISORDERS; SUBCORTICAL LESIONS; FUTURE-RESEARCH; METABOLIC-RATE; DEPRESSION; BLOCKADE; IDAZOXAN AB Background: Regional brain activity was measured before and after electroconvulsive therapy (ECT) using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Methods: 6 patients (4 females) with major depression were free of psychotropic medications for at least 2 weeks prior to baseline FDG scans. Patients were treated with bifrontotemporal ECT, and posttreatment scans were obtained after the last treatment. Results: A region of interest (ROI) analysis of absolute metabolic rate showed a decrease in CMRglu after ECT in all 61 regions examined. In 17 of the 61 regions, the decrease was significant at the p < 0.05 level. In the right parietal lobe, and the right anterior and left posterior frontal lobes, the decrease in CMRglu significantly correlated with the decrease in Hamilton Depression Rating Scale (HDRS) scores (r = 0.83, 0.82, and 0.84, respectively). The analysis of CMRglu normalized to global metabolic rate showed significant increases in 8 of 61 regions, including basal ganglia, upper brainstem, and occipital lobe. Discussion: The decreases in global glucose metabolism and correlation of changes in frontal metabolism with decreases in HDRS are consistent with earlier brain imaging studies of ECT. The relative increases in CMRglu observed in regions with known dopaminergic innervation (caudate and upper brainstem) have not been previously reported. C1 McLean Hosp, Belmont, MA 02178 USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Lilly Res Labs, Indianapolis, IN USA. Natl Inst Drug Abuse, Brain Imaging Ctr, Baltimore, MD 21224 USA. RP Henry, ME (reprint author), McLean Hosp, Adm Bldg,Rm G21,115 Mill St, Belmont, MA 02178 USA. NR 29 TC 42 Z9 43 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1095-0680 J9 J ECT JI J. ECT PD MAR PY 2001 VL 17 IS 1 BP 33 EP 40 DI 10.1097/00124509-200103000-00007 PG 8 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 411RK UT WOS:000167512900007 PM 11281513 ER PT J AU Rodgers, BD Bernier, M Levine, MA AF Rodgers, BD Bernier, M Levine, MA TI Endocrine regulation of G-protein subunit production in an animal model of type 2 diabetes mellitus SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; ADIPOCYTE PLASMA-MEMBRANES; ADENYLATE-CYCLASE; BETA-SUBUNIT; MOLECULAR-CLONING; BINDING PROTEINS; INSULIN-RECEPTOR; PERTUSSIS-TOXIN; OBESE OB/OB; EXPRESSION AB Adipocyte beta -adrenergic sensitivity is compromised in animal models of obesity and type 2 diabetes. Although changes in the membrane concentrations of G-protein alpha subunits (G alpha) have been implicated, it remains to be determined how these changes are affected by insulin resistance in the different animal models. Because previous studies used young animals, we measured the concentrations of G alpha and G beta subunits in epididymal fat from aged (48 weeks old) db/db mice and from their lean littermates to more closely reproduce the model of type 2 diabetes mellitus. Levels of immunoreactive G alphas, G alphai(1/2), G alphao and G alphaq/11 were all significantly greater in adipocyte membranes from the db/db mice than in membranes from their lean non-diabetic littermate controls. Levels of G alphai(1) and G alphai(2) were also individually determined and although they appeared to be slightly higher in db/db membranes, these differences were not significant. Although the levels of both G alphas isoforms were elevated, levels of the 42 and 46 kDa proteins rose by approximately 42% and 20% respectively, indicating differential protein processing of G alphas. By contrast, levels of G alpha i3 were similar in the two groups. The levels of common G beta and G beta2 were also elevated in db/db mice, whereas G beta1 and G beta4 levels were not different. To determine whether these changes were due to insulin resistance per se or to elevated glucocorticoid production, G-protein subunit levels were quantified in whole cell lysates from 3T3-L1 adipocytes that were stimulated with different concentrations of either insulin or corticosterone. Although none of the subunit levels was affected by insulin, the levels of both G alphas isoforms were increased equally by corticosterone in a concentration-dependent manner. Since glucocorticoids are known regulators of G alphas gene expression in many cell types and in adipocytes from diabetic rodents, the results presented herein appear to more accurately reflect diabetic pathophysiology than do those of previous studies which report a decrease in G alphas levels. Taken together, these results indicate that most of the selective changes in G-protein subunit production in adipocytes from this animal model of type 2 diabetes may not be due to diminished insulin sensitivity, but may be due to other endocrine or metabolic abnormalities associated with the diabetic phenotype. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. NIA, Gerontol Res Ctr, Diabet Sect, NIH, Baltimore, MD 21224 USA. RP Rodgers, BD (reprint author), Johns Hopkins Univ, Sch Med, 600 N Wolfe St,Pk 211, Baltimore, MD 21287 USA. OI Bernier, Michel/0000-0002-5948-368X; Levine, Michael/0000-0003-0036-7809 FU NIDDK NIH HHS [DK34281, T32DK07751] NR 39 TC 7 Z9 8 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD MAR PY 2001 VL 168 IS 3 BP 509 EP 515 DI 10.1677/joe.0.1680509 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413PR UT WOS:000167621400016 PM 11241182 ER PT J AU Klabunde, C Bouchard, F Taplin, S Scharpantgen, A Ballard-Barbash, R AF Klabunde, C Bouchard, F Taplin, S Scharpantgen, A Ballard-Barbash, R CA Int Breast Canc Screening Network TI Quality assurance for screening mammography: an international comparison SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID COUNTRIES AB Study objective-In 1998, the International Breast Cancer Screening Network (IBSN) sponsored an assessment of quality assurance policies and practices to define their scope for population-based screening mammography programmes across IBSN countries. Design-Analysis of data from a survey designed to assess multiple elements of screening programme quality assurance, including organisation of quality assurance activities, mechanisms for site visits and accreditation, requirements for quality control and data systems, and inclusion of treatment, follow up, and programme evaluation in screening mammography quality assurance activities. Participants and Setting-IESN representatives in 23 countries completed a comprehensive questionnaire between May and December 1998. Main results-Completed questionnaires were obtained from all 23 countries. Responses indicated that countries vary in their approaches to implementing quality assurance, although all monitor components of structure, process, and outcome. Nearly all have in place laws, surveillance mechanisms, or standards for quality assurance. in all countries, quality assurance activities extend beyond the screening mammography examination. Conclusions-The assessment has enhanced understanding of the organisation of screening mammography programmes across countries, as well as the comparability of screening mammography data. All countries have established mechanisms for assuring the quality of screening mammography in population-based programmes, although these mechanisms vary across countries. C1 NCI, DCCPS, ARP, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. Hlth Canada, Ottawa, ON K1A 0L2, Canada. Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. Minist Sante, Programme Mammog, Luxembourg, Luxembourg. RP Klabunde, C (reprint author), NCI, DCCPS, ARP, Hlth Serv & Econ Branch, EPN Room 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. NR 17 TC 26 Z9 26 U1 1 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD MAR PY 2001 VL 55 IS 3 BP 204 EP 212 DI 10.1136/jech.55.3.204 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 402QW UT WOS:000167000500014 PM 11160176 ER PT J AU Li-Smerin, Y Swartz, KJ AF Li-Smerin, Y Swartz, KJ TI Helical structure of the COOH terminus of S3 and its contribution to the gating modifier toxin receptor in voltage-gated ion channels SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE secondary structure; scanning mutagenesis; voltage-dependent gating; Fourier transformation ID SHAKER K+ CHANNEL; POTASSIUM CHANNEL; S3-S4 LINKER; MOLECULAR DETERMINANTS; MEMBRANE-PROTEINS; SCORPION TOXIN; HANATOXIN; FLUORESCENCE; MOVEMENT; SCALE AB The voltage-sensing domains in voltage-gated K+ channels each contain four transmembrane (TM) segments, termed S1 to S4. Previous scanning mutagenesis studies suggest that S1 and S2 are amphipathic membrane spanning alpha -helices that interface directly with the lipid membrane. In contrast, the secondary structure of and/or the environments surrounding S3 and 84 are more complex. For S3, although the NH2-terminaI part displays significant helical character in both tryptophan- and alanine-scanning mutagenesis studies, the structure of the COOH-terminal portion of this TM is less clear. The COOH terminus of S3 is particularly interesting because this is where gating modifier toxins like Hanatoxin interact with different voltage-gated ion channels. To further examine the secondary structure of the COOH terminus of S3, we lysine-scanned this region in the drk1 K+ channel and examined the mutation-induced changes in channel gating and Hanatoxin binding affinity looking for periodicity characteristic of an alpha -helix. Both the mutation-induced perturbation in the toxin-channel interaction and in gating support the presence of an alpha -helix of at least 10 residues in length in the COOH terminus of S3. Together with previous scanning mutagenesis studies, these results suggest that, in voltage-gated K+ channels, the entire S3 segment is helical, but that it can be divided into two parts. The NH2-terminal part of S3 interfaces with both lipid and protein, whereas the COOH-terminal part interfaces with water (where Hanatoxin binds) and possibly protein. A conserved proline residue is located near the boundary between the two parts of S3, arguing for the presence of a kink in this region. Several lines of evidence suggest that these structural features of S3 probably exist in all voltage-gated ion channels. C1 NINDS, Mol Physiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Unit, NIH, Bldg 36,room 2C19,36 Convent Dr,MSC 4066, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS002945-13] NR 39 TC 82 Z9 83 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD MAR PY 2001 VL 117 IS 3 BP 205 EP 217 DI 10.1085/jgp.117.3.205 PG 13 WC Physiology SC Physiology GA 411WC UT WOS:000167521400001 PM 11222625 ER PT J AU Eizirik, E Murphy, WJ O'Brien, SJ AF Eizirik, E Murphy, WJ O'Brien, SJ TI Molecular dating and biogeography of the early placental mammal radiation SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT Symposium on DNA-Based Profiling of Mating Systems and Reproductive Behaviors in Poikilothermic Vertebrates CY JUN 17-20, 2000 CL YALE UNIV, NEW HAVEN, CONNECTICUT SP Amer Genet Assoc HO YALE UNIV ID EUTHERIAN MAMMALS; EVOLUTION; BIRDS; DIVERGENCE; PHYLOGENY; ORIGINS; RODENTS; SEQUENCES; RATES; DATES AB The timing and phylogenetic hierarchy of early placental mammal divergences was determined based on combined DNA sequence analysis of 18 gene segments (9779 bp) from 64 species. Using rooted and unrooted phylogenies derived from distinct theoretical approaches, strong support for the divergence of four principal clades of eutherian mammals was achieved. Minimum divergence dates of the earliest nodes in the placental mammal phylogeny were estimated with a quartet-based maximum-likelihood method that accommodates rate variation among lineages using conservative fossil calibrations from nine different nodes in the eutherian tree. These minimum estimates resolve the earliest placental mammal divergence nodes at periods between 64 and 104 million years ago, in essentially every case predating the Cretaceous-Tertiary (K-T) boundary. The pattern and timing of these divergences allow a geographic interpretation of the primary branching events In eutherian history, likely originating in the southern supercontinent Gondwanaland coincident with its breakup into Africa and South America 95-105 million years ago. We propose an integrated genomic, paleontological, and biogeographic hypothesis to account for these earliest splits on the placental mammal family tree and address current discrepancies between fossil and molecular evidence. C1 NCI, Lab Genome Divers, Frederick, MD 21702 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP Eizirik, E (reprint author), NCI, Lab Genome Divers, Frederick, MD 21702 USA. RI Eizirik, Eduardo/K-8034-2012 OI Eizirik, Eduardo/0000-0002-9658-0999 NR 38 TC 149 Z9 154 U1 1 U2 25 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD MAR-APR PY 2001 VL 92 IS 2 BP 212 EP 219 DI 10.1093/jhered/92.2.212 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 437RE UT WOS:000169006700016 PM 11396581 ER PT J AU Green, DE Sherman, CK AF Green, DE Sherman, CK TI Diagnostic histological findings in Yosemite toads (Bufo canorus) from a die-off in the 1970s SO JOURNAL OF HERPETOLOGY LA English DT Article ID CALIFORNIA CENTRAL VALLEY; SIERRA-NEVADA MOUNTAINS; CURRENT-USE PESTICIDES; UV-B RADIATION; MASS MORTALITY; MOLECULAR CHARACTERIZATION; POPULATION DECLINES; AMPHIBIAN DECLINES; AMBYSTOMA-TIGRINUM; PACIFIC-NORTHWEST AB Twelve adult and 25 larval Yosemite toad (Bufo canorus) specimens from the eastern Sierra Nevada of California were examined histologically for evidence of infectious, toxicological, and degenerative diseases. The preserved toads were selected from 21 that had been salvaged or collected during a die-off in 1976-1979 that immediately preceded a population decline. Causes of death of four toads were determined histologically; clinical signs and field observations suggested causes of death of three more. Four toads died of infectious diseases, including chytridiomycosis of the skin (N = 1) bacillary septicemia (N = 2), and combined chytridiomycosis and bacterial septicemia (N = I). infections by a funguslike organism (Dermosporidium penneri) renal myxozoa (Leptotheca ohlmacheri) larval Rhabdias, various gastrointestinal nematodes, urinary bladder flukes, and lung flukes were detected in five specimens. No evidence of degenerative diseases, virus infections, or intoxications was found. The variety of lethal diseases and our inability to determine the causes of death of five specimens suggests that one or more histologically undetectable diseases or intoxications may have also contributed to the deaths and population decline. C1 NIH, Off Res Support, Vet Resources Program, Bethesda, MD 20892 USA. RP Green, DE (reprint author), US Geol Survey, Natl Wildlife Hlth Ctr, US Dept Interior, 6006 Schroeder Rd, Madison, WI 53711 USA. EM David_Green@USGS.gov NR 75 TC 56 Z9 59 U1 1 U2 14 PU SOC STUDY AMPHIBIANS REPTILES PI ST LOUIS PA C/O ROBERT D ALDRIDGE, ST LOUIS UNIV, DEPT BIOLOGY, 3507 LACLEDE, ST LOUIS, MO 63103 USA SN 0022-1511 EI 1937-2418 J9 J HERPETOL JI J. Herpetol. PD MAR PY 2001 VL 35 IS 1 BP 92 EP 103 DI 10.2307/1566028 PG 12 WC Zoology SC Zoology GA 413BE UT WOS:000167589400013 ER PT J AU Anderson, DE Scuteri, A Metter, EJ Chesney, MA AF Anderson, DE Scuteri, A Metter, EJ Chesney, MA TI Association of high resting end tidal CO2 with carotid artery thickness in women, but not men SO JOURNAL OF HYPERTENSION LA English DT Article DE anger; blood pressure; carotid artery; end tidal CO2; gender; hypertension; intima-media thickness ID ESTROGEN REPLACEMENT THERAPY; BLOOD-PRESSURE; RISK-FACTORS; POSTMENOPAUSAL WOMEN; MEDIA THICKNESS; OLDER ADULTS; NITRIC-OXIDE; ATHEROSCLEROSIS; HYPERTENSION; POPULATION AB Background A previous study found high resting end tidal CO2 (PetCO(2)) to be an independent determinant of systolic blood pressure in women, but not men. The present study investigates the association of PetCO(2), with the common carotid artery intima-media thickness (IMT) and wall-to-lumen (W/L) ratio in a sample of normotensive men and women. Design and methods Resting PetCO(2) of 188 healthy volunteers, including 88 men and 100 women, in the Baltimore Longitudinal Study on Aging was monitored continuously for 25 min via a respiratory gas monitor. At another session, carotid artery IMT was determined via high-resolution B-mode carotid ultrasonography, The ratio of IMT to carotid artery diameter was calculated as W/L ratio. Resting blood pressure was determined oscillometrically every 5 min for 20 min during each session. Results Univariate associations of PetCO(2) with systolic blood pressure (SBP) (P< 001), IMT(P< 001) and W/L ratio (P< 001) were significant in women, but not men, Multiple regression analyses showed that high resting PetCO(2) was a predictor of SBP(P< 01), IMT (P< 01) and W/L ratio (P< 01) in women, independent of age, body mass index and SEP. For men, age (P< 001) and SEP (P< 01) were independent predictors of carotid IMT, while age (P < 001) was the only independent predictor of W/L ratio in men. Conclusions This study indicates that PetCO(2) can play a role in cardiovascular structure, as well as function, in women, and that the relationship is independent of the association of PetCO(2) with blood pressure. I Hypertens 19:459-463 (C) 2001 Lippincott Williams & Wilkins. C1 NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Anderson, DE (reprint author), NIA, Lab Cardiovasc Sci, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD MAR PY 2001 VL 19 IS 3 BP 459 EP 463 DI 10.1097/00004872-200103000-00014 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 407GL UT WOS:000167263800014 PM 11288816 ER PT J AU Chowdhury, PS Gallo, M Pastan, I AF Chowdhury, PS Gallo, M Pastan, I TI Generation of high titer antisera in rabbits by DNA immunization SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article ID CYTOTOXIC T-LYMPHOCYTE; IMMUNE-RESPONSE; MEDIATED IMMUNIZATION; GENETIC IMMUNIZATION; DENDRITIC CELLS; ANTIBODY; VACCINATION; INDUCTION; AFFINITY; ANTIGEN AB Mesothelin is a GPI-linked, membrane-associated differentiation antigen that is over-expressed in several forms of human cancers. Intradermal injection into rabbits of plasmid DNA encoding full length mesothelin resulted in antisera with titers as high as 1:100,000. Each immunization consisted of 320 mug of DNA delivered into 4 sites. After the initial three injections antisera titers were moderate (between 10 to 30,000) and fell over the course of about 7 weeks. When the titers had fallen, an injection of a booster dose of DNA resulted in very high titers of antisera. These antisera contained IgGs that could bind to both recombinant mesothelin made in Eschericha coli and to mesothelin present on human cells in Western blots and in immunofluorescence assays. These observations indicate that simple intradermal DNA immunization of rabbits can result in high titers of antibodies that can be used for a variety of purposes. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Div Basic Sci, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Div Basic Sci, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr Msc 4255, Bethesda, MD 20892 USA. NR 24 TC 18 Z9 19 U1 0 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 2001 VL 249 IS 1-2 BP 147 EP 154 DI 10.1016/S0022-1759(00)00353-7 PG 8 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 408UY UT WOS:000167346900014 PM 11226472 ER PT J AU Welniak, LA Khaled, AR Anver, MR Komschlies, KL Wiltrout, RH Durum, S Ruscetti, FR Blazar, BR Murphy, WJ AF Welniak, LA Khaled, AR Anver, MR Komschlies, KL Wiltrout, RH Durum, S Ruscetti, FR Blazar, BR Murphy, WJ TI Gastrointestinal cells of IL-7 receptor null mice exhibit increased sensitivity to irradiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; KERATINOCYTE GROWTH-FACTOR; STEM-CELLS; T-CELLS; DEFICIENT MICE; GAMMA-IRRADIATION; INDUCED APOPTOSIS; PROGENITOR CELLS; RADIATION-DAMAGE; BONE-MARROW AB IL-7 is a critical cytokine in the development of T and B cells but little is known about its activity on nonhematopoietic cells. An unexpected finding was noted in allogeneic bone marrow transplant studies using IL-7 receptor null (LL-7R alpha (-/-)) mice as recipients. These mice exhibited a significantly greater weight loss after total body irradiation compared with wild type, IL-7R alpha (+/+), mice. Pathological assessment indicated greater intestinal crypt damage in IL-7R alpha (-/-) recipients, suggesting these mice may be predisposed to gut destruction. Therefore, we determined the effect of the conditioning itself on the intestinal tract of these mice. IL-7R(alpha-/-) mice and IL-7R alpha (+/+) mice were irradiated and examined for lesions and apoptosis within the small intestine, In moribund animals, LL-7 alpha (-/-) mice had extensive damage in the small intestine, including marked ablation of the crypts and extreme shortening of villi following 1500 cGy total body irradiation. In contrast, by 8 days after irradiation, the small intestines of IL-7R alpha (+/+) mice had regenerated as distinguished by normal villus length and hyperplastic crypts, Following 750 cGy irradiation, IL-7R alpha (-/-) mice had a higher proportion of apoptotic cells in the crypts and an accompanying increase in the proapoptotic protein Bak was expressed in intestinal epithelial cells. These results demonstrate the increased radiosensitivity of intestinal stem cells within the crypts in IL-7R alpha (-/-) mice and a role for IL-7 in the protection of radiation-induced apoptosis in these same cells. This study describes a novel role of IL-7 in nonhematopoietic tissues. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Lab Leukocyte Biol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Expt Immunol Lab,Div Basic Sci, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp Frederick, Intramural Res Support Program, Bldg 567,Room 210, Frederick, MD 21702 USA. NR 51 TC 4 Z9 5 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 2001 VL 166 IS 5 BP 2923 EP 2928 PG 6 WC Immunology SC Immunology GA 404RW UT WOS:000167115300004 ER PT J AU Geiselhart, LA Humphries, CA Gregorio, TA Mou, S Subleski, J Komschlies, KL AF Geiselhart, LA Humphries, CA Gregorio, TA Mou, S Subleski, J Komschlies, KL TI IL-7 administration alters the CD4 : CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN CORD-BLOOD; B-LINEAGE CELLS; GROWTH-FACTOR; HUMAN INTERLEUKIN-7; IN-VIVO; MICE; LYMPHOCYTES; PROLIFERATION; STIMULATION; MOLECULES AB IL-7 is vital for the development of the immune system and profoundly enhances the function of mature T cells. Chronic administration of IL-7 to mice markedly increases T cell numbers, especially CD8(+) T cells, and enhances T cell functional potential, However, the mechanism by which these effects occur remains unclear. This report demonstrates that only 2 days of IL-7 treatment is needed for maximal enhancement of T cell function, as measured by proliferation, with a 6- to 12-fold increase in the proportion of CD4(+) and CD8(+) T cells in cell cycle by 18 h of ex vivo stimulation. Moreover, a 2-day administration of IL-7 in vivo increases basal proliferation by 4- and 14-fold in CD4(+) and CD8(+) T cells, respectively. These effects occur in the absence of cytokine production, increases in most activation markers, and changes in memory markers. This enhanced basal proliferation is the basis for the increase in T cell numbers in that IL-7 induces an additional 60% and 85% of resting CD4(+) and CD8(+) T cells, respectively: to enter cell cycle in mice given IL-7 for 7 days. These results demonstrate that in vivo administration of IL-7 increases T cell numbers and functional potential via a homeostatic, nonactivating process. These findings may suggest a unique clinical niche for IL-7 in that IL-7 therapy may increase T cell numbers and enhance responses to specific antigenic targets while avoiding a general, nonspecific activation of the T cell population. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Expt Immunol Lab, Frederick, MD 21702 USA. RP Komschlies, KL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM komschliesk@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 31 TC 94 Z9 101 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 2001 VL 166 IS 5 BP 3019 EP 3027 PG 9 WC Immunology SC Immunology GA 404RW UT WOS:000167115300015 PM 11207251 ER PT J AU Chougnet, C Freitag, C Schito, M Thomas, EK Sher, A Shearer, GM AF Chougnet, C Freitag, C Schito, M Thomas, EK Sher, A Shearer, GM TI In vivo CD40-CD154 (CD40 ligand) interaction induces integrated HIV expression by APC in an HIV-1-transgenic mouse model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; DENDRITIC CELLS; TRANSGENIC MICE; IMMUNE-RESPONSES; T-CELLS; IN-VIVO; INFECTION; VIRUS; RESERVOIRS; REPLICATION AB Because of their relative resistance to viral cytopathic effects, APC can provide an alternative reservoir for latently integrated HIV. We used an HIV-transgenic mouse model in which APC serve as the major source of inducible HIV expression to study mechanisms by which integrated virus can be activated in these cells. When admixed with transgenic APC, activated T lymphocytes provided a major contact-dependent stimulus for viral protein expression in vitro. Using blocking anti-CD154 mAb as well as CD154-deficient T cells, the HIV response induced by activated T lymphocytes was demonstrated to require CD40-CD154 interaction. The role of this pathway in the induction of HIV expression from APC in vivo was further studied in an experimental model involving infection of the HIV-transgenic mice with Plasmodium chabaudi parasites. Enhanced viral production by dendritic cells and macrophages in infected mice was associated with up-regulated CD40 expression. More importantly, in vivo treatment with blocking anti-CD154 mAb markedly reduced viral expression in P. chabaudi-infected animals. Together, these findings indicate that immune activation of integrated HIV fan be driven by the costimulatory interaction of activated T cells with APC. Because chronic T cell activation driven by coinfections as well as HIV-1 itself is a characteristic of HIV disease, this pathway may be important in sustaining viral expression from APC reservoirs. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36,4 Ctr Dr,MS 0425, Bethesda, MD 20892 USA. NR 42 TC 16 Z9 16 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 2001 VL 166 IS 5 BP 3210 EP 3217 PG 8 WC Immunology SC Immunology GA 404RW UT WOS:000167115300038 PM 11207274 ER PT J AU McKean, DJ Huntoon, CJ Bell, MP Tai, XG Sharrow, S Hedin, KE Conley, A Singer, A AF McKean, DJ Huntoon, CJ Bell, MP Tai, XG Sharrow, S Hedin, KE Conley, A Singer, A TI Maturation versus death of developing double-positive thymocytes reflects competing effects on Bcl-2 expression and can be regulated by the intensity of CD28 costimulation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; NEGATIVE SELECTION; SURFACE MOLECULES; DEFICIENT MICE; ACTIVATION; APOPTOSIS; THYMUS; SIGNALS; LIGAND; DIFFERENTIATION AB Immature double-positive (DP) thymocytes mature into CD4(+)CD8(-) cells in response to coengagement of TCR with any of a variety of cell surface "coinducer" receptors, including CD2, In contrast, DP thymocytes are signaled to undergo apoptosis by coengagement of TCR with CD28 costimulatory receptors, but the molecular basis for DP thymocyte apoptosis by TCR plus CD28 coengagement is not known. In the present study, we report that TCR plus CD28 coengagement does not invariably induce DP thymocyte apoptosis but, depending on the intensity of CD28 costimulation, can induce DP thymocyte maturation. We demonstrate that distinct but interacting signal transduction pathways mediate DP thymocyte maturation signals and DP thymocyte apoptotic signals. Specifically, DP maturation signals are transduced by the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and up-regulate expression of the antiapoptotic protein Bcl-2. In contrast, the apoptotic response stimulated by CD28 costimulatory signals is mediated by ERK/MAPK-independent pathways, Importantly, when TCR-activated thymocytes are simultaneously coengaged by both CD28 and CD2 receptors, CD28 signals can inhibit ERK/MAPK-dependent Bcl-2 protein up-regulation, Thus, there is cross-talk between the signal transduction pathways that transduce apoptotis and maturation responses, enabling CD28-initiated signal transduction pathways to both stimulate DP thymocyte apoptosis and also negatively regulate maturation responses initiated by TCR plus CD2 coengagement. C1 Mayo Clin & Mayo Fdn, Mayo Grad Sch, Dept Immunol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Mayo Grad Sch, Dept Surg, Rochester, MN 55905 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP McKean, DJ (reprint author), Mayo Clin & Mayo Fdn, Mayo Grad Sch, Dept Immunol, 321 Guggenheim Bldg,200 1st St SW, Rochester, MN 55905 USA. NR 49 TC 28 Z9 29 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 2001 VL 166 IS 5 BP 3468 EP 3475 PG 8 WC Immunology SC Immunology GA 404RW UT WOS:000167115300069 PM 11207305 ER PT J AU Boirivant, M Fuss, IJ Ferroni, L De Pascale, M Strober, W AF Boirivant, M Fuss, IJ Ferroni, L De Pascale, M Strober, W TI Oral administration of recombinant cholera toxin subunit B inhibits IL-12-mediated murine experimental (trinitrobenzene sulfonic acid) colitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEAT-LABILE ENTEROTOXIN; ADP-RIBOSYLTRANSFERASE ACTIVITY; CROHNS-DISEASE; T-CELLS; MUCOSAL ADJUVANTS; INTERFERON-GAMMA; IMMUNE-RESPONSES; VIBRIO-CHOLERAE; INDUCTION; MICE AB Trinitrobenzene sulfonic acid (TNBS)-induced colitis is an IL-12-driven, Th1 T cell-mediated colitis that resembles human Crohn's disease, In the present study, we showed initially that the oral administration of recombinant subunit B of cholera toxin (rCT-B) at the time of TNBS-induced colitis by intrarectal TNBS instillation inhibits the development of colitis or, at later time when TNBS-induced colitis is well established, brings about resolution of the colitis. Dose-response studies showed that a majority of mice (68%) treated with rCT-B at a dose of 100 mug (times four daily doses) exhibited complete inhibition of the development of colitis, whereas a minority (30%) treated with rCT-B at a dose of 10 mug (times four daily doses) exhibited complete inhibition; in both cases, however, the remaining mice exhibited some reduction in the severity of inflammation. In further studies, we showed that rCT-B administration is accompanied by prevention/reversal of increased IFN-gamma secretion (the hallmark of a Th1 response) without at the same time causing an increase in IL-4 secretion. This decreased IFN-gamma secretion was not associated with the up-regulation of the secretion of counterregulatory cytokines (IL-10 or TGF-beta), but was associated with a marked inhibition of IL-12 secretion, i.e., the secretion of the cytokine driving the Th1 response. Finally, we showed that rCT-B administration results in increased apoptosis of lamina propria cells, an effect previously shown to be indicative of IL-12 deprivation. From these studies, rCT-B emerges as a powerful inhibitor of Th1 T cell-driven inflammation that can conceivably be applied to the treatment of Crohn's disease. C1 Ist Super Sanita, Immunol Lab, I-00161 Rome, Italy. NIH, Mucosal Immun Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Boirivant, M (reprint author), Ist Super Sanita, Immunol Lab, Vle R Elena 299, I-00161 Rome, Italy. RI BOIRIVANT, MONICA/B-9977-2016 NR 42 TC 34 Z9 39 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 2001 VL 166 IS 5 BP 3522 EP 3532 PG 11 WC Immunology SC Immunology GA 404RW UT WOS:000167115300076 PM 11207312 ER PT J AU Onda, M Olafsen, T Tsutsumi, Y Bruland, OS Pastan, I AF Onda, M Olafsen, T Tsutsumi, Y Bruland, OS Pastan, I TI Cytotoxicity of antiosteosarcoma recombinant immunotoxins composed of TP-3 Fv fragments and a truncated Pseudomonas exotoxin A SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotoxin; Pseudomonas exotoxin; Fv; osteosarcoma; TP-3 ID HUMAN OSTEOSARCOMA; MONOCLONAL-ANTIBODIES; IN-VITRO; CANINE OSTEOSARCOMA; MURAMYL TRIPEPTIDE; OSTEOGENIC-SARCOMA; CANCER-THERAPY; CHEMOTHERAPY; EXPRESSION; CELLS AB Regrowth of drug-resistant tumor cells is responsible for approximately half of an unselected osteosarcoma population still dying of the disease despite aggressive combination therapy. Two monoclonal antibodies, TP-1 (immunoglobulin 2a) and TP-3 (immunoglobulin 2b) are available, which specifically recognize an antigen on osteosarcoma cells. In this work, we have fused the variable (V) genes of TP-3 to a truncated fragment of Pseudomonas exotoxin A, referred to as PE38. Two immunotoxins were made that differed in the Fv portion: TP-3(scFv)-PE38, which contains a peptide linker, and TP-3(dsFv)-PE38, which contains a disulfide bond for stabilization of the association between the V domains. Recombinant TP-3 immunotoxins were expressed in Escherichia coli and purified from inclusion bodies. We describe the design and expression of these immunotoxins, and their properties with regard to antigen binding, stability, and cytotoxicity. Toxicity studies were done in mice. We found that the immunotoxins exhibited very similar in vitro properties, whereas in vivo TP-3(dsFv)-PE38 was much better tolerated than TP-3(scFv)-PE38. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Norwegian Radium Hosp, Dept Oncol, Oslo, Norway. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 4E16,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 38 TC 12 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD MAR-APR PY 2001 VL 24 IS 2 BP 144 EP 150 DI 10.1097/00002371-200103000-00009 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 406CP UT WOS:000167197600009 PM 11265772 ER PT J AU Weiser, TS Guo, ZS Ohnmacht, GA Parkhurst, ML Tong-On, P Marincola, FM Fischette, MR Yu, XD Chen, GA Hong, JA Stewart, JH Nguyen, DM Rosenberg, SA Schrump, DS AF Weiser, TS Guo, ZS Ohnmacht, GA Parkhurst, ML Tong-On, P Marincola, FM Fischette, MR Yu, XD Chen, GA Hong, JA Stewart, JH Nguyen, DM Rosenberg, SA Schrump, DS TI Sequential 5-aza-2 '-deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1 SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE lung cancer; esophageal cancer; malignant pleural mesothelioma; melanoma; gene induction; 5-aza-2 '-deoxycytidine; depsipeptide FR901228; NY-ESO-1; apoptosis; tumor immunology ID CHROMOBACTERIUM-VIOLACEUM NO-968; TESTIS ANTIGEN NY-ESO-1; HUMAN TUMOR-ANTIGENS; DNA METHYLATION; GENE-EXPRESSION; HISTONE DEACETYLASE; DENDRITIC CELLS; LUNG-CANCER; CPG-ISLAND; IMMUNE-RESPONSE AB Global alterations in chromatin structure profoundly influence gene expression in thoracic neoplasms, silencing tumor suppressors while facilitating the expression of various cancer testis antigens such as NY-ESO-I. Although recent studies have shown that histone deacetylase inhibitors can potentiate tumor suppressor gene induction mediated by demethylating agents in cancer cells, the ability of these agents to augment cancer testis antigen expression have not been fully defined. The authors designed the current study to determine whether the histone deacetylase inhibitor, depsipeptide FR901228 (DP), could enhance NY-ESO-I induction mediated by the DNA demethylating agent 5-Aza-2'-deoxycytidine (DAC) in cell lines established primarily from thoracic cancers. Quantitative reverse-transcriptase polymerase chain reaction analysis revealed that, under exposure conditions potentially achievable in clinical settings, DAC dramatically induced NY-ESO-I expression in cultured cancer lines. DP alone mediated negligible target gene induction but significantly augmented DAC-mediated induction of NY-ESO-1. After DAC or sequential DAC-DP treatment, HLA-A*0201 cancer cells were recognized by an HLA-A*0201 CTL specific for NY-ESO-I. Although sequential DAC/DP exposure did not uniformly enhance immune recognition of target cells compared with DAC alone, this treatment mediated profound induction of apoptosis in cancer cells but not normal human bronchial epithelia. The apoptotic effects of DAC, BP, or sequential DAC-DP did not correlate in an obvious manner with histology, or the magnitude of NY-ESO-1 induction in cancer cells. Although the mechanisms have not been fully defined, sequential DAC-DP treatment may be a novel strategy to augment antitumor immunity in cancer patients. C1 NCI, Thorac Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. NCI, Tumor Immunol Sect, Surg Branch, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Bldg 10,Room 2B-07,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [K08 CA131482] NR 57 TC 122 Z9 125 U1 0 U2 5 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 2001 VL 24 IS 2 BP 151 EP 161 DI 10.1097/00002371-200103000-00010 PG 11 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 406CP UT WOS:000167197600010 PM 11265773 ER PT J AU Ohnmacht, GA Phan, GQ Mavroukakis, SA Steinberg, SM Shea, YR Witebsky, FG McIntyre, LS Goodwin, RS Muehlbauer, PM Morton, KE Rogers-Freezer, LJ Seipp, CA Rosenberg, SA Marincola, FM AF Ohnmacht, GA Phan, GQ Mavroukakis, SA Steinberg, SM Shea, YR Witebsky, FG McIntyre, LS Goodwin, RS Muehlbauer, PM Morton, KE Rogers-Freezer, LJ Seipp, CA Rosenberg, SA Marincola, FM TI A prospective, randomized, double-blind, placebo-controlled trial evaluating the effect of nystatin on the development of oral irritation in patients receiving high-dose intravenous interleukin-2 SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE interleukin-2; nystatin; thrush; oral pain; oral irritation; prospective randomized trial; placebo ID CANDIDIASIS; TOXICITY; CANCER AB Interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and renal cell cancer for nearly two decades, and much progress has been made in ameliorating its adverse effects. One bothersome adverse effect, oral pain ol oral irritation, is usually treated with an oral antifungal antibiotic, nystatin. The authors performed a prospective, randomized, double-blind, placebo-controlled trial involving 64 patients to evaluate the effect of prophylactic administration of nystatin or placebo on the development of oral irritation in patients receiving high-dose intravenous IL-2. No difference was found between patients randomized to receive nystatin or placebo in their rates of development of oral irritation, the severity of IL-2 adverse effects, the duration of their treatment, the rate of development of positive studies for oral yeast, or their pattern of experiencing other adverse effects. Thus, patients who receive high-dose intravenous IL-2 should not be treated prophylactically with nystatin to prevent oral irritation, and clinicians should seek evidence of the presence of oral thrush before using antifungal agents to treat oral pain in these patients. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B56,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. NR 10 TC 5 Z9 5 U1 0 U2 0 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 2001 VL 24 IS 2 BP 188 EP 192 DI 10.1097/00002371-200103000-00014 PG 5 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 406CP UT WOS:000167197600014 PM 11265777 ER PT J AU Hwang, ST Fitzhugh, DJ AF Hwang, ST Fitzhugh, DJ TI Aberrant expression of adhesion molecules by sezary cells: Functional consequences under physiologic shear stress conditions SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE adhesion molecules; integrin; L-selectin; lymphoma ID MEMORY T-CELLS; L-SELECTIN; ENDOTHELIAL-CELLS; CHEMOKINE RECEPTOR-6; MONOCLONAL-ANTIBODY; IN-VITRO; LYMPHOMA; ANTIGEN; SKIN; ACTIVATION AB Although aberrations in adhesion molecule expression by lymphoma cells have been reported, the functional consequences of these changes are unclear. Herein, we report a patient with Sezary syndrome whose malignant peripheral blood T cells were TCRV beta 17(+). Malignant T cell adhesion molecule abnormalities included an 80% downregulation of LFA-1 compared with normal controls and no detectable expression of alpha4 integrin. Under shear stress conditions, malignant T cells failed to arrest on recombinant ICAM-1 in the presence of chemokines and displayed an 80% decrease in the ability to arrest on TNF-alpha activated dermal microvascular endothelial cells compared with normal CD4(+) memory T cells. Cutaneous lymphocyte-associated antigen expression was detected in similar to 25% of malignant T cells in the peripheral blood, but was substantially less than this in TCRV beta 17(+) T cells in the dermis. By contrast, > 95% of malignant T cells in peripheral blood expressed L-selectin (CD62L), and L-selectin ligand was detected in dermal blood vessels at affected skin sites. Compared with normal CD4(+), malignant T cells attached and rolled 6-fold more efficiently on L-selectin ligand (p < 0.0001). Thus, despite aberrant expression of LFA-1 and functional defects in the ability to arrest on activated endothelial cells, malignant T cells in this patient entered skin and produced significant clinical disease. We propose a mechanism by which the upregulated expression of L-selectin and L-selectin ligands may partially compensate for altered LFA-1 function. C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), NCI, Dermatol Branch, Bldg 10,Rm 12N246,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 26 TC 8 Z9 8 U1 1 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2001 VL 116 IS 3 BP 466 EP 470 DI 10.1046/j.1523-1747.2001.01282.x PG 5 WC Dermatology SC Dermatology GA 406NN UT WOS:000167222200018 PM 11231324 ER PT J AU Hampshire, VA Thomas, ML Bacher, JD Alling, DW Kindt, TJ Wyatt, RG Simpson, RM AF Hampshire, VA Thomas, ML Bacher, JD Alling, DW Kindt, TJ Wyatt, RG Simpson, RM TI Thoracoscopy as a nonpharmacotherapeutic research modification for limiting postoperative chest pain SO JOURNAL OF INVESTIGATIVE SURGERY LA English DT Article DE animal testing alternatives; disease model in animals; endoscopy; nonsteroidal anti-inflammatory agents (therapeutic and toxic effects); one-lung anesthesia; pain measurement/veterinary; research/procedures ID ANIMAL USE; KETOPROFEN; SURGERY; PHARMACOKINETICS; THORACOTOMY; REFINEMENT; ANESTHESIA; MORBIDITY; ENDOCRINE; HORSES AB Diminished tissue injury and shortened clinical recovery are benefits of using an endoscopic approach for patients needing operative procedure. In the course of developing an experimental model requiring procurement of topographically precise lung biopsy specimens, we sought to apply thoracoscopy as a research alternative to thoracotomy. In addition, we investigated the influence of thoracoscopy on postprocedure recovery practices using rabbits divided into four treatment groups. Rabbit groups 1 and 2 underwent thoracoscopy and lung biopsy while maintained by one-lung anesthesia. Additionally, group 2 had ketoprofen and bupivacaine HCl analgesics injected for treatment during postprocedure recovery. These two groups were compared to control rabbits in groups 3 and 4, which underwent inhalant anesthesia without thoracoscopy. Control group 3 also received the injection analgesic combination. During recovery, rabbit behavior was systematically assessed for evidence of pain. No behavior considered indicative of pain needing intervention was observed regardless of treatment group. Limited changes in plasma corticosterone, catecholamines, and prostaglandin E-2 levels measured during recovery were difficult to associate with any treatment. Unexpectedly, significantly different mean corticosterone and catecholamines levels were detected in rabbits given the injection analgesic combination in the absence of thoracoscopic procedure, as compared to other treatment groups. The results highlight the importance of awareness that analgesic drug administration has the potential to alter homeostasis and affect interpretation of some study findings by its own guise. Correlation of the mean pain study results with plasma biochemical data supports preferential use of thoracoscopy as a refinement for limiting postprocedural pain in research models. C1 NIAID, Immunogenet Lab, Twinbrook Facil, Rockville, MD 20852 USA. NIAID, Off Sci Director, Rockville, MD 20852 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIH, Off Intramural Res, Off Director, Bethesda, MD 20892 USA. NIH, Biostat Sect, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Simpson, RM (reprint author), NIAID, Immunogenet Lab, Twinbrook Facil, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 28 TC 1 Z9 1 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0894-1939 J9 J INVEST SURG JI J. Invest. Surg. PD MAR-APR PY 2001 VL 14 IS 2 BP 109 EP 120 PG 12 WC Surgery SC Surgery GA 439AJ UT WOS:000169086400008 PM 11396618 ER PT J AU Monson, NL Fenske, TJ Wei, S Okragly, AJ de Jong, JLO Haak-Frendscho, M O'Shea, J Djeu, J Sondel, PM AF Monson, NL Fenske, TJ Wei, S Okragly, AJ de Jong, JLO Haak-Frendscho, M O'Shea, J Djeu, J Sondel, PM TI A p74 common gamma receptor chain isoform facilitates IL-2 and IL-15 responses by the myelomonocytic cell line Tf-1 beta 2 SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE monocytes; cytokines; cytokine receptors; signaling ID SEVERE COMBINED IMMUNODEFICIENCY; COLONY-STIMULATING FACTOR; MEMBRANE-PROXIMAL REGION; NATURAL-KILLER-CELLS; INTERLEUKIN-2 RECEPTOR; GROWTH-FACTOR; HUMAN MONOCYTES; BETA-CHAIN; FUNCTIONAL COMPONENT; INTERFERON-GAMMA AB Functional forms of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors require the gammac receptor component. We have described previously a myeloid cell line called Tf-1 beta, which binds IL-2 with intermediate-affinity and proliferates in response to IL-2, In this study, we characterize gammac expression on Tf-1 beta2 cells, a derivative of Tf-1 beta cells stimulated exclusively with IL-2. Although Tf-1 beta2 cells bind IL-2 with intermediate-affinity and proliferate in response to IL-2, this cell line does not express the p64 gammac chain at the protein level. This result was surprising because prior studies suggest these cells should not be expected to proliferate in response to IL-2 or IL-15 in the absence of the p64 gammac chain. A p74 protein was detected by western blot following immunoprecipitation with an anti-gammac polyclonal antibody, and a p74 protein was identified consistently in complex with IL-2 and IL-15 on these cells. However, the gammac gene in these Tf-1 beta2 cells shows no evidence of mutation by sequence analysis. Furthermore, inhibition of glycosylation of these Tf-1 beta2 cells by tunicamycin treatment yields a standard 39-kDa molecule recognized on western blot with anti-gammac antibody, as seen for the standard 64-kDa isoform of gammac. These results demonstrate that a 74-kDa gammac receptor isoform was involved in the response of the Tf-1 beta2 cells to cytokines which normally interact with the 64-kDa gammac chain. C1 Univ Wisconsin, Dept Human Oncol, Madison, WI USA. Univ Wisconsin, Dept Mol & Cellular Biol, Madison, WI USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. Univ Wisconsin, Dept Genet, Madison, WI 53706 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. H Lee Moffit Canc Ctr & Res Inst, Tampa, FL USA. Promega Corp, Madison, WI USA. NIH, Arthrit & Rheumatoid Branch, Bethesda, MD 20892 USA. RP Monson, NL (reprint author), Univ Texas, SW Med Ctr, Dept Neurol, Dallas, TX 75390 USA. FU NCI NIH HHS [CM-87290, CA-32685, P30-CA14520-2] NR 48 TC 1 Z9 1 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 2001 VL 69 IS 3 BP 419 EP 425 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 411TD UT WOS:000167514600014 PM 11261789 ER PT J AU Moriguchi, T Loewke, J Garrison, M Catalan, JN Salem, N AF Moriguchi, T Loewke, J Garrison, M Catalan, JN Salem, N TI Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum SO JOURNAL OF LIPID RESEARCH LA English DT Article DE docosapentaenoic acid; arachidonic acid; nervous system; n-3 fatty acid deficiency; diet; essential fatty acids; omega-3 fatty acids ID POLYUNSATURATED FATTY-ACIDS; ALPHA-LINOLENIC ACID; VISUAL-ACUITY DEVELOPMENT; PRETERM INFANTS; RHESUS-MONKEYS; GUINEA-PIG; RANDOMIZED TRIAL; LEARNING-TASKS; SLOW RECOVERY; TERM INFANTS AB The loss of docosahexaenoic acid (DHA) from the retina or brain has been associated with a loss in nervous system function in experimental animals, as well as in human infants fed vegetable oil-based formulas. The reversibility of the loss of DHA and the compensation by an increase in the n-6 docosapentaenoic acid (DPAn-6) was studied in young adult rats. Long-Evans rats were subjected to a very low level of n-3 fatty acids through two generations. The F2 generation, n-3-deficient animals at 7 weeks of age were provided a repletion diet containing both alpha -linolenate and DHA, A separate group of F2 generation rats had been maintained on an n-3-adequate diet of the same composition. Tissues from the brain, retina, liver, and serum were collected on weeks 0, 1, 2, 4, and 8 from both groups of animals. The concentrations of DHA, DPAn-6, and other fatty acids were determined and the rate of recovery and length of time needed to complete? DHA recovery were determined for each tissue. The DHA level in the brain at 1 and 2 weeks after diet reversal was only partially recovered, rising to approximately 20% and 35%, respectively, of the n-3-adequate group level. Full recovery was not obtained until 8 weeks after initiation of the repletion diet. Although the initial rate of retinal DHA accretion was greater than that of brain DHA, the half-time for DHA recovery was only marginally greater. On the other hand, the levels of DHA in the serum and liver were approximately 90% and 100% replaced, respectively within 2 weeks of diet reversal. A consideration of the total amounts and time courses of DHA repleted in the nervous system compared with the liver and circulation suggests that transport-related processes may limit the rate of DHA repletion in the retina and brain. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Salem, N (reprint author), 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. NR 56 TC 120 Z9 120 U1 2 U2 7 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 2001 VL 42 IS 3 BP 419 EP 427 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 416XY UT WOS:000167806800013 PM 11254754 ER PT J AU Sternin, E Schafer, H Polozov, IV Gawrisch, K AF Sternin, E Schafer, H Polozov, IV Gawrisch, K TI Simultaneous determination of orientational and order parameter distributions from NMR spectra of partially oriented model membranes SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID POWDER SPECTRA; BILAYERS C1 Brock Univ, Dept Phys, St Catharines, ON L2S 3A1, Canada. Catholic Univ Nijmegen, HF NMR Facil, NL-6525 ED Nijmegen, Netherlands. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Sternin, E (reprint author), Brock Univ, Dept Phys, St Catharines, ON L2S 3A1, Canada. NR 12 TC 24 Z9 26 U1 0 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAR PY 2001 VL 149 IS 1 BP 110 EP 113 DI 10.1006/jmre.2000.2278 PG 4 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 421TC UT WOS:000168078800015 PM 11273758 ER PT J AU Blanco, FJ Tycko, R AF Blanco, FJ Tycko, R TI Determination of polypeptide backbone dihedral angles in solid state NMR by double quantum C-13 chemical shift anisotropy measurements SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE peptide; backbone structure; solid state NMR; carbon-13 NMR; double quantum filtered spectroscopy; magic angle spinning ID NUCLEAR-MAGNETIC-RESONANCE; MOLECULAR TORSIONAL ANGLE; HYDROGEN-BONDED STRUCTURE; RESIDUE CARBONYL CARBONS; ALANYL-GLYCYL-GLYCINE; SPINNING NMR; 2-DIMENSIONAL NMR; EXCHANGE SPECTROSCOPY; AMYLOID FIBRIL; SECONDARY STRUCTURE AB A solid state NMR technique for the determination of peptide backbone conformations at specific sites in unoriented samples under magic angle spinning (MAS) is described and demonstrated on a doubly labeled polycrystalline sample of the tripeptide AlaClyGly and a sextuply labeled lyophilized sample of the 17-residue peptide MB(i + 4)EK. The technique is applicable to peptides and proteins that are labeled with C-13 at two (or more) consecutive backbone carbonyl sites. Double quantum (DQ) coherences are excited with a radiofrequency-driven recoupling sequence and evolve during a constant-time t(1) period at the sum of the two anisotropic chemical shifts. The relative orientation of the two chemical shift anisotropy (CSA) tensors, which depends on the phi and psi backbone dihedral angles, determines the t(1)-dependence of spinning sideband intensities in the DQ-filtered C-13 MAS spectrum. Experiments and simulations show that both dihedral angles can be extracted from a single data set. This technique, called DQCSA spectroscopy, may be especially useful when analyzing the backbone conformation of a polypeptide at a particular doubly labeled site in the presence of additional labeled carbons along the sequence. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Blanco, FJ (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RI Blanco, Francisco/D-4401-2009 OI Blanco, Francisco/0000-0003-2545-4319 NR 55 TC 53 Z9 54 U1 0 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAR PY 2001 VL 149 IS 1 BP 131 EP 138 DI 10.1006/jmre.2000.2281 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 421TC UT WOS:000168078800019 ER PT J AU Barrientos, LG Louis, JM Gronenborn, AM AF Barrientos, LG Louis, JM Gronenborn, AM TI Characterization of the cholesteric phase of filamentous bacteriophage fd for molecular alignment SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE residual dipolar couplings; bacteriophages; fd; Pf1; liquid crystal ID RESIDUAL DIPOLAR COUPLINGS; LIQUID-CRYSTAL; NEMATIC PHASE; COAT PROTEIN; NMR; MACROMOLECULES; SUSPENSIONS; DIFFRACTION; TRANSITION; RESOLUTION AB Residual dipolar couplings arise from small degrees of alignment of molecules in a magnetic field and have proven to provide valuable structural information. Colloidal suspensions of rod-shaped viruses and bacteriophages constitute a frequently employed medium for imparting such alignment onto biomolecules. The stability and behavior of the liquid crystalline phases with respect to solution conditions such as pH, ionic strength, and temperature vary, and characterization should benefit practical applications as well as theoretical understanding. In this Communication we describe the pH dependence of the cholesteric liquid crystalline phase of the filamentous bacteriophage fd and demonstrate that the alignment tensor of the solute protein is modulated by pH. We also report the interesting observation that the relative sign of the residual dipolar coupling changes at low pH values. In addition, we demonstrate that the degree of alignment inversely scales with the lengths of the phage particles for phages with identical mass and charge per unit length. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 21 TC 18 Z9 18 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD MAR PY 2001 VL 149 IS 1 BP 154 EP 158 DI 10.1006/jmre.2000.2276 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 421TC UT WOS:000168078800023 PM 11273766 ER PT J AU Wang, P Conrad, JT Shahabuddin, M AF Wang, P Conrad, JT Shahabuddin, M TI Localization of midgut-specific protein antigens from Aedes aegypti (Diptera : Culicidae) using monoclonal antibodies SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Aedes aegypti; midgut; brush border; peritrophic membrane; monoclonal antibodies ID LUCILIA-CUPRINA; PLASMODIUM-GALLINACEUM; PERITROPHIC MEMBRANE; BOOPHILUS-MICROPLUS; PROTECTIVE ANTIGEN; MOSQUITO-MIDGUT; MALARIA; INHIBITION; IDENTIFICATION; TRANSMISSION AB Most insect transmitted pathogens interact with the midgut of their vectors for infection and in some cases, development Therefore, molecules associated with the midgut epithelium in direct contact with pathogens may be potential targets of infection-blocking measures. Here, we identify midgut-specific protein antigens from Aedes aegypti (L.) using monoclonal antibodies. Sixty-four monoclonal antibodies were generated with reactivity to the mosquito midgut, five of which are reported in this article. Three monoclonal antibodies identified protein antigens localized at the midgut epithelial surface (the brush border) and the peritrophic membrane. In addition, two monoclonal antibodies recognized mosquito nucleus-specific proteins by immunofluorescence microscopy. Because potential target antigens for blocking transmission of pathogens most likely are located at the interface of mosquito-pathogen interactions, these monoclonal antibodies could provide valuable tools for studying midgut-specific proteins and interactions of the mosquito midgut with pathogens. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cornell Univ, Boyce Thompson Inst, Ithaca, NY 14853 USA. NR 31 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD MAR PY 2001 VL 38 IS 2 BP 223 EP 230 DI 10.1603/0022-2585-38.2.223 PG 8 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 414CV UT WOS:000167649100016 PM 11296827 ER PT J AU Frattali, C Worrall, LE AF Frattali, C Worrall, LE TI Evidence-based practice: Applying science to the art of clinical care SO JOURNAL OF MEDICAL SPEECH-LANGUAGE PATHOLOGY LA English DT Article C1 NIH, Speech Language Pathol Sect, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20894 USA. Univ Queensland, Dept Speech Pathol & Audiol, Brisbane, Qld, Australia. RP Frattali, C (reprint author), NIH, Speech Language Pathol Sect, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 6S 235,MSC 1604, Bethesda, MD 20894 USA. RI Worrall, Linda/D-2579-2010 OI Worrall, Linda/0000-0002-3283-7038 NR 4 TC 2 Z9 2 U1 0 U2 1 PU SINGULAR PUBLISHING GROUP INC PI SAN DIEGO PA 401 WEST A ST, STE 325, SAN DIEGO, CA 92101-7904 USA SN 1065-1438 J9 J MED SPEECH-LANG PA JI J. Med. Speech-Lang. Pathol. PD MAR PY 2001 VL 9 IS 1 BP IX EP XIV PG 6 WC Audiology & Speech-Language Pathology; Clinical Neurology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology GA 412PB UT WOS:000167562600002 ER PT J AU Meragelman, KM McKee, TC Boyd, MR AF Meragelman, KM McKee, TC Boyd, MR TI New cytotoxic isomalabaricane triterpenes from the sponge Jaspis species SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID MARINE SPONGE; MALABARICANE TRITERPENES; STELLETTA-GLOBOSTELLATA; TRACE STEROLS; STELLIFERA; INVERTEBRATES; DERIVATIVES; COLLECTION; PIGMENT AB Three new isomalabaricane triterpenes, 29-hydroxystelliferin E (1), 29-hydroxystelliferin A (2), and stelliferin G (3), together with the known triterpene 3-epi-29-tiydroxystelliferin E (4), were isolated from the organic extract of the sponge Jaspis sp. collected in the South Pacific. All the compounds isolated showed antiproliferative activity against melanoma cells (MALME-3M). C1 NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick, MD 21702 USA. NR 24 TC 28 Z9 30 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAR PY 2001 VL 64 IS 3 BP 389 EP 392 DI 10.1021/np000478g PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 415MP UT WOS:000167725600028 PM 11277766 ER PT J AU Bienvenu, OJ Nestadt, G Samuels, JF Costa, PT Howard, WT Eaton, WW AF Bienvenu, OJ Nestadt, G Samuels, JF Costa, PT Howard, WT Eaton, WW TI Phobic, panic, and major depressive disorders and the five-factor model of personality SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article ID DIAGNOSTIC-INTERVIEW-SCHEDULE; AREA FOLLOW-UP; 5-FACTOR MODEL; ANXIETY DISORDERS; NATURAL-HISTORY; SOCIAL PHOBIA; ONSET; STATE AB This study investigated five-factor model personality traits in anxiety (simple phobia, social phobia agoraphobia, and panic disorder) and major depressive disorders in a population-based sample. In the Baltimore Epidemiologic Catchment Area Follow-up Study, psychiatrists administered the Schedules for Clinical Assessment in Neuropsychiatry to 333 adult subjects who also completed the Revised NEO Personality Inventory. AU of the disorders except simple phobia were associated with high neuroticism. Social phobia and agoraphobia were associated with low extraversion. Ln addition, lower-order facets of extraversion, agreeableness, and conscientiousness were associated with certain disorders (i.e., low positive emotions in panic disorder; low trust and compliance in certain phobias; and low competence, achievement striving, and self-discipline in several disorders). This study emphasizes the utility of lower-order personality assessments and underscores the need for further research on personality/psychopathology etiologic relationships. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21218 USA. NIA, NIH, Baltimore, MD USA. Johns Hopkins Bayview Med Ctr, Dept Community Psychiat, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. RP Bienvenu, OJ (reprint author), 600 N Wolfe St,Meyer 125, Baltimore, MD 21287 USA. OI Samuels, Jack/0000-0002-6715-7905; Costa, Paul/0000-0003-4375-1712 FU NIMH NIH HHS [R01-MH47447, R01-MH50616, T32-MH14592] NR 35 TC 104 Z9 109 U1 15 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAR PY 2001 VL 189 IS 3 BP 154 EP 161 DI 10.1097/00005053-200103000-00003 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 412QM UT WOS:000167565900003 PM 11277351 ER PT J AU Strong, MJ Strong, WL Jaffe, H Traggert, B Sopper, MM Pant, HC AF Strong, MJ Strong, WL Jaffe, H Traggert, B Sopper, MM Pant, HC TI Phosphorylation state of the native high-molecular-weight neurofilament subunit protein from cervical spinal cord in sporadic amyotrophic lateral sclerosis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE amyotrophic lateral sclerosis; motor neuron disease; neurofilament; phosphorylation ID NEURONAL INTERMEDIATE FILAMENTS; MOTOR-NEURONS; NF-H; AXONAL-TRANSPORT; CATHEPSIN-D; HEAVY GENE; IN-VIVO; DEPHOSPHORYLATION; DEGRADATION; EXPRESSION AB The intraneuronal aggregation of phosphorylated high-molecular-weight neurofilament protein (NFH) in spinal cord motor neurons is considered to be a key pathological marker of amyotrophic lateral sclerosis (ALS). In order to determine whether this observation is due to the aberrant or hyperphosphorylation of NFH, we have purified and characterized NFH from the cervical spinal cords of ALS patients and controls. We observed no differences between ALS and normal controls in the physicochemical properties of NFH in Triton X-100 insoluble protein fractions, with respect to migration patterns on 2D-iso electrofocusing (IEF) gels, the rate of Escherichia coli alkaline phosphatase mediated dephosphorylation, or the rate of calpain-mediated proteolysis. The rate of calpain-mediated proteolysis was unaffected by either exhaustive NFH dephosphorylation or by the addition of calmodulin to the reaction. Phosphopeptides and the phosphorylated motifs characterized by liquid chromatography tandem mass spectroscopy (LC/MS/MS) analysis demonstrated that all the phosphorylated residues found in ALS NFH were-also found to be phosphorylated in normal human NFH samples. Hence, we have observed no difference in the physicochemical properties of normal and ALS NFH extracted from cervical spinal cords, suggesting that the perikaryal aggregation of highly phosphorylated NF in ALS neurons reflects the aberrant somatotopic localization of normally phosphorylated NFH. C1 NINDS, Cytoskeletal Prot Regulat Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. John P Robarts Res Inst, Neurodegenerat Res Grp, London, ON N6A 5K8, Canada. RP Strong, MJ (reprint author), UC, LHSC, Room 7OF 10,339 Windermere Rd, London, ON N6A 5A5, Canada. RI Strong, Michael/H-9689-2012 NR 42 TC 55 Z9 55 U1 1 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 5 BP 1315 EP 1325 DI 10.1046/j.1471-4159.2001.00094.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 407GX UT WOS:000167264800006 PM 11238716 ER PT J AU Garrido, R Mattson, MP Hennig, B Toborek, M AF Garrido, R Mattson, MP Hennig, B Toborek, M TI Nicotine protects against arachidonic-acid-induced caspase activation, cytochrome c release and apoptosis of cultured spinal cord neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cell death; free fatty acids; neuroprotection; nicotine; spinal cord trauma ID BETA-AMYLOID TOXICITY; GLUTAMATE NEUROTOXICITY; CORTICAL-NEURONS; NERVE INJURY; FATTY-ACIDS; RECEPTORS; CELLS; DEATH; INDUCTION; CASCADE AB Hydrolysis of membrane phospholipids of spinal cord neurons is one of the first events initiated in spinal cord trauma. In this process, free fatty acids, and in particular arachidonic acid, are released. Exposure of spinal cord neurons to free arachidonic acid can compromise cell survival and initiate apoptotic cell death. In order to determine potential mechanisms of apoptosis induced by arachidonic acid, activation of caspases -3, -8, and -9, as well as the release of cytochrome c into the cytoplasm were measured in cultured spinal cord neurons exposed to 10 muM Of this fatty acid. In addition, because nicotine can exert a variety of neuroprotective effects, we hypothesized that it can prevent arachidonic acid induced apoptosis of spinal cord neurons. To study this hypothesis, spinal cord neurons were pretreated with nicotine (10 muM for 2 h) before arachidonic acid exposure and caspase activation as well as markers of apoptotic cell death were studied. Treatment of spinal cord neurons with arachidonic acid for up to 24 h significantly increased cytoplasmic levels of cytochrome c, induced caspase activation and induced DNA laddering, a hallmark of apoptotic cell death. Nicotine pretreatment markedly attenuated all these effects. In addition, antagonist studies suggest that the alpha7 nicotinic receptor is primarily responsible for these anti-apoptotic effects of nicotine. These results indicate that nicotine can exert potent neuroprotective effects by inhibiting arachidonic acid induced apoptotic cascades of spinal cord neurons. C1 Univ Kentucky, Med Ctr, Dept Surg, Div Neurosurg, Lexington, KY 40536 USA. Univ Kentucky, Dept Anim Sci, Lexington, KY USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Toborek, M (reprint author), Univ Kentucky, Med Ctr, Dept Surg, Div Neurosurg, 800 Rose St, Lexington, KY 40536 USA. RI Mattson, Mark/F-6038-2012 FU NIEHS NIH HHS [P42 ES007380] NR 48 TC 82 Z9 87 U1 0 U2 4 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 5 BP 1395 EP 1403 DI 10.1046/j.1471-4159.2001.00135.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 407GX UT WOS:000167264800014 PM 11238724 ER PT J AU Gary, DS Mattson, MP AF Gary, DS Mattson, MP TI Integrin signaling via the PI3-kinase-Akt pathway increases neuronal resistance to glutamate-induced apoptosis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer; Bcl-2; excitotoxicity; hippocampus; laminin; wortmanin ID NF-KAPPA-B; METABOLIC EXCITOTOXIC INSULTS; CEREBELLAR GRANULE NEURONS; REGULATES BCL-2 EXPRESSION; CULTURED CORTICAL-NEURONS; FIBROBLAST-GROWTH-FACTOR; PROTEIN-KINASE PATHWAY; FOCAL ADHESION KINASE; NMDA RECEPTOR PROTEIN; NECROSIS-FACTOR-ALPHA AB Integrins are integral membrane proteins that mediate adhesive interactions of cells with the extracellular matrix and with other cells. Integrin engagement results in activation of intracellular signaling cascades that effect several different cellular responses including motility, proliferation and survival. Although integrins are known to provide cell survival signaling in various types of non-neuronal cells, the possibility that integrins modulate neuron survival has not been explored. We now report data demonstrating a neuroprotective function of integrins in embryonic hippocampal neurons. Neurons grown on laminin, an integrin ligand, exhibit increased resistance to glutamate-induced apoptosis compared with neurons grown on polylysine. Neurons expressed integrin beta1 and treatment of cultures with an antibody against integrin beta1 abolished the protective effect of laminin. Neurons maintained on laminin exhibited a sustained activation of the AM signaling pathway demonstrated in immunoblot analyses using an antibody that selectively recognizes phosphorylated Akt. The neuroprotective effect of integrin engagement by laminin was mimicked by an IKLLI-containing integrin-binding peptide and was abolished by treatment of neurons with the P13 kinase inhibitor wortmanin. Levels of the anti-apoptotic protein Bcl-2 were increased in neurons grown on laminin and decreased by wortmanin, suggesting a mechanism for the neuroprotective effect of integrin-mediated signaling. The ability of integrin-mediated signaling to prevent glutamate-induced apoptosis suggests a mechanism whereby neuron-substrate interactions can promote neuron survival under conditions of glutamate receptor overactivation. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 99 TC 88 Z9 93 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 5 BP 1485 EP 1496 DI 10.1046/j.1471-4159.2001.00173.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 407GX UT WOS:000167264800023 PM 11238733 ER PT J AU Edsall, LC Cuvillier, O Twitty, S Spiegel, S Milstien, S AF Edsall, LC Cuvillier, O Twitty, S Spiegel, S Milstien, S TI Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Akt; apoptosis; caspases; sphingosine kinase; sphingosine-1-phosphate; trkA ID PROTEIN-COUPLED RECEPTOR; NERVE GROWTH-FACTOR; CERAMIDE INDUCES APOPTOSIS; CULTURED MESENCEPHALIC NEURONS; MULTIPLE SIGNALING PATHWAYS; FUNCTIONAL-CHARACTERIZATION; 1-PHOSPHATE RECEPTOR; SYMPATHETIC NEURONS; MOLECULAR-CLONING; NEURITE OUTGROWTH AB Sphingosine-1-phosphate (SPP), a bioactive sphingolipid metabolite, suppresses apoptosis of many types of cells, including rat pheochromocytoma PC12 cells. Elucidating the molecular mechanism of action of SPP is complicated by many factors, including uptake and metabolism, as well as activation of specific G-protein-coupled SPP receptors, known as the endothelial differentiation gene-1 (EDG-1) family. In this study, we overexpressed type 1 sphingosine kinase (SPHK1), the enzyme that converts sphingosine to SPP, in order to examine more directly the role of intracellularly generated SPP. in neuronal survival. Enforced expression of SPHK1 in PC12 cells resulted in significant increases in kinase activity, with corresponding increases in intracellular SPP levels and concomitant decreases in both sphingosine and ceramide, and marked suppression of apoptosis induced by trophic factor withdrawal or by C-2-ceramide. NGF, which protects PC12 cells from serum withdrawal-induced apoptosis, also stimulated SPHK1 activity. Surprisingly, overexpression of SPHK1 had no effect on activation of two known NGF-stimulated survival pathways, extracellular signal regulated kinase ERK 1/2 and AM. However, trophic withdrawal-induced activation of the stress activated protein kinase, c-Jun amino terminal kinase (SAPK/JNK), and activation of the executionary caspases 2, 3 and 7, were markedly suppressed. Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface G(1)-coupled SPP receptors. In agreement, there was no detectable release of SPP into the culture medium, even after substantially increasing cellular SPP levels by NGF or sphingosine treatment. In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells. Collectively, our results indicate that SPHK/SPP may play an important role in neuronal survival by regulating activation of SAPKs and caspases. C1 NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. RP Milstien, S (reprint author), NIH, Bldg 36,Room 2A-11, Bethesda, MD 20892 USA. RI CUVILLIER, Olivier/B-2567-2009 OI CUVILLIER, Olivier/0000-0003-3346-375X FU NIGMS NIH HHS [GM43880] NR 68 TC 152 Z9 155 U1 0 U2 8 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 5 BP 1573 EP 1584 DI 10.1046/j.1471-4159.2001.00164.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 407GX UT WOS:000167264800031 PM 11238741 ER PT J AU Klein, RC Siarey, RJ Caruso, A Rapoport, SI Castellino, FJ Galdzicki, Z AF Klein, RC Siarey, RJ Caruso, A Rapoport, SI Castellino, FJ Galdzicki, Z TI Increased expression of NR2A subunit does not alter NMDA-evoked responses in cultured fetal trisomy 16 mouse hippocampal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Down's syndrome; mouse trisomy 16; NMDA receptor; NR2A; polyamine; spermine ID METHYL-D-ASPARTATE; DEVELOPMENTAL-CHANGES; CORTICAL-NEURONS; ZINC INHIBITION; DOWNS-SYNDROME; ION CHANNELS; RECEPTOR; POLYAMINES; MODEL; SENSITIVITY AB The trisomy 16 (Ts16) mouse is an animal model for human trisomy 21 (Down's syndrome). The gene encoding the NR2A subunit of the NMDA receptor has been localized to mouse chromosome 16. In the present study, western blot analysis revealed a 2.5-fold increase of NR2A expression in cultured Ts16 embryonic hippocampal neurons. However, this increase did not affect the properties of NMDA-evoked currents in response to various modulators. The sensitivity of NMDA receptors to transient applications of NMDA, spermine, and Zn2+ was investigated in murine Ts16 and;control diploid cultured embryonic hippocampal neurons. Peak and steady-state currents evoked by NMDA were potentiated by spermine at concentrations <1 mM, and inhibited by Zn2+ in a dose-dependent and voltage-independent manner. No marked difference was observed between Ts16 and control diploid neurons for any of these modulators with regard to IC50 and EC50 values or voltage dependency. Additionally, inhibition by the NR2B selective inhibitor, ifenprodil, was similar. These results demonstrate that NMDA-evoked currents are not altered in cultured embryonic Ts16 neurons and suggest that Ts16 neurons contain similar functional properties of NMDA receptors as diploid control neurons despite an increased level of NR2A expression. C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. Univ Notre Dame, Ctr Transgene Res, Notre Dame, IN 46556 USA. NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. RP Galdzicki, Z (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU NHLBI NIH HHS [HL 19982] NR 32 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 6 BP 1663 EP 1669 DI 10.1046/j.1471-4159.2001.00170.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 411TC UT WOS:000167514500009 PM 11259484 ER PT J AU D'Souza, UM Wang, W Gao, DQ Kanda, S Lee, G Junn, E Hwang, CK Jose, PA Mouradian, MM AF D'Souza, UM Wang, W Gao, DQ Kanda, S Lee, G Junn, E Hwang, CK Jose, PA Mouradian, MM TI Characterization of the 5 ' flanking region of the rat D-3 dopamine receptor gene SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE dopamine receptor gene; D-3 gene; 5 ' flanking region; promoter region; transcription regulation ID INSITU HYBRIDIZATION HISTOCHEMISTRY; HUMAN COCAINE FATALITIES; MESSENGER-RNA; PROMOTER REGION; D3 RECEPTOR; ALTERNATIVE TRANSCRIPTS; MOLECULAR-CLONING; UP-REGULATION; CELL-LINE; SCHIZOPHRENIA AB The D-3 dopamine receptor has a restricted regional distribution in brain and is regulated by dopaminergic agents. Additionally, the D-3 gene is implicated in the pathogenesis of several neuropsychiatric disorders or in their response to pharmacological agents. Elucidating its transcription control mechanisms is therefore of interest in order to explain these biological features of the D-3 gene. In this study, the 5' flanking region of the rat D-3 gene was characterized by isolating the 5' end of its cDNA as well as 4.6 kb of genomic sequence. Analysis of this region revealed the presence of two new exons 196-bp and 120-bp long, separated by an 855-bp intron, located several kilobases upstream of the previously published coding exons. Thus, current evidence indicates that the rat D-3 gene is organized into eight exons. Transcription initiation site was determined by primer extension analysis and repeated rounds of 5' RACE and was found to localize at a pyrimidine-rich consensus 'initiator' sequence, similar to the rat D-2 gene. The D-3 promoter lacks TATA or CAAT boxes but unlike that of other dopamine receptor genes has only 52% GC content. Functional analysis of D-3 promoter deletion mutants fused to a reporter gene in TE671 cells, which endogenously express this gene, revealed strong transcriptional activity localized within 36 nucleotides upstream of transcription start site, and a potent silencer between bases -37 and -537. The D-3 promoter is inactive in C6 and COS7 cells. We conclude that the D-3 gene, similar to the closely related D-2 gene, is transcribed from a tissue specific promoter which is under intense negative control. C1 NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Pediat, Washington, DC 20007 USA. RP Mouradian, MM (reprint author), NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 44 TC 16 Z9 16 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 6 BP 1736 EP 1744 DI 10.1046/j.1471-4159.2001.00155.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 411TC UT WOS:000167514500016 PM 11259491 ER PT J AU Yim, SH Hammer, JA Quarles, RH AF Yim, SH Hammer, JA Quarles, RH TI Differences in signal transduction pathways by which platelet-derived and fibroblast growth factors activate extracellular signal-regulated kinase in differentiating oligodendrocytes SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE extracellular signal-regulated kinase; fibroblast growth factor; kinase; oligodendroglial progenitor; platelet-derived growth factor ID CENTRAL-NERVOUS-SYSTEM; PDGF-ALPHA-RECEPTOR; PROTEIN-KINASES; MATURE OLIGODENDROCYTES; MAP KINASE; IN-VIVO; PROGENITOR CELLS; GLIAL-CELLS; PC12 CELLS; RAT-BRAIN AB Treatment of cultured rat oligodendroglial progenitors with either platelet-derived growth factor (PDGF) or fibroblast growth factor-2 (FGF-2) activated extracellular signal regulated kinase 2 (ERK2). Activation was transient in response to PDGF, whereas it was greater and more prolonged in response to FGF-2. ERK2 activation by PDGF was preceded by a very rapid, robust and transient tyrosine phosphorylation of the PDGF receptor. Although there was consistently more activation of ERK2 in response to FGF-2 than to PDGF, immunostaining of FGF receptors 1 (FGFR1) and 2 (FGFR2) and their tyrosine phosphorylation in progenitors was very weak, and both receptors were up-regulated during differentiation to oligodendrocytes. Tyrosine phosphorylation of the FGF receptors was maximal from 15 to 60 min of treatment and was sustained for many hours. Binding of radioiodinated FGF-2 to FGFR1 was predominant in progenitors, whereas binding to FGFR2 was predominant in oligodendrocytes. ERK2 activation by PDGF was more sensitive to inhibition of tyrosine kinases, whereas ERK2 activation by FGF-2 was relatively more sensitive to inhibitors of protein kinase C. These differences in signal-transduction pathways probably contribute to the different cellular responses of oligodendroglial lineage cells to PDGF and FGF-2, respectively. C1 NINDS, Myelin & Brain Dev Sect, Cellular & Mol Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Quarles, RH (reprint author), NINDS, Myelin & Brain Dev Sect, Cellular & Mol Neurobiol Lab, NIH, Bldg 49,Rm 2A28, Bethesda, MD 20892 USA. NR 45 TC 24 Z9 24 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2001 VL 76 IS 6 BP 1925 EP 1934 DI 10.1046/j.1471-4159.2001.00199.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 411TC UT WOS:000167514500036 PM 11259511 ER PT J AU Busettini, C Fitzgibbon, EJ Miles, FA AF Busettini, C Fitzgibbon, EJ Miles, FA TI Short-latency disparity vergence in humans SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID MACAQUE VISUAL-CORTEX; FRONTAL EYE FIELD; OCULAR-FOLLOWING RESPONSES; SLOW OCULOMOTOR CONTROL; RANDOM-DOT STEREOGRAMS; CORTICAL AREA V1; BINOCULAR DISPARITY; STEREOSCOPIC DEPTH; MOTION SELECTIVITY; VERTICAL VERGENCE AB Eye movement recordings from humans indicated that brief exposures (200 ms) to horizontal disparity steps applied to large random-dot patterns elicit horizontal vergence at short latencies (80.9 +/- 3.9 ms, mean +/- SD; n = 7). Disparity tuning curves, describing the dependence of the initial vergence responses (measured over the period 90-157 ms after the step) on the magnitude of the steps, resembled the derivative of a Gaussian, with nonzero asymptotes and a roughly linear servo region that extended only a degree or two on either side of zero disparity. Responses showed transient postsaccadic enhancement: disparity steps applied in the immediate wake of saccadic eye movements yielded higher vergence accelerations than did the same steps applied some time later (mean time constant of the decay, 200 ms). This enhancement seemed to be dependent, at least in part, on the visual reafference associated with the prior saccade because similar enhancement was observed when the disparity steps were applied in the wake of saccadelike shifts of the textured pattern. Vertical vergence responses to vertical disparity steps were qualitatively similar: latencies were longer (on average, by 3 ms), disparity tuning curves had the same general form but were narrower (by approximate to 20%), and their peak-to-peak amplitudes were smaller (by approximate to 70%). Initial vergence responses usually had directional errors (orthogonal components) with a very systematic dependence on step size that often approximated an exponential decay to a nonzero asymptote (mean space constant +/- SD, 1.18 +/- 0.66 degrees). Based on the asymptotes of these orthogonal responses, horizontal errors (with vertical steps) were on average more than three times greater than vertical errors (with horizontal steps). Disparity steps >7 degrees generated "default" responses that were independent of the direction of the step, idiosyncratic, and generally had both horizontal and vertical components. We suggest that the responses depend on detectors that sense local disparity matches, and that orthogonal and "default" responses result from globally "false" matches. Recordings from three monkeys, using identical disparity stimuli, confirmed that monkeys also show short-latency disparity vergence responses (latency approximate to 25 ms shorter than that of humans), and further indicated that these responses show all of the major features seen in humans, the differences between the two species being solely quantitative. Based on these data and those of others implying that foveal images normally take precedence, we suggest that the mechanisms under study here ordinarily serve to correct small vergence errors, automatically, especially after saccades. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Univ Alabama, Sch Optometry, Dept Physiol Opt, Birmingham, AL 35294 USA. RP Miles, FA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Rm 2A50,49 Convent Dr, Bethesda, MD 20892 USA. NR 95 TC 51 Z9 52 U1 0 U2 4 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 2001 VL 85 IS 3 BP 1129 EP 1152 PG 24 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 410KK UT WOS:000167439000013 PM 11247983 ER PT J AU Li, BS Ma, W Zhang, L Barker, JL Stenger, DA Pant, HC AF Li, BS Ma, W Zhang, L Barker, JL Stenger, DA Pant, HC TI Activation of phosphatidylinositol-3 kinase (PI-3K) and extracellular regulated kinases (Erk1/2) is involved in muscarinic receptor-mediated DNA synthesis in neural progenitor cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE progenitor cell; proliferation; muscarinic receptors; phosphorylation; protein kinase-B; MAP kinase ID PROTEIN-COUPLED RECEPTORS; GLYCOGEN-SYNTHASE KINASE-3; FIBROBLAST-GROWTH-FACTOR; INTEGRIN-LINKED KINASE; MAPK SIGNALING PATHWAY; CENTRAL-NERVOUS-SYSTEM; BETA-GAMMA-SUBUNITS; PHOSPHOINOSITIDE-3-OH KINASE; TYROSINE KINASES; PRECURSOR CELLS AB Muscarinic acetylcholine receptor (mAChR), a member of the G-protein-coupled receptors (GPCRs) gene superfamily, has been shown to mediate the effects of acetylcholine on differentiation and proliferation in the CNS. However, the mechanism or mechanisms whereby mAChRs regulate cell proliferation remain poorly understood. Here we show that in vitro bFGF-expanded neural progenitor cells dissociated from rat cortical neuroepithelium express muscarinic acetylcholine receptor subtype mRNAs. We demonstrate that stimulation of these mAChRs with carbachol, a muscarinic agonist, activated extracellular-regulated kinases (Erk1/2) and phosphatidylinositol-3 kinase (PI-3K). This, in turn, stimulated DNA synthesis in neural progenitor cells. MEK inhibitor PD98059 and PI-3K inhibitors wortmannin and LY294002 inhibited a carbachol-induced increase in DNA synthesis. These findings indicate that the activation of both PI-3 kinase and MEK signaling pathways via muscarinic receptors is involved in stimulating DNA synthesis in the neural progenitor cells during early neurogenesis. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. NIMH, Behav & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 61 TC 86 Z9 88 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 2001 VL 21 IS 5 BP 1569 EP 1579 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 404YG UT WOS:000167129700019 PM 11222647 ER PT J AU Rossi, AF Desimone, R Ungerleider, LG AF Rossi, AF Desimone, R Ungerleider, LG TI Contextual modulation in primary visual cortex of macaques SO JOURNAL OF NEUROSCIENCE LA English DT Article DE figure-ground segregation; surface perception; striate cortex; visual perception; contextual modulation; nonclassical receptive field; texture segregation ID CAT STRIATE CORTEX; ORIENTATION DISCRIMINATION; RECEPTIVE-FIELD; ALERT MONKEYS; NEURONS; RESPONSES; CELLS; V1; INTEGRATION; SEGREGATION AB Recent studies have suggested that V1 neurons extract figures from their backgrounds, in that they respond better to interior features of figures than to equivalent features of background stimuli. This is reportedly true even when the figure boundaries are distant from the borders of the classical receptive field (RF). To test the role of V1 neurons in figure-ground segregation, we recorded their responses to texture figures on texture backgrounds, centered on the RF. The texture elements of the figures remained identical across trials, and figure boundaries were defined by orientation differences between the elements in the background texture relative to elements in the figure. For nearly all neurons (98/102), responses to a large texture figure did not differ from the responses to a uniform-texture background. Although many neurons gave enhanced responses to texture boundaries, this occurred only when the boundaries were within or close to the RF borders. Similar effects were found in V2. For neurons in V1, the limited spatial extent of the contextual modulation was not increased either at low stimulus contrast or when the animal was rewarded for detecting an orientation-defined figure. Thus, V1 neurons appear to signal texture boundaries rather than figures per se. Unexpectedly, many V1 neurons gave significant long-latency responses to texture stimuli located entirely outside the classical RF, up to 5 degrees from the RF border in some cases. However, these responses did not depend on the stimulus forming a figure that contained the RF. Although V1 neurons are influenced by stimuli outside the classical RF, they do not appear to segregate figures from ground. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Rossi, AF (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. NR 26 TC 108 Z9 108 U1 0 U2 7 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 2001 VL 21 IS 5 BP 1698 EP 1709 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 404YG UT WOS:000167129700031 PM 11222659 ER PT J AU Wisor, JP Nishino, S Sora, I Uhl, GH Mignot, E Edgar, DM AF Wisor, JP Nishino, S Sora, I Uhl, GH Mignot, E Edgar, DM TI Dopaminergic role in stimulant-induced wakefulness SO JOURNAL OF NEUROSCIENCE LA English DT Article DE sleep-wake cycle; modafinil; amphetamine; caffeine; hypocretin; dopamine; narcolepsy ID MICE LACKING; CANINE NARCOLEPSY; MONOAMINE CONTENT; KNOCKOUT MICE; SLEEP; TRANSPORTER; RAT; MODAFINIL; NEURONS; CAT AB The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil. C1 Stanford Univ, Sch Med, Sleep Disorders Res Ctr, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wisor, JP (reprint author), Stanford Univ, Sch Med, Sleep Disorders Res Ctr, Dept Psychiat & Behav Sci, 701 Welch Rd 2226, Palo Alto, CA 94304 USA. FU NHLBI NIH HHS [HL61594, HL64243]; NIMH NIH HHS [MH01600, MH12244]; NINDS NIH HHS [NS-23724] NR 56 TC 390 Z9 402 U1 9 U2 24 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 2001 VL 21 IS 5 BP 1787 EP 1794 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 404YG UT WOS:000167129700040 PM 11222668 ER PT J AU Luo, JJ Wallace, MS Hawver, DB Kusiak, JW Wallace, WC AF Luo, JJ Wallace, MS Hawver, DB Kusiak, JW Wallace, WC TI Characterization of the neurotrophic interaction between nerve growth factor and secreted alpha-amyloid precursor protein SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE amyloid precursor protein; neurotrophic activity; NGF; insulin signaling pathway; PC12 cells; cortical neurons ID NEURITE OUTGROWTH; PC12 CELLS; NEURONAL DIFFERENTIATION; BETA-PROTEIN; EXTRACELLULAR-MATRIX; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE; RAT-BRAIN; EXPRESSION; PHOSPHORYLATION AB The expression and secretion of amyloid precursor protein (beta APP) is increased in rat cerebral cortices that have been denervated by subcortical lesions of the nucleus basalis of Meynert. The physiological role of the secreted PARR in response to this injury has not been established. We have previously shown that secreted PARR produced by alpha -secretase activity (sAPP(alpha)) potentiates the neuritogenic activity of nerve growth factor (NGF) in vitro on naive PC12 cells. In this investigation, we have further characterized the neurotrophic interaction of NGF and sAPP(alpha) using differentiated PC12 cells and rat primary cortical neurons. NGF required the expression of beta APP to maintain a neuronal phenotype. Reduction of endogenous PARR expression by introduction of antisense oligonucleotides in the presence of NGF resulted in loss of neurites from differentiated PC12 cells but no apparent cell death. Addition of exogenous sAPP(alpha) (60-200 pM) potentiated the protective activity of NGF in serum-deprived differentiated PC12 cells as determined by retention of neurites and cell viability. In addition, exogenous sAPP(alpha) increased neuron viability in both short-term (3 days) cortical neuron cultures grown in the absence of serum and in long-term (9 days) cultures grown with serum. Disruption of the insulin signaling pathway by reduction of IRS-1 expression inhibited the ability of sAPP(alpha) to potentiate neurotrophic activity. These observations suggest that sAPP(alpha) acts as an injury-induced neurotrophic factor that interacts with NGF to enhance neuronal viability using the insulin signaling pathway. Published 2001 Wiley-Liss, Inc. C1 NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Wallace, WC (reprint author), Georgetown Day Sch, 4200 Davenport Rd NW, Washington, DC 20006 USA. NR 40 TC 28 Z9 28 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR 1 PY 2001 VL 63 IS 5 BP 410 EP 420 DI 10.1002/1097-4547(20010301)63:5<410::AID-JNR1036>3.3.CO;2-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 405LV UT WOS:000167161900006 PM 11223916 ER PT J AU Yamanaka, R Zullo, SA Tanaka, R Blaese, M Xanthopoulos, KG AF Yamanaka, R Zullo, SA Tanaka, R Blaese, M Xanthopoulos, KG TI Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki Forest virus-mediated complementary DNA SO JOURNAL OF NEUROSURGERY LA English DT Article DE dendritic cell; antigen; Semliki Forest virus; apoptosis; gene therapy; glioma; mouse ID CENTRAL-NERVOUS-SYSTEM; SINDBIS VIRUS; GENE-THERAPY; PEPTIDE; RNA; ANTIGEN; TUMORS; EXPRESSION; CFTR; LUNG AB Object. The aim of this study was to further investigate dendritic cell (DC)-based immunotherapy for malignant glioma to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from the bone marrow and pulsed with phosphate-buffered saline, tumor RNA, tumor lysate, Semliki Forest virus (SFV)-LacZ, SFV-mediated B16 complementary (c)DNA, or SFV-mediated 203 glioma cDNA, respectively, to treat mice bearing tumors of the 203 glioma cell line. The results indicated that preimmunization with DCs pulsed with the same type of cDNA as in the tumor by a self-replicating RNA vector (that is, SFV) protected mice from tumor challenge, and that therapeutic immunization prolonged the survival of mice with established tumors. The SFV induced apoptosis in DCs and their death facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated tumor cDNA may be an excellent procedure for the development of new cancer vaccines. C1 Niigata Univ, Brain Res Inst, Dept Neurosurg, Niigata 9518122, Japan. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. RP Yamanaka, R (reprint author), Niigata Univ, Brain Res Inst, Dept Neurosurg, Asahimachi Dori 1-757, Niigata 9518122, Japan. NR 23 TC 50 Z9 59 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 2001 VL 94 IS 3 BP 474 EP 481 DI 10.3171/jns.2001.94.3.0474 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 405KB UT WOS:000167157600015 PM 11235953 ER PT J AU Lane, MA Black, A Handy, AM Shapses, SA Tilmont, EM Kiefer, TL Ingram, DK Roth, GS AF Lane, MA Black, A Handy, AM Shapses, SA Tilmont, EM Kiefer, TL Ingram, DK Roth, GS TI Energy restriction does not alter bone mineral metabolism or reproductive cycling and hormones in female rhesus monkeys SO JOURNAL OF NUTRITION LA English DT Article DE aging; bone loss; primate; reproduction; energy restriction ID DIETARY RESTRICTION; CYNOMOLGUS MONKEYS; MACACA-FASCICULARIS; FOOD RESTRICTION; CALORIE RESTRICTION; ESTROUS CYCLICITY; PHYSICAL-ACTIVITY; BODY-COMPOSITION; AGE; DENSITY AB Energy restriction (ER) extends the life span and slows aging and age-related diseases in short-lived mammalian species. Although a wide variety of physiological systems have been studied using this paradigm, little is known regarding the effects of ER on skeletal health and reproductive aging. Studies in rhesus monkeys have reported that ER delays sexual and skeletal maturation in young male monkeys and reduces bone mass in adult males. No studies have examined the chronic effects on bone health and reproductive aging in female rhesus monkeys. The present cross-sectional study examined the effects of chronic (6 y) ER on skeletal and reproductive indices in 40 premenopausal and perimenopausal (7-27 y old) female rhesus macaques (Macaca mulatta). Although ER monkeys weighed less and had lower fat mass, ER did not alter bone mineral density, bone mineral content, osteocalcin, 25-hydroxyvitamin D, 1,25-hydroxyvitamin D or parathyroid hormone concentrations, menstrual cycling or reproductive hormone concentrations. Body weight and lean mass were significantly related to bone mineral density and bone mineral content at all skeletal sites (total body, lumbar spine, mid and distal radius; P less than or equal to 0.04). The number of total menstrual cycles over 2 y, as well as the percentage of normal-length cycles (24-31 d), was lower in older than in younger monkeys (P less than or equal to 0.05). Older monkeys also had lower estradiol (P = 0.02) and higher follicle-stimulating hormone (P = 0.02) concentrations than did younger monkeys. We conclude that ER does not negatively affect these indices of skeletal or reproductive health and does not alter age-associated changes in the same variables. C1 NIA, Neurosci Lab, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. ROW Sci, Rockville, MD 20850 USA. Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08901 USA. RP Lane, MA (reprint author), NIA, Neurosci Lab, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 55 TC 39 Z9 41 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 2001 VL 131 IS 3 BP 820 EP 827 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 409VB UT WOS:000167405400020 PM 11238765 ER PT J AU Moriguchi, T Takasugi, N Itakura, Y AF Moriguchi, T Takasugi, N Itakura, Y TI The effects of aged garlic extract on lipid peroxidation and the deformability of erythrocytes SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Recent Advances on the Nutritional Benefits Acaompanying the Use of Garlic as a Supplement CY NOV 15-17, 1998 CL NEWPORT BEACH, CALIFORNIA SP Amer Soc Nutrit Sci, Amer Soc Clin Nutrit DE lipid peroxidation; erythrocytes; garlic; antioxidant ID VASCULAR ENDOTHELIAL-CELLS; SENESCENCE-ACCELERATED MOUSE; ORGANOSULFUR COMPOUNDS; VITAMIN-E; MALONYLDIALDEHYDE; CONSTITUENTS; ANTIOXIDANT; INJURY; RATS AB The effects of aged garlic extract (AGE) on lipid peroxidative damage and the deformability of erythrocytes were evaluated in rats. The deformability of erythrocytes was measured using the micropore filtration method. AGE significantly prevented the decrease of erythrocyte deformability induced by lipid peroxidation in a dose-dependent manner. The addition of AGE significantly inhibited an increase in thiobarbituric acid-reactive substances (TBARS) and hemolysis rate and prevented the loss of intraerythrocytic ATP and 2,3-diphosphoglycerate (2,3-DPG) in oxidized erythrocytes. Moreover, AGE significantly suppressed not only the hemolysis rate induced by peroxidation but also hemolysis due to nonperoxidation. These results suggest the possibility that AGE improves microcirculation and rheological blood properties and preserves the structure and function of erythrocytes not only through an antioxidant process, but also via the glycolysis pathway and membrane stabilization of erythrocytes. C1 Wakunaga Pharmaceut Co, Inst OTC Res, Hiroshima 7291195, Japan. RP Moriguchi, T (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Nihon Univ, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. EM torum@exchange.nih.gov NR 38 TC 25 Z9 26 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 2001 VL 131 IS 3 SU 3 BP 1016S EP 1019S PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410ZA UT WOS:000167469900015 PM 11238808 ER PT J AU Song, K Milner, JA AF Song, K Milner, JA TI The influence of heating on the anticancer properties of garlic SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Recent Advances on the Nutritional Benefits Acaompanying the Use of Garlic as a Supplement CY NOV 15-17, 1998 CL NEWPORT BEACH, CALIFORNIA SP Amer Soc Nutrit Sci, Amer Soc Clin Nutrit DE garlic; heating; DNA adducts ID MAMMARY DNA-ADDUCTS; ALLIUM-SATIVUM; ORGANOSULFUR COMPOUNDS; DIALLYL SULFIDE; COLON-CANCER; TUMOR-PROMOTION; INHIBITION; CARCINOGENESIS; MICE; CHEMOPREVENTION AB Allyl sulfur compounds are the major active constituents found in crushed garlic. Research has revealed that garlic and its lipid- or water-soluble components have many pharmacologic properties; however, studies also demonstrate that heating has a negative influence on these beneficial effects. We recently conducted several studies to investigate the influence of microwave or oven heating on the anticarcinogenesis property of garlic. Our studies showed that as little as 60 s of microwave heating or 45 min of oven heating can block garlic's ability to inhibit in vivo binding of mammary carcinogen [7,12-dimethylbenzene(a)anthracene (DMBA)] metabolites to rat mammary epithelial cell DNA. Allowing crushed garlic to "stand" for 10 min before microwave heating for 60 s prevented the total loss of anticarcinogenic activity. Our studies demonstrated that this blocking of the ability of garlic was consistent with inactivation of alliinase. These studies suggest that heating destroyed garlic's active allyl sulfur compound formation, which may relate to its anticancer properties. C1 Penn State Univ, Grad Program Nutr, University Pk, PA 16802 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. RP Milner, JA (reprint author), NCI, Natl Sci Res Grp, Div Canc Prevent, 6130 Execut Blvd,EPN 212, Bethesda, MD 20892 USA. EM milnerj@mail.nih.gov NR 51 TC 30 Z9 30 U1 1 U2 8 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 2001 VL 131 IS 3 SU 3 BP 1054S EP 1057S PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410ZA UT WOS:000167469900022 PM 11238815 ER PT J AU Knowles, LM Milner, JA AF Knowles, LM Milner, JA TI Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Recent Advances on the Nutritional Benefits Acaompanying the Use of Garlic as a Supplement CY NOV 15-17, 1998 CL NEWPORT BEACH, CALIFORNIA SP Amer Soc Nutrit Sci, Amer Soc Clin Nutrit DE garlic; allyl sulfide; cell cycle; apoptosis; p34(cdc2) kinase ID P34(CDC2) KINASE-ACTIVITY; DIALLYL DISULFIDE; TUMOR CELLS; S-ALLYLMERCAPTOCYSTEINE; ORGANOSULFUR COMPOUNDS; CANCER; APOPTOSIS; LINES; RISK; ERYTHROLEUKEMIA AB Both oil- and water-soluble allyl sulfur compounds from garlic have been found to possess antitumorigenic properties. These antitumorigenic properties increase as exposure increases both in vitro and in vivo. Generally, oil-soluble allyl sulfur compounds are more effective antiproliferative agents than their water-soluble counterparts. The ability of these compounds to suppress proliferation is associated with a depression in cell cycle progression and the induction of apoptosis. This depression in cell division coincides with an increase in the percentage of cells blocked in the G(2)/M phase of the cell cycle. A depression in p34(cdc2) kinase may account for this blockage in cell division. C1 Penn State Univ, Grad Program Nutr, University Pk, PA 16802 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. RP Milner, JA (reprint author), NCI, Natl Sci Res Grp, Div Canc Prevent, 6130 Execut Blvd,EPN 212, Bethesda, MD 20892 USA. EM milnerj@mail.nih.gov NR 35 TC 45 Z9 50 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 2001 VL 131 IS 3 SU 3 BP 1061S EP 1066S PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410ZA UT WOS:000167469900024 PM 11238817 ER PT J AU Lan, Q Feng, ZM Tian, DF He, XZ Rothman, N Tian, LW Lu, XB Terry, MB Mumford, JL AF Lan, Q Feng, ZM Tian, DF He, XZ Rothman, N Tian, LW Lu, XB Terry, MB Mumford, JL TI p53 gene expression in relation to indoor exposure to unvented coal smoke in Xuan Wei, China SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CELL LUNG-CANCER; PROTEIN ACCUMULATION; RISK-FACTORS; MUTATIONS; SPUTUM AB Lung cancer mortality rates in Xuan Wei County which are among the highest in China, have previously been associated with exposure to indoor emissions from burning smoky coal. To determine if this association is stronger among lung cancer patients with abnormal expression of p53, we performed a population-based case-control study. Ninety-seven newly diagnosed lung cancer patients and 97 controls, individually matched by age, sex, and home fuel type were enrolled. We used immunocytochemical methods to assess p53 protein accumulation in exfoliated tumor cells isolated from sputum samples. As expected the amount of lifetime smoky coal use was associated with an overall increase in lung cancer risk. Compared with subjects who used bs than 130 tons of smoky coal during their lifetime, the odds ratios (OR)for lung cancer were 1.48 (95% confidence interval [CI] 0.73 to 3.02)for subjects exposed to 130 to 240 tons, and 3.21 (95% CI, 1.23 to 9.03) for subjects who used more than 240 tons of smoky coal (P for trend 0.01). The effect was due almost exclusively to the pattern in women, almost all of whom were nonsmokers. Further, among highly exposed women, the association was substantially larger and achieved statistical significance only among patients with sputum samples that were positive for p53 overexpression (OR, 18.72; 95% CI, 1.77 to 383.38 vs OR 4.80; 95% CI, 0.66 to 43.87 for p53-negative cases). This study suggests that exposure to the combustion products of smoky coal in Xuan Wei is more strongly associated with women who have lung cancer accompanied by p53 protein overexpression in exfoliated tumor cells. C1 NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Chinese Acad Prevent Med, Beijing, Peoples R China. Univ Calif Berkeley, Berkeley, CA 94720 USA. Xuan Wei Hosp, Yunnan, Peoples R China. Columbia Univ, Joseph L Mailman Sch Publ Hlth, Div Epidemiol, New York, NY 10027 USA. US EPA, Res Triangle Pk, NC 27711 USA. RP Lan, Q (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, MSC 7240,6120 Execut Blvd,EPS 8109, Bethesda, MD 20892 USA. RI Tian, Linwei/A-9736-2009 OI Tian, Linwei/0000-0002-4739-1534 NR 24 TC 14 Z9 19 U1 0 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 2001 VL 43 IS 3 BP 226 EP 230 DI 10.1097/00043764-200103000-00010 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 414TR UT WOS:000167682700010 PM 11285870 ER PT J AU Lamba, AB Ward, MH Weeks, JL Dosemeci, M AF Lamba, AB Ward, MH Weeks, JL Dosemeci, M TI Cancer mortality patterns among hairdressers and barbers in 24 US states, 1984 to 1995 SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID HAIR DYE USE; NON-HODGKINS-LYMPHOMA; CALIFORNIA OCCUPATIONAL MORTALITY; BREAST-CANCER; BLADDER-CANCER; CIGARETTE-SMOKING; MULTIPLE-MYELOMA; UNITED-STATES; LUNG-CANCER; PANCREATIC-CANCER AB We evaluated cancer mortality patterns among hairdressers and barbers, according to occupation, coded on 7.2 million death certificates in 24 states from 1984 to 1995. Of the 38,721 deaths among white and black hairdressers and barbers of both sexes, 9495 were from all malignant neoplasms. Mortality odds ratios were significantly elevated for all malignant neoplasms, lung cancer, and all lymphatic and hemopoietic cancers among black and white female hairdressers. White female hairdressers had significant excess mortality from cancers of the stomach, colon, pancreas, breast, and bladder and from non-Hodgkin's lymphoma and lymphoid leukemia; mortality from these cancers was also elevated among black female hairdressers. White male hairdressers had significantly elevated mortality from non-melanoma skin cancer and non-Hodgkin's lymphoma. Mortality from all malignant neoplasms, although significantly elevated among both white and black female hairdressers, was significantly below the null for white male hairdressers. Black and white male barbers had significantly elevated mortality from stomach and pharyngeal cancer, respectively. A significant deficit in mortality from all neoplasms and cancers of the pancreas, lung, and prostate was noted for white male barbers. This large study of cancer mortality among hairdressers and barbers showed some differences in mortality patterns by gender and race. Further studies are required to determine if specific occupational exposures may explain some of the elevated cancer rates. C1 Natl Canc Inst, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Environm & Occupat Hlth, Washington, DC 20052 USA. RP Lamba, AB (reprint author), 144 Haycock Rd A-2, Falls Church, VA 22046 USA. NR 89 TC 21 Z9 21 U1 2 U2 9 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 2001 VL 43 IS 3 BP 250 EP 258 DI 10.1097/00043764-200103000-00013 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 414TR UT WOS:000167682700013 PM 11285873 ER PT J AU Paci, E Miccinesi, G Toscani, F Tamburini, M Brunelli, C Constantini, M Peruselli, C Di Giulio, P Gallucci, M Addington-Hall, J Higginson, IJ AF Paci, E Miccinesi, G Toscani, F Tamburini, M Brunelli, C Constantini, M Peruselli, C Di Giulio, P Gallucci, M Addington-Hall, J Higginson, IJ TI Quality of life assessment and outcome of palliative care SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE quality of life; outcome; palliative care ID TERMINAL CANCER-PATIENTS; OF-LIFE; COHORT AB Quality of life (Qol) assessment is crucial for the evaluation of palliative care outcome. IN this paper, our methodological approach was based on the creation of summary measures. Fifty-eight Palliative are Units (PCUs) in Italy participated in the study. Each PCU randomly selected patients to be 'evaluated' among the consecutively 'registered' patients. At baseline (first visit) and each week the patient was asked to fil lin a QoL questionnaire, the Therapy Impact Questionnaire (TIQ). Short-survivors (<7 days) were not included in the QoL study. The random sample of patients (n = 601) was highly representative of the general patient population card for by the PCUs in Italy. The mediation survival was 37.9 days. We collected 3546 TIQ, 71.4% completed by the patients. A Summary Measure Outcome score was calculated for 409 patients (81% of the patients included in QoL study). The results of this national study showed that cooperative clinical research in palliative care is possible and QoL measures can be used to assess the outcome. J Pain Symptom Manage 2001;21: 179-188. (C) U.S. Cancer Pain Relief Committee, 2001. C1 Ctr Study & Prevent Canc, Epidemiol Unit, I-50135 Florence, Italy. Natl Canc Inst, Psychol Div, Milan, Italy. Natl Canc Inst, Genoa, Italy. Mario Negri Inst, Milan, Italy. Gen Hosp, Palliat Care Serv, Desio, Italy. Univ London Kings Coll, Sch Med & Dent, Dept Palliat Care & Policy, London, England. RP Paci, E (reprint author), Ctr Study & Prevent Canc, Epidemiol Unit, Via San Salvi 12, I-50135 Florence, Italy. RI Higginson, Irene/C-7309-2012; costantini, massimo/G-1443-2012; Brunelli , Cinzia/B-9361-2017 OI Brunelli , Cinzia/0000-0003-3905-1289 NR 17 TC 16 Z9 17 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2001 VL 21 IS 3 BP 179 EP 188 DI 10.1016/S0885-3924(01)00263-9 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 406NG UT WOS:000167221600005 PM 11239736 ER PT J AU Hertle, RW Wilson, MC AF Hertle, RW Wilson, MC TI Adjunctive use of alpha-chymotrypsin during infantile lensectomy and vitrectomy SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Article ID COMPLICATIONS; CATARACTS C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hertle, RW (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49 Rm 2A50, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD MAR-APR PY 2001 VL 38 IS 2 BP 109 EP 111 PG 3 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 414TY UT WOS:000167683300013 PM 11310703 ER PT J AU Leschek, EW Troendle, JF Yanovski, JA Rose, SR Bernstein, DB Cutler, GB Baron, J AF Leschek, EW Troendle, JF Yanovski, JA Rose, SR Bernstein, DB Cutler, GB Baron, J TI Effect of growth hormone treatment on testicular function, puberty, and adrenarche in boys with non-growth hormone-deficient short stature: A randomized, double-blind, placebo-controlled trial SO JOURNAL OF PEDIATRICS LA English DT Article ID FEMALE RHESUS-MONKEYS; FINAL HEIGHT; CHILDREN; THERAPY; MATURATION; RADIOIMMUNOASSAY; GH AB Objective: To evaluate the effect of growth hormone (GH) therapy on pubertal onset, pubertal pace, adult testicular function, and adrenarche in boys with non-GH-deficient short stature. Study design: Randomized, double-blind, placebo-controlled trial. GH (0.074 mg/kg, subcutaneously, 3 times per week) or placebo treatment was initiated in prepubertal or early pubertal boys and continued until near final height was reached (n = 49). Statistical significance was assessed by survival analysis, repeated-measures analysis of variance, and Student t test. Results: GH therapy did not affect the age at pubertal onset, defined either by testicular volume >4 mt or by testosterone concentration >1.0 nmol/L (30 ng/dL). GI-I treatment also did not affect the pace of puberty, defined either by the rate of change in testicular volume or testosterone concentration during the 4 years after pubertal onset. In boys followed up to age greater than or equal to 16 years during the study, there were no significant differences in final testicular volume or in plasma testosterone, luteinizing hormone, or follicle-stimulating hormone concentrations. The pace of adrenarche, assessed by change in dehydroepiandrosterone sulfate levels over time, also did not differ significantly between the GH and placebo groups. Conclusion: Our findings suggest that GH treatment does not cause testicular damage, alter the onset or pace of puberty, or alter the pace of adrenarche in boys with non-GH-deficient short stature. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Biometry & Math Stat Branch, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Leschek, EW (reprint author), NICHD, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. OI Yanovski, Jack/0000-0001-8542-1637 NR 22 TC 21 Z9 21 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAR PY 2001 VL 138 IS 3 BP 406 EP 410 DI 10.1067/mpd.2001.111332 PG 5 WC Pediatrics SC Pediatrics GA 413BZ UT WOS:000167591200021 PM 11241051 ER PT J AU Cheung, AP Struble, E Nguyen, N Liu, P AF Cheung, AP Struble, E Nguyen, N Liu, P TI Stability-indicating HPLC assay and solution stability of a new diaziridinyl benzoquinone SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article; Proceedings Paper CT 11th International Symposium on Pharmaceutical and Biomedical Analysis (PBA 2000) CY MAY 14-18, 2000 CL BASEL, SWITZERLAND DE RH1; 3-methyl-6-hydroxymethyl-2,5-diaziridinyl-1,4-benzoquinone; HPLC assay; aqueous stability; decomposition products ID DT-DIAPHORASE; MITOMYCIN-C; ANTITUMOR AGENT; DNA DAMAGE; QUINONES; METABOLISM; 2,5-DIAZIRIDINYL-3,6-BIS(CARBOETHOXYAMINO)-1,4-BENZOQUINONE; CYTOTOXICITY; CARCINOMA; RH1 AB RH1, 3-methyl-6-hydroxymethyl-2,5-diaziridinyl-1,4-benzoquinone, is a NQO1 (NAD(P)H quinone oxidoreductase) directed anti-tumor agent. It is designed as a water soluble analog of MeDZQ (3,6-dimethyl-2,5-diaziridinyl-1,4-benzoquinone) and is ii drug candidate for clinical evaluation. A HPLC assay has been developed for its analysis. The assay is sensitive (1dl < 0.2 ng), precise (rsd < 1%), linear (r(2) = 0.9997), accurate (error < 0.6%), and stability-indicating. Using the developed assay, aqueous stability of RH1 has been evaluated. Both aziridine rings in MeDZQ are known to be easily hydrolyzable in aqueous solutions, however, hydrolysis of the second aziridine ring in RH1 appears inhibited. (C) 2001 Elsevier Science B.V. All rights reserved. C1 SRI Int, Menlo Park, CA 94025 USA. NCI, Pharmaceut Resources Branch, DCTD, Bethesda, MD 20892 USA. RP Cheung, AP (reprint author), SRI Int, 333 Ravenswood Ave, Menlo Park, CA 94025 USA. FU NCI NIH HHS [N01-CM-77104] NR 19 TC 7 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAR PY 2001 VL 24 IS 5-6 BP 957 EP 966 DI 10.1016/S0731-7085(00)00566-5 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 416DD UT WOS:000167764200024 PM 11248489 ER PT J AU Chen, ZP Wang, ZM Carter, CA Alley, MC Mohr, G Panasci, LC AF Chen, ZP Wang, ZM Carter, CA Alley, MC Mohr, G Panasci, LC TI Both extraneuronal monoamine transporter and O-6-methylguanine-DNA methyltransferase expression influence the antitumor efficacy of 2-chloroethyl-3-sarcosinamide-1-nitrosourea in human tumor xenografts SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GLIOMA CELL-LINES; AMINO-ACID AMIDES; CYTOTOXICITY; CHLOROETHYLNITROSOUREA; SARCNU; BCNU; (2-CHLOROETHYL)-3-SARCOSINAMIDE-1-NITROSOUREA; 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA; CONGENERS; SK-MG-1 AB We previously have found that 2-chloroethyl-3-sarcosinamide1-nitrosourea (SarCNU) is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT). Both in vitro and in vivo studies demonstrated that SarCNU was more effective than BCNU against human gliomas. To clarify whether EMT expression correlates with antitumor efficacy of SarCNU, we determined human EMT (EMTh) and O-6-methylguanine-DNA methyltransferase (MGMT) expression in nine human xenograft models using semiquantitative reverse-transcription polymerase chain reaction. These results were compared with the antitumor effects of SarCNU and the standard chloroethylnitrosourea antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). There was no significant correlation between EMTh expression and antitumor efficacy of SarCNU or BCNU. Also, there was no significant correlation between MGMT expression and SarCNU efficacy. However, a significant correlation was found between MGMT expression and BCNU antitumor efficacy. Interestingly, multiple regression analysis demonstrated a significant correlation between SarCNU efficacy and EMTh plus MGMT expression, whereas there was no correlation between BCNU efficacy and MGMT plus EMTh expression. Thus, the absence of a linear correlation between SarCNU efficacy and EMTh expression appears to be due, at least in part, to the presence of DNA repair, specifically, MGMT, in these xenograft models. These studies suggest that MGMT expression alone correlates with BCNU activity, whereas both EMTh and MGMT expression are important determinants of SarCNU activity against human tumor xenograft models. SarCNU is in clinical trials and these results may have important clinical implications. C1 McGill Univ, Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. Sun Yat Sen Univ Med Sci, Ctr Canc, Guangzhou, Peoples R China. Bayer Corp, W Haven, CT USA. NCI, Dev Therapeut Program, Div Canc Treatment Diag & Ctr, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Panasci, LC (reprint author), McGill Univ, Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, 3755 Cote St Catherine, Montreal, PQ H3T 1E2, Canada. FU NCI NIH HHS [R03CA78205] NR 21 TC 2 Z9 2 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 2001 VL 296 IS 3 BP 712 EP 715 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000008 PM 11181897 ER PT J AU Sun, MK Dahl, D Alkon, DL AF Sun, MK Dahl, D Alkon, DL TI Heterosynaptic transformation of GABAergic gating in the hippocampus and effects of carbonic anhydrase inhibition SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID SEPTAL CHOLINERGIC NEURONS; SYNAPTIC PLASTICITY; PYRAMIDAL NEURONS; RAT HIPPOCAMPUS; ACETYLCHOLINE-RELEASE; GABA(A) RECEPTORS; SPATIAL MEMORY; CELLS; EXCITATION; PERFORMANCE AB Recordings from CA1 pyramidal cells were made in rat hippocampal slices (in vitro). Activation of cholinergic receptors associated with tetanization of GABAergic inputs from stratum pyramidale transformed the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials into depolarizing responses of rat hippocampal CA1 pyramidal neurons. The synaptic transformation was characterized by a significant shift of reversal potential of postsynaptic responses toward positive membrane potentials. This effect lasted more than 1 h and changed the function of the GABAergic synapses from excitation filter to amplifier. This long-term synaptic transformation was prevented by carbonic anhydrase inhibitors or the presence of HEPES buffer, indicating a dependence on HCO3-. The presence or absence of an associated activation of cholinergic with GABAergic inputs thus gates the information processing through the pyramidal cells and network, forming an amplified "center" of attention and a filtered "surround". Information flow through the neural circuit is thereby directed according to temporal association of the relevant signals. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Sun, MK (reprint author), Blanchette Rockefeller Neurosci Inst, 9601 Med Ctr Dr,Acad & Res Bldg,Room 319, Rockville, MD 20850 USA. NR 41 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 2001 VL 296 IS 3 BP 811 EP 817 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000022 PM 11181911 ER PT J AU Brandt, MR Furness, MS Mello, NK Rice, KC Negus, SS AF Brandt, MR Furness, MS Mello, NK Rice, KC Negus, SS TI Antinociceptive effects of delta-opioid agonists in rhesus monkeys: Effects on chemically induced thermal hypersensitivity SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RECEPTOR-MEDIATED PHENOMENA; PRIMARY AFFERENT; SPINAL-CORD; MU; RAT; INVOLVEMENT; BW373U86; HYPERALGESIA; INFLAMMATION; COCAINE AB The effects of SNC80 and other structurally related delta -opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degreesC), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys dose dependently decreased the T10, indicating that capsaicin increased sensitivity to thermal stimuli. A dose of 0.1 mg of capsaicin decreased the T(10) from 48.0 to 42.1 degreesC (a 25.9 degreesC change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose dependently blocked the capsaicin-induced decrease in the T(10), and 10.0 mg/kg SNC80 fully blocked the effects of capsaicin. The delta -selective antagonist naltrindole (0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80, whereas a mu -selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other delta -selective agonists, SNC162 (1.0-10.0 mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta -agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs. C1 Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02178 USA. NIDDKD, Med Chem Lab, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Negus, SS (reprint author), Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, 115 Mill St, Belmont, MA 02178 USA. EM negus@mclean.org FU NIDA NIH HHS [R01-DA11460, DA04059, T32-DA0752] NR 35 TC 46 Z9 46 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2001 VL 296 IS 3 BP 939 EP 946 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000038 PM 11181927 ER PT J AU Pegg, AE Goodtzova, K Loktionova, NA Kanugula, S Pauly, GT Moschel, RC AF Pegg, AE Goodtzova, K Loktionova, NA Kanugula, S Pauly, GT Moschel, RC TI Inactivation of human O-6-alkylguanine-DNA alkyltransferase by modified oligodeoxyribonucleotides containing O-6-benzylguanine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HUMAN-TUMOR-CELLS; ANTISENSE OLIGONUCLEOTIDES; PLUS O-6-BENZYLGUANINE; ALKYLATING-AGENTS; ESCHERICHIA-COLI; REPAIR; METHYLTRANSFERASE; THERAPEUTICS; CHEMOTHERAPY; SENSITIVITY AB Inactivation of the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT) enhances tumor cell killing by therapeutic alkylating agents. O-6-Benzylguanine (b(6)G) can inactivate AGT and is currently in clinical trials to enhance therapy. Short oligodeoxyribonucleotides containing b(6)G are much more effective inactivators, but their use for therapeutic purposes is likely to be compromised by metabolic instability. We have therefore examined the ability to inactivate AGT of an 11-mer oligodeoxyribonucleotide containing b(6)G (11-mpBG) when modified with terminal methylphosphonate linkages to protect it from nucleases. This modification did not reduce the ability to serve as a substrate/inactivator for AGT, and 11-mpBG had an ED50 value of 1.3 nM, more than 300-fold lower than that for b(6)G. A similar oligodeoxyribonucleotide containing O-6-methyl-guanine (m(6)G) was also found to be a good substrate (ED50 value of 10 nM), but the benzylated form was repaired more rapidly and preferentially. When added to HT29 cell cultures, 5 muM 11-mpBG was able to cause a prolonged inactivation of cellular AGT for at least 72 h and to greatly sensitize the cells to killing by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The 11-mpMG was ineffective at up to 20 muM, suggesting that the benzyl group allows better uptake into the cell. However, even with 11-mpBG, the 1000-fold decrease in potency toward AGT in HT29 cells compared to that toward the protein in vitro suggests that uptake may be a limiting factor. These results suggest that oligodeoxyribonucleotides such as 11-mpBG may prove to be useful drugs for potentiation of alkylating agent chemotherapy if uptake can be improved. C1 Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Pegg, AE (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Room C4739B,POB 850,500 Univ Dr, Hershey, PA 17033 USA. FU NCI NIH HHS [CA-57725, CA-71976, CA-18138] NR 39 TC 14 Z9 14 U1 0 U2 3 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 2001 VL 296 IS 3 BP 958 EP 965 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000040 PM 11181929 ER PT J AU Gobbi, G Murphy, DL Lesch, KP Blier, P AF Gobbi, G Murphy, DL Lesch, KP Blier, P TI Modifications of the serotonergic system in mice lacking serotonin transporters: An in vivo electrophysiological study SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article; Proceedings Paper CT 38th Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 12-16, 1999 CL ACAPULO, MEXICO SP Amer Coll Neuropsychopharmacol ID DORSAL RAPHE NEURONS; HIPPOCAMPAL PYRAMIDAL CELLS; NEUROENDOCRINE RESPONSES; 5-HT NEUROTRANSMISSION; KNOCKOUT MICE; RECEPTORS; RAT; DESENSITIZATION; FLUOXETINE; PAROXETINE AB The serotonin transporter (5-HTT) plays a key role in the regulation of serotonin (5-hydroxytryptamine, 5-HT) transmission in the pathophysiology and therapeutics of several psychiatric disorders. The mean spontaneous firing rate of midbrain dorsal raphe 5-HT neurons was recorded in chloral hydrate-anesthetized mice. The serotonin transporter (5-HTT), which plays a key role in the regulation of serotonin was significantly decreased in homozygous mice lacking the 5-HT transporter (5-HTT-/-) by 66% and in heterozygous (5-HTT +/-) mice by 36% compared with their normal littermates (5-HTT +/-). Systemic injection of the selective 5-HT1A receptor antagonist WAY 100635 enhanced 5-HT neuronal firing by 127% in 5-HT -/- mice, thus indicating an enhanced synaptic availability of 5-HT at inhibitory 5-HT1A receptors. Nevertheless, the cell body 5-HT1A autoreceptors were desensitized in both 5-HTT -/- and 5-HTT +/- mice. At the postsynaptic level, the recovery time (RT50)of the firing rate of hippocampus CA(3) pyramidal neurons following iontophoretic applications of 5-HT was significantly prolonged only in 5-HTT -/- mice. The selective 5-HT reuptake inhibitor paroxetine significantly prolonged the RT50 in 5-HTT +/+ and 5-HTT +/- mice, without altering the maximal inhibitory effect of 5-HT. These neurons in 5-HTT -/- mice showed an attenuated response to the 5-HT1A agonist 8-hydroxy-2-diproplyaminotetralin, but not to 5-HT itself. These results establish that the lack of 5-HTT causes a prolonged recovery of firing activity following 5-HT applications. The genetic deletion of the 5-HTT plays a key role on 5-HT1A receptor adaptation: a desensitization at pre- and postsynaptic levels in 5-HTT -/- mice, but to a different extent, and only at the presynaptic level in the 5-HTT +/- group. C1 Univ Florida, Inst Brain, Dept Psychiat, Gainesville, FL 32610 USA. McGill Univ, Dept Psychiat, Neurobiol Psychiat Unit, Montreal, PQ, Canada. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Psychiat, D-8700 Wurzburg, Germany. RP Blier, P (reprint author), Univ Florida, Inst Brain, Dept Psychiat, POB 100256, Gainesville, FL 32610 USA. RI Gobbi, Gabriella/I-2786-2013; Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 43 TC 119 Z9 119 U1 0 U2 1 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 2001 VL 296 IS 3 BP 987 EP 995 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000044 PM 11181933 ER PT J AU Miller, DK Crooks, PA Teng, LH Witkin, JM Munzar, P Goldberg, SR Acri, JB Dwoskin, LP AF Miller, DK Crooks, PA Teng, LH Witkin, JM Munzar, P Goldberg, SR Acri, JB Dwoskin, LP TI Lobeline inhibits the neurochemical and behavioral effects of amphetamine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RAT STRIATAL SLICES; SYNAPTIC VESICLES; NICOTINIC AGONISTS; NUCLEUS-ACCUMBENS; MONOAMINE-OXIDASE; DOPAMINE RELEASE; DOPAMINE; METHAMPHETAMINE; OVERFLOW; NOREPINEPHRINE AB Lobeline interacts with the dopamine transporter and vesicular monoamine transporter, presynaptic proteins involved in dopamine storage and release. This study used rodent models to assess lobeline-induced inhibition of the neurochemical and behavioral effects of amphetamine. Rat striatal slices were preloaded with [H-3] dopamine and superfused with lobeline for 30 min, and then with d-amphetamine (0.03-3.00 muM) plus lobeline for 60 min. As predicted, lobeline (1-3 muM) intrinsically increased H-3 overflow but did not inhibit d-amphetamineevoked H-3 overflow. Consequently, the effect of lobeline on d-amphetamine-evoked endogenous dopamine and dihydroxyphenylacetic acid overflow was assessed. Lobeline (0.1-1 mM) inhibited d-amphetamine (1 muM)-evoked dopamine overflow but did not inhibit electrically evoked H-3 overflow, indicating a selective inhibition of this effect of d-amphetamine. To determine whether the in vitro results translated into in vivo inhibition, the effect of lobeline (0.3-10.0 mg/kg) pretreatment on d-amphetamine (0.1-1.0 mg/kg)-induced hyperactivity in rats and on d-methamphetamine (0.1-3.0 mg/kg)-induced hyperactivity in mice was determined. Doses of lobeline that produced no effect alone attenuated the stimulant-induced hyperactivity. Lobeline also attenuated the discriminative stimulus properties of d-methamphetamine in rats. Acute, intermittent, or continuous in vivo administration of lobeline (1-30 mg/kg) did not deplete striatal dopamine content. Thus, lobeline inhibits amphetamine-induced neurochemical and behavioral effects, and is not toxic to dopamine neurons. These results support the hypothesis that lobeline redistributes dopamine pools within the presynaptic terminal, reducing pools available for amphetamine-induced release. Collectively, the results support a role for lobeline as a potential pharmacotherapy for psychostimulant abuse. C1 Univ Kentucky, Coll Pharm, Lexington, KY 40536 USA. NIDA, Addict Res Ctr, Behav Neurosci Branch, Baltimore, MD 21224 USA. RP Dwoskin, LP (reprint author), Univ Kentucky, Coll Pharm, Lexington, KY 40536 USA. RI Garland, Charolette/B-6091-2011; OI Miller, Dennis/0000-0003-4422-7197 FU NIDA NIH HHS [DA00399, DA06043, DA13519] NR 45 TC 67 Z9 68 U1 2 U2 3 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 2001 VL 296 IS 3 BP 1023 EP 1034 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000048 PM 11181937 ER PT J AU Hayakawa, T Chang, MCJ Rapoport, SI Appel, NM AF Hayakawa, T Chang, MCJ Rapoport, SI Appel, NM TI Selective dopamine receptor stimulation differentially affects [H-3] arachidonic acid incorporation, a surrogate marker for phospholipase A(2)-mediated neurotransmitter signal transduction, in a rodent model of Parkinson's disease SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CEREBRAL GLUCOSE-UTILIZATION; SUBSTANTIA NIGRA LESIONS; RAT-BRAIN; SUBTHALAMIC NUCLEUS; FATTY-ACIDS; AUTORADIOGRAPHIC LOCALIZATION; CHOLINERGIC STIMULATION; UNANESTHETIZED RATS; QUINPIROLE BINDING; STRIATAL NEURONS AB Our laboratory has developed a technique whereby radiolabeled long-chain fatty acids are injected intravenously in awake rats to pulse-label brain lipids, mainly phospholipids, to measure regional brain lipid metabolism by autoradiography. The brain incorporation of [H-3] arachidonic acid ([H-3]AA), a polyunsaturated fatty acid, may reflect regional changes in neurotransmitter signal transduction using phospholipase A(2). Using this radiotracer, we examined the brain dopamine system in rats with a chronic unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta, a model of Parkinson's disease. Four weeks after lesioning, rats received either vehicle; SKF38393 or quinpirole (LY-171,555) (D-1- and D-2-dopamine-like agonists, respectively); or (+)-butaclamol (D-1/D-2 antagonist) followed by either vehicle, SKF38393, or quinpirole. They then were infused with [H-3] AA and their brains processed for autoradiography. SKF38393 increased [H-3] AA incorporation into the lesioned side compared with the intact side in the caudate putamen, somatosensory and motor cortices and subthalamic nucleus, but decreased incorporation in the ipsilateral ventrolateral thalamus. Quinpirole increased ipsilateral [H-3] AA incorporation in the caudate putamen and somatosensory and motor cortices, and decreased it in the ventrolateral thalamus. (+)-Butaclamol blocked this effect. The data suggest up-regulation in basal ganglia and cortical dopamine circuits mediated by phospholipase A(2) ipsilateral to the substantia nigra lesion. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. Tokyo Med & Dent Univ, Dept Neurosurg, Bunkyo Ku, Tokyo, Japan. US FDA, Ctr Drug Evaluat & Res, Off Testing & Res, Div Appl Pharmcol Res, Laurel, MD USA. RP Appel, NM (reprint author), NIDA, Div Treatment Res & Dev, NIH, 6001 Execut Blvd,Room 4123,MSC 9551, Bethesda, MD 20892 USA. NR 60 TC 37 Z9 37 U1 0 U2 1 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 2001 VL 296 IS 3 BP 1074 EP 1084 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 404TD UT WOS:000167116000054 PM 11181943 ER PT J AU Sher, L AF Sher, L TI Candidate gene studies in psychiatric disorders: promises and limitations SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Editorial Material DE case-control studies; generic predisposition to disease; genetics, biochemical; genetics, behavioral; mental disorders ID BEHAVIORAL-GENETICS; ASSOCIATION; PITFALLS C1 NIMH, Bethesda, MD 20892 USA. RP Sher, L (reprint author), New York State Psychiat Inst, Dept Neurosci, 1051 Riverside Dr,Box 42, New York, NY 10032 USA. NR 18 TC 4 Z9 4 U1 1 U2 2 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD MAR PY 2001 VL 26 IS 2 BP 103 EP 105 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 416EQ UT WOS:000167767700002 PM 11291526 ER PT J AU Gajendiran, N Tanaka, K Kumaravel, TS Kamada, N AF Gajendiran, N Tanaka, K Kumaravel, TS Kamada, N TI Neutron-induced adaptive response studied in go human lymphocytes using the comet assay SO JOURNAL OF RADIATION RESEARCH LA English DT Article DE adaptive response; comet assay; DNA damage; neutron; atomic bomb survivors ID ATOMIC-BOMB SURVIVORS; LOW-DOSE IRRADIATION; DNA-DAMAGE; IONIZING-RADIATION; X-IRRADIATION; GAMMA-RAYS; CELLS; REPAIR; CHROMOSOME; INDUCTION AB This study demonstrates that cells adapted to ionizing radiation developed reduced initial DNA damage when compared to non-adapted cells. The results were obtained by subjecting in vitro irradiated whole blood from 10 healthy volunteers (including 2 A-bomb survivors carrying 1.5-2 Gy in vivo exposure) in an unstimulated condition (G(0)) using the comet assay. The intensity of DNA damage was assessed by computing the 'tail moment'. Adaptive response (AR) was noticed in only donor 3, as indicated by reduced tail moment when the blood samples received priming + challenging doses over a 4 h interval. The priming dose was either 0.01 Gy (137)Cs gamma -rays or 0.0025 Gy (252)Cf neutrons. The delivered challenging dose was either 1 Gy (60)Co g-rays or 0.25 Gy (252)Cf neutrons. The irradiation was conducted using the HIRRAC facility. A prior exposure to 0.0025 Oy (252)Cf neutrons nullified the excess tail moment caused by 0.25 Gy neutrons given during a 4 h gap. In a similar way, 0.01 Gy (137)Cs gamma -rays offered a cross-adaptive response to the neutron challenging dose. The tail moment of A-bomb survivors after in vitro irradiation was less than that of the age-matched control and, at the same time, was not influenced by the priming dose. An altered subset and the immunological status of blood after A-bomb exposure were cited as possible factors. Because AR can affect the outcome of RBE, its individual variability only emphasizes the need to have individual biodosimetry for better risk assessment, especially in planning for a long space voyage. C1 Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Canc Cytogenet, Hiroshima 7348553, Japan. Indira Gandhi Ctr Atom Res, Hlth & Safety Div, Kalpakkam 603102, Tamil Nadu, India. NIA, Mol Genet Lab, GRC, NIH, Baltimore, MD 21224 USA. RP Gajendiran, N (reprint author), Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Canc Cytogenet, Hiroshima 7348553, Japan. EM ngj@igcar.ernet.in NR 34 TC 26 Z9 28 U1 0 U2 2 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD MAR PY 2001 VL 42 IS 1 BP 91 EP 101 DI 10.1269/jrr.42.91 PG 11 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 433VZ UT WOS:000168782500009 PM 11393893 ER PT J AU McCrae, RR AF McCrae, RR TI 5 years of progress: A reply to Block SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article ID FACET-LEVEL TRAITS; 5-FACTOR MODEL; PERSONALITY-INVENTORY; EXAMPLES; SCALES AB During the past 5 years, no coherent and persuasive critique of the methods or findings of the FFM has appeared. In addition to a wealth of personality correlates, research has made important contributions to understanding the biological bases of personality, its cross-cultural universality, and its lifespan development. Theoretical efforts, though incomplete, have begun to integrate the study of traits into a broader understanding of the personality system. The FFM continues to thrive. C1 NIA, Gerontol Res Ctr, Personal Stress & Coping Sect, NIH, Baltimore, MD 21224 USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, Personal Stress & Coping Sect, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 16 Z9 17 U1 1 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD MAR PY 2001 VL 35 IS 1 BP 108 EP 113 DI 10.1006/jrpe.2000.2294 PG 6 WC Psychology, Social SC Psychology GA 408TZ UT WOS:000167344900008 ER PT J AU Speaker, SL AF Speaker, SL TI "The struggle of mankind against its deadliest foe": Themes of counter subversion in anti-narcotic campaigns, 1920-1940 SO JOURNAL OF SOCIAL HISTORY LA English DT Article ID ADDICTION AB During the 1920s and 1930s, newspaper and magazine accounts of narcotics problems, and the propaganda of various anti narcotic organizations used certain stock ideas and images to construct an intensely fearful public rhetoric about drugs. Authors routinely described drugs, users, and sellers as "evil," described sinister conspiracies to undermine American society and values, credited drugs with immense power to corrupt users, and called for complete eradication of the problem. That rhetoric became the standard template for American public discourse about drugs, and is still in use. Very similar themes and images, however, were used in earlier crusades against Masons, Catholics, and Mormons. This suggests that anti-drug discourse is linked to a larger American rherorical tradition, one that stems from Protestant-Republican ideology and cultural concerns-fears of being owned or controlled, fears of anarchy, fears of loss of dynamism, fears of falling away from past virtue and promise. In casting drugs and drug users as a "Great American Enemy" reformers not only addressed the existing social problems posed by drug use, but attempted, through a culturally resonant rhetorical form, to provide their audience with explanations and rallying points, and help them define or recover a sense of cultural identity and purpose. C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Speaker, SL (reprint author), Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. NR 76 TC 8 Z9 8 U1 3 U2 4 PU CARNEGIE MELLON UNIV PRESS PI PITTSBURGH PA CARNEGIE MELLON UNIV J SOCIAL HIST, PITTSBURGH, PA 15213 USA SN 0022-4529 J9 J SOC HIST JI J. Soc. Hist. PD SPR PY 2001 VL 34 IS 3 BP 591 EP + DI 10.1353/jsh.2001.0031 PG 21 WC History SC History GA 407EK UT WOS:000167259100004 ER PT J AU Robbins, JM Taylor, JL Rost, KM Burns, BJ Phillips, SD Burnam, MA Smith, GR AF Robbins, JM Taylor, JL Rost, KM Burns, BJ Phillips, SD Burnam, MA Smith, GR TI Measuring outcomes of care for adolescents with emotional and behavioral problems SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE Adolescent Treatment Outcomes Module; outcomes; validity; functioning; respondent burden; case mix ID CHILDREN; SCALES AB Objectives: To validate the prototype Adolescent Treatment Outcomes Module (ATOM), examine its sensitivity to clinical change, and determine its feasibility for administration in routine clinical settings. Method: A sample of 67 adolescents, aged 11 through 18, was selected from new patients at two inpatient and two outpatient mental health programs. Adolescents and parents completed the ATOM and validating instruments at intake, 1 week postintake, and again at 6 months. Results: Nine self-report symptoms predicted positive diagnoses of oppositional defiant, conduct, anxiety, and depressive disorders on the basis of structured diagnoses, with sensitivities of 0.7 to 0.8. Test-retest correlations for outcome scales were largely excellent (>0.70). Scales that measured functioning at home, in school. and in the community were moderately correlated in the expected direction with global functioning. Decreases in symptom severity and functional impairment were generally associated with decreases in validating instruments. Administration time averaged 25 minutes for adolescents and 28 minutes for parents. Conclusions: Both parents and adolescents readily completed the ATOM. Module scales demonstrated excellent reliability and good to fair concurrent validity. The ATOM was able to detect change and its absence. C1 Univ Arkansas Med Sci, Ctr Appl Res & Evaluat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, NIMH, Ctr Rural Mental Healthcare Res, Little Rock, AR 72205 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Serv Effectiveness Res Program, Durham, NC 27706 USA. Ctr Youth, Little Rock, AR USA. Ctr Families, Little Rock, AR USA. RAND Corp, Santa Monica, CA USA. RP Robbins, JM (reprint author), Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, 1120 Marshall St, Little Rock, AR 72202 USA. OI Robbins, James/0000-0003-2200-1947 FU NIMH NIH HHS [R01 MH 57882] NR 22 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2001 VL 40 IS 3 BP 315 EP 324 DI 10.1097/00004583-200103000-00011 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 406DQ UT WOS:000167200000011 PM 11288773 ER PT J AU Weissenberger, AA Leschek, EW Zametkin, AJ AF Weissenberger, AA Leschek, EW Zametkin, AJ TI Case study: Sexual hyperactivity treated with psychostimulants in familial male precocious puberty SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE familial male precocious puberty; stimulants; sexual aggression; attention-deficit/hyperactivity disorder ID MANAGEMENT; DISORDERS AB Familial male precocious puberty is a form of precocious puberty resulting from an activating mutation of the luteinizing hormone receptor. Behavior problems are associated with the early onset of puberty. In this case. sexual hyperactivity was treated with psychostimulants. Implications for the effectiveness of methylphenidate in reducing sexual hyperactivity with and without familial male precocious puberty are discussed, and testable hypotheses are proposed for the effects of stimulants on sexual behavior in adolescents. C1 NIMH, Bethesda, MD 20814 USA. NICHHD, Bethesda, MD 20892 USA. RP Zametkin, AJ (reprint author), NIMH, Bldg 10,Room 3N 238 MSC 1276, Bethesda, MD 20814 USA. NR 14 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2001 VL 40 IS 3 BP 373 EP 376 DI 10.1097/00004583-200103000-00018 PG 4 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 406DQ UT WOS:000167200000018 PM 11288780 ER PT J AU Takayama, H Nagashima, Y Hara, M Takagi, H Mori, M Merlino, G Nakazato, Y AF Takayama, H Nagashima, Y Hara, M Takagi, H Mori, M Merlino, G Nakazato, Y TI Immunohistochemical detection of the c-met proto-oncogene product in the congenital melanocytic nevus of an infant with neurocutaneous melanosis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; FACTOR SCATTER FACTOR; MALIGNANT-MELANOMA; RECEPTOR; RHABDOMYOSARCOMA AB Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF) demonstrate extensive pigmented nevi in both skin and leptomeninges of the central nervous system resembling human neurocutaneous melanosis. We immunohistochemically detected HGF/SF receptor; Met, in a congenital nevus of an infant with neurocutaneous melanosis, the critical period of development may lead to this indicating that deregulation of HGF/SF-Met signaling in fatal syndrome. C1 Gunma Univ, Sch Med, Dept Internal Med 1, Gunma 3718511, Japan. Gunma Univ, Sch Med, Dept Pathol 1, Gunma 3718511, Japan. Yokohama City Univ, Sch Med, Dept Pathol, Yokohama, Kanagawa 232, Japan. Yokohama City Univ, Urafune Hosp, Div Lab Med, Yokohama, Kanagawa 232, Japan. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Takayama, H (reprint author), Gunma Univ, Sch Med, Dept Internal Med 1, Gunma 3718511, Japan. NR 14 TC 31 Z9 32 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2001 VL 44 IS 3 BP 538 EP 540 DI 10.1067/mjd.2001.112403 PG 3 WC Dermatology SC Dermatology GA 407FE UT WOS:000167260900025 PM 11209133 ER PT J AU Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Merz, CNB Sopko, G Cornell, CE Sharaf, B Matthews, KA AF Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Merz, CNB Sopko, G Cornell, CE Sharaf, B Matthews, KA TI History of anxiety disorders is associated with a decreased likelihood of angiographic coronary artery disease in women with chest pain: The WISE study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID SILENT-MYOCARDIAL-ISCHEMIA; ANGINA-PECTORIS; CARDIOVASCULAR-DISEASE; PSYCHOLOGICAL-FACTORS; PROGNOSTIC VALUE; RISK-FACTORS; INFARCTION; GENDER; MEN; DEPRESSION AB OBJECTIVES We sought to evaluate the ability of psychiatric anxiety-disorder history to discriminate between women with and without angiographic coronary artery disease (CAD) in a population with chest pain. BACKGROUND A total of 435 women with chest pain underwent a diagnostic battery including coronary angiography in order to improve testing guidelines for women with suspected CAD. METHODS Women referred far coronary angiography completed questionnaires assessing prior treatment history for anxiety disorder and current anxiety-related symptoms. Analyses controlled for standard CAD risk factors. RESULTS Forty-four women (10%) reported receiving prior treatment for an anxiety disorder. This group acknowledged significantly higher levels of autonomic symptoms (e.g. headaches, muscle tension [F = 25.0, p < 0.001] and higher behavioral avoidance scores (e.g., avoidance of open places or traveling alone by bus EF = 4.2, p < 0.05]) at baseline testing compared with women without prior anxiety problems. Women with an anxiety-disorder history did not differ from those without such a history with respect to the presence of inducible ischemia or use of nitroglycerin, although they were younger and more likely to describe both "tight" and "sharp" chest pain symptoms and to experience back pain and episodes of nocturnal chest pain. Logistic regression results indicated that the positive-anxiety history group was more likely to be free of underlying significant angiographic CAD (odds ratio = 2.74, 95% confidence interval 1.15 to 6.5, p = 0.03). CONCLUSIONS Among women with chest pain symptoms, a history of anxiety disorders is associated with a lower probability of significant angiographic CAD. Knowledge of anxiety disorder history may assist in the clinical evaluation of women with chest pain. (J Am Call Cardiol 2001;37: 780-5) (C) 2001 by the American College of Cardiology. C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Florida, Gainesville, FL USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Alabama, Birmingham, AL USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NHLBI, Bethesda, MD 20892 USA. Rhode Isl Hosp, Providence, RI USA. RP Rutledge, T (reprint author), WISE Coordinating Ctr, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014 FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68162, N01-HV-68163, N01-HV-68164, N01-HV-68161] NR 28 TC 24 Z9 26 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 1 PY 2001 VL 37 IS 3 BP 780 EP 785 DI 10.1016/S0735-1097(00)01163-3 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 406PE UT WOS:000167223700014 PM 11693752 ER PT J AU Ryan, AS Hurlbut, DE Lott, ME Ivey, FM Fleg, J Hurley, BF Goldberg, AP AF Ryan, AS Hurlbut, DE Lott, ME Ivey, FM Fleg, J Hurley, BF Goldberg, AP TI Insulin action after resistive training in insulin resistant older men and women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the American-Diabetes-Association CY JUN 19-22, 1999 CL SAN DIEGO, CALIFORNIA SP Amer Diabet Assoc DE exercise; aging; glucose metabolism; strength training ID IMPAIRED GLUCOSE-TOLERANCE; POSTMENOPAUSAL WOMEN; BODY-COMPOSITION; HUMAN OBESITY; WEIGHT-LOSS; STRENGTH; EXERCISE; FAT; SENSITIVITY; SECRETION AB OBJECTIVES: To determine the effects of resistive training (RT) on insulin action and assess the determinants of the changes in insulin action. DESIGN: Longitudinal study. SETTING: Outpatient setting. PARTICIPANTS: Eighteen older men and older postmenopausal women (65-74 years) with normal (6 men and 5 women) or impaired glucose tolerance (4 men and 3 women). INTERVENTION: Six months of progressive whole-body RT. MEASUREMENTS: Upper and lower body strength was assessed by the one repetition maximum test. Total body fat and fat-free mass (FFM) were determined by dual-energy x-ray absorptiometry before and after 6 months of RT. Insulin sensitivity was estimated from the relationship of glucose utilization (M) to the concentration of insulin (I) during the last 30 minutes of 3-hour hyperinsulinemic-euglycemic clamps (240 pmol.m(-2).min(-1)) (M/I) before and after RT. RESULTS: RT significantly improved upper- and lower-body muscular strength (P < .005). FFM increased after RT in the entire group (P < .01) with no significant change in body fat. Although the change in M was larger in men (13%) than women (3%), the difference was not significant. The change in M was a function of initial M (r = -0.53, P < .05). There was a trend (0.060 +/- 0.006 vs 0.066 +/- 0.006 mol.kg(-1).min(-1)/pmol/l, n = 18) for M/I to increase after RT in the combined group of men and women (P = .06). There were no significant relationships between changes in M or M/I with changes in body composition or strength. CONCLUSION: A 6-month RT program tends to improve insulin action in insulin-resistant older adults. These results suggest that RT may be useful in ameliorating insulin resistance that often occurs with physical inactivity, obesity, and loss of muscular strength in older insulin resistant men and women. C1 Baltimore VA Med Ctr, Div Gerontol, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Ryan, AS (reprint author), Baltimore VA Med Ctr, Div Gerontol, Ctr Geriatr Res Educ & Clin, BT-18-GR, Baltimore, MD 21201 USA. FU NIA NIH HHS [1T32-AG00219, 5K07-AG00608]; PHS HHS [KO1-A600747] NR 44 TC 53 Z9 53 U1 0 U2 3 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2001 VL 49 IS 3 BP 247 EP 253 DI 10.1046/j.1532-5415.2001.4930247.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 412FG UT WOS:000167543900001 PM 11300234 ER PT J AU Burke, GL Arnold, AM Bild, DE Cushman, M Fried, LP Newman, A Nunn, C Robbins, J AF Burke, GL Arnold, AM Bild, DE Cushman, M Fried, LP Newman, A Nunn, C Robbins, J CA CHS Collaborative Res Grp TI Factors associated with healthy aging: The cardiovascular health study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE epidemiology; cardiovascular disease; cancer; health; risk factors; disease prevention; aging ID CORONARY HEART-DISEASE; OLDER ADULTS; RISK-FACTORS; MEN; ATHEROSCLEROSIS; CHOLESTEROL; PREVENTION; WOMEN AB OBJECTIVES: To identify factors associated with remaining healthy in older adults. DESIGN: Longitudinal cohort study. SETTING: Data were collected at the four Cardiovascular Health Study field centers. PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study. MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes. RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal medial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smelting, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults. CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smelting, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults. C1 Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, JP Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Vermont, Dept Med, Burlington, VT USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. RP Burke, GL (reprint author), Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [N01-HC-85080, N01-HC-85079, N01-HC-85081] NR 30 TC 86 Z9 89 U1 1 U2 8 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2001 VL 49 IS 3 BP 254 EP 262 DI 10.1046/j.1532-5415.2001.4930254.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 412FG UT WOS:000167543900002 PM 11300235 ER PT J AU Piniewski-Bond, JF Buck, GM Horowitz, RS Schuster, JHR Weed, DL Weiner, JM AF Piniewski-Bond, JF Buck, GM Horowitz, RS Schuster, JHR Weed, DL Weiner, JM TI Comparison of information processing technologies SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID HUMAN PAPILLOMAVIRUS INFECTION; CERVICAL-CANCER; KNOWLEDGE; TEXT AB Objective: To examine the type of information obtainable from scientific papers, using three different methods for the extraction, organization, and preparation of literature reviews. Design: A set of three review papers was identified, and the ideas represented by the authors of those papers were extracted. The 161 articles referenced in those three reviews were then analyzed using 1) a formalized data extraction approach, which uses a protocol-driven manual process to extract the variables, values, and statistical significance of the stated relationships; and 2) a computerized approach known as "Idea Analysis," which uses the abstracts of the original articles and processes them through a computer software program that reads the abstracts and organizes the ideas presented by the authors. The results were then compared. The literature focused on the human papillomavirus and its relationship to cervical cancer. Results: Idea Analysis was able to identify 68.9 percent of the ideas considered by the authors of the three review papers to be of importance in describing the association between human papillomavirus and cervical cancer. The formalized data extraction identified 27 percent of the authors' ideas. The combination of the two approaches identified 74.3 percent of the ideas considered important in the relationship between human papillomavirus and cervical cancer, as reported by the authors of the three review articles. Conclusion: This research demonstrated that both a technically derived and a computer derived collection, categorization, and summarization of original articles and abstracts could provide a reliable, valid, and reproducible source of ideas duplicating, to a major degree, the ideas presented by subject specialists in review articles. As such, these tools may be useful to experts preparing literature reviews by eliminating many of the clerical-mechanical features associated with present-day scientific text processing. C1 SUNY Buffalo, Buffalo, NY 14260 USA. NCI, Bethesda, MD 20892 USA. RP Piniewski-Bond, JF (reprint author), New York State Dept Hlth, Roswell Pk Canc Inst, Educ Affairs Off, Buffalo, NY 14263 USA. OI Buck Louis, Germaine/0000-0002-1774-4490 NR 28 TC 2 Z9 2 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 2001 VL 8 IS 2 BP 174 EP 184 PG 11 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 411FG UT WOS:000167487000007 PM 11230385 ER PT J AU Ojo, AO Hanson, JA Meier-Kriesche, HU Okechukwu, CN Wolfe, RA Leichtman, AB Agodoa, LY Kaplan, B Port, FK AF Ojo, AO Hanson, JA Meier-Kriesche, HU Okechukwu, CN Wolfe, RA Leichtman, AB Agodoa, LY Kaplan, B Port, FK TI Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; EXPANDED CRITERIA DONORS; SINGLE-CENTER EXPERIENCE; RACIAL-DIFFERENCES; AGE; MORTALITY; OLDER; TERM; DIALYSIS AB An increasing number of cadaveric kidney transplants are now performed with organs from donors who would have been deemed unsuitable in earlier times. Although good allograft outcomes have been obtained with these marginal donor transplants, it is unclear whether recipients of marginal kidney transplants achieve a reduction in long-term mortality as do recipients of "ideal" kidneys. Patients with end-stage renal disease registered on the cadaveric renal transplant waiting list between January 1, 1992, and June 30, 1997, were studied for mortality risks according to three outcomes: wait-listed on dialysis treatment with no transplant (WLD); transplantation with marginal donor kidney (MDK); and "ideal" or optimal donor kidney transplantation (IDK). Thirty-four percent of wait-list registrants had received a cadaveric kidney transplant by June 30, 1998. Of these, 18% received a marginal kidney that had one or more of the following pretransplant factors: donor age >55 yr, non-heartbeating donor, cold ischemia time >36 h, and donor hypertension or diabetes mellitus of >10 yr duration. Five-year graft and patient survival was 53% and 74% for MDK recipients compared with 67% (P < 0.001) and 80% (P < 0.001) for IDK recipients. Adjusted annual death rate and estimated remaining life time was 6.3%, 4.7%, and 3.3% and 15.3 yr, 20.4 yr, and 28.7 yr for WLD, MDK, and IDK groups, respectively. The average increase in life expectancy for MDK recipients compared with the WLD cohort was 5 yr, although this benefit Varied from 3 to 10 yr depending on the recipient's characteristics. It is concluded that transplantation of a marginal kidney is associated with a significant survival benefit when compared with maintenance dialysis. C1 Univ Michigan, Dept Med, Ann Arbor, MI USA. Univ Michigan, Dept Biostat, Ann Arbor, MI USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI USA. NIDDKD, US Renal Data Syst, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Ojo, AO (reprint author), Univ Michigan, Dept Internal Med, Div Nephrol, Med Ctr, TC 3914,Box 0364, Ann Arbor, MI 48109 USA. FU NIDDK NIH HHS [5 K08 DK02519] NR 48 TC 445 Z9 466 U1 0 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 2001 VL 12 IS 3 BP 589 EP 597 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 406NE UT WOS:000167221400021 PM 11181808 ER PT J AU Dalakas, MC AF Dalakas, MC TI Peripheral neuropathy and antiretroviral drugs SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Article; Proceedings Paper CT NIH Workshop on HIV and the Peripheral Nervous System CY SEP 17-18, 2000 CL ARLINGTON, VIRGINIA DE peripheral neuropathy; antiretroviral drugs; AIDS; mitochondrial DNA ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS-RELATED COMPLEX; PHASE-I TRIAL; REVERSE-TRANSCRIPTASE INHIBITORS; ZIDOVUDINE-INDUCED MYOPATHY; MITOCHONDRIAL-DNA; 2',3'-DIDEOXYCYTIDINE DDC; 2',3'-DIDEOXYINOSINE DDI; HIV-INFECTION; MUSCLE MITOCHONDRIA AB Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddI) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddI, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 59 TC 116 Z9 118 U1 0 U2 0 PU WOODLAND PUBLICATIONS, INC PI NEW YORK PA 69 MURRAY ST, NEW YORK, NY 10007 USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD MAR PY 2001 VL 6 IS 1 BP 14 EP 20 DI 10.1046/j.1529-8027.2001.006001014.x PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 412RH UT WOS:000167567800004 PM 11293802 ER PT J AU Armando, I Carranza, A Nishimura, Y Barontini, M Ito, T Saavedra, JM AF Armando, I Carranza, A Nishimura, Y Barontini, M Ito, T Saavedra, JM TI Candesartan decreases the sympatho-adrenal and hormonal response to isolation stress SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Article DE renin-angiotensin system; angiotensin receptors; adrenal gland; catecholamines; pituitary gland; corticoids; brain ID II RECEPTOR SUBTYPES; BLOOD-BRAIN-BARRIER; ANGIOTENSIN-II; PARAVENTRICULAR NUCLEUS; RAT-BRAIN; PHOSPHOINOSITIDE HYDROLYSIS; SUBFORNICAL ORGAN; GENE-EXPRESSION; AT(2); AUTORADIOGRAPHY AB A change from group housing to isolation in unfamiliar metabolic cages represents, for rodents, a significant emotional stress. We studied the effect of candesartan, a peripheral and central angiotensin Il ATI-receptor antagonist, on the hormonal and sympathetic response to acute isolation. We pretreated rats with I mg/kg/day candesartan for 13 days via subcutaneously implanted osmotic minipumps, followed by 24-hour isolation in individual metabolic cages. We measured brain, pituitary and adrenal angiotensin II (Ang II) receptor binding by quantitative autoradiography and adrenal hormones and catecholamines by RIA and HPLC. Isolation increased adrenal catecholamines, aldosterone and corticosterone, AT(1)-receptor binding in the zona glomerulosa. and AT(2)-receptor binding in the adrenal medulla. Candesartan pretreatment decreased adrenal catecholamines, aldosterone and corticosterone, AT(1)-receptor binding in adrenal zona glomerulosa and medulla, pituitary gland and the hypothalamic paraventricular nucleus, and AT(2)-receptor binding in adrenal medulla, but increased AT(2)-receptor binding in zona glomerulosa. We conclude that peripheral and central AT(1)-receptor blockade with candesartan decreases the sympatho-adrenal and hormonal response to acute stress. Our results indicate that Ang II is an important stress hormone and suggest that blockade of the physiologically active AT(1)-receptors could influence stress-related disorders. C1 NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. Consejo Nacl Invest Cient & Tecn, Ctr Invest Endocrinol, RA-1033 Buenos Aires, DF, Argentina. RP Armando, I (reprint author), NIMH, Pharmacol Sect, NIH, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. NR 40 TC 0 Z9 0 U1 0 U2 0 PU J R A A S LTD PI BIRMINGHAM PA EDGBASTON HOUSE, 3 DUCHESS PLACE, EDGBASTON, BIRMINGHAM B16 8NH, ENGLAND SN 1470-3203 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD MAR PY 2001 VL 2 SU 1 BP S130 EP S135 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 488MB UT WOS:000171938000023 PM 28095244 ER PT J AU Hunyady, L Gaborik, Z Vauquelin, G Catt, KJ AF Hunyady, L Gaborik, Z Vauquelin, G Catt, KJ TI Structural requirements for signalling and regulation of AT(1)-receptors SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Review DE angiotensin II; G protein; Ca2+ signal; tyrosine kinase.; receptor phosphorylation; receptor internalisation; candesartan ID ANGIOTENSIN-II RECEPTOR; PROTEIN-COUPLED RECEPTORS; AGONIST-INDUCED INTERNALIZATION; SMOOTH-MUSCLE-CELLS; SITE-DIRECTED MUTAGENESIS; TRUNCATED AT(1A) RECEPTOR; 3RD INTRACELLULAR LOOP; CARBOXYL-TERMINAL TAIL; TYPE-1 RECEPTOR; CYTOPLASMIC LOOP C1 Semmelweis Univ, Sch Med, Dept Physiol, H-1444 Budapest 8, Hungary. Univ Libre Brussels, Dept Mol Pharmacol & Biochem, Inst Mol Biol & Biotechnol, B-1640 Rhode St Genese, Belgium. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Sch Med, Dept Physiol, POB 259, H-1444 Budapest 8, Hungary. EM Hunyady@puskin.sote.hu NR 82 TC 8 Z9 8 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1470-3203 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD MAR PY 2001 VL 2 SU 1 BP S16 EP S23 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 488MB UT WOS:000171938000003 PM 28095246 ER PT J AU Saavedra, JM Ito, T Nishimura, Y AF Saavedra, JM Ito, T Nishimura, Y TI The role of angiotensin II AT(1)-receptors in the regulation of the cerebral blood flow and brain ischaemia SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Review DE renin-angiotensin system; angiotensin receptors; hypertension; stroke; brain injury; cerebrovascular blood flow ID SPONTANEOUSLY HYPERTENSIVE-RATS; RECEPTOR ANTAGONIST CV-11974; CONVERTING-ENZYME; ANTIHYPERTENSIVE TREATMENT; AT(1) RECEPTORS; BINDING-SITES; AUTOREGULATION; STROKE; INHIBITION; ENALAPRIL C1 NIMH, Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, NIH, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@irp.nimh.nih.gov NR 67 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1470-3203 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD MAR PY 2001 VL 2 SU 1 BP S102 EP S109 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 488MB UT WOS:000171938000018 PM 28095215 ER PT J AU Schnermann, J Huang, YNG Briggs, JP AF Schnermann, J Huang, YNG Briggs, JP TI Angiotensin II blockade causes acute renal failure in eNOS-deficient mice SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Article DE candesartan; quinapril; nitric oxide synthase; glomerular filtration rate; renal blood flow; endothelium ID NITRIC-OXIDE SYNTHESIS; SYNTHESIS INHIBITION; SYNTHASE; RESPONSES; LACKING; GENE; RAT; VASOCONSTRICTION; HYPERTENSION; EXPRESSION AB Compared with wild-type mice, adult endothelial nitric oxide synthase (eNOS) knockout mice (eight months of age) have increased blood pressure (BP) (126 +/-9 mmHg VS. 100 +/-4 mmHg), and an increased renal vascular resistance (155 +/- 16 vs. 65 +/-4 mmHg.min/ml). Renal vascular resistance responses to Lv. administration of noradrenaline were markedly enhanced in eNOS knockout mice. Glomerular filtration rate (GFR) of anaesthetised eNOS -/- mice was 324 +/- 57 mul/min gKW significantly lower than the GFR of 761 +/- 126 mul/min.gKW in wild-type mice. AT(1)-receptor blockade with ix. candesartan (1-1.5 mg/kg) reduced arterial blood pressure and renal vascular resistance, and increased renal blood flow (RBF) to about the same extent in wild-type and eNOS -/- mice. Candesartan did not alter GFR in wild-type mice (761 +/- 126 vs. 720 +/- 95 mul/min.gKW), but caused a marked decrease in GFR in eNOS -/- mice (324.5 +/- 75.2 vs. 77 +/- 18 mul/min.gKW). A similar reduction in GFR of eNOS deficient mice was also caused by angiotensin-converting enzyme (ACE) inhibition. Afferent arteriolar granularity a measure of renal renin expression, was found to be reduced in eNOS -/- compared with wild-type mice. In chronically eNOS-deficient mice, angiotensin II (Ang II) is critical for maintaining glomerular filtration pressure and GFR, presumably through its effect on efferent arteriolar tone. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Room 4 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU J R A A S LTD PI BIRMINGHAM PA EDGBASTON HOUSE, 3 DUCHESS PLACE, EDGBASTON, BIRMINGHAM B16 8NH, ENGLAND SN 1470-3203 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD MAR PY 2001 VL 2 SU 1 BP S199 EP S203 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 488MB UT WOS:000171938000035 PM 28095225 ER PT J AU Herring, JC Enquist, EG Chernoff, A Linehan, WM Choyke, PL Walther, MM AF Herring, JC Enquist, EG Chernoff, A Linehan, WM Choyke, PL Walther, MM TI Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience SO JOURNAL OF UROLOGY LA English DT Article DE carcinoma, renal cell; Hippel-Lindau disease; nephrectomy; surgery; therapeutics ID HIPPEL-LINDAU-DISEASE; NATURAL-HISTORY; FAMILIES; TUMORS; TRANSPLANTATION; MANIFESTATIONS; IDENTIFICATION; PREVALENCE; PATHOLOGY; KIDNEY AB Purpose: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dube syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm., then performing parenchymal sparing surgery. We present a 5-year update on our experience. Materials and Methods: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including von Hippel-Lindau disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dube syndrome in I, and I with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205). Results: A total of 50 patients underwent 71 operations resulting in unilateral nephrectomy in 6, bilateral nephrectomy in I and partial nephrectomy in 65, with 1 to 51 tumors removed from each kidney (mean 14.7). Mean patient age was 39.5 years (range 18 to 70). Of the 65 (40%) partial nephrectomies 26 were performed with cold renal ischemia. Mean blood loss was 2.9 +/- 0.5 l. (range 0.15 to 23). Postoperative complications included renal atrophy in 3 patients. Mean preoperative serum creatinine was 1.05 +/- 0.03 mg./dl. (range 0.6 to 1.8), and postoperative creatinine was 1.06 +/- 0.04 mg./dl. (range 0.6 to 2.0). No patient who underwent renal parenchymal sparing surgery required renal replacement therapy. Metastatic disease developed in 1 patient with a 4.5 cm. renal tumor. Conclusions: Parenchymal sparing surgery with a 3 cm. threshold in patients with hereditary renal cancer appears to be an effective therapeutic option to maximize renal function while minimizing the risk of metastatic disease. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol & Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Herring, JC (reprint author), NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 33 TC 110 Z9 115 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 2001 VL 165 IS 3 BP 777 EP 781 DI 10.1016/S0022-5347(05)66524-X PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 401AT UT WOS:000166905300009 PM 11176466 ER PT J AU Gilliland, FD Gleason, DF Hunt, WC Stone, N Harlan, LC Key, CR AF Gilliland, FD Gleason, DF Hunt, WC Stone, N Harlan, LC Key, CR TI Trends in Gleason score for prostate cancer diagnosed between 1983 and 1993 SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; mass screening; epidemiology ID INCIDENCE RATES; NEW-MEXICO; ANTIGEN; ADENOCARCINOMA; SPECIMENS; CARCINOMA; MORTALITY; BIOPSIES; DECLINE; THERAPY AB Purpose: During the 1980s and 1990s the number, incidence rate and proportion of moderately differentiated prostate cancer cases ascertained by population based cancer registries increased substantially. The increase is thought to have resulted from the widespread use of prostate specific antigen (PSA) for screening because it occurred coincidentally with the introduction of PSA for early detection of prostate cancer. We investigate this increase in a population based study. Materials and Methods: To report the trends in tumor grade we conducted a blinded, standardized pathological study and reviewed medial records of a stratified random sample of cases diagnosed before and after the introduction of PSA (1983 to 1984 and 1992 to 1993). Archival tumor biopsy specimens or transurethral resection of the prostate specimens were reviewed for the diagnosis of cancer and assignment of Gleason score. Medical records were reviewed to determine the method of prostate cancer detection for each case. Results: We found a small but statistically insignificant shift in the distribution of Gleason scores assigned after review of biopsy or transurethral resection specimens. The proportion of Gleason score 2, 3 and 4 tumors decreased, and the proportion of 7, 8, 9 and 10 tumors as a group did not change. The shifts in Gleason score resulted in a slight statistically nonsignificant increase in mean Gleason score. There was a significant shift in the method of detection from predominately incidental detection in the earlier period to predominately screen detection in the later period. Because the proportion of screen detected tumors increased and they had a significantly higher mean Gleason scare than incidentally detected tumors within each interval, the overall mean Gleason score increased. Conclusions: After a standardized pathological review a small shift in the distribution of Gleason scores occurred resulting in a small increase in mean Gleason score between 1983 and 1984, and 1992 and 1993. There was little change in the proportion of Gleason score 7, 8, 9 and 10 tumors between the 2 periods. C1 Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ New Mexico, Sch Med, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. NCI, Bethesda, MD 20892 USA. RP Gilliland, FD (reprint author), Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. FU NCI NIH HHS [N01-CN-05228] NR 35 TC 20 Z9 23 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2001 VL 165 IS 3 BP 846 EP 850 DI 10.1016/S0022-5347(05)66542-1 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 401AT UT WOS:000166905300030 PM 11176484 ER PT J AU Jacobson, ER Origgi, F Pessier, AP Lamirande, EW Walker, I Whitaker, B Stalis, IH Nordhausen, R Owens, JW Nichols, DK Heard, D Homer, B AF Jacobson, ER Origgi, F Pessier, AP Lamirande, EW Walker, I Whitaker, B Stalis, IH Nordhausen, R Owens, JW Nichols, DK Heard, D Homer, B TI Paramyxovirus infection in caiman lizards (Draecena guianensis) SO JOURNAL OF VETERINARY DIAGNOSTIC INVESTIGATION LA English DT Article ID OPHIDIAN PARAMYXOVIRUS; SNAKES; VIRUS; COLLECTION; PNEUMONIA AB Three separate epidemics occurred in caiman lizards (Dracaena guianensis) that were imported into the USA from Peru in late 1998 and early 1999. Histologic evaluation of tissues from necropsied lizards demonstrated a proliferative pneumonia. Electron microscopic examination of lung tissue revealed a virus that was consistent with members of the family Paramyxoviridae. Using a rabbit polyclonal antibody against an isolate of ophidian (snake) paramyxovirus, an immunoperoxidase staining technique demonstrated immunoreactivity within pulmonary epithelial cells of I lizard. Homogenates. of lung, brain, liver, or kidney from affected lizards were placed in flasks containing monolayers of either terrapene heart cells or viper heart cells. Five to 10 days later, syncytial cells formed. When Vero cells were inoculated with supernatant of infected terrapene heart cells, similar syncytial. cells developed. Electron microscopic evaluation of infected terrapene heart cells revealed intracytoplasmic inclusions consisting of nucleocapsid strands. Using negative-staining electron microscopy, abundant filamentous nucleocapsid material with a herringbone structure typical of the Paramyxoviridae was observed in culture medium of infected viper heart cells. Seven months following the initial epizootic, blood samples were collected from surviving group 1 lizards, and a hemagglutination inhibition assay was performed to determine presence of specific antibody against the caiman lizard isolate. Of the 17 lizards sampled, 7 had titers of less than or equal to1:20 and 10 had titers of >1:20 and less than or equal to1:80. This report is only the second of a paramyxovirus identified in a lizard and is the first to snow the relationship between histologic and ultrastructural findings and virus isolation. C1 Univ Florida, Coll Vet Med, Gainesville, FL 32610 USA. Zool Soc San Diego, Dept Pathol, San Diego, CA 92112 USA. Smithsonian Inst, Natl Zool Pk, Dept Pathol, Washington, DC 20008 USA. Natl Aquarium, Baltimore, MD 21202 USA. Calif Vet Diagnost Lab Syst, Davis, CA 95616 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. RP Jacobson, ER (reprint author), Univ Florida, Coll Vet Med, Gainesville, FL 32610 USA. NR 18 TC 19 Z9 20 U1 0 U2 4 PU AMER ASSOC VETERINARY LABORATORY DIAGNOSTICIANS INC PI TURLOCK PA PO BOX 1522, TURLOCK, CA 95381 USA SN 1040-6387 J9 J VET DIAGN INVEST JI J. Vet. Diagn. Invest. PD MAR PY 2001 VL 13 IS 2 BP 143 EP 151 PG 9 WC Veterinary Sciences SC Veterinary Sciences GA 458XQ UT WOS:000170221100008 PM 11289210 ER PT J AU Shamloul, AM Abdallah, NA Madkour, MA Hadidi, A AF Shamloul, AM Abdallah, NA Madkour, MA Hadidi, A TI Sensitive detection of the Egyptian species of sugarcane streak virus by PCR-probe capture hybridization (PCR-ELISA) and its complete nucleotide sequence SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE sugarcane; SSV; mastreviruses; geminivirus; detection; amplification; PCR-ELISA; cDNA probe; cRNA probe; nucleotide sequence ID IMMUNOSORBENT-ASSAY METHOD; GEMINIVIRUSES; CASSAVA; DNA AB A rapid and sensitive assay for the specific detection of Sugarcane streak virus (SSV) using PCR-probe capture hybridization (PCR-ELISA) was developed. Nucleic acids suitable for PCR were extracted from SSV-infected tissue using organic solvents or Fast DNA kit. SSV cDNA was amplified using viral specific primers and the amplified SSV cDNA (amplicon) was DIG-labelled during the amplification process. The amplicon was then detected in a colorimetric hybridization system by a microtiter plate using a biotinylated cDNA (22 nt), cDNA (789 nt) or cRNA (789 nt) capture probe. This system combines the specificity of molecular hybridization, the ease of the colorimetric protocol, and is 10-100 fold more sensitive than agarose gel electrophoretic analysis in detecting the amplified product. Long cDNA or cRNA capture probe was 2-7 fold more sensitive than the oligo cDNA probe for the detection. Complete nucleotide sequence of SSV from Naga Hammady, Egypt, revealed that SSV-EG is a new species of SSV that shares 66% nucleotide identity with the virus species from Natal, South Africa. (C) 2001 Elsevier Science B.V. All rights reserved. C1 USDA ARS, Fruit Lab, Beltsville, MD 20705 USA. Minist Agr, Agr Genet Engn Res Inst, Giza, Egypt. RP Shamloul, AM (reprint author), Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. OI Abdallah, Naglaa/0000-0002-9290-5944; MADKOUR, LOUTFY/0000-0002-3101-8356 NR 22 TC 6 Z9 9 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD MAR PY 2001 VL 92 IS 1 BP 45 EP 54 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 401HF UT WOS:000166921600006 PM 11164917 ER PT J AU Patton, JT Taraporewala, Z Chen, DY Chizhikov, V Jones, M Elhelu, A Collins, M Kearney, K Wagner, M Hoshino, Y Gouvea, V AF Patton, JT Taraporewala, Z Chen, DY Chizhikov, V Jones, M Elhelu, A Collins, M Kearney, K Wagner, M Hoshino, Y Gouvea, V TI Effect of intragenic rearrangement and changes in the 3 ' consensus sequence on NSP1 expression and rotavirus replication SO JOURNAL OF VIROLOGY LA English DT Article ID MINUS-STRAND SYNTHESIS; MESSENGER-RNA; GENOME REARRANGEMENTS; BOVINE ROTAVIRUS; PROTEIN NSP3; NS53 NSP1; VIRUS; GENE; BINDING; HETEROGENEITY AB The nonpolyadenylated mRNAs of rotavirus are templates for the synthesis of protein and the segmented double-stranded RNA (dsRNA) genome. During serial passage of simian SA11 rotaviruses in cell culture, two variants emerged with gene 5 dsRNAs containing large (1.1 and 0.5 kb) sequence duplications within the open reading frame (ORF) for NSP1. Due to the sequence rearrangements, both variants encoded only C-truncated forms of NSP1. Comparison of these and other variants encoding defective NSP1 with their corresponding wild-type viruses indicated that the inability to encode authentic NSP1 results in a small-plaque phenotype. Thus, although nonessential, NSP1 probably plays an active role in rotavirus replication in cell culture. In determining the sequences of the gene 5 dsRNAs of the SA11 variants and wild-type viruses, it was unexpectedly found that their 3' termini ended with 5'-UGAACC-3' instead of the 3' consensus sequence 5'-UGACC-3', which is present on the mRNAs of nearly all other group A rotaviruses. Cell-free assays indicated that the A insertion into the 3' consensus sequence interfered with its ability to promote dsRNA synthesis and to function as a translation enhancer. The results provide evidence that the 3' consensus sequence of the gene 5 dsRNAs of SA11 rotaviruses has undergone a mutation causing it to operate suboptimally in RNA replication and in the expression of NSP1 during the virus life cycle. Indeed, just as rotavirus variants which encode defective NSP1 appear to have a selective advantage over those encoding wild-type NSP1 in cell culture, it may be that the atypical 3' end of SA11 gene 5 has been selected for because it promotes the expression of lower levels of NSP1 than the 3' consensus sequence. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941590 Rio De Janeiro, Brazil. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0720,Room 117, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 42 TC 40 Z9 47 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 2001 VL 75 IS 5 BP 2076 EP 2086 DI 10.1128/JVI.75.5.2076-2086.2001 PG 11 WC Virology SC Virology GA 400PQ UT WOS:000166881000006 PM 11160712 ER PT J AU Kibler, KV Jeang, KT AF Kibler, KV Jeang, KT TI CREB/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein SO JOURNAL OF VIROLOGY LA English DT Article ID ELEMENT-BINDING PROTEIN; HERPES-SIMPLEX VIRUS; WILD-TYPE P53; GENE-EXPRESSION; I TAX; HTLV-1 TAX; KAPPA-B; TRANSCRIPTIONAL REPRESSION; DOWN-REGULATION; MEDIATED TRANSCRIPTION AB Expression of the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax is correlated with cellular transformation contributing to the development of adult T-cell leukemia. Tax has been shown to modulate the activities of several cellular promoters. Existing evidence suggests that Tax need not directly bind to DNA to accomplish these effects but rather that it can act through binding to cellular factors, including members of the CREB/ATF family. Exact mechanisms of HTLV-1 transformation of cells have yet to be fully defined, but the process is likely to include both activation of cellular-growth-promoting factors and repression of cellular tumor-suppressing functions. While transcriptional activation has been well studied, transcriptional repression by Tax, reported recently from several studies, remains less well understood. Here, we show that Tax represses the TATA-less cyclin A promoter. Repression of the cyclin A promoter was seen in both ts13 adherent cells and Jurkat T lymphocytes, Two other TATA-less promoters, cyclin D3 and DNA polymerase alpha, were also found to be repressed by Tax. Interestingly, all three promoters share a common feature of at least one conserved upstream CREB/ATF binding site. In electrophoretic mobility shift assays, we observed that Tax altered the formation of a complex(es) at the cyclin A promoter-derived ATF site. Functionally, we correlated removal of the CREB/ATF site from the promoter with loss of repression by Tax. Furthermore, since a Tax mutant protein which binds CREB repressed the cyclin A promoter while another mutant protein which does not bind CREB did not, we propose that this Tax repression occurs through protein-protein contact with CREB/ATF. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, LMM, NIH, Bldg 4,Room 306,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 96 TC 42 Z9 43 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 2001 VL 75 IS 5 BP 2161 EP 2173 DI 10.1128/JVI.75.5.2161-2173.2001 PG 13 WC Virology SC Virology GA 400PQ UT WOS:000166881000014 PM 11160720 ER PT J AU Cho, MW Kim, YB Lee, MK Gupta, KC Ross, W Plishka, R Buckler-White, A Igarashi, T Theodore, T Byrum, R Kemp, C Montefiori, DC Martin, MA AF Cho, MW Kim, YB Lee, MK Gupta, KC Ross, W Plishka, R Buckler-White, A Igarashi, T Theodore, T Byrum, R Kemp, C Montefiori, DC Martin, MA TI Polyvalent envelope glycoprotein vaccine elicits a broader neutralizing antibody response but is unable to provide sterilizing protection against heterologous Simian/human immunodeficiency virus infection in pigtailed macaques SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; PBL-SCID MICE; RECOMBINANT VACCINIA; HIV TYPE-1; PASSIVE-IMMUNIZATION; RHESUS MACAQUES; CHIMERIC VIRUS; T-LYMPHOCYTES; GP120; CHALLENGE AB The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-l) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability. Most previously evaluated vaccine candidates have utilized envelope glycoprotein from a single virus isolate. Here we compare the breadth of NAb and protective immune response following vaccination of pigtailed macaques with envelope protein(s) derived from either single or multiple viral isolates. Animals were challenged with Simian/human immunodeficiency virus strain DH12 (SHTVDH12) following priming with recombinant vaccinia virus(es) expressing gp160(s) and boosting with gp120 protein(s) from (1) LAI, RIF, 89.6, ADS, and Bal (Polyvalent); (ii) LAI, RF, 89.6, AD8, Bal, and DH12 (Polyvalent-DH12); (iii) 89.6 (Monovalent-89.6); and (iv) DH12 (Monovalent-DH12). Animals in the two polyvalent vaccine groups developed NAbs against more HIV-1 isolates than those in the two monovalent vaccine groups (P = 0.0054). However, the increased breadth of response was directed almost entirely against the vaccine strains. Resistance to SHIVDH12 strongly correlated with the level of NAbs directed against the virus on the day of challenge (P = 0.0008). Accordingly, the animals in the Monovalent-DH12 and Polyvalent-DH12 vaccine groups were more resistant to the SHIVDH12 challenge than the macaques immunized with preparations lacking a DH12 component (viz. Polyvalent and Monovalent-89.6) (P = 0.039). Despite the absence of any detectable NAb, animals in the Polyvalent vaccine group, but not those immunized with Monovalent-89.6, exhibited markedly lower levels of plasma virus than those in the control group, suggesting a superior cell-mediated immune response induced by the polyvalent vaccine. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Bioqual, Rockville, MD 20850 USA. Kemp Biotechnol Inc, Frederick, MD 21704 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Cho, MW (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike,Bldg 4,Rm 339, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-85343] NR 57 TC 75 Z9 76 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 2001 VL 75 IS 5 BP 2224 EP 2234 DI 10.1128/JVI.75.5.2224-2234.2001 PG 11 WC Virology SC Virology GA 400PQ UT WOS:000166881000020 PM 11160726 ER PT J AU Barouch, DH Craiu, A Santra, S Egan, MA Schmitz, JE Kuroda, MJ Fu, TM Nam, JH Wyatt, LS Lifton, MA Krivulka, GR Nickerson, CE Lord, CI Moss, B Lewis, MG Hirsch, VM Shiver, JW Letvin, NL AF Barouch, DH Craiu, A Santra, S Egan, MA Schmitz, JE Kuroda, MJ Fu, TM Nam, JH Wyatt, LS Lifton, MA Krivulka, GR Nickerson, CE Lord, CI Moss, B Lewis, MG Hirsch, VM Shiver, JW Letvin, NL TI Elicitation of high-frequency cytotoxic T-lymphocyte responses against both dominant and subdominant simian-human immunodeficiency virus epitopes by DNA vaccination of rhesus monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID CELL RESPONSES; IMMUNE-RESPONSE; INFECTION; COMPLEX; VIREMIA; GENE; DEFINITION; INDUCTION; MACAQUES; BINDING AB Increasing evidence suggests that the generation of cytotoxic T-lymphocyte (CTL) responses specific for a diversity of viral epitopes will be needed for an effective human immunodeficiency virus type 1 (HIV-1) vaccine. Here, we determine the frequencies of CTL responses specific for the simian immunodeficiency virus Gag p11C and HIV-1 Env p41A epitopes in simian-human immunodeficiency virus (SHIV)-infected and vaccinated rhesus monkeys. The p11C-specific CTL response was high frequency and dominant and the p41A-specific CTL response was low frequency and subdominant in both SHIV-infected monkeys and in monkeys vaccinated with recombinant modified vaccinia virus Ankara vectors expressing these viral antigens. Interestingly, we found that plasmid DNA vaccination led to high-frequency CTL responses specific for both of these epitopes. These data demonstrate that plasmid DNA may be useful in eliciting a broad CTL response against multiple epitopes. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Merck Res Labs, W Point, PA 19486 USA. NIAID, Viral Dis Lab, NIH, Rockville, MD 20852 USA. NIAID, Mol Microbiol Lab, NIH, Rockville, MD 20852 USA. So Res Inst, Frederick, MD 21701 USA. RP Barouch, DH (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, 330 Brookline Ave,Res E Room 113, Boston, MA 02215 USA. FU NCI NIH HHS [CA-50139, R01 CA050139]; NIAID NIH HHS [N01-AI-65301, R01 AI065301, AI-85343] NR 32 TC 73 Z9 73 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 2001 VL 75 IS 5 BP 2462 EP 2467 DI 10.1128/JVI.75.5.2462-2467.2001 PG 6 WC Virology SC Virology GA 400PQ UT WOS:000166881000044 PM 11160750 ER PT J AU Scholl, D Rogers, S Adhya, S Merril, CR AF Scholl, D Rogers, S Adhya, S Merril, CR TI Bacteriophage K1-5 encodes two different tail fiber proteins, allowing it to infect and replicate on both K1 and K5 strains of Escherichia coli SO JOURNAL OF VIROLOGY LA English DT Article ID COMPLETE NUCLEOTIDE-SEQUENCE; CAPSULAR POLYSACCHARIDE; COLIPHAGE; EVOLUTION; EXPRESSION; ANTIGEN; ADHESIN; GENOME; GENES; PHAGE AB A virulent double-stranded DNA bacteriophage, Phi K1-5, has been isolated and found to be capable of infecting Escherichia coli strains that possess either the K1 or the K5 polysaccharide capsule. Electron micrographs show that the virion consists of a small icosohedral head with short tail spikes, similar to members of the Podoviridae family. DNA sequence analysis of the region encoding the tail fiber protein showed two open reading frames encoding previously characterized hydrolytic phage tail fiber proteins, The first is the K5 lyase protein gene of Phi K5, which allows this phage to specifically infect K5 E, coli strains, A second open reading frame encodes a protein almost identical in amino acid sequence to the N-acetylneuraminidase (endosialidase) protein of Phi K1E, which allows this phage to specifically infect K1 strains off. coli, We provide experimental evidence that mature phage particles contain both tail fiber proteins, and mutational analysis indicates that each protein can be independently inactivated. A comparison of the tail gene regions of Phi K5, Phi K1E, and Phi K1-5 shows that the genes are arranged in a modular or cassette configuration and suggests that this family of phages can broaden host range by horizontal gene transfer. C1 NIMH, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Merril, CR (reprint author), NIMH, NIH, 9000 Rockville Pike,Bldg 10,Room 2D54, Bethesda, MD 20892 USA. NR 38 TC 84 Z9 87 U1 1 U2 12 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 2001 VL 75 IS 6 BP 2509 EP 2515 DI 10.1128/JVI.75.6.2509-2515.2001 PG 7 WC Virology SC Virology GA 405LG UT WOS:000167160400001 PM 11222673 ER PT J AU Hong, S Choi, G Park, S Chung, AS Hunter, E Rhee, SS AF Hong, S Choi, G Park, S Chung, AS Hunter, E Rhee, SS TI Type D retrovirus gag polyprotein interacts with the cytosolic chaperonin TRiC SO JOURNAL OF VIROLOGY LA English DT Article ID PFIZER MONKEY VIRUS; T-COMPLEX POLYPEPTIDE-1; ROUS-SARCOMA VIRUS; MOLECULAR CHAPERONES; EUKARYOTIC CYTOSOL; MATRIX PROTEIN; IN-VIVO; DNA-BINDING; BETA-ACTIN; PARTICLE AB The carboxy terminus-encoding portion of the gag gene of Mason-Pfizer monkey virus (M-PMV), the prototype immunosuppressive primate type D retrovirus, encodes a 36-amino-acid, proline-rich protein domain that, in the mature virion, becomes the p4 capsid protein. The p4 domain has no known role in M-PMV replication. We found that two mutants,vith premature termination codons that remove half or all of the p4 domain produced lower levels of stable Gag protein and of self-assembled capsids. Interestingly, yeast two-hybrid screening revealed that p4 specifically interacted with TCP-1 gamma, a subunit of the chaperonin TRiC (TCP-I ring complex). TRiC is a cytosolic chaperonin that is known to be involved in both folding and subunit assembly of a variety of cellular proteins. TCP-1 gamma also associated with high specificity with the M-PMV pp24/16-p12 domain and human immunodeficiency virus p6. Moreover, in cells, Gag polyprotein associated with the TRiC chaperonin complex and this association depended on ATP hydrolysis. In the p4 truncation mutants, the Gag-TRiC association was significantly reduced. These results strongly suggest that cytosolic chaperonin TRiC is involved in Gag folding and/or capsid assembly. We propose that TRiC associates transiently with nascent M-PMV Gag molecules to assist in their folding. Consequently, properly folded Gag molecules carry out the intermolecular interactions involved in self-assembly of the immature capsid. C1 Samsung Biomed Res Inst, Mol Virol Lab, Seoul, South Korea. Korea Adv Inst Sci & Technol, Dept Sci Biol, Taejon 305701, South Korea. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. RP Rhee, SS (reprint author), NIMH, Mol Biol Lab, Bldg 36,Room 1D03,MSC 4034, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01 CA027834, R37 CA027834, R39 CA27834] NR 54 TC 33 Z9 36 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 2001 VL 75 IS 6 BP 2526 EP 2534 DI 10.1128/JVI.75.6.2526-2534.2001 PG 9 WC Virology SC Virology GA 405LG UT WOS:000167160400003 PM 11222675 ER PT J AU Askovic, S Favara, C McAtee, FJ Portis, JL AF Askovic, S Favara, C McAtee, FJ Portis, JL TI Increased expression of MIP-1 alpha and MIP-1 beta mRNAs in the brain correlates spatially and temporally with the spongiform neurodegeneration induced by a murine oncornavirus SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INDUCED DEMYELINATING DISEASE; MOTOR NEURON DISEASE; C RNA VIRUS; INFLAMMATORY RESPONSE; CHEMOKINE EXPRESSION; LEUKEMIA-VIRUS; GENE-EXPRESSION; MESSENGER-RNA AB The chimeric murine oncornavirus FrCas(E) causes a rapidly progressive paralytic disease associated with spongiform neurodegeneration throughout the neuroaxis, Neurovirulence is determined by the sequence of the viral envelope gene and by the capacity of the virus to infect microglia. The neurocytopathic effect of this virus appears to be indirect, since the cells which degenerate are not infected. In the present study we have examined the possible role of inflammatory responses in this disease and have used as a control the virus F43, F43 is an highly neuroinvasive but avirulent virus which differs from FrCas(E) only in 3' pol and env sequences. Like FrCas(E), F43 infects large numbers of microglial cells, but it does not induce spongiform neurodegeneration, RNAase protection assays were used to detect differential expression of genes encoding a variety of cytokines, chemokines, and inflammatory cell-specific markers. Tumor necrosis factor alpha (TNF-alpha) and TNF-beta mRNAs were upregulated in advanced stages of disease but not early, even in regions with prominent spongiosis, Surprisingly there was no evidence for upregulation of the cytokines interleukin-1 alpha. (IL-1 alpha), IL-1 beta, and IL-6 or of the microglial marker F4/80 at any stage of this disease. In contrast, increased levels of the beta -chemokines MIP-1 alpha and -beta were seen early in the disease and were concentrated in regions of the brain rich in spongiosis, and the magnitude of responses was similar to that observed in the brains of mice injected with the glutamatergic neurotoxin ibotenic acid. MIP-1 alpha and MIP-1 beta mRNAs were also upregulated in F43-inoculated mice, but the responses were three- to fivefold lower and occurred later in the course of infection than was observed in FrCas(E)-inoculated mice. These results suggest that the robust increase in expression of MIP-1 alpha and MIP-1 beta in the brain represents a correlate of neurovirulence in this disease, whereas the TNF responses are likely secondary events. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Portis, JL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. NR 45 TC 19 Z9 19 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 2001 VL 75 IS 6 BP 2665 EP 2674 DI 10.1128/JVI.75.6.2665-2674.2001 PG 10 WC Virology SC Virology GA 405LG UT WOS:000167160400018 PM 11222690 ER PT J AU Peterson, KE Robertson, SJ Portis, JL Chesebro, B AF Peterson, KE Robertson, SJ Portis, JL Chesebro, B TI Differences in cytokine and chemokine responses during neurological disease induced by polytropic murine retroviruses map to separate regions of the viral envelope gene SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; TYPE-1 INFECTION; LEUKEMIA-VIRUS; PROTEIN GP120; MESSENGER-RNA; FACTOR-ALPHA; CNS DISEASE; HIV-1 TAT AB Infection of the central nervous system (CNS) by several viruses can lead to upregulation of proinflammatory cytokines and chemokines. In immunocompetent adults, these molecules induce prominent inflammatory infiltrates. However, with immunosuppressive retroviruses, such as human immunodeficiency virus (HIV), little CNS inflammation is observed yet proinflammatory cytokines and chemokines are still upregulated in some patients and may mediate pathogenesis. The present study examined expression of cytokines and chemokines in brain tissue of neonatal mice infected with virulent (Fr98) and avirulent (Fr54) polytropic murine retroviruses. While both viruses infect microglia and endothelia primarily in the white matter areas of the CNS, only Fr98 induces clinical CNS disease. The pathology consists of gliosis with minimal morphological changes and no inflammation, similar to HIV. In the present experiments, mice infected with Fr98 had increased cerebellar mRNA levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), TNF-beta, and interleukin-1 alpha and chemokines macrophage inflammatory protein-lot (MIP-1 alpha), MIP-1 beta, monocyte chemoattractant protein 1 (MCP-I), gamma-interferon-inducible protein 10 (IP-10), and RANTES compared to mice infected with Fr54 or mock-infected controls. The increased expression of these genes occurred prior to the development of clinical symptoms, suggesting that these cytokines and chemokines might be involved in induction of neuropathogenesis. Two separate regions of the Fr98 envelope gene are associated,vith neurovirulence, CNS disease associated with the N-terminal portion of the Fr98 env gene was preceded by upregulation of cytokines and chemokines. In contrast, disease associated with the central region of the Fr98 env gene showed no upregulation of cytokines or chemokines and thus did not require increased expression of these genes for disease induction. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 NR 46 TC 44 Z9 44 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 2001 VL 75 IS 6 BP 2848 EP 2856 DI 10.1128/JVI.75.6.2848-2856.2001 PG 9 WC Virology SC Virology GA 405LG UT WOS:000167160400038 PM 11222710 ER PT J AU Trus, BL Heymann, JB Nealon, K Cheng, NQ Newcomb, WW Brown, JC Kedes, DH Steven, AC AF Trus, BL Heymann, JB Nealon, K Cheng, NQ Newcomb, WW Brown, JC Kedes, DH Steven, AC TI Capsid structure of Kaposi's sarcoma-associated herpesvirus, a gammaherpesvirus, compared to those of an alphaherpesvirus, herpes simplex virus type 1, and a betaherpesvirus, cytomegalovirus SO JOURNAL OF VIROLOGY LA English DT Article ID CHANNEL CATFISH VIRUS; RECOMBINANT BACULOVIRUSES; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; SCAFFOLDING PROTEINS; CLEAVAGE SITE; DENSITY MAPS; VP26; CELLS; HUMAN-HERPESVIRUS-8 AB The capsid of Kaposi's sarcoma-associated herpesvirus (KSHV) was visualized at 24-Angstrom resolution by cryoelectron microscopy. Despite limited sequence similarity between corresponding capsid proteins, KSHV has the same T=16 triangulation number and much the same capsid architecture as herpes simplex virus (HSV) and cytomegalovirus (CMV). Its capsomers are hexamers and pentamers of the major capsid protein, forming a shell with a flat, close-packed, inner surface (the "floor") and chimney-like external protrusions. Overlying the floor at trigonal positions are (alpha beta (2)) heterotrimers called triplexes. The floor structure is well conserved over all three viruses, and the most variable capsid features reside on the outer surface, i.e., in the shapes of the protrusions and triplexes, in which KSHV resembles CMV and differs from HSV. Major capsid protein sequences from the three subfamilies have some similarity, which is closer between KSHV and CMV than between either virus and HSV. The tripler proteins are less highly conserved, but sequence analysis identifies relatively conserved tracts. In alphaherpesviruses, the alpha -subunit (VP19c in HSV) has a 100-residue N-terminal extension and an insertion near the C terminus. The small basic capsid protein sequences are highly divergent: whereas the HSV and CMV proteins bind only to herons, difference mapping suggests that the KSHV protein, ORF65, binds around the tips of both herons and pentons. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Computat Biosci & Engn Lab, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Dept Microbiol, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Dept Internal Med, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Myles H Thaler Ctr AIDS & Human Retrovirus Res, Charlottesville, VA 22908 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bldg 6,Rm B2-34,MSC 2717, Bethesda, MD 20892 USA. RI Heymann, Bernard/F-6825-2011; OI Heymann, Bernard/0000-0002-8872-5326 FU NCI NIH HHS [P30-CA44579, P30 CA044579]; NIAID NIH HHS [R-01 AI41644-04, R01 AI041644]; PHS HHS [R-01 5-23924] NR 56 TC 51 Z9 53 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2001 VL 75 IS 6 BP 2879 EP 2890 DI 10.1128/JVI.75.6.2879-2890.2001 PG 12 WC Virology SC Virology GA 405LG UT WOS:000167160400041 PM 11222713 ER PT J AU Nam, YS Petrovic, A Jeong, KS Venkatesan, S AF Nam, YS Petrovic, A Jeong, KS Venkatesan, S TI Exchange of the basic domain of human immunodeficiency virus type 1 Rev for a polyarginine stretch expands the RNA binding specificity, and a minimal arginine cluster is required for optimal RRE RNA binding affinity, nuclear accumulation, and trans-activation SO JOURNAL OF VIROLOGY LA English DT Article ID RESPONSIVE ELEMENT RNA; VIRAL MESSENGER-RNA; GENE-EXPRESSION REQUIRES; AMINO-TERMINAL DOMAIN; R17 COAT PROTEIN; HUMAN T-CELLS; HIV-1 REV; TARGET SEQUENCE; IMPORTIN-BETA; I REX AB The Rev regulatory protein of human immunodeficiency virus (HIV) facilitates the nuclear export of unspliced and partially spliced HIV RNAs. Using a Rev:MS2 phage coat protein fusion that could be targeted to bind and activate the Rev-responsive element (RRE) RNA or heterologous MS2 phage operator RNA, we analyzed the role(s) of the arginine-rich RNA binding domain in RNA binding and transactivation. The arginine-rich domain could be functionally replaced by a stretch of nine arginines. However, polyarginine substitutions expanded the RNA binding specificity of the resultant mutant Rev protein. Polyarginine insertions in place of residues 24 to 60 that excised the RNA binding and oligomerization domains of Rev preserved the activation for MS2 RNA, but not for the RRE. A nine-arginine insertion outside of the natural context of the Rev nuclear localization signal domain was incompatible with activation of either RNA target. Insertions of fewer than eight arginines impaired RRE activation. Interrupted lysine clusters and disruption of the arginine stretch with lysine or neutral residues resulted in a similar phenotype. Some of these mutants,vith a null phenotype for RRE activated the heterologous MS2 RNA target. Under steady-state conditions, mutants that preserved the Rev response for RRE RNA localized to the nuclei; those with poor or no Rev response accumulated mostly in the cytoplasm. Many of the cytoplasmically resident derivatives became nuclear when leptomycin B (LMB) treatment inhibited nuclear export of nuclear export signal-containing proteins. Mutants that had a null activation potential for either RNA target were particularly resistant to LMB treatment. Abbreviated nuclear residence times and differences in RRE binding affinity may have compromised their activation potential for RRE. High-affinity binding to MS2 RNA through the intact coat protein was sufficient to overcome the short nuclear residence times and to facilitate MS2 activation by some derivatives. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. RP Venkatesan, S (reprint author), NIAID, LMM, NIH, Bldg 10,Rm 6A05, Bethesda, MD 20892 USA. NR 97 TC 10 Z9 11 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2001 VL 75 IS 6 BP 2957 EP 2971 DI 10.1128/JVI.75.6.2957-2971.2001 PG 15 WC Virology SC Virology GA 405LG UT WOS:000167160400049 PM 11222721 ER PT J AU Hadley, EC Dutta, C Finkelstein, J Harris, TB Lane, MA Roth, GS Sherman, SS Starke-Reed, PE AF Hadley, EC Dutta, C Finkelstein, J Harris, TB Lane, MA Roth, GS Sherman, SS Starke-Reed, PE TI Human implications of caloric restriction's effects on aging in laboratory animals: An overview of opportunities for research SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Caloric-Restriction-Clinical-Implications-Advisory-Group Meeting CY MAR 08-10, 1999 CL BETHESDA, MARYLAND SP Calor Restrict Clin Implicat Advisory Grp C1 NIA, Geriatr Program, NIH, Bethesda, MD 20892 USA. NIA, Neurosci & Neuropsychol Aging Program, NIH, Bethesda, MD 20892 USA. NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. NIA, Biol Aging Program, NIH, Bethesda, MD 20892 USA. NIA, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hadley, EC (reprint author), NIA, Geriatr Program, NIH, Gateway Bldg,Suite 3E327,7201 Wisconsin Ave, Bethesda, MD 20892 USA. NR 2 TC 31 Z9 31 U1 0 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2001 VL 56 SI SI BP 5 EP 6 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 422KX UT WOS:000168118000001 PM 12088212 ER PT J AU Lee, IM Blair, SN Allison, DB Folsom, AR Harris, TB Manson, JE Wing, RR AF Lee, IM Blair, SN Allison, DB Folsom, AR Harris, TB Manson, JE Wing, RR TI Epidemiologic data on the relationships of caloric intake, energy balance, and weight gain over the life span with longevity and morbidity SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Caloric-Restriction-Clinical-Implications-Advisory-Group Meeting CY MAR 08-10, 1999 CL BETHESDA, MARYLAND SP Calor Restrict Clin Implicat Advisory Grp ID RANDOMIZED CONTROLLED TRIAL; CORONARY HEART-DISEASE; RISK FACTOR REDUCTION; ALL-CAUSE MORTALITY; IOWA WOMENS HEALTH; AGED 40-64 YEARS; BODY-WEIGHT; FOLLOW-UP; OLDER WOMEN; OVERWEIGHT MEN AB Animal experiments have shown that calorically restricted (CR) animals weigh less and live longer than their ad libitum-fed peers. Are these observations applicable to human beings? This is an important question because the prevalence of obesity in America has increased markedly over recent years. We examine whether there are physiologic effects that occur with CR in humans that could plausibly explain the observed longevity of laboratory animals associated with CR. We also review epidemiologic data from observational and interventional studies on the relationships of caloric intake, energy balance, and weight gain with age-related diseases and longevity. Additionally, data on whether long-term, sustained maintenance of weight loss is feasible, as well as the degree of CR achieved in clinical trials, are summarized. Finally, we provide recommendations regarding further epidemiologic research that will help clarify unanswered questions in these areas. C1 Harvard Univ, Sch Med, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Cooper Inst Aerob Res, Dallas, TX USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Univ Minnesota, Minneapolis, MN 55455 USA. NIA, NIH, Bethesda, MD 20892 USA. Brown Univ, Providence, RI 02912 USA. RP Lee, IM (reprint author), Harvard Univ, Sch Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. OI Allison, David/0000-0003-3566-9399 NR 55 TC 35 Z9 36 U1 1 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2001 VL 56 SI SI BP 7 EP 19 PG 13 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 422KX UT WOS:000168118000002 PM 12088215 ER PT J AU Mobbs, CV Bray, GA Atkinson, RL Bartke, A Finch, CE Maratos-Flier, E Crawley, JN Nelson, JF AF Mobbs, CV Bray, GA Atkinson, RL Bartke, A Finch, CE Maratos-Flier, E Crawley, JN Nelson, JF TI Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Caloric-Restriction-Clinical-Implications-Advisory-Group Meeting CY MAR 08-10, 1999 CL BETHESDA, MARYLAND SP Calor Restrict Clin Implicat Advisory Grp ID MELANIN-CONCENTRATING HORMONE; HYPOTHALAMIC NEUROPEPTIDE-Y; MICE OVEREXPRESSING LEPTIN; GENE-EXPRESSION PROFILE; AGE-RELATED-CHANGES; FOOD RESTRICTION; GROWTH-HORMONE; INFUNDIBULAR NUCLEUS; SYMPATHETIC ACTIVITY; INSULIN SENSITIVITY AB As part of an effort to review current understanding of the mechanisms by which caloric restriction (CR) extends maximum life span, the authors of the present review were requested to develop a list of key issues concerning the potential role of neuroendocrine systems in mediating these effects. It has long been hypothesized that failure of specific neuroendocrine functions during aging leads to key age-related systemic and physiological failures, and more recently it has been postulated that physiological neuroendocrine responses to CR may increase life span. However, although the acute neuroendocrine responses to fasting have been well studied, it is not clear that these responses are necessarily identical to those observed ill response to the chronic moderate (30% to 50% reduction) CR that increases maximum lift: span. Therefore the recommendations of this panel fall into two categories. First, further characterization of neuroendocrine responses to CR over the entire life span is needed. Second, rigorous interventional studies are needed to test the extent to which neuroendocrine responses to CR mediate the effects of CR on life span, or alternatively if CR protects the function of essential neuroendocrine cells whose impairment reduces life span. Complimentary studies using rodent models, nonhuman primates, and humans will be essential to assess the generality of elucidated mechanisms, and to determine if such mechanisms might apply to humans. C1 CUNY Mt Sinai Sch Med, Dept Neurobiol, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Geriatr, New York, NY 10029 USA. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Univ Wisconsin, Sch Med, Dept Nutr Sci, Madison, WI 53706 USA. So Illinois Univ, Sch Med, Dept Physiol, Carbondale, IL 62901 USA. Univ So Calif, Andrus Gerontol Ctr, Los Angeles, CA 90089 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. NIMH, Sect Behav Neuropharmacol, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. RP Mobbs, CV (reprint author), CUNY Mt Sinai Sch Med, Neurobiol Aging Lab, Box 1639, New York, NY 10029 USA. RI Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X NR 83 TC 60 Z9 60 U1 1 U2 4 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2001 VL 56 SI SI BP 34 EP 44 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 422KX UT WOS:000168118000004 PM 12088210 ER PT J AU Roberts, SB Pi-Sunyer, X Kuller, L Lane, MA Ellison, P Prior, JC Shapses, S AF Roberts, SB Pi-Sunyer, X Kuller, L Lane, MA Ellison, P Prior, JC Shapses, S TI Physiologic effects of lowering caloric intake in nonhuman primates and nonobese humans SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT Caloric-Restriction-Clinical-Implications-Advisory-Group Meeting CY MAR 08-10, 1999 CL BETHESDA, MARYLAND SP Calor Restrict Clin Implicat Advisory Grp ID BONE-MINERAL DENSITY; TERM DIETARY RESTRICTION; EVERYDAY EATING BEHAVIOR; LACTATING GAMBIAN WOMEN; HEALTHY-YOUNG WOMEN; HIP FRACTURE RISK; LEAN TISSUE MASS; AGE 50 YEARS; ENERGY-EXPENDITURE; WEIGHT CHANGE AB Caloric restriction (CR) reduces the rate of aging and increases life span in all small animal species studied to date, but the effects of CR in humans remain uncertain. This review summarizes current knowledge of the effects of CR in nonhuman primates and humans. The results suggest that CR has a range of beneficial effects in nonhuman primates studied under laboratory conditions, and short-term markers of CR seen in animal models appear to occur in humans subject to CR also. However, the overall benefit of CR in human populations remains to be established, and studies in human populations are needed. C1 Tufts Univ, USDA, Human Nutr Res Ctr Aging, Energy Metab Lab, Boston, MA 02111 USA. St Lukes Roosevelt Hosp, Obes Res Ctr, New York, NY 10025 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Harvard Univ, Dept Anthropol, Cambridge, MA 02138 USA. Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. RP Roberts, SB (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, Energy Metab Lab, 711 Washington St, Boston, MA 02111 USA. NR 83 TC 40 Z9 40 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2001 VL 56 SI SI BP 66 EP 75 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 422KX UT WOS:000168118000007 PM 12088214 ER PT J AU Black, A Allison, DB Shapses, SA Tilmont, EM Handy, AM Ingram, DK Roth, GS Lane, MA AF Black, A Allison, DB Shapses, SA Tilmont, EM Handy, AM Ingram, DK Roth, GS Lane, MA TI Calorie restriction and skeletal mass in rhesus monkeys (Macaca mulatta): Evidence for an effect mediated through changes in body size SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID BONE-MINERAL DENSITY; DIETARY RESTRICTION; WEIGHT-LOSS; ADULT MALE; ENERGY RESTRICTION; WOMEN; RATS; METABOLISM; TURNOVER; FAT AB Little is known regarding the effects of prolonged calorie restriction (CR) on skeletal health. We investigated long-term(ll years) and short-term (12 months) effects of moderate CR on bone mass and biochemical indices of bone metabolism in male rhesus monkeys across a range of ages. A lower bone mass in long-term CR monkeys was accounted for by adjusting for age and body weight differences. A further analysis indicated that lean mass, but not fat mass, was a strong predictor of bone mass in both CR and control monkeys. No effect of short-term CR on bone mass was observed in older monkeys (mean age, 19 years), although young monkeys (4 years) subjected to short-term CR exhibited slower gains in total body bone density and content than age-matched controls. Neither biochemical markers of bone turnover nor hormonal regulators of bone metabolism were affected by long-term CR. Although osteocalcin concentrations were significantly lower in young restricted males after 1 month on 30% CR in the short-term study, they were no longer different from control values by 6 months on 30% CR. C1 NIA, Mol & Nutrit Physiol Unit, Ctr Gerontol Res, Baltimore, MD 21224 USA. St Lukes Roosevelt Hosp, Obes Res Ctr, New York, NY 10025 USA. Rutgers State Univ, Dept Nutrit Sci, New Brunswick, NJ 08903 USA. RP Lane, MA (reprint author), NIA, Mol & Nutrit Physiol Unit, Ctr Gerontol Res, 5600 Nathan Shock Blvd, Baltimore, MD 21224 USA. EM MLANE@vms.grc.nia.nih.gov NR 43 TC 25 Z9 26 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2001 VL 56 IS 3 BP B98 EP B107 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 407WP UT WOS:000167294000001 PM 11253152 ER PT J AU Seto, B AF Seto, B TI Required education on the protection of human subjects: An NIH initiative SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article C1 NIH, Off Extramural Res, Off Director, Bethesda, MD 20892 USA. RP Seto, B (reprint author), NIH, Off Extramural Res, Off Director, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD MAR PY 2001 VL 11 IS 1 BP 87 EP 90 DI 10.1353/ken.2001.0007 PG 4 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 426WR UT WOS:000168371900005 PM 12166447 ER PT J AU Taylor, K Wolff, A AF Taylor, K Wolff, A TI Pass the baton SO LAB ANIMAL LA English DT Editorial Material C1 Off Anim Care & Use, Bethesda, MD USA. NIH, Div Anim Welf, Bethesda, MD 20892 USA. RP Taylor, K (reprint author), Off Anim Care & Use, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2001 VL 30 IS 3 BP 21 EP 21 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 408PW UT WOS:000167337700005 ER PT J AU Hoffman, JM Croft, BY AF Hoffman, JM Croft, BY TI Future directions in small animal imaging SO LAB ANIMAL LA English DT Article AB The adaptation and development of imaging technologies for use in small animals has the potential to be a refinement with profound effects on how basic cancer research using animals is conducted. The authors describe how NCI funding is helping to advance research in this area. C1 NCI, DCTD, Biomed Imaging Program, NIH, Bethesda, MD 20892 USA. RP Hoffman, JM (reprint author), NCI, DCTD, Biomed Imaging Program, NIH, EPN 6066,6130 Execut Blvd,MSC 7412, Bethesda, MD 20892 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 0 TC 9 Z9 10 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAR PY 2001 VL 30 IS 3 BP 32 EP 35 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 408PW UT WOS:000167337700008 PM 11385755 ER PT J AU Takayama, H Takagi, H LaRochelle, WJ Kapur, RP Merlino, G AF Takayama, H Takagi, H LaRochelle, WJ Kapur, RP Merlino, G TI Ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction in transgenic mice overexpressing hepatocyte growth factor/scatter factor SO LABORATORY INVESTIGATION LA English DT Article ID FACTOR SCATTER FACTOR; INFLAMMATORY BOWEL-DISEASE; ENTERIC NERVOUS-SYSTEM; ENDOTHELIN-B RECEPTOR; C-MET RECEPTOR; INTERSTITIAL-CELLS; LACKING GDNF; ABNORMAL-DEVELOPMENT; TYROSINE KINASE; IN-VIVO AB Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro; however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (]BD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent. C1 NCI, Mol Biol Lab, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. Gunma Univ, Sch Med, Dept Internal Med 1, Gunma, Japan. Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. RP Merlino, G (reprint author), NCI, Mol Biol Lab, Mol Genet Sect, NIH, Bldg 37,Room 2E24,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK52530] NR 55 TC 11 Z9 11 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 2001 VL 81 IS 3 BP 297 EP 305 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 418JU UT WOS:000167887800005 PM 11310823 ER PT J AU Phillips, TM AF Phillips, TM TI Analysis of single-cell cultures by immunoaffinity capillary electrophoresis with laser-induced fluorescence detection SO LUMINESCENCE LA English DT Article; Proceedings Paper CT IXth International Symposium on Luminescence Spectrometry in Biomedical and Environmental Analysis CY MAY 15-17, 2000 CL MONTPELLIER, FRANCE DE microdialysis; immunoaffinity capillary electrophoresis; laser-induced fluorescence detection ID INFLAMMATORY-BOWEL-DISEASE; NEUROPEPTIDES SUBSTANCE-P; GENE-RELATED PEPTIDE; LYMPHOCYTE-PROLIFERATION; PRECOLUMN DERIVATIZATION; BODY-FLUIDS; MICRODIALYSIS; SECRETION; RECEPTOR; ONLINE AB Neuropeptide regulation of immunological activity is becoming an important issue in both basic and clinical sciences, necessitating the need for analysis to be performed at the single-cell level. A microsampling procedure has been developed for studying secretion of biologically important peptides from neuropeptide-stimulated lymphocytes, based on microdialysis sampling coupled to immunoaffinity capillary electrophoresis (ICE), with laser-induced fluorescence (LIF) detection using a fibre-optic spectrometer and diode laser excitation. The system demonstrated a limit of detection in the high attomole (10(-18) mol/L) range with pure standards and was capable of monitoring secretion from a single cell over time. Using this system it was possible to differentiate the effects of four neuropeptides on both T and B cell release of regulatory cytokines. CB4(+) lymphocytes demonstrated a 7.5-fold increase in cytokine secretion over baseline following stimulation with substance P (SP) and calcitonin gene-related peptide (CGRP). B cells responded to CGRP and vasoactive intestinal peptide (VIP) stimulation (5.5-fold increase), but not to SP. These changes took place 12-20 h post-stimulation and, once the peak secretion had been reached, remained at that level for the duration of the experiment, This system demonstrates the ability to perform high sensitivity measurements on microsamples of biological fluids. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 George Washington Univ, Med Ctr, Immunochem Lab, Washington, DC 20037 USA. RP Phillips, TM (reprint author), NIH, UAIR, DBEPS, ORS,OD, Bldg 13,Room 3N17,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 48 TC 35 Z9 35 U1 2 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1522-7235 J9 LUMINESCENCE JI Luminescence PD MAR-APR PY 2001 VL 16 IS 2 BP 145 EP 152 DI 10.1002/bio.645.abs PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425YB UT WOS:000168318300011 PM 11312540 ER PT J AU Kobayashi, H Sato, N Hiraga, A Saga, T Nakamoto, Y Ueda, H Konishi, J Togashi, K Brechbiel, MW AF Kobayashi, H Sato, N Hiraga, A Saga, T Nakamoto, Y Ueda, H Konishi, J Togashi, K Brechbiel, MW TI 3D-micro-MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; angiography; microcirculation; contrast media; dendrimer ID GADOLINIUM CHLORIDE TOXICITY; GD-DTPA; MONOCLONAL-ANTIBODY; GLOMERULAR-FILTRATION; ENHANCING AGENT; BLOOD; ANGIOGENESIS; CANCER; RATS; BIODISTRIBUTION AB Four novel macromolecular MRI contrast agents, all of which had the same chemical composition but different molecular weights, were prepared using generation-3, -4, -5, and -6 polyamidoamine (PAMAM(TM)) dendrimers conjugated with a bifunctional diethylenetriaminepentaacetic acid derivative to change the blood retention, tissue perfusion, and excretion. Size-dependent changes in the pharmacokinetics were observed in the biodistribution study. Gd-153-labeled generation-6 PAMAM(TM)- conjugates remained in the blood significantly longer than all of the other preparations (P < 0.001). The increase in blood-to-organ ratio of the preparations was found to correlate with increasing molecular size (P < 0.001). Additionally, 3D-micro MR images and angiography of mice of high quality and detail were obtained using PAMAM(TM)-(1B4M-Gd)x as a macro-molecular MRI contrast agent with a 1.5-T clinical MRI instrument. Numerous fine vessels of similar to 200 mum diameter were visualized on subtracted 3D-MR angiographms with G6D-(1B4M-Gd)(192). The quality of the images was sufficient to estimate the microvasculature of cancerous tissue for anti-angiogenesis therapy and to investigate knockout mice. (C) 2001 Wiley-Liss, Inc. C1 Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Hitachi Med Co Chair,Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Dept Nucl Med & Diagnost Imaging, Kyoto, Japan. Kyoto Univ, Dept Radiol, Kyoto, Japan. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), Kyoto Univ, Grad Sch Med, Dept Diagnost & Intervent Imagiol, Hitachi Med Co Chair,Sakyo Ku, 54 Kawahara Cho, Kyoto 6068507, Japan. NR 35 TC 116 Z9 119 U1 1 U2 7 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2001 VL 45 IS 3 BP 454 EP 460 DI 10.1002/1522-2594(200103)45:3<454::AID-MRM1060>3.0.CO;2-M PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 405MP UT WOS:000167163800016 PM 11241704 ER PT J AU Mandelblatt, JS Berg, CD Meropol, NJ Edge, SB Gold, K Hwang, YT Hadley, J AF Mandelblatt, JS Berg, CD Meropol, NJ Edge, SB Gold, K Hwang, YT Hadley, J TI Measuring and predicting surgeons' practice styles for breast cancer treatment in older women SO MEDICAL CARE LA English DT Article DE breast cancer; elderly; treatment; case simulation; clinical vignettes; practice styles ID CLINICAL COMORBIDITY INDEX; COMPARING TOTAL MASTECTOMY; PRIMARY-CARE PHYSICIANS; CONSERVING SURGERY; RHEUMATOID-ARTHRITIS; RADIATION-THERAPY; FOLLOW-UP; STAGE-I; PATIENT; PATTERNS AB BACKGROUND. Few measures exist to assess physicians' practice style, and there are few data on physicians' practice styles and patterns of care. OBJECTIVES. TO use clinical vignettes to measure surgeons' "propensity" for local treatments for early-stage breast cancer and to describe factors associated with propensity. RESEARCH DESIGN AND SUBJECTS. A cross-sectional mailed survey with telephone follow-up of a random sample of 1,000 surgeons treating Medicare beneficiaries in fee-for-service settings. MEASURES. Outcome measures include treatment propensity, self-reported practice, and actual treatment received by the surgeons' patients. RESULTS. Propensities were significantly associated with actual treatment, controlling for covariates, Area Medicare fees were the strongest predictor of propensity, followed by region, attitudes, volume, and gender. For instance, after other factors were considered, surgeons practicing in areas with the highest breast-conserving surgery (BCS) fees were 8.61 (95% CI2.26-32.73) times more likely to have a BCS propensity than surgeons in areas with the lowest fees. Surgeons with the strongest beliefs in patient participation in treatment decisions were nearly 6 times (95% CI 1.67-20.84) more likely to have a BCS propensity than surgeons with the lowest such beliefs, controlling for covariates, Male surgeons were also independently more likely to have a mastectomy propensity than female surgeons. CONCLUSIONS. Surgeons' propensities explain some of the observed variations in breast cancer treatment patterns among older women, Standardized scenarios provide a practical method to measure practice style and could be used to evaluate physician contributions to shared decision making, practice patterns, costs and outcomes, and adherence to guidelines. C1 Georgetown Univ, Sch Med, Vincent T Lombardi Canc Res Ctr, Div Canc Prevent & Control,Dept Oncol, Washington, DC 20007 USA. NCI, Div Canc Prevent & Control, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. SUNY Buffalo, Roswell Pk Canc Inst, Buffalo, NY 14260 USA. Georgetown Univ, Sch Med, Dept Biomath & Biostat, Washington, DC USA. ABC Associates, Bethesda, MD USA. Georgetown Univ, Sch Med, Inst Hlth Care Policy & Res, Washington, DC USA. RP Mandelblatt, JS (reprint author), Georgetown Univ, Sch Med, Vincent T Lombardi Canc Res Ctr, Div Canc Prevent & Control,Dept Oncol, 2233 Wisconsin Ave,Suite 440, Washington, DC 20007 USA. FU AHRQ HHS [HS08395] NR 70 TC 62 Z9 62 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2001 VL 39 IS 3 BP 228 EP 242 DI 10.1097/00005650-200103000-00004 PG 15 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 407PF UT WOS:000167279400004 PM 11242318 ER PT J AU Tarr, PE Sneller, MC Mechanic, LJ Economides, A Eger, CM Strober, W Cunningham-Rundles, C Lucey, DR AF Tarr, PE Sneller, MC Mechanic, LJ Economides, A Eger, CM Strober, W Cunningham-Rundles, C Lucey, DR TI Infections in patients with immunodeficiency with thymoma (Good syndrome) - Report of 5 cases and review of the literature SO MEDICINE LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; RED-CELL APLASIA; MYASTHENIA-GRAVIS; IGG REPLACEMENT; HYPOGAMMAGLOBULINEMIA; DISEASE; MANIFESTATIONS; DEFICIENCY; DISORDERS; DIARRHEA C1 NIAID, NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Div Allergy & Immunol, Washington, DC 20010 USA. Washington Hosp Ctr, Div Cardiothorac Surg, Washington, DC 20010 USA. Washington Hosp Ctr, Div Infect Dis, Washington, DC 20010 USA. Mt Sinai Med Ctr, Div Clin Immunol, New York, NY 10029 USA. RP Tarr, PE (reprint author), Albert Einstein Coll Med, Div Infect Dis, 1300 Morris Pk Ave,Ullmann 1209, Bronx, NY 10461 USA. NR 69 TC 105 Z9 118 U1 0 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 2001 VL 80 IS 2 BP 123 EP 133 DI 10.1097/00005792-200103000-00005 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 418LJ UT WOS:000167893400005 PM 11307588 ER PT J AU Makarova, KS Aravind, L Wolf, YI Tatusov, RL Minton, KW Koonin, EV Daly, MJ AF Makarova, KS Aravind, L Wolf, YI Tatusov, RL Minton, KW Koonin, EV Daly, MJ TI Genome of the extremely radiation-resistant bacterium Deinococcus radiodurans viewed from the perspective of comparative genomics SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review ID DNA-POLYMERASE-BETA; MIXED WASTE ENVIRONMENTS; UV ENDONUCLEASE-BETA; DOUBLE-STRAND BREAKS; ESCHERICHIA-COLI; MICROCOCCUS-RADIODURANS; GENE-EXPRESSION; IONIZING-RADIATION; BACILLUS-SUBTILIS; TARGETED MUTAGENESIS AB The bacterium Deinococcus radiodurans shows remarkable resistance to a range of damage caused by ionizing radiation, desiccation, UV radiation, oxidizing agents, and electrophilic mutagens. D. radiodurans is best known for its extreme resistance to ionizing radiation; not only can ii grow continuously in the presence of chronic radiation (6 kilorads/h), but also it can survive acute exposures to gamma radiation exceeding 1,500 kilorads without dying or undergoing induced mutation. These characteristics were the impetus for sequencing the genome of D. radiodurans and the ongoing development of its use for bioremediation of radioactive wastes. Although it is known that these multiple resistance phenotypes stem from efficient DNA repair processes, the mechanisms underlying these extraordinary repair capabilities remain poorly understood. In this work we present an extensive comparative sequence analysis of the Deinococcus genome. Deinococcus is the first representative with a completely sequenced genome from a distinct bacterial lineage of extremophiles, the Thermus-Deinococcus group. Phylogenetic tree analysis, combined with the identification of several synapomorphies between Thermus and Deinococcus, supports the hypothesis that it is an ancient group with no clear affinities to any of the other known bacterial lineages. Distinctive features of the Deinococcus genome as well as features shared with other free-living bacteria were revealed by comparison of its proteome to the collection of clusters of orthologous groups of proteins. Analysis of paralogs in Deinococcus has revealed several unique protein families. In addition, specific expansions of several other families including phosphatases, proteases, acyltransferases, and Nudix family pyrophosphohydrolases were detected. Genes that potentially affect DNA repair and recombination and stress responses were investigated in detail. Some proteins appear to have been horizontally transferred from eukaryotes and are not present in other bacteria. For example, three proteins homologous to plant desiccation resistance proteins were identified and these are particularly interesting because of the correlation between desiccation and radiation resistance. Compared to other bacteria, the D. radiodurans genome is enriched in repetitive sequences, namely, IS-like transposons and small intergenic repeats. In combination these observations suggest that several different biological mechanisms contribute to the multiple DNA repair-dependent phenotypes of this organism. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20814 USA. RP Daly, MJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, Room B3153,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU NIGMS NIH HHS [5R01-GM39933-09] NR 224 TC 380 Z9 417 U1 6 U2 72 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD MAR PY 2001 VL 65 IS 1 BP 44 EP + DI 10.1128/MMBR.65.1.44-79.2001 PG 38 WC Microbiology SC Microbiology GA 408TF UT WOS:000167343200002 PM 11238985 ER PT J AU Sanchez, LB Elmendorf, H Nash, TE Muller, M AF Sanchez, LB Elmendorf, H Nash, TE Muller, M TI NAD(P)H : menadione oxidoreductase of the amitochondriate eukaryote Giardia lamblia: a simpler homologue of the vertebrate enzyme SO MICROBIOLOGY-UK LA English DT Article DE menadione oxidoreductase; Giardia lamblia; DT-diaphorase ID DT-DIAPHORASE; NAD(P)H-QUINONE OXIDOREDUCTASE; 2-ELECTRON REDUCTION; DUODENALIS; METABOLISM; BINDING; NQO1 AB The amitochondriate eukaryote Giardia lamblia contains an NAD(P)H:menadione oxidoreductase (EC 1.6.99.2) (gIQR) that catalyses the two-electron transfer oxidation of NAD(P)H with a quinone as acceptor. The gene encoding this protein in G. lamblia was expressed in Escherichia coli. The purified recombinant protein had an NAD(P)H oxidoreductase activity, with NADPH being a more efficient electron donor than NADH. Menadione, naphthoquinone and several artificial electron accepters served as substrate for the enzyme. gIQR shows high amino acid similarity to its homologues in vertebrates and also to a series of hypothetical proteins from bacteria. Although gIQR is considerably smaller than the mammalian enzymes, three-dimensional modelling shows similar arrangement of the secondary structural elements. Most amino acid residues of the mammalian enzymes that participate in substrate binding or catalysis are conserved. Conservation of these features and the similarity in substrate specificity and in susceptibility to inhibitors establish gIQR as an authentic member of this protein family. C1 Rockefeller Univ, Biochem Parasitol Lab, New York, NY 10021 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sanchez, LB (reprint author), Rockefeller Univ, Biochem Parasitol Lab, 1230 York Ave, New York, NY 10021 USA. FU NIAID NIH HHS [AI 11942] NR 31 TC 12 Z9 12 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-UK JI Microbiology-(UK) PD MAR PY 2001 VL 147 BP 561 EP 570 PN 3 PG 10 WC Microbiology SC Microbiology GA 410FW UT WOS:000167430800007 PM 11238963 ER PT J AU Jaffe, ES AF Jaffe, ES TI Anaplastic large cell lymphoma: The shifting sands of diagnostic hematopathology SO MODERN PATHOLOGY LA English DT Article DE anaplastic large cell lymphoma; CD30; tyrosine kinase; T-cell lymphoma; oncogenes; cytogenetics; immunohistochemistry ID NON-HODGKINS-LYMPHOMA; POLYMERASE CHAIN-REACTION; HEALTH-ORGANIZATION CLASSIFICATION; MONOCLONAL-ANTIBODY ALK1; STERNBERG-REED CELLS; T-CELL; KI-1 LYMPHOMA; MALIGNANT HISTIOCYTOSIS; ANTIGEN EXPRESSION; NPM-ALK AB Anaplastic large cell lymphoma (ALCL) is a paradigm for the process used to define new disease entities, and provides a model that is applicable to all areas of pathology. ALCL was first recognized based on characteristic histologic features (sinusoidal invasion) and a distinctive immunophenotype (CD30+), However, neither sinusoidal invasion nor CD30-positivity proved to be entirely specific. Subsequently, a characteristic cytogenetic abnormality was identified, the t(2;5), that led to identification of the genes involved in the translocation (NPM/ALK) and insights into the pathogenesis, Generation of monoclonal antibodies to the aberrantly expressed anaplastic large cell lymphoma kinase (ALK) such as ALK-1 can be used diagnostically, and have led to improved definition of the diagnostic entity with important clinical and prognostic implications. These studies also have clarified the relationship of ALCL to Hodgkin's disease, another lymphoid malignancy associated with CD30 expression. We have learned that the ultimate histologic spectrum of ALCL is both narrower and broader than originally believed. The small cell and lymphohistiocytic variants of ALCL are ALK-positive, and are an accepted part, of the disease entity, although the neoplastic cells may appear neither large nor anaplastic. Conversely, most cases of Hodgkin's-like AI,CL have proved to be more closely related to true Hodgkin's disease, and are unrelated to ALCL. C1 NCI, Pathol Lab, Hematopathol Sect, Div Clin Sci, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Hematopathol Sect, Div Clin Sci, NCI Bldg 10-2N202,MSC-1500, Bethesda, MD 20892 USA. NR 84 TC 108 Z9 108 U1 0 U2 1 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 2001 VL 14 IS 3 BP 219 EP 228 DI 10.1038/modpathol.3880289 PG 10 WC Pathology SC Pathology GA 417KL UT WOS:000167834100014 PM 11266530 ER PT J AU Elmendorf, HG Singer, SM Pierce, J Cowan, J Nash, TE AF Elmendorf, HG Singer, SM Pierce, J Cowan, J Nash, TE TI Initiator and upstream elements in the alpha 2-tubulin promoter of Giardia lamblia SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Giardia lamblia; transcription; promoter; initiator element; transfection ID DEPENDENT GLUTAMATE-DEHYDROGENASE; PROTEIN-CODING GENES; PRIMITIVE EUKARYOTE; PHYLOGENETIC PLACE; LACKING PROTOZOAN; TATA BOX; TRANSCRIPTION; EXPRESSION; SEQUENCE; RNA AB Giardia lamblia, one of the earliest diverging eukaryotes and a major cause of diarrhea world-wide, has unusually short intergenic regions, raising questions concerning its regulation of gene expression. We have approached this issue through examination of the alpha2-tubulin promoter and in particular investigated the function of an AT-rich element surrounding the transcription start site. Its placement and the ability of this sequence to direct transcription initiation in the absence of any other promoter elements is similar to the initiator element in higher eukaryotes. However, the sequence diversity of extremely short (8-10 bp) initiator elements is surprising, as is their ability to independently direct substantial levels of transcription. We also identified a large AT-rich element located between - 64 and - 29 bp upstream of the transcriptional start site and show using both deletions and site-specific mutations of this region that sequences between - 60 and the start of transcription are important for promoter strength; interestingly this AT-rich sequence is not highly conserved among different Giardia promoters. These data suggest that while the overall structure of the core promoter has been conserved throughout eukaryotic evolution, significant variation and flexibility is allowed in element consensus sequences and roles in transcription. In particular, the short and diverse sequences that function in transcription initiation in Giardia suggest the potential for relaxed transcriptional regulation. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Elmendorf, HG (reprint author), Georgetown Univ, Dept Biol, 306A Reiss BLdg,37th & O St NW, Washington, DC 20057 USA. NR 52 TC 69 Z9 71 U1 0 U2 2 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 2001 VL 113 IS 1 BP 157 EP 169 DI 10.1016/S0166-6851(01)00211-0 PG 13 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 415ZJ UT WOS:000167753200016 PM 11254964 ER PT J AU Esteban, LM Vicario-Abejon, C Fernandez-Salguero, P Fernandez-Medarde, A Swaminathan, N Yienger, K Lopez, E Malumbres, M McKay, R Ward, JM Pellicer, A Santos, E AF Esteban, LM Vicario-Abejon, C Fernandez-Salguero, P Fernandez-Medarde, A Swaminathan, N Yienger, K Lopez, E Malumbres, M McKay, R Ward, JM Pellicer, A Santos, E TI Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID II MUTANT MICE; KINASE-II; K-RAS; SIGNALING PATHWAY; EXPRESSION; PROTEINS; GENE; HIPPOCAMPUS; NEURONS; TRANSDUCTION AB Mammalian cells harbor three highly homologous and widely expressed members of the ras family (H-ras, N-ras, and Ii-ras), but it remains unclear whether they play specific or overlapping cellular roles. To gain insight into such functional roles, here we generated and analyzed H-ras nun mutant mice, which were then also bred with N-ras knockout animals to ascertain the viability and properties of potential double null mutations in both loci. Mating among heterozygous H-ras(+/-) mice produced H-ras(-/-) offspring with a normal Mendelian pattern of inheritance, indicating that the loss of II-ras did not interfere with embryonic and fetal viability in the uterus. Homozygous mutant H-ras(-/-) mice reached sexual maturity at the same age as their littermates, and both males and females were fertile. Characterization of lymphocyte subsets in the spleen and thymus showed no significant differences between wild-type and H-ras(-/-) mice. Analysis of neuronal markers in the brains of knockout and wild-type H-ras mice showed that disruption of this locus did not impair or alter neuronal development. Breeding between our K-ras mutant animals and previously available N-ras null mutants gave rise to viable double knockout (H-ras(-/-)/N-ras(-/-)) offspring expressing only K-ras genes which grew normally, were fertile, and did not show any obvious phenotype. Interestingly, however, lower-than-expected numbers of adult, double knockout animals were consistently obtained in Mendelian crosses between heterozygous N-ras/H-ras mice, Our results indicate that, as for N-ras, H-ras gene function is dispensable for normal mouse development growth, fertility, and neuronal development. Additionally, of the three ras genes, K-ras appears to be not only essential but also sufficient for normal mouse development. C1 Univ Salamanca, USAL, CSIC, Ctr Invest Canc,IBMCC, Salamanca 37007, Spain. Univ Extremadura, Dept Bioquim & Biol Mol, Badajoz, Spain. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Frederick, MD 21701 USA. NYU, Med Ctr, Dept Pathol, New York, NY 10016 USA. NYU, Med Ctr, Kaplan Canc Ctr, New York, NY 10016 USA. RP Santos, E (reprint author), Univ Salamanca, USAL, CSIC, Ctr Invest Canc,IBMCC, Campus Unamuno, Salamanca 37007, Spain. RI Malumbres, Marcos/E-8834-2011; Vicario-Abejon, Carlos/G-2814-2016; OI Malumbres, Marcos/0000-0002-0829-6315; Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 50 TC 188 Z9 190 U1 0 U2 7 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 2001 VL 21 IS 5 BP 1444 EP 1452 DI 10.1128/MCB.21.5.1444-1452.2001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 401RU UT WOS:000166942700002 PM 11238881 ER PT J AU Wu, CH Madabusi, L Nishioka, H Emanuel, P Sypes, M Arkhipova, I Gilmour, DS AF Wu, CH Madabusi, L Nishioka, H Emanuel, P Sypes, M Arkhipova, I Gilmour, DS TI Analysis of core promoter sequences located downstream from the TATA element in the hsp70 promoter from Drosophila melanogaster SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; HEAT-SHOCK; TRANSCRIPTION FACTOR; NONTEMPLATE STRAND; CROSS-LINKING; TFIID COMPLEX; DNA; GENE; BOX; BINDING AB TFIID recognizes multiple sequence elements in the hsp70 promoter of Drosophila. Here, we investigate the function of sequences downstream from the TATA element. A mutation in the initiator was identified that caused an eightfold reduction in binding of TFIID and a fourfold reduction in transcription in vitro. Another mutation in the +24 to +29 region was somewhat less inhibitory, but a mutation in the +14 to +19 region had essentially no effect. The normal promoter and the mutants in the initiator and the +24 to +29 region were transformed into flies by P element-mediated transformation. The initiator mutation reduced expression an average of twofold in adult flies, whereas the mutation in the +24 to +29 region had essentially no effect. In contrast, a promoter combining the two mutations was expressed an average of sixfold less than the wild type. The results suggest that the initiator and the +24 to +29 region could serve overlapping functions in vivo. Protein-DNA cross-linking was used to identify which subunits of TFIID contact the +24 to +29 region and the initiator. No specific subunits mere found to cross-link to the +24 to +29 region. In contrast, the initiator cross-linked exclusively to dTAF230. Remarkably, dTAF230 cross-links approximately 10 times more efficiently to the nontranscribed strand than to the transcribed strand at the initiator. C1 Penn State Univ, Dept Biochem & Mol Biol, Ctr Gene Regulat, University Pk, PA 16802 USA. Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78742 USA. NIH, Bethesda, MD 20892 USA. USA, ERDEC, SCBRD, RT,Bioproc Engn Facil, Aberdeen Proving Ground, MD 21010 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Gilmour, DS (reprint author), Penn State Univ, Dept Biochem & Mol Biol, Ctr Gene Regulat, University Pk, PA 16802 USA. FU NIGMS NIH HHS [R01 GM047477, GM47477] NR 43 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 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2001 VL 21 IS 5 BP 1593 EP 1602 DI 10.1128/MCB.21.5.1593-1602.2001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 401RU UT WOS:000166942700017 PM 11238896 ER PT J AU Kraemer, SM Ranallo, RT Ogg, RC Stargell, LA AF Kraemer, SM Ranallo, RT Ogg, RC Stargell, LA TI TFIIA interacts with TFIID via association with TATA-binding protein and TAF40 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION FACTOR-IIA; YEAST TFIIA/TBP/DNA COMPLEX; CELL-CYCLE PROGRESSION; HISTONE-LIKE TAFS; TBP-DNA BINDING; IN-VIVO; SACCHAROMYCES-CEREVISIAE; PROMOTER SELECTIVITY; GENE ACTIVATION AB TFIIA and TATA-binding protein (TBP) associate directly at the TATA element of genes transcribed by RNA polymerase II. In vivo, TBP is complexed with approximately 14 TBP-associated factors (TAFs) to form the general transcription factor TFIID. How TFIIA and TFIID communicate is not well understood. We show that in addition to making direct contacts with TBP, yeast TAF40 interacts directly and specifically with TFIIA Mutational analyses of the Toa2 subunit of TFIIA indicate that loss of functional interaction between TFIIA and TAF40 results in conditional growth phenotypes and defects in transcription. These results demonstrate that the TFIIA-TAF40 interaction is important in vivo and indicate a functional role for TAF40 as a bridging factor between TFIIA and TFIID. C1 Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Stargell, LA (reprint author), Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. FU NIGMS NIH HHS [R01 GM056884, GM56884] NR 89 TC 20 Z9 21 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 2001 VL 21 IS 5 BP 1737 EP 1746 DI 10.1128/MCB.21.5.1737-1746.2001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 401RU UT WOS:000166942700032 PM 11238911 ER PT J AU Menissier-de Murcia, J Mark, M Wendling, O Wynshaw-Boris, A de Murcia, G AF Menissier-de Murcia, J Mark, M Wendling, O Wynshaw-Boris, A de Murcia, G TI Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BASE-EXCISION-REPAIR; DNA-POLYMERASE-BETA; POLY(ADP-RIBOSE) POLYMERASE; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; DEFICIENT MICE; XRCC1 PROTEIN; DAMAGE; GENE; REQUIREMENT AB PARP-1 and ATM are bath involved in the response to DNA strand breaks, resulting in induction of a signaling network responsible for DNA surveillance, cellular recovery, and cell survival. ATM interacts with double-strand break repair pathways and induces signals resulting in the control of the cell cycle-coupled checkpoints. PARP-1 acts as a DNA break sensor in the base excision repair pathway of DNA. Mice with mutations inactivating either protein show radiosensitivity and high radiation-induced chromosomal aberration frequencies. Embryos carrying double mutations of both PARP-1 and ATM genes were generated, These mutant embryos show apoptosis in the embryo but not in extraembryonic tissues and die at embryonic day 8.0, although extraembryonic tissues appear normal for up to 10.5 days of gestation. These results reveal a functional synergy between PARP-1 and ATM during a period of embryokenesis embryokenesis when cell cycle checkpoints are not active and the embryo is particularly sensitive to DNA. damage. These results suggest that ATM and PARP-1 have synergistic phenotypes due to the effects of these proteins on signaling DNA damage and/or on distinct pathways of DNA repair. C1 Ecole Super Biotechnol Strasbourt, CNRS, UPR 9003, Cancerogenese & Mutagenes Mol & Sturct, F-67400 Illkirch, France. Coll France, ULP, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67400 Illkirch, France. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Menissier-de Murcia, J (reprint author), Ecole Super Biotechnol Strasbourt, Commissariat Energie Atom, Lab Convent, CNRS,UPR 9003, Blvd Sebastien Brant, F-67400 Illkirch, France. NR 36 TC 56 Z9 56 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2001 VL 21 IS 5 BP 1828 EP 1832 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 401RU UT WOS:000166942700040 PM 11238919 ER PT J AU Klenova, EM Chernukhin, IV El-Kady, A Lee, RE Pugacheva, EM Loukinov, DI Goodwin, GH Delgado, D Filippova, GN Leon, J Morse, HC Neiman, PE Lobanenkov, VV AF Klenova, EM Chernukhin, IV El-Kady, A Lee, RE Pugacheva, EM Loukinov, DI Goodwin, GH Delgado, D Filippova, GN Leon, J Morse, HC Neiman, PE Lobanenkov, VV TI Functional phosphorylation sites in the C-terminal region of the multivalent multifunctional transcriptional factor CTCF SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CASEIN KINASE-II; PROTEIN PRECURSOR PROMOTER; DNA-BINDING PROTEINS; ZINC-FINGER PROTEIN; MYC GENE; NUCLEAR FACTOR; MEDIATED PHOSPHORYLATION; 5'-FLANKING SEQUENCE; REPRESSION ACTIVITY; THYROID-HORMONE AB CTCF is a widely expressed and highly conserved multi-Zn-finger (ZF) nuclear factor. Binding to various CTCF target sites (CTSs) is mediated by combinatorial contributions of different ZFs. Different CTSs mediate distinct CTCF functions in transcriptional regulation, including promoter repression or activation and hormone-responsive gene silencing. In addition, the necessary and sufficient core sequences of diverse enhancer-blocking (insulator) elements, including CpG methylation-sensitive ones, have recently been pinpointed to CTSs. To determine whether a posttranslational modification may modulate CTCF functions, we studied CTCF phosphorylation. We demonstrated that most of the modifications that occur at the carboxy terminus in vivo can be reproduced in vitro with casein kinase II (CKII). Major modification sites map to four serines within the (SKKEDSSDSE)-K-604-S-609-D-610-E-612 motif that is highly conserved in vertebrates. Specific mutations of these serines abrogate phosphorylation of CTCF in vivo and CKII-induced phosphorylation in vitro. In addition, we showed that completely preventing phosphorylation by substituting all serines within this site resulted in markedly enhanced repression of the CTS-bearing vertebrate c-myc promoters, but did not alter CTCF nuclear localization or in vitro DNA-binding characteristics assayed with c-myc CTSs. Moreover, these substitutions manifested a profound effect on negative cell growth regulation by wild-type CTCF. CKII may thus be responsible for attenuation of CTCF activity, either acting on its own or by providing the signal for phosphorylation by other kinases and for CTCF-interacting protein partners. C1 NIAID, Immunopathol Lab, Sect Mol Pathol, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, Virol & Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. Univ Oxford, Dept Biochem, Genet Lab, Oxford OX1 3QU, England. Inst Canc Res, Haddow Labs, Sutton, Surrey, England. Univ Cantabria, Fac Med, Santander 39011, Spain. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Lobanenkov, VV (reprint author), NIAID, Immunopathol Lab, Sect Mol Pathol, NIH, Bldg 7,Room 303,7 Ctr Dr,MSC 0760, Bethesda, MD 20892 USA. RI Elkady, Ayman/J-5738-2012; OI Morse, Herbert/0000-0002-9331-3705 FU NCI NIH HHS [R01 CA68360, R01 CA068360, R01 CA71732, R01 CA020068, R01 CA20068] NR 65 TC 68 Z9 69 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2001 VL 21 IS 6 BP 2221 EP 2234 DI 10.1128/MCB.21.6.2221-2234.2001 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426UG UT WOS:000168366300030 PM 11238955 ER PT J AU Herzog, CR Crist, KA Sabourin, CLK Kelloff, GJ Boone, CW Stoner, GD You, M AF Herzog, CR Crist, KA Sabourin, CLK Kelloff, GJ Boone, CW Stoner, GD You, M TI Chromosome 3p tumor-suppressor gene alterations in cervical carcinomas SO MOLECULAR CARCINOGENESIS LA English DT Article DE 3p; loss of heterozygosity; transforming growth factor-beta type II receptor; fragile histidine triad; cervical carcinoma ID GROWTH-FACTOR-BETA; RECEPTOR-TYPE-II; SQUAMOUS-CELL CARCINOMAS; FHIT GENE; HUMAN PAPILLOMAVIRUS; TGF-BETA; LUNG-CANCER; MICROSATELLITE INSTABILITY; RENAL-CARCINOMA; HUMAN OVARIAN AB Loss of heterozygosity (LOH) on chromosome 3p is a common event in cervical cancer and typically occurs in a dispersed pattern involving several loci. This implies that more than one resident tumor-suppressor gene is involved in the genesis of these tumors; however, specific targets remain to be identified. The region of 3p 14.2-pter encompasses a region of frequent loss and contains at least three tumor-suppressor genes: fragile histidine triad (FHIT), transforming growth factor-beta receptor II (T betaR-II), and Von Hippel-Lindau. To identify those loci within 3p 14.2-pter that are important in cervical cancer, invasive tumors were first subjected to high-density LOH analysis. With 25 microsatellite markers, LOH was detected in seven of 15 cervical carcinomas (47%). Losses always included markers mapping to 3p22, and markers at this location were exclusively lost in two tumors, implicating this as a site of a cervical tumor-suppressor gene. Because it is a known tumor-suppressor gene located at 3p22 and thus a potential target for inactivation in these tumors, the T betaR-II gene was subsequently screened for mutation and altered expression levels. Whereas no tumor-derived mutations were detected in any of the tumors, six of ten tumors showed T betaR-II transcript levels reduced by greater than or equal to 50% when compared with normal cervical epithelium. Nine of 15 (60%) tumors exhibited LOH at 3p22 or reduced expression of T betaR-II, suggesting that reduced T betaR-II levels contribute to cervical tumorigenesis. Two cases exhibited silent germline polymorphisms of T betaR-II: one corresponding to a C1167T transversion and the other to an A1266G transition. The FHIT gene, which is located at 3p 14.2, also frequently incurred LOH and abnormal transcription in these tumors. LOH of FHIT was observed in five of the 15 tumors analyzed. Neither mutations nor homozygous deletions of FHIT were detected in the tumors. However, aberrantly short transcripts of the FHIT gene were evident in six of nine (67%) tumors. Only one of these also displayed LOH, indicating that this gene was altered in at least 10 of 15 (67%) tumors. These results provide evidence that the inactivation of two known tumor-suppressor genes, T betaR-II and FHIT, on chromosome 3p is involved in cervical carcinogenesis. (C) 2001 Wiley-Liss, Inc. C1 Ohio State Univ, James Canc Ctr, Div Human Canc Genet, Med Res Facil 646, Columbus, OH 43210 USA. Amer Hlth Fdn, Div Nutr Carcinogenesis, Valhalla, NY 10595 USA. Med Coll Ohio, Toledo, OH 43699 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Ohio State Univ, James Canc Ctr, Div Human Canc Genet, Med Res Facil 646, 420 W 12th Ave, Columbus, OH 43210 USA. FU NCI NIH HHS [CN 25486, CA 58554, CA 78797] NR 50 TC 9 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAR PY 2001 VL 30 IS 3 BP 159 EP 168 DI 10.1002/mc.1024 PG 10 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 419TM UT WOS:000167964800004 PM 11301476 ER PT J AU Nakano, K Vousden, KH AF Nakano, K Vousden, KH TI PUMA, a novel proapoptotic gene, is induced by p53 SO MOLECULAR CELL LA English DT Article ID DNA-DAMAGE; P53-DEPENDENT APOPTOSIS; P53-MEDIATED APOPTOSIS; CANCER-CELLS; ARREST; MITOCHONDRIA; EXPRESSION; ACTIVATION; PATHWAYS; MEDIATOR AB The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named PUMA (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (PUMA-alpha and PUMA-beta) that are induced in cells following p53 activation. PUMA-a( and PUMA-P show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway. 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 37 TC 1350 Z9 1407 U1 5 U2 57 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR PY 2001 VL 7 IS 3 BP 683 EP 694 DI 10.1016/S1097-2765(01)00214-3 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 419UG UT WOS:000167966600022 PM 11463392 ER PT J AU Krsmanovic, LZ Mores, N Navarro, CE Tomic, M Catt, KJ AF Krsmanovic, LZ Mores, N Navarro, CE Tomic, M Catt, KJ TI Regulation of Ca2+-sensitive adenylyl cyclase in gonadotropin-releasing hormone neurons SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID CAPACITATIVE CA2+ ENTRY; INTERCELLULAR CALCIUM WAVES; HYPOTHALAMIC GT1-7 NEURONS; C6-2B GLIOMA-CELLS; GNRH NEURONS; CYCLIC-AMP; G-PROTEINS; NEUROPEPTIDE RELEASE; ACTION-POTENTIALS; LHRH NEURONS AB In immortalized GnRH neurons, cAMP production is elevated by increased extracellular Ca2+ and the Ca2+ channel agonist, BK-8644, and is diminished by low extracellular Ca2+ and treatment with nifedipine, consistent with the expression of adenylyl cyclase type I (AC I). Potassium-induced depolarization of GT1-7 neurons causes a dose-dependent monotonic increase in [Ca2+](i) and elicits a bell-shaped cAMP response. The inhibitory phase of the cAMP response is prevented by pertussis toxin (PTX), consistent with the activation of G(i)-related proteins during depolarization. Agonist activation of the endogenous GnRH receptor in GT1-7 neurons also elicits a bell-shaped change in cAMP production. The inhibitory action of high GnRH concentrations is prevented by PTX, indicating coupling of the GnRH receptors to G(i)-related proteins. The stimulation of cAMP production by activation of endogenous LH receptors is enhanced by low (nanomolar) concentrations of GnRH but is abolished by micromolar concentrations of GnRH, again in a PTX-sensitive manner. These findings indicate that GnRH neuronal cAMP production is maintained by Ca2+ entry through voltage-sensitive calcium channels, leading to activation of Ca2+-stimulated AC I. Furthermore, the Ca2+ influx-dependent activation of AC I acts in conjunction with AC-regulatory G proteins to determine basal and agonist-stimulated levels of cAMP production. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36, Bethesda, MD 20892 USA. EM catt@helix.nih.gov RI Tomic, Melanija/C-3371-2016; OI MORES, Nadia/0000-0002-4197-0914 NR 60 TC 36 Z9 36 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2001 VL 15 IS 3 BP 429 EP 440 DI 10.1210/me.15.3.429 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 408TB UT WOS:000167342800009 PM 11222744 ER PT J AU Weyer, C Wolford, JK Hanson, RL Foley, JE Tataranni, PA Bogardus, C Pratley, RE AF Weyer, C Wolford, JK Hanson, RL Foley, JE Tataranni, PA Bogardus, C Pratley, RE TI Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21-q23 and is associated with a common polymorphism in LMNA in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE adipose tissue; lamin A/C; lipodystrophy; genomic scan; candidate gene ID FAMILIAL PARTIAL LIPODYSTROPHY; INSULIN SECRETORY DYSFUNCTION; AUTOSOMAL GENOMIC SCAN; ADIPOSE-TISSUE; DUNNIGAN SYNDROME; LAMIN A/C; MELLITUS; RESISTANCE; LINKAGE; PATHOGENESIS AB Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h(2) = 0.48, P < 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21-q23, a region containing LMNA, the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNA were recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C T substitution) in exon 10 of LMNA (GenBank: X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 +/- 0.17 (CC), 0.76 +/- 0.15 (CT), 0.73 +/- 0.16 (TT) mu cg lipid/cell, P < 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNA might not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population, <(c)> 2001 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. RP Weyer, C (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 38 TC 45 Z9 46 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2001 VL 72 IS 3 BP 231 EP 238 DI 10.1006/mgme.2001.3147 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 413MD UT WOS:000167615200006 PM 11243729 ER PT J AU Luneberg, E Mayer, B Daryab, N Kooistra, O Zahringer, U Rohde, M Swanson, J Frosch, M AF Luneberg, E Mayer, B Daryab, N Kooistra, O Zahringer, U Rohde, M Swanson, J Frosch, M TI Chromosomal insertion and excision of a 30 kb unstable genetic element is responsible for phase variation of lipopolysaccharide and other virulence determinants in Legionella pneumophila SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI K-12; HAEMOPHILUS-INFLUENZAE; NEISSERIA-MENINGITIDIS; HUMAN MACROPHAGES; SEROGROUP-1 LIPOPOLYSACCHARIDE; INTRACELLULAR MULTIPLICATION; LEGIONNAIRES-DISEASE; PHENOTYPIC VARIATION; VARIABLE EXPRESSION; MOLECULAR ANALYSIS AB We recently described the phase-variable expression of a virulence-associated lipopolysaccharide (LPS) epitope in Legionella pneumophila. In this study, the molecular mechanism for phase variation was investigated. We identified a 30 kb unstable genetic element as the molecular origin for LPS phase variation. Thirty putative genes were encoded on the 30 kb sequence, organized in two putative opposite transcription units. Some of the open reading frames (ORFs) shared homologies with bacteriophage genes, suggesting that the 30 kb element was of phage origin. In the virulent wild-type strain, the 30 kb element was located on the chromosome, whereas excision from the chromosome and replication as a high-copy plasmid resulted in the mutant phenotype, which is characterized by alteration of an LPS epitope and loss of virulence. Mapping and sequencing of the insertion site in the genome revealed that the chromosomal attachment site was located in an intergenic region flanked by genes of unknown function. As phage release could not be induced by mitomycin C, it is conceivable that the 30 kb element is a non-functional phage remnant. The protein encoded by ORF T on the 30 kb plasmid could be isolated by an outer membrane preparation, indicating that the genes encoded on the 30 kb element are expressed in the mutant phenotype. Therefore, it is conceivable that the phenotypic alterations seen in the mutant depend on high-copy replication of the 30 kb element and expression of the encoded genes. Excision of the 30 kb element from the chromosome was found to occur in a RecA-independent pathway, presumably by the involvement of RecE, RecT and RusA homologues that are encoded on the 30 kb element. C1 Univ Wurzburg, Inst Hyg & Mikrobiol, D-97080 Wurzburg, Germany. GBF GEsell Biotechnol Forsch, Braunschweig, Germany. Forschungszentrum Borstel, Borstel, Germany. NIH, Rocky Mt Labs, Hamilton, MT USA. RP Luneberg, E (reprint author), Univ Wurzburg, Inst Hyg & Mikrobiol, Josef Schneider Str 2, D-97080 Wurzburg, Germany. RI Frosch, Matthias/H-2411-2013 NR 57 TC 43 Z9 48 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2001 VL 39 IS 5 BP 1259 EP 1271 DI 10.1046/j.1365-2958.2001.02314.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 414AU UT WOS:000167644400014 PM 11251842 ER PT J AU Majdalani, N Chen, S Murrow, J John, KS Gottesman, S AF Majdalani, N Chen, S Murrow, J John, KS Gottesman, S TI Regulation of RpoS by a novel small RNA: the characterization of RprA SO MOLECULAR MICROBIOLOGY LA English DT Article ID SIGMA-FACTOR SIGMA(S); ESCHERICHIA-COLI; SALMONELLA-TYPHIMURIUM; STRESS TOLERANCE; HOST FACTOR; HF-I; GENE; TRANSLATION; EXPRESSION; PROTEIN AB Translational regulation of the stationary phase sigma factor RpoS is mediated by the formation of a double-stranded RNA stem-loop structure in the upstream region of the rpoS messenger RNA, occluding the translation initiation site. The interaction of the rpoS mRNA with a small RNA, DsrA, disrupts the double-strand pairing and allows high levels of translation initiation. We screened a multicopy library of Escherichia coli DNA fragments for novel activators of RpoS translation when DsrA is absent. Clones carrying rprA (RpoS regulator RNA) increased the translation of RpoS. The rprA gene encodes a 106 nucleotide regulatory RNA. As with DsrA, RprA is predicted to form three stem-loops and is highly conserved in Salmonella and Klebsiella species. Thus, at least two small RNAs, DsrA and RprA, participate in the positive regulation of RpoS translation. Unlike DsrA, RprA does not have an extensive region of complementarity to the RpoS leader, leaving its mechanism of action unclear. RprA is non-essential. Mutations in the gene interfere with the induction of RpoS after osmotic shock when DsrA is absent, demonstrating a physiological role for RprA. The existence of two very different small RNA regulators of RpoS translation suggests that such additional regulatory RNAs are likely to exist, both for regulation of RpoS and for regulation of other important cellular components. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37 Room 2E 18, Bethesda, MD 20892 USA. NR 43 TC 188 Z9 191 U1 3 U2 9 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2001 VL 39 IS 5 BP 1382 EP 1394 DI 10.1046/j.1365-2958.2001.02329.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 414AU UT WOS:000167644400024 PM 11251852 ER PT J AU Scidmore, MA Hackstadt, T AF Scidmore, MA Hackstadt, T TI Mammalian 14-3-3 beta associates with the Chlamydia trachomatis inclusion membrane via its interaction with IncG SO MOLECULAR MICROBIOLOGY LA English DT Article ID YEAST 2-HYBRID SYSTEM; INFECTED-CELLS; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTOR; ELECTRON-MICROSCOPY; ENDOCYTIC PATHWAY; KINASE-ACTIVITY; HELA-CELLS; HOST-CELL; PROTEIN AB Chlamydiae replicate intracellularly within a vacuole that is modified early in infection to become fusogenic with a subset of exocytic vesicles. We have recently identified four chlamydial inclusion membrane proteins, IncD-G, whose expression is detected within the first 2 h after internalization. To gain a better understanding of how these Inc proteins function, a yeast two-hybrid screen was employed to identify interacting host proteins. One protein, 14-3-3 beta, was identified that interacted specifically with IncG. The interaction between 14-3-3 beta and IncG was confirmed in infected HeLa cells by indirect immunofluorescence microscopy and interaction with a GFP-14-3-3 beta fusion protein. 14-3-3 proteins are phosphoserine-binding proteins. Immunoprecipitation studies with [P-32]-orthophosphate-labelled cells demonstrated that IncG is phosphorylated in both chlamydia-infected HeLa cells and in yeast cells expressing IncG. Site-directed mutagenesis of predicted 14-3-3 phosphorylation sites demonstrated that IncG binds to 14-3-3 beta via a conserved 14-3-3-binding motif (RS164RS166F). Finally, indirect immunofluorescence demonstrated that 14-3-3 beta interacts with Chlamydia trachomatis inclusions but not C. psittaci or C. pneumoniae inclusions. 14-3-3 beta is the first eukaryotic protein found to interact with the chlamydial inclusion; however, its unique role in C. trachomatis pathogenesis remains to be determined. C1 NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. NR 64 TC 105 Z9 113 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAR PY 2001 VL 39 IS 6 BP 1638 EP 1650 DI 10.1046/j.1365-2958.2001.02355.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 414AY UT WOS:000167644800020 PM 11260479 ER PT J AU Nguyen, T Shapiro, DA George, SR Setola, V Lee, DK Cheng, R Rauser, L Lee, SP Lynch, KR Roth, BL O'Dowd, BF AF Nguyen, T Shapiro, DA George, SR Setola, V Lee, DK Cheng, R Rauser, L Lee, SP Lynch, KR Roth, BL O'Dowd, BF TI Discovery of a novel member of the histamine receptor family SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; H-3 RECEPTOR; MOLECULAR-CLONING; IN-VITRO; EXPRESSION; GENE; PHARMACOLOGY; BINDING AB We report the discovery, tissue distribution and pharmacological characterization of a novel receptor, which we have named H4. Like the three histamine receptors reported previously (H1, H2, and H3), the H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18. These sequences were used to retrieve a partial cDNA clone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revealed a 3.0-kb transcript in rat testis and intestine. Radioligand binding studies indicated that the H4 receptor has a unique pharmacology and binds [H-3] histamine (K-d = 44 nM) and [H-3] pyrilamine (K-d = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mianserin) with moderate affinity (K-i range of 33-750 nM). Additionally, histamine induced a rapid internalization of HA-tagged H4 receptors in transfected human embryonic kidney 293 cells. C1 Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada. Ctr Addict & Mental Hlth, Toronto, ON, Canada. Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH USA. Univ Virginia, Hlth Sci Ctr, Dept Pharmacol, Charlottesville, VA 22908 USA. RP O'Dowd, BF (reprint author), Univ Toronto, Dept Pharmacol, Med Sci Bldg,8 Taddle Creek Rd,Rm 4353, Toronto, ON M5S 1A8, Canada. RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [K02-MH01366]; PHS HHS [N01-80005] NR 23 TC 261 Z9 274 U1 2 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2001 VL 59 IS 3 BP 427 EP 433 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 405GN UT WOS:000167151800004 PM 11179435 ER PT J AU Bai, RL Verdier-Pinard, P Gangwar, S Stessman, CC McClure, KJ Sausville, EA Pettit, GR Bates, RB Hamel, E AF Bai, RL Verdier-Pinard, P Gangwar, S Stessman, CC McClure, KJ Sausville, EA Pettit, GR Bates, RB Hamel, E TI Dolastatin 11, a marine depsipeptide, arrests cells at cytokinesis and induces hyperpolymerization of purified actin SO MOLECULAR PHARMACOLOGY LA English DT Article ID NATURAL PRODUCT; TUBULIN POLYMERIZATION; ANTIMITOTIC AGENTS; BINDING; CYTOSKELETON; INHIBITION; JASPLAKINOLIDE; PHALLOIDIN; SPONGE; GROWTH AB The successful synthesis of dolastatin 11, a depsipeptide originally isolated from the mollusk Dolabella auricularia, permitted us to study its effects on cells. The compound arrested cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network. In a dose- and time- dependent manner, F-actin was rearranged into aggregates, and subsequently the cells displayed dramatic cytoplasmic retraction. The effects of dolastatin 11 were most similar to those of the sponge-derived depsipeptide jasplakinolide, but dolastatin 11 was about 3-fold more cytotoxic than jasplakinolide in the cells studied. Like jasplakinolide, dolastatin 11 induced the hyperassembly of purified actin into filaments of apparently normal morphology. Dolastatin 11 was qualitatively more active than jasplakinolide and, in a quantitative assay we developed, dolastatin 11 was twice as active as jasplakinolide and 4-fold more active than phalloidin. However, in contrast to jasplakinolide and phalloidin, dolastatin 11 did not inhibit the binding of a fluorescent phalloidin derivative to actin polymer nor was it able to displace the phalloidin derivative from polymer. Thus, despite its structural similarity to other agents that induce actin assembly (all are peptides or depsipeptides), dolastatin 11 may interact with actin polymers at a distinct drug binding site. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Rockville, MD USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ USA. Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, POB B,Bldg 469,Room 104, Frederick, MD 21702 USA. NR 21 TC 50 Z9 52 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2001 VL 59 IS 3 BP 462 EP 469 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 405GN UT WOS:000167151800009 PM 11179440 ER PT J AU Xu, GH Rabadan-Diehl, C Nikodemova, M Wynn, P Spiess, J Aguilera, G AF Xu, GH Rabadan-Diehl, C Nikodemova, M Wynn, P Spiess, J Aguilera, G TI Inhibition of corticotropin releasing hormone type-1 receptor translation by an upstream AUG triplet in the 5 ' untranslated region SO MOLECULAR PHARMACOLOGY LA English DT Article ID MESSENGER-RNA; FUNCTIONAL EXPRESSION; RAT-BRAIN; PITUITARY; BINDING; STRESS; SEQUENCES; CLONING; SECRETION; DOMAINS AB The influence of an upstream open reading frame (ORF) in the 5'-untranslated region (UTR) of the mRNA on corticotropin-releasing hormone receptor type 1 (CRHR1) translation was studied in constructs containing the 5'-UTR of CRHR1, with or without an ATG-to-ATA mutation in the upstream ORF, and the main ORF of luciferase or CRHR1. Upstream mutation in luciferase constructs increased luciferase activity when transfected into COS-7 or AtT20 cells compared with the native 5'-UTR. Transfection of CRHR1 constructs containing the upstream mutation into AtT20 or LVIP2.0zc reporter cells, resulted in higher I-125-Tyr-oCRH binding and corticotropin-releasing hormone-stimulated cAMP production, without changes in CRHR1 mRNA levels (measured by RNase protection assay). In vitro translation of luciferase or CRHR constructs with or without mutation of the upstream ATG, and Western blot analysis with anti-luciferase and anti-CRHR1 antibodies confirmed that mutation of the upstream ATG increases translation of the main ORF. The mechanism by which the upstream ORF inhibits translation may involve translation of the upstream peptide, because in vitro translation, or transfection into LVIP2.0zc cells of a fusion construct of the upstream ORF and green fluorescent protein (GFP) yielded a band consistent with the molecular size of GFP protein. The study shows that the upstream AUG in 5'-UTR of CRHR1 mRNA inhibits receptor expression by inhibiting mRNA translation and suggests the short open reading frame in the 5'-UTR plays a role in regulating translation of the CRH receptor. C1 NICHHD, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. Max Planck Inst Expt Med, D-37075 Gottingen, Germany. RP Aguilera, G (reprint author), NICHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,Rm 10N262, Bethesda, MD 20892 USA. EM greti@helix.nih.gov NR 37 TC 34 Z9 35 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2001 VL 59 IS 3 BP 485 EP 492 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 405GN UT WOS:000167151800012 PM 11179443 ER PT J AU Garcia-Caballero, A Olivares-Reyes, JA Catt, KJ Garcia-Sainz, JA AF Garcia-Caballero, A Olivares-Reyes, JA Catt, KJ Garcia-Sainz, JA TI Angiotensin AT(1) receptor phosphorylation and desensitization in a hepatic cell line. Roles of protein kinase C and phosphoinositide 3-kinase SO MOLECULAR PHARMACOLOGY LA English DT Article ID AGONIST-INDUCED PHOSPHORYLATION; ADRENAL GLOMERULOSA CELLS; RAT-LIVER CELLS; II RECEPTOR; INDUCED INTERNALIZATION; CYTOPLASMIC TAIL; PERTUSSIS TOXIN; ACTIVATION; EXPRESSION; IDENTIFICATION AB Desensitization and phosphorylation of the endogenous angiotensin II AT(1) receptor were studied in clone 9 liver cells. Agonist activation of AT(1) receptors blunted the response to subsequent addition of angiotensin II. Partial inhibition of the angiotensin II-induced calcium response was observed when cells were pretreated with dibutyryl cyclic AMP, tetradecanoyl phorbol acetate (TPA), vasopressin, or lysophosphatidic acid. All of these desensitization processes were associated with receptor phosphorylation. Angiotensin II-induced AT(1) receptor phosphorylation was partially blocked by the protein kinase C inhibitor bisindolylmaleimide I and by phosphoinositide 3-kinase inhibitors (wortmannin and LY294002); the actions of these inhibitors were not additive. Pertussis toxin pretreatment of cells also partially inhibited angiotensin II-induced AT(1) receptor phosphorylation. TPA-induced AT(1) receptor phosphorylation was completely blocked by bisindolylmaleimide I. AT(1) receptor phosphorylation was also induced by vasopressin and lysophosphatidic acid, and these effects were partially inhibited by bisindolylmaleimide I. Angiotensin II increased Akt/PKB (protein kinase B) phosphorylation and protein kinase C membrane association. The effect on Akt/PKB phosphorylation was blocked by phosphoinositide 3-kinase inhibitors. These findings indicate that clone 9 cells exhibit both homologous and heterologous desensitization in association with AT(1) receptor phosphorylation. In these hepatic cells, angiotensin II-induced receptor phosphorylation involves pertussis toxin-sensitive and -snsensitive G proteins, and is mediated in part through protein kinase C and phosphoinositide 3-kinase. C1 Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Mexico City 04510, DF, Mexico. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Garcia-Sainz, JA (reprint author), Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Ap Postal 70-248, Mexico City 04510, DF, Mexico. RI GARCIA-SAINZ, JESUS ADOLFO/A-5389-2008 OI GARCIA-SAINZ, JESUS ADOLFO/0000-0002-5235-0657 NR 38 TC 29 Z9 29 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2001 VL 59 IS 3 BP 576 EP 585 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 405GN UT WOS:000167151800022 PM 11179453 ER PT J AU Feng, J Zheng, J Gelernter, J Kranzler, H Cook, E Goldman, D Jones, IR Craddock, N Heston, LL Delisi, L Peltonen, L Bennett, WP Sommer, SS AF Feng, J Zheng, J Gelernter, J Kranzler, H Cook, E Goldman, D Jones, IR Craddock, N Heston, LL Delisi, L Peltonen, L Bennett, WP Sommer, SS TI An in-frame deletion in the alpha(2C) adrenergic receptor is common in African-Americans SO MOLECULAR PSYCHIATRY LA English DT Article DE adrenergic receptor; schizophrenia; genetic polymorphism; case-control series; gene deletion; behavior disorder ID CLONIDINE TREATMENT; AUTISTIC DISORDER; MESSENGER-RNA; DOPAMINE; ASSOCIATION; MUTATIONS; GENE; POLYMORPHISMS; PHARMACOLOGY; POPULATION AB alpha (2) adrenergic receptors are activated by adrenaline and noradrenaline, and three subtypes (ie, A, B, C) have differential affinities for antagonists and medications. The alpha (2c) adrenergic receptor (ADRA2C), located on chromosome 4p16.3, is a candidate gene for schizophrenia because it binds clozapine, an atypical neuroleptic useful for treatment-resistant schizophrenia, In addition, ADRA2C binds clonidine which is prescribed for three psychiatric diseases. This report communicates the findings of the genetic scanning of this gene of very tough GC content. The complete coding sequences and splice junctions were scanned with [DOVAM]-S in 104 schizophrenics, and pilot probes of patients with alcoholism (41 patients), cocaine abuse (25 patients), puerperal psychosis (30 patients), attention deficient/hyperactivity disorder (25 patients) and autism (25 patients). Six sequence variants were found, including five silent polymorphisms (allele frequencies 0.6-25%) and an in-frame deletion of a homologous repeat at nucleotides 967-978 (ie, TIDRU1). Genotyping of the normal two repeat unit of the Third Intracytoplasmic Domain Repeat Unit (TIDRU2) and the deleted variant (TIDRU1) revealed that TIDRU1 had allelic frequencies of 39% (11/28) and 3.5% (6/172) in African-American and Caucasian schizophrenics, respectively, and it occurred with equal frequency in controls (44%, 31/70 and 3.0%, 6/198). TIDRU1 occurs at a location similar to the third intracytoptasmic 48-nucleotide repeat unit in the DRD4 that is associated with ADHD. Although these data do not suggest an association of TIDRU1 with schizophrenia, additional studies are needed to see whether TIDRU1 confers a clinical phenotype. C1 City Hope Natl Med Ctr, Dept Mol Genet, Duarte, CA 91010 USA. Beckman Res Inst, Duarte, CA 91010 USA. VA CT Healthcare Syst, Dept Psychiat, W Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, W Haven, CT 06516 USA. Univ Connecticut, Sch Med, Dept Psychiat, Farmington, CT 06030 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60611 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Univ Birmingham, Div Neurosci, Birmingham B15 2QZ, W Midlands, England. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. Univ Calif Los Angeles, Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. RP Sommer, SS (reprint author), City Hope Natl Med Ctr, Dept Mol Genet, Fox Plaza S,Room 2001,1500 E Duarte Rd, Duarte, CA 91010 USA. RI Jones, Ian/B-4925-2009; turton, miranda/F-4682-2011; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 28 TC 14 Z9 14 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2001 VL 6 IS 2 BP 168 EP 172 DI 10.1038/sj.mp.4000817 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 402CH UT WOS:000166968100009 PM 11317218 ER PT J AU Yoshikawa, T Kikuchi, M Saito, K Watanabe, A Yamada, K Shibuya, H Nankai, M Kurumaji, A Hattori, E Ishiguro, H Shimizu, H Okubo, Y Toru, M Detera-Wadleigh, SD AF Yoshikawa, T Kikuchi, M Saito, K Watanabe, A Yamada, K Shibuya, H Nankai, M Kurumaji, A Hattori, E Ishiguro, H Shimizu, H Okubo, Y Toru, M Detera-Wadleigh, SD TI Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples SO MOLECULAR PSYCHIATRY LA English DT Article DE chromosome 18; affective disorder; polymorphism; linkage disequilibrium; haplotype; LightCycler ID BIPOLAR-DISORDER; SUSCEPTIBILITY; CHROMOSOME-18; LINKAGE; FAMILIES; LITHIUM; TARGET; LOCUS; BRAIN AB In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1-15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031-0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese. C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Tokyo Med & Dent Univ, Dept Neuropsychiat, Tokyo, Japan. Tokyo Metropolitan Police Hosp, Dept Neuropsychiat, Tokyo, Japan. Hokushin Gen Hosp, Nagano, Japan. NIMH, Intramural Program, NIH, Bethesda, MD 20892 USA. RP Yoshikawa, T (reprint author), RIKEN, Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. NR 22 TC 39 Z9 40 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2001 VL 6 IS 2 BP 202 EP 210 DI 10.1038/sj.mp.4000835 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 402CH UT WOS:000166968100014 PM 11317223 ER PT J AU Iwata, N Ozaki, N Inada, T Goldman, D AF Iwata, N Ozaki, N Inada, T Goldman, D TI Association of a 5-MT5A receptor polymorphism, Pro15Ser, to schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE serotin 5-HT5A receptor; schizophrenia; association study; single nucleotide polymorphism (SNP); amino acid substitution; single-stranded conformational polymorphism (SSCP) ID LINKAGE DISEQUILIBRIUM; 5-HT5A RECEPTOR; GENE; REGION AB Several different lines of evidence suggest that genes involved in serotonergic neurotransmission are factors in the pathogenesis of schizophrenia. For example, 5-HT5A knockout mice revealed decreased locomotor response to lysergic diethylamide (LSD), which produces a psychotic-like state in healthy people. Recently, we reported a naturally occurring conservative Pro15Ser substitution in the 5-HT5A receptor. Here, we evaluate whether this substitution is associated with schizophrenia in a sample including 249 unrelated Japanese schizophrenia patients and 253 unrelated controls. Patients and controls were genotyped for the Pro15Ser polymorphism by a PCR-RFLP assay. Ser15 allele frequencies were 0.07 in patients with schizophrenia and 0.02 in controls (chi (2) = 17.42, df =1, P < 0.0001), Thus, We detected a highly significant association of Pro15Ser to schizophrenia in a large population of Japanese schizophrenia patients and controls, Since case-control studies have an inherent potential for false-positive results due to population stratification, this finding is preliminary pending further studies, including studies using the transmission/disequilibrium test to eliminate stratification bias or control loci to assess ethnic matching of cases and controls. C1 NIAAA, Neurogenet Lab, Natl Ctr Neurol & Psychiat, Rockville, MD 20852 USA. Fujita Hlth Univ, Sch Med, Dept Psychiat, Aichi, Japan. NIAAA, Neurogenet Lab, Rockville, MD 20854 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, Natl Ctr Neurol & Psychiat, Pk Bldg 431,12501 Washington Ave, Rockville, MD 20852 USA. RI Ozaki, Norio/M-8908-2014; Goldman, David/F-9772-2010 OI Ozaki, Norio/0000-0002-7360-4898; Goldman, David/0000-0002-1724-5405 NR 16 TC 20 Z9 20 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2001 VL 6 IS 2 BP 217 EP 219 DI 10.1038/sj.mp.4000829 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 402CH UT WOS:000166968100016 PM 11317225 ER PT J AU Koch, PE Guo, ZS Kagawa, S Gu, J Roth, JA Fang, B AF Koch, PE Guo, ZS Kagawa, S Gu, J Roth, JA Fang, B TI Augmenting transgene expression from carcinoembryonic antigen (CEA) promoter via a GAL4 gene regulatory system SO MOLECULAR THERAPY LA English DT Article DE gene therapy; tumor; tissue-specific expression; Bax ID CROSS-REACTING ANTIGEN; TISSUE-SPECIFIC EXPRESSION; THYMIDINE KINASE GENE; ADENOVIRAL VECTOR; BAX GENE; IN-VIVO; THERAPY; CANCER; IDENTIFICATION; SEQUENCES AB Though extensively studied, the use of tissue- or cell-type-specific promoters to target transgene expression is hampered by their weak activity. We hypothesized that this problem could be addressed by using a GAL4 gene regulatory system, wherein a weak, tissue-specific promoter would drive expression of the GAL4/VP16 fusion protein (GV16), which in turn would transactivate a minimal synthetic promoter, GAL4/TATA (GT), upstream of a transgene. To test this hypothesis, we constructed adenoviral vectors expressing a IacZ or GV16 gene driven by a carcinoembryonic antigen (CEA) promoter (Ad/CEA-LacZ or Ad/CEA-GV16) and evaluated levels of transgene expression they produced in cultured cells and in subcutaneous tumors after intratumoral administration. In CEA-positive cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ versus Ad/CEA-LacZ increased transgene expression 20- to 100-fold. In CEA-negative cells, treatment with Ad/CEA-GV16 + Ad/GT-LacZ increased transgene expression to a much lower degree (6- to 8-fold). In addition, analysis of Bax gene-mediated cell death revealed that this system can be used to avoid Bax's toxic effects on CEA-negative cells without compromising its ability to kill CEA-positive cells in vitro and in vivo. Thus, the combination of a tissue-specific promoter with the GAL4 gene regulatory system could be useful for targeting transgene expression. C1 Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Sect Thorac Mol Oncol, Houston, TX 77030 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Fang, B (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Sect Thorac Mol Oncol, 1515 Holcombe Blvd,Box 23, Houston, TX 77030 USA. RI KAGAWA, Shunsuke/B-2189-2011 FU NCI NIH HHS [CA78778-01A1, CA 16672, P50-CA70907] NR 22 TC 38 Z9 40 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2001 VL 3 IS 3 BP 278 EP 283 DI 10.1006/mthe.2001.0273 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 419UV UT WOS:000167967900002 PM 11273768 ER PT J AU Donahue, RE Sorrentino, BP Hawley, RG An, DS Chen, ISY Wersto, RP AF Donahue, RE Sorrentino, BP Hawley, RG An, DS Chen, ISY Wersto, RP TI Fibronectin fragment CH-296 inhibits apoptosis and enhances ex vivo gene transfer by murine retrovirus and human lentivirus vectors independent of viral tropism in nonhuman primate CD34(+) cells SO MOLECULAR THERAPY LA English DT Article DE CH-296; gene therapy; hematopoietic stem cells; retrovirus; lentivirus; cell cycle ID HEMATOPOIETIC STEM-CELLS; APE LEUKEMIA-VIRUS; GREEN FLUORESCENT PROTEIN; COLONY-STIMULATING FACTOR; BONE-MARROW; PERIPHERAL-BLOOD; PROGENITOR CELLS; IN-VIVO; EXTRACELLULAR-MATRIX; REPOPULATING CELLS AB The fibronectin fragment CH-296 improved gene transfer to cytokine-mobilized nonhuman primate CD34(+) cells irrespective of tropism to the MoMLV, GaLV, and VSV-C envelope proteins using murine stem cell virus (MSCV) and human immunodeficiency virus-1 (HIV-1)-based retrovirus vectors. For the HIV-1 lentivirus vector, CH-296 enhanced gene transfer in the absence of added hematopoietic growth factors necessary for ex vivo stem cell expansion. In the presence of CH-296, apoptosis of CD34+ cells was inhibited, and in mobilized peripheral blood CD34+ cells, cell division was stimulated as measured by cell history/tracking experiments. C1 NIA, Ctr Gerontol Res, Flow Cytometry Unit, NIH, Baltimore, MD 21224 USA. Univ Calif Los Angeles, Sch Med, AIDS Inst, Los Angeles, CA 90095 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 21892 USA. RP Wersto, RP (reprint author), NIA, Ctr Gerontol Res, Flow Cytometry Unit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 57 TC 32 Z9 33 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2001 VL 3 IS 3 BP 359 EP 367 DI 10.1006/mthe.2001.0269 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 419UV UT WOS:000167967900012 PM 11273778 ER PT J AU Sommer, M Grafman, J Litvan, I Hallett, M AF Sommer, M Grafman, J Litvan, I Hallett, M TI Impairment of eyeblink classical conditioning in progressive supranuclear palsy SO MOVEMENT DISORDERS LA English DT Article DE eyeblink classical conditioning; progressive supranuclear palsy (PSP); implicit and explicit memory; California verbal learning task (CVLT); serial reaction time task (SRTT) ID RICHARDSON-OLSZEWSKI-SYNDROME; CEREBRAL BLOOD-FLOW; CEREBELLAR DEGENERATION; PARKINSONS-DISEASE; REACTION-TIME; ABNORMALITIES; PERFORMANCE; DEMENTIA AB In a previous study we showed that learning in eyeblink classical conditioning (EBCC) is normal in Parkinson's disease (PD) and that the serial reaction time task (SRTT) is only marginally impaired. Since pathological lesions are more widespread in the atypical parkinsonian disorder of progressive supranuclear palsy (PSP) than in PD, we hypothesized that PSP patients may show more profound deficits in the EBCC and SRTT learning tasks. We therefore investigated EBCC with a delay and two trace paradigms. an SRTT and the California Verbal Learning Test (CVLT) in eight patients with PSP and an age-matched control group. In all EBCC paradigms, we found a significant difference between groups with no significant learning in PSP patients. In the SRTT, implicit learning may have been impaired, but verbal and manual sequence recall were only marginally impaired. Verbal memory was significantly worse in PSP patients than in the control group. Our study shows a dissociated pattern of learning abilities in PSP, where the EBCC as a measure of implicit learning is impaired, the explicit sequence detection in the SRTT is relatively preserved, and the verbal memory impaired. We hypothesize that the PSP patients' deficits in EBCC learning may be due to lesions of deep cerebellar nuclei. There may be a clinical role for EBCC in distinguishing PD and PSP patients. (C) 2001 Movement Disorder Society. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5 N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. RI Sommer, Martin/F-1503-2015; OI Grafman, Jordan H./0000-0001-8645-4457; Litvan, Irene/0000-0002-3485-3445 NR 47 TC 7 Z9 7 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2001 VL 16 IS 2 BP 240 EP 251 DI 10.1002/mds.1050 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 417YY UT WOS:000167864100010 PM 11295776 ER PT J AU Healy, LN Pluta, LJ James, RA Janszen, DB Torous, D French, JE Recio, L AF Healy, LN Pluta, LJ James, RA Janszen, DB Torous, D French, JE Recio, L TI Induction and time-dependent accumulation of micronuclei in peripheral blood of transgenic p53 +/- mice, Tg.AC (v-Ha-ras) and parental wild-type (C57BL/6 and FVB/N) mice exposed to benzene by inhalation SO MUTAGENESIS LA English DT Article ID BONE-MARROW DAMAGE; B6C3F1 MICE; BIOASSAYS; DURATION; REGIMEN; CARCINOGENICITY; ERYTHROCYTES; RISK AB In this study, we determined the induction and time-dependent accumulation of micronuclei in the peripheral blood of transgenic C57BL/6 p53 +/- mice (p53 +/- mice), FVB/N Tg.AC v-Ha-ras mice (Tg.AC mice) and their isogenic parental strains, FVB/N and C57BL/6 following inhalation exposure to benzene. Our objective was to determine the impact of p53 heterozygosity in p53 +/- mice and the v-Ha-ras transgene in Tg.AC mice on micronuclei induction following exposure to inhaled benzene. A flow cytometric technique that distinguishes micronucleated red blood cells (MN-RBC) from micronucleated reticulocytes (MN-RET) was used. Mice were exposed to 0, 100 or 200 p.p.m. benzene using three different exposure regimens that resulted in an equal meekly cumulative exposure (3000 p.p.m. x hours) to benezene: 100 p.p.m. for 6 h/day, 5 days/ week, Monday to Friday (M-F); 100 p.p.m. for 10 h/day, 3 days/week, Monday, Wednesday, Friday (MWF); and 200 p.p.m, for 5 h/day, 3 days/week MWF. Significant elevations of MN-RBC and MN-RET were observed from 1 week exposure in all of the benzene-exposed groups that increased in a time-dependent manner for up to 13 weeks exposure. Fewer MN-RBC and MN-RET were induced in the 200 p.p.m. benzene exposure group than in mice exposed to 100 p.p.m. The reduction in the frequency of MN-RBC in the 200 p.p.m. x 5 h benzene exposure group is probably due to metabolic saturation resulting in a lower bone marrow dose (concentration x time) than in the 100 p.p.m. exposure groups. No differences were observed in the frequency of MN-RBC or MN-RET in Tg,AC compared with the FVB/N isogenic controls, At certain time points the frequency of micronuclei was less in the heterozygous p53 +/- mice than determined in the wild-type C57BL/6 isogenic parental strain. These results indicate that the heterozygous state in p53 +/- mice, but not the v-Ha-ras transgene in Tg.AC mice can influence the induction of micronuclei by benzene. C1 CIIT, Res Triangle Pk, NC 27709 USA. Litron Labs, Rochester, NY 14620 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Recio, L (reprint author), CIIT, 6 Davis Dr,POB 12137, Res Triangle Pk, NC 27709 USA. NR 27 TC 16 Z9 16 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD MAR PY 2001 VL 16 IS 2 BP 163 EP 168 DI 10.1093/mutage/16.2.163 PG 6 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 406WY UT WOS:000167240200012 PM 11230560 ER PT J AU Liotta, LA AF Liotta, LA TI Cancer - An attractive force in metastasis SO NATURE LA English DT Editorial Material ID EXPRESSION C1 NCI, Invas & Metastasis Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, Invas & Metastasis Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 7 TC 131 Z9 137 U1 0 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 1 PY 2001 VL 410 IS 6824 BP 24 EP 25 DI 10.1038/35065180 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 406BD UT WOS:000167194300024 PM 11242022 ER PT J AU Stock, RP Olvera, A Sanchez, R Saralegui, A Scarfi, S Sanchez-Lopez, R Ramos, MA Boffa, LC Benatti, U Alagon, A AF Stock, RP Olvera, A Sanchez, R Saralegui, A Scarfi, S Sanchez-Lopez, R Ramos, MA Boffa, LC Benatti, U Alagon, A TI Inhibition of gene expression in Entamoeba histolytica with antisense peptide nucleic acid oligomers SO NATURE BIOTECHNOLOGY LA English DT Article ID LOCALIZATION SIGNAL; RECEPTOR; CELL; DNA; VIRULENCE; ERD2; RNA AB Peptide nucleic acids (PNAs) may be a potent tool for gene function studies in medically important parasitic organisms, especially those that have not before been accessible to molecular genetic knockout approaches. One such organism is Entamoeba histolytica, the causative agent of amebiasis, which infects about 500 million people and is the cause of clinical disease in over 40 million each year, mainly in the tropical and subtropical world. We used PNA antisense oligomers to inhibit expression of an episomally expressed gene (neomycin phosphorotransferase, NPT) and a chromosomal gene (EhErd2, a homolog of Erd2, a marker of the Golgi system in eukaryotic cells) in axenically cultured trophozoites of E. histolytica. Measurement of NPT enzyme activity and EhErd2 protein levels, as well as measurement of cellular proliferation, revealed specific decreases in expression of the target genes, and concomitant inhibition of cell growth, in trophozoites treated with micromolar concentrations of unmodified antisense PNA oligomers. C1 Univ Nacl Autonoma Mexico, Inst Biotecnol, Cuernavaca 62210, Morelos, Mexico. Univ Genoa, Inst Biochem, I-16132 Genoa, Italy. IST, Natl Canc Inst, I-16132 Genoa, Italy. RP Alagon, A (reprint author), Univ Nacl Autonoma Mexico, Inst Biotecnol, Av Univ 2001, Cuernavaca 62210, Morelos, Mexico. EM alagon@ibt.unam.mx RI Ramos, Marco/D-5438-2012; OI Ramos, Marco/0000-0002-8950-2079; Scarfi, Sonia/0000-0002-7079-6919 NR 24 TC 36 Z9 36 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAR PY 2001 VL 19 IS 3 BP 231 EP 234 DI 10.1038/85671 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 407QW UT WOS:000167283100022 PM 11231555 ER PT J AU Hunter, N Borner, GV Lichten, M Kleckner, N AF Hunter, N Borner, GV Lichten, M Kleckner, N TI gamma-H2AX illuminates meiosis SO NATURE GENETICS LA English DT Editorial Material ID DOUBLE-STRAND BREAKS; MEIOTIC RECOMBINATION; SACCHAROMYCES-CEREVISIAE; CHROMOSOME SYNAPSIS; MECHANISM; REPAIR; SPO11 AB The temporal and functional relationships between the DNA events of meiotic recombination and the synaptonemal complex (SC). a meiosis-specific structure formed between homolog axes, are subjects of intense discussion and investigation. A new study provides evidence that initiation of recombination (through programmed double-strand breaks (DSBs)) precedes initiation of SC formation, and further suggests that progression of recombination is required for formation of SC on a region-by-region basis. These conclusions derive from immunocytological analysis of a phosphorylated histone variant. gamma -H2AX, previously found to be characteristic of DSB repair in mitotic cells, and shown here to be recruited for specialized use during meiosis. C1 Harvard Univ, Cambridge, MA 02138 USA. NCI, Div Basic Sci, Biochem Lab, Bethesda, MD 20892 USA. RP Hunter, N (reprint author), Harvard Univ, Cambridge, MA 02138 USA. RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 16 TC 55 Z9 55 U1 0 U2 5 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 2001 VL 27 IS 3 BP 236 EP 238 DI 10.1038/85781 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 408AK UT WOS:000167304200006 PM 11242097 ER PT J AU Mahadevaiah, SK Turner, JMA Baudat, F Rogakou, EP de Boer, P Blanco-Rodriguez, J Jasin, M Keeney, S Bonner, WM Burgoyne, PS AF Mahadevaiah, SK Turner, JMA Baudat, F Rogakou, EP de Boer, P Blanco-Rodriguez, J Jasin, M Keeney, S Bonner, WM Burgoyne, PS TI Recombinational DNA double-strand breaks in mice precede synapsis SO NATURE GENETICS LA English DT Letter ID HOMOLOGOUS CHROMOSOME SYNAPSIS; SEX-CHROMOSOMES; SYNAPTONEMAL COMPLEXES; MEIOTIC RECOMBINATION; MOUSE SPERMATOCYTES; XY BODY; MEIOSIS; PROTEIN; GENE; RAD51 AB In Saccharomyces cerevisiae, meiotic recombination is initiated by Spo11-dependent double-strand breaks (DSBs), a process that precedes homologous synapsis. Here we use an antibody specific for a phosphorylated histone (gamma -H2AX, which marks the sites of DSBs) to investigate the timing, distribution and Spo11-dependence of meiotic DSBs in the mouse. We show that, as in yeast, recombination in the mouse is initiated by Spo11-dependent DSBs that form during leptotene. Loss of gamma -H2AX staining (which in irradiated somatic cells is temporally linked with DSB repair) is temporally and spatially correlated with synapsis, even when this synapsis is 'non-homologous'. C1 Natl Inst Med Res, Div Dev Genet, London NW7 1AA, England. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Wageningen Inst Anim Sci, Genet Lab, Wageningen, Netherlands. Univ Valladolid, Sch Med, Dept Cell Biol, Valladolid, Spain. RP Burgoyne, PS (reprint author), Natl Inst Med Res, Div Dev Genet, Mill Hill, London NW7 1AA, England. OI Keeney, Scott/0000-0002-1283-6417 NR 36 TC 533 Z9 551 U1 4 U2 18 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 2001 VL 27 IS 3 BP 271 EP 276 DI 10.1038/85830 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 408AK UT WOS:000167304200018 PM 11242108 ER PT J AU Doffinger, R Smahi, A Bessia, C Geissmann, F Feinberg, J Durandy, A Bodemer, C Kenwrick, S Dupuis-Girod, S Blanche, S Wood, P Rabia, SH Headon, DJ Overbeek, PA Le Deist, F Holland, SM Belani, K Kumararatne, DS Fischer, A Shapiro, R Conley, ME Reimund, E Kalhoff, H Abinun, M Munnich, A Israel, A Courtois, G Casanova, JL AF Doffinger, R Smahi, A Bessia, C Geissmann, F Feinberg, J Durandy, A Bodemer, C Kenwrick, S Dupuis-Girod, S Blanche, S Wood, P Rabia, SH Headon, DJ Overbeek, PA Le Deist, F Holland, SM Belani, K Kumararatne, DS Fischer, A Shapiro, R Conley, ME Reimund, E Kalhoff, H Abinun, M Munnich, A Israel, A Courtois, G Casanova, JL TI X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa B signaling SO NATURE GENETICS LA English DT Letter ID GAMMA-DEFICIENT MICE; CELL WALL COMPONENTS; TOLL-LIKE RECEPTOR-2; HUMAN T-CELLS; INCONTINENTIA PIGMENTI; KINASE COMPLEX; CUTTING EDGE; HOST-DEFENSE; IFN-GAMMA; IKK-GAMMA AB The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds. and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID. and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (I kappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally. we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1 beta, IL-18, TNF alpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects. C1 Fac Med Necker Enfants Malades, Lab Genet Humaine Malad Infect, Paris, France. Hop Necker Enfants Malad, INSERM U 393, Unite Rech Handicaps Genet Enfant, Paris, France. Inst Pasteur, URA CNRS 1773, Unite Biol Mol Express Gen, Paris, France. Hop Necker Enfants Malad, INSERM U 429, URA CNRS 1461, Paris, France. Hop Necker Enfants Malad, INSERM U 429, Dev Normal & Pathol Syst Immunitaire, Paris, France. Hop Necker Enfants Malad, Serv Dermatol, Paris, France. Univ Cambridge, Addenbrookes Hosp, Dept Med, Wellcome Trust Ctr Mol Mechanisms Dis, Cambridge CB2 2QQ, England. Hop Necker Enfants Malad, Unite Immunol Pediat, Paris, France. Heartlands Hosp, Dept Paediat, Birmingham, W Midlands, England. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. NIH, Host Def Lab, Bethesda, MD 20892 USA. Midwest Immunol Clin, Plymouth, MN USA. Addenbrookes Hosp, Dept Clin Immunol, Cambridge, England. St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. Med S Pathol Associates, Greenville, MS USA. Childrens Hosp, Dept Paediat, Dortmund, Germany. Newcastle Gen Hosp, Childrens Dept, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. RP Casanova, JL (reprint author), Fac Med Necker Enfants Malades, Lab Genet Humaine Malad Infect, Paris, France. RI Dupuis-Girod, Sophie/D-6268-2014 NR 50 TC 481 Z9 491 U1 1 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 2001 VL 27 IS 3 BP 277 EP 285 DI 10.1038/85837 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 408AK UT WOS:000167304200019 PM 11242109 ER PT J AU Schaner, P Richards, N Wadhwa, A Aksentijevich, I Kastner, D Tucker, P Gumucio, D AF Schaner, P Richards, N Wadhwa, A Aksentijevich, I Kastner, D Tucker, P Gumucio, D TI Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states SO NATURE GENETICS LA English DT Letter ID FAMILIAL MEDITERRANEAN-FEVER; HIGH GENE-FREQUENCY; MEFV; SUBSTITUTION; INHERITANCE; SELECTION; SITES; FMF AB Familiar Mediterranean fever (FMF; MIM 249100) is an autosomal recessive disease characterized by recurrent attacks of fever with synovial, pleural or peritoneal inflammation(1). The disease is caused by mutations in the gene encoding the pyrin protein(2-4), Human population studies have revealed extremely high allele frequencies for several different pyrin mutations, leading to the conclusion that the mutant alleles confer a selective advantage(5-7). Here we examine the ret finger protein (rfp) domain (which contains most of the disease-causing mutations) of pyrin during primate evolution. Amino acids that cause human disease are often present as wild type in other species. This is true at positions 653 (a novel mutation), 680, 681. 726. 744 and 761, For several of these human mutations, the mutant represents the reappearance of an ancestral amino acid state. Examination of lineage-specific d(N)/d(S) ratios revealed a pattern consistent with the signature of episodic positive selection, Our data, together with previous human population studies, indicate that selective pressures may have caused functional evolution of pyrin in humans and other primates. C1 Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. Univ Michigan, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. Univ Michigan, Museum Zool, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biol, Ann Arbor, MI 48109 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gumucio, D (reprint author), Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. FU NICHD NIH HHS [T32-HD07505] NR 24 TC 68 Z9 70 U1 0 U2 3 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 2001 VL 27 IS 3 BP 318 EP 321 DI 10.1038/85893 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 408AK UT WOS:000167304200026 PM 11242116 ER PT J AU Reboul, J Vaglio, P Tzellas, N Thierry-Mieg, N Moore, T Jackson, C Shin-i, T Kohara, Y Thierry-Mieg, D Thierry-Mieg, J Lee, H Hitti, J Doucette-Stamm, L Hartley, JL Temple, GF Brasch, MA Vandenhaute, J Lamesch, PE Hill, DE Vidal, M AF Reboul, J Vaglio, P Tzellas, N Thierry-Mieg, N Moore, T Jackson, C Shin-i, T Kohara, Y Thierry-Mieg, D Thierry-Mieg, J Lee, H Hitti, J Doucette-Stamm, L Hartley, JL Temple, GF Brasch, MA Vandenhaute, J Lamesch, PE Hill, DE Vidal, M TI Open-reading-frame sequence tags (OSTs) support the existence of at least 17,300 genes in C-elegans SO NATURE GENETICS LA English DT Letter ID DNA-SEQUENCE; GENOME AB The genome sequences of Caenorhabditis elegans. Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively(1-3). Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. First, the gene number estimates obtained in silico and not yet supported by any experimental data need to be verified. For example, it seems biologically paradoxical that C.elegans would have 50% more genes than Drosophilia. Second, intron/exon predictions need to be tested experimentally. Third, complete sets of open reading frames (ORFs). or "ORFeomes."(4) need to be cloned into various expression vectors. To address these issues simultaneously, we have designed and applied to C. elegans the following strategy. Predicted ORFs are amplified by PCR from a highly representative cDNA library(4) using ORF-specific primers, cloned by Gateway recombination cloning(4-6) and then sequenced to generate ORF sequence tags (OSTs) as a way to verify identity and splicing. In a sample (n=1,222) of the nearly 10,000 genes predicted ab initio (that is, for which no expressed sequence tag (EST) is available so far), at least 70% were verified by OSTs. We also observed that 27% of these experimentally confirmed genes have a structure different from that predicted by GeneFinder. We now have experimental evidence that supports the existence of at least 17,300 genes in C. elegans. Hence we suggest that gene counts based primarily on ESTs may underestimate the number of genes in human and in other organisms. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. IMAG, Lab LSR, St Martin Dheres, France. Res Genet Huntsville, Huntsville, AL USA. Natl Inst Genet, Genome Biol Lab, Mishima, Shizuoka 411, Japan. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Genome Therapeut Corp, Waltham, MA USA. Life Technol Inc, Rockville, MD USA. Fac Univ Notre Dame Paix, Dept Biol, B-5000 Namur, Belgium. RP Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Hill, David/B-6617-2011; Thierry-Mieg, Nicolas/M-6007-2014; Reboul, Jerome/P-9103-2016; THIERRY-MIEG, Jean/F-1975-2017 OI Reboul, Jerome/0000-0002-5513-4546; THIERRY-MIEG, Jean/0000-0002-0396-6789 FU NCI NIH HHS [R21 CA81658 A 01]; NHGRI NIH HHS [R01 HG01715-01] NR 13 TC 117 Z9 117 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2001 VL 27 IS 3 BP 332 EP 336 DI 10.1038/85913 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 408AK UT WOS:000167304200029 PM 11242119 ER PT J AU Jain, A Ma, CA Liu, SY Brown, M Cohen, J Strober, W AF Jain, A Ma, CA Liu, SY Brown, M Cohen, J Strober, W TI Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia SO NATURE IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; X-LINKED IMMUNODEFICIENCY; CD40 LIGAND; DEFECTIVE INTERLEUKIN-1; IMMUNE-RESPONSES; KINASE COMPLEX; HUMAN HOMOLOG; ACTIVATION; CELLS; PROTEIN AB The gene that encodes nuclear factor kappaB (NF-kappaB) essential modulator (or NEMO, also known as IKK gamma) is required for activation of the transcription factor NF-kappaB. We describe mutations in the putative zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-kappaB alpha (I kappaB-alpha) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-kappaB-regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor alpha (TNF-alpha) when stimulated with CD40L. Nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-kappaB activation for B cell immunoglobulin class-switching. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nursing, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Clin Invest Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 30 TC 270 Z9 280 U1 0 U2 5 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 2001 VL 2 IS 3 BP 223 EP 228 DI 10.1038/85277 PG 6 WC Immunology SC Immunology GA 409YT UT WOS:000167413800014 PM 11224521 ER PT J AU Restifo, NP AF Restifo, NP TI Countering the 'counterattack' hypothesis SO NATURE MEDICINE LA English DT Letter ID CONFER IMMUNE PRIVILEGE; FAS LIGAND; CELLS; EXPRESSION; APOPTOSIS; CD95 C1 NCI, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, NIH, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 12 TC 56 Z9 56 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2001 VL 7 IS 3 BP 259 EP 259 DI 10.1038/85357 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 409JK UT WOS:000167380400003 PM 11231598 ER PT J AU Tomarev, SI AF Tomarev, SI TI Eyeing a new route along an old pathway SO NATURE MEDICINE LA English DT Editorial Material ID NECROSIS-FACTOR-ALPHA; OPTIC-NERVE HEAD; E-SELECTIN; TRABECULAR MESHWORK; GENE-EXPRESSION; ADHESION; GLAUCOMA; CELLS C1 NEI, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 13 TC 18 Z9 18 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2001 VL 7 IS 3 BP 294 EP 295 DI 10.1038/85432 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 409JK UT WOS:000167380400028 PM 11231625 ER PT J AU Buseyne, F Le Gall, S Boccaccio, C Abastado, JP Lifson, JD Arthur, LO Riviere, Y Heard, JM Schwartz, O AF Buseyne, F Le Gall, S Boccaccio, C Abastado, JP Lifson, JD Arthur, LO Riviere, Y Heard, JM Schwartz, O TI MHC-I-restricted presentation of HIV-1 virion antigens without viral replication SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; DENDRITIC CELLS; EXOGENOUS ANTIGENS; CHEMOKINE-CORECEPTORS; NEF PROTEIN; MOLECULES; INFECTION; RESPONSES; TYPE-1 AB Dendritic cells and macrophages can process extracellular antigens for presentation by MHC-I molecules. This exogenous pathway may have a crucial role in the activation of CD8(+) cytotoxic T lymphocytes during human viral infections. We show here that HIV-1 epitopes derived from incoming virions are presented through the exogenous MHC-I pathway in primary human dendritic cells, and to a lower extent in macrophages, leading to cytotoxic T-lymphocyte activation in the absence of viral protein synthesis. Exogenous antigen presentation required adequate virus-receptor interactions and fusion of viral and cellular membranes. These results provide new insights into how anti-HIV cytotoxic T lymphocytes can be activated and have implications for anti-HIV vaccine design. C1 Inst Pasteur, Unite Retrovirus & Transfert Genet, Paris, France. Inst Pasteur, Lab Immunopathol Virale, Paris, France. Inst Cordeliers, ImmunoDesigned Mol Res Labs, Paris, France. NCI, Retroviral Pathogenesis Lab, AIDS Vaccine Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Schwartz, O (reprint author), Inst Pasteur, Unite Retrovirus & Transfert Genet, Paris, France. FU NCI NIH HHS [N01-CO-56000] NR 45 TC 118 Z9 119 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2001 VL 7 IS 3 BP 344 EP 349 DI 10.1038/85493 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 409JK UT WOS:000167380400041 PM 11231634 ER PT J AU Lahn, BT Pearson, NM Jegalian, K AF Lahn, BT Pearson, NM Jegalian, K TI The human Y chromosome, in the light of evolution SO NATURE REVIEWS GENETICS LA English DT Review ID HUMAN X-CHROMOSOME; HUMAN PSEUDOAUTOSOMAL REGION; SEX-CHROMOSOME; DROSOPHILA-MELANOGASTER; SPERMATOGENESIS GENE; AMELOGENIN GENE; TURNER-SYNDROME; MOLECULAR EVOLUTION; EXPRESSION ANALYSIS; EMBRYONIC GROWTH AB Most eukaryotic chromosomes, akin to messy toolboxes, store jumbles of genes with diverse biological uses. The linkage of a gene to a particular chromosome therefore rarely hints strongly at that gene's function. One striking exception to this pattern of gene distribution is the human Y chromosome. far from being random and diverse, known human Y-chromosome genes show just a few distinct expression profiles. Their relative functional conformity reflects evolutionary factors inherent to sex-specific chromosomes. C1 Univ Chicago, Howard Hughes Med Inst, Dept Human Genet, Chicago, IL 60637 USA. Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Lahn, BT (reprint author), Univ Chicago, Howard Hughes Med Inst, Dept Human Genet, 920 E 58th St, Chicago, IL 60637 USA. NR 108 TC 129 Z9 137 U1 2 U2 30 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD MAR PY 2001 VL 2 IS 3 BP 207 EP 216 DI 10.1038/35056058 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 407UP UT WOS:000167289400014 PM 11256072 ER PT J AU Weissman, AM AF Weissman, AM TI Themes and variations on ubiquitylation SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID UBIQUITIN-PROTEIN LIGASE; ANAPHASE-PROMOTING COMPLEX; TUMOR-SUPPRESSOR PROTEIN; KAPPA-B-ALPHA; GROWTH-FACTOR RECEPTOR; RING FINGER PROTEINS; MULTIUBIQUITIN-CHAIN; ACTIVATING ENZYME; DNA-REPAIR; SACCHAROMYCES-CEREVISIAE AB Ubiquitylation - the conjugation of proteins with a small protein called ubiquitin - touches upon all aspects of eukaryotic biology, and its defective regulation is manifest in diseases that range from developmental abnormalities and autoimmunity to neurodegenerative diseases and cancer. A few years ago, we could only have dreamt of the complex arsenal of enzymes dedicated to ubiquitylation. Why has nature come up with so many ways of doing what seems to be such a simple job?. C1 NCI, Canc Res Ctr, Lab Immune Cell Biol, Bethesda, MD 20892 USA. RP Weissman, AM (reprint author), NCI, Canc Res Ctr, Lab Immune Cell Biol, Bethesda, MD 20892 USA. NR 107 TC 1063 Z9 1110 U1 10 U2 72 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD MAR PY 2001 VL 2 IS 3 BP 169 EP 178 DI 10.1038/35056563 PG 10 WC Cell Biology SC Cell Biology GA 408JN UT WOS:000167323200013 PM 11265246 ER PT J AU Schreurs, BG Bahro, M Molchan, SE Sunderland, T McIntosh, AR AF Schreurs, BG Bahro, M Molchan, SE Sunderland, T McIntosh, AR TI Interactions of prefrontal cortex during eyeblink conditioning as a function of age SO NEUROBIOLOGY OF AGING LA English DT Article DE positron emission tomography; eyeblink conditioning; aging; prefrontal cortex; functional connectivity; regional cerebral blood flow; cerebellum ID POSITRON-EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; WORKING-MEMORY; FRONTAL-CORTEX; PET IMAGES; BRAIN; ACTIVATION; LESIONS; HUMANS; MOTOR AB Changes in regional cerebral blood flow (rCBF) in eleven elderly subjects during pairings of tone and air puff were compared to rCBF changes during pairings in young subjects. Although all subjects reported being aware of the relationship between tone and air puff, elderly subjects did not condition as well as young subjects and their rCBF measures were attenuated. Covarying the performance differences between young and old subjects did not change this conclusion suggesting that differences in neural activation during learning are related to binding of CS-US information prior to the impact of the association on performance. Both groups showed learning-specific rCBF changes in cerebellum, inferior right prefrontal cortex and posterior cingulate. However, only in young subjects were there learning-specific changes in rCBF in left temporal cortex, midbrain, caudate, and inferior left prefrontal cortex. Analysis of learning-dependent patterns of functional connectivity of inferior left prefrontal cortex showed only young subjects had a strong left prefrontal functional connectivity with cerebellum, hippocampus, thalamus and temporal cortex. Thus, beyond changes in regional activity, these data also suggest that age may alter the operations of functional networks underlying learning and memory. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NINDS, Behav Neurol Unit, Lab Adapt Syst, Bethesda, MD 20892 USA. Univ Bern, Geriatr Psychiat Dept, CH-3072 Ostermundigen Berne, Switzerland. NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. Univ Toronto, Baycrest Ctr, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. RP Schreurs, BG (reprint author), W Virginia Univ, Dept Physiol, POB 9300, Morgantown, WV 26506 USA. RI McIntosh, Anthony/G-4955-2011; OI McIntosh, Anthony/0000-0002-1784-5662; Schreurs, Bernard/0000-0002-5776-0807 NR 41 TC 20 Z9 20 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 BP 237 EP 246 DI 10.1016/S0197-4580(00)00224-4 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800008 PM 11182473 ER PT J AU Resnick, S Davatzikos, C Kraut, M Zonderman, A AF Resnick, S Davatzikos, C Kraut, M Zonderman, A TI Longitudinal changes in MRI volumes in older adults SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract C1 NIA, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 MA 5 BP 332 EP 332 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800023 ER PT J AU Rapoport, SI Chang, MC Connolly, K Bokde, A Carson, RE Eckelman, WC AF Rapoport, SI Chang, MC Connolly, K Bokde, A Carson, RE Eckelman, WC TI Can we use PET to image defective brain signal transduction in vivo in Alzheimer disease? SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract C1 NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. NIH, PET Dept, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR-APR PY 2001 VL 22 IS 2 MA 26 BP 337 EP 337 PG 1 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 405HW UT WOS:000167154800044 ER PT J AU Linden, AM Storvik, M Lakso, M Haapasalo, A Lee, D Witkin, JM Sei, Y Castren, E Wong, G AF Linden, AM Storvik, M Lakso, M Haapasalo, A Lee, D Witkin, JM Sei, Y Castren, E Wong, G TI Increased expression of neuronal Src and tyrosine phosphorylation of NMDA receptors in rat brain after systemic treatment with MK-801 SO NEUROPHARMACOLOGY LA English DT Article DE cloning; dizocilpine; phencyclidine; tyrosine kinase; cerebral cortex ID POSTSYNAPTIC DENSITY FRACTION; LONG-TERM POTENTIATION; MESSENGER-RNA; CEREBROCORTICAL NEURONS; PHENCYCLIDINE; ANTAGONISTS; SUBUNITS; PROTEIN; GENE; CHANNELS AB We have observed that systemic treatment with the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 increases Src expression and NMDA receptor phosphorylation in rat brain. A partial cDNA encoding rat neuronal Src was isolated and its sequence was used to design specific oligonucleotide probes. Systemically administered MK-801 (5 mg/kg for 4 h) increased by 28+/-4% mRNA expression of neuronal Src in the superficial layers of the parietal cortex. This effect was observed at doses as low as 0.2 mg/kg. A similar, although more modest, induction was observed 6 h after phencyclidine (15 mg/kg) administration, but not after high doses of memantine and ketamine. The MK-801-induced effect was not blocked by pretreatment with clozapine. Consistent with the increase in mRNA levels, cortical Src protein was increased to 186 +/- 24% of control 24 h after MK-801 treatment. Total cellular Src activity was also increased in parietal cortex homogenates 4 h after MK-801 (5 mg/kg). Moreover, MK-SOI treatment (0.5 mg/kg and 5 mg/kg for 4 h) increased tyrosine phosphorylation, but not protein levels, of the NMDA receptor subunit NR2A. These results provide evidence for a contribution of Src and tyrosine phosphorylation of NMDA receptors in the pharmacological actions of uncompetitive NMDA receptor antagonists. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Kuopio, AI Virtanen Inst, FIN-70211 Kuopio, Finland. NIDA, Drug Dev Grp, Addict Res Ctr, Baltimore, MD 21224 USA. Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20892 USA. Univ Kuopio, Dept Psychiat, FIN-70211 Kuopio, Finland. RP Castren, E (reprint author), Univ Kuopio, AI Virtanen Inst, POB 1627, FIN-70211 Kuopio, Finland. RI Castren, Eero/A-4618-2010; OI Castren, Eero/0000-0002-1402-2791; Linden, Anni-Maija/0000-0003-1573-8051 NR 43 TC 8 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD MAR PY 2001 VL 40 IS 4 BP 469 EP 481 DI 10.1016/S0028-3908(00)00185-4 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 411ZQ UT WOS:000167529900002 PM 11249956 ER PT J AU Weinstein, JN AF Weinstein, JN TI The DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Natl Canc Inst, Bethesda, MD 20892 USA. RP Weinstein, JN (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 1 PY 2001 VL 344 IS 9 BP 688 EP 688 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 405TR UT WOS:000167177100019 ER PT J AU Biggar, RJ Goedert, JJ AF Biggar, RJ Goedert, JJ TI Mucosal shedding of human herpesvirus 8. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; HOMOSEXUAL MEN; RISK-FACTORS C1 Natl Canc Inst, Bethesda, MD 20852 USA. RP Biggar, RJ (reprint author), Natl Canc Inst, Bethesda, MD 20852 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 1 PY 2001 VL 344 IS 9 BP 690 EP 691 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 405TR UT WOS:000167177100026 PM 11229344 ER PT J AU Vozarova, B Wang, J Weyer, C Tataranni, PA AF Vozarova, B Wang, J Weyer, C Tataranni, PA TI Comparison of two software versions for assessment of body-composition analysis by DXA SO OBESITY RESEARCH LA English DT Article DE soft-tissue analysis; phantoms; intermachine variability; DXA; software ID X-RAY ABSORPTIOMETRY; ENERGY; INSTRUMENTS AB Objective: To compare two software versions provided by Lunar Co. for assessment of body composition analysis by DXA. Research Methods and Procedures: Soft-tissue phantoms for lean tissue (water) and fat tissue (methanol) were repeatedly scanned using DXA machines (DPX-L; Lunar Co., Madison, WI) and analyzed using software version 1.33 and the updated year 2000-compatible version 1.35. For the intersoftware comparison, the phantoms were scanned 10 times (each scan was analyzed once) with both software versions using all three scanning modes (slow, medium, and fast) for a total of 60 scans and analyses. For the intermachine comparison, the same phantoms were scanned three times (each scan was analyzed once) with a second machine from the same manufacturer using all three scanning modes and version 1.35 only. Percentage of fat was the variable of interest. Results: For version 1.33, fat was 9.9 +/- 0.4%, 10.0 +/- 0.5%, and 11.0 +/- 0.5% (mean +/- SD) for the lean-tissue phantom and 50.8 +/- 0.3%, 50.9 +/- 0.5%, and 51.1 +/- 0.6% for the fat-tissue phantom using the slow, medium, and fast scanning modes, respectively. For version 1.35, the respective fat values were 9.8 +/- 0.7%, 9.9 +/- 0.4%, and 10.3 +/- 0.7%, and 50.6 +/- 0.5%, 50.9 +/- 0.6%, and 50.8 +/- 0.8%, respectively. For the lean-tissue phantom, the estimation of percentage of fat was significantly (p < 0.05) affected by scanning mode but not by software version. For the fat-tissue phantom, the estimation of percentage of fat was not affected by either scanning mode or software version. The use of version 1.35 did not effect intermachine variability. Discussion: Versions 1.33 and 1.35 of the Lunar body composition software appear to be comparable. Soft-tissue phantoms, such as the ones described in this paper, may be useful in monitoring the reproducibility of body composition analyses within and between DXA machines, particularly in longitudinal studies. C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. St Lukes Roosevelt Hosp, Body Composit Unit, New York, NY 10025 USA. RP Vozarova, B (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 541A, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 11 TC 10 Z9 10 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI ROCHESTER PA C/O DR MICHAEL JENSEN, MAYO MEDICAL CENTER, MAYO CLIN 200 FIRST ST, SW, ROCHESTER, MN 55905 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD MAR PY 2001 VL 9 IS 3 BP 229 EP 232 DI 10.1038/oby.2001.26 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 428DH UT WOS:000168445600009 PM 11323450 ER PT J AU Maxwell, GL Risinger, JI Alvarez, AA Barrett, JC Berchuck, A AF Maxwell, GL Risinger, JI Alvarez, AA Barrett, JC Berchuck, A TI Favorable survival associated with microsatellite instability in endometrioid endometrial cancers SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MISMATCH REPAIR; COLORECTAL-CANCER; PATHOLOGICAL CHARACTERISTICS; GENOMIC INSTABILITY; PTEN MUTATION; CARCINOMA; HMLH1; CONSEQUENCES; METHYLATION; SEQUENCES AB Objective: To determine whether microsatellite instability in endometrioid endometrial cancer is associated with favorable survival. Methods: Microsatellite instability analysis was performed in 131 patients with endometrioid endometrial cancer using three polymorphic markers in paired cancer and normal DNA. Logistic regression and multivariable analyses calculated the relation between microsatellite instability, clinical features, and survival. Results: Microsatellite instability was detected in 29 of 131 (22%) endometrioid endometrial cancers. There was no correlation between microsatellite instability and age, race, grade, stage, or depth of myometrial invasion. Microsatellite instability was associated with better survival in univariate and multivariable analyses after controlling for confounding influences (P = .03). The 5-year survival rate of those with microsatellite instability was 77% (95% confidence interval 55%, 90%) compared with only 48% (95% confidence interval 39%, 57%) in other eases. Microsatellite instability was associated with other molecular features that predict favorable outcome including PTEN mutation (P = .002) and the absence of p53 overexpression (P = .01). Conclusion: Microsatellite instability is a molecular alteration associated with favorable outcome in endometrioid endometrial cancers, even when accounting for other prognostic factors. This association might be explained by the finding that the pathway of molecular carcinogenesis characterized by loss of DNA mismatch repair favors alteration of genes that result in a less virulent clinical phenotype. (C) 2001 by The American College of Obstetricians and Gynecologists. C1 Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Durham, NC 27710 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Berchuck, A (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Box 3079, Durham, NC 27710 USA. NR 32 TC 59 Z9 62 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2001 VL 97 IS 3 BP 417 EP 422 DI 10.1016/S0029-7844(00)01165-0 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 405JD UT WOS:000167155500018 PM 11239648 ER PT J AU Walsh, TJ Wayne, AS Chanock, SJ Groll, AH AF Walsh, TJ Wayne, AS Chanock, SJ Groll, AH TI Empiric antifungal therapy for the neutropenic patient - The Wingard/Leather article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID LIPOSOMAL AMPHOTERICIN-B; FEVER; GRANULOCYTOPENIA; MANAGEMENT; GUIDELINES; AGENTS; CANCER C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2001 VL 15 IS 3 BP 368 EP 369 PG 2 WC Oncology SC Oncology GA 444AX UT WOS:000169376700019 ER PT J AU Rodriguez-Burford, C Lubet, RA Steele, VE Eto, I Bandy, M Juliana, MM Weiss, HL Grizzle, WE Kelloff, GJ Crubbs, CJ AF Rodriguez-Burford, C Lubet, RA Steele, VE Eto, I Bandy, M Juliana, MM Weiss, HL Grizzle, WE Kelloff, GJ Crubbs, CJ TI Effects of acute and chronic body weight gain reductions in the evaluation of agents for efficacy in mammary cancer prevention SO ONCOLOGY REPORTS LA English DT Article DE body weight; mammary cancer; chemoprevention; methylnitrosourea (MNU); toremifene ID CHEMICALLY-INDUCED MAMMARY; DIETARY-FAT; CALORIC RESTRICTION; RATS; TUMORIGENESIS; CARCINOGENESIS; INHIBITION; PROMOTION; DEHYDROEPIANDROSTERONE; CHEMOPREVENTION AB Studies were performed to determine the effects of moderate decreases in body weight gain on mammary carcinogenesis. The levels of depressions in weight gain were those often observed in the evaluation of chemopreventive agents. In the first experiment, the effects of acute and chronic reductions of body weight gain when started after carcinogen treatment were examined in young rats (MNU at 50 days of age). Significant decreases (36%) in mammary cancers occurred in groups of rats that underwent a 12% acute reduction in body weight gain as compared with ad libitum controls. In contrast, chronic weight reductions of up to 12% had minimal effects on cancer multiplicities, while a 15% chronic reduction significantly decreased cancer numbers (26%down arrow). A second experiment evaluated the efficacy of toremifene (7.0 mg/kg diet), an estrogen/anti-estrogen, and the effect of toremifene-matched body weight gain reduction that occurred during the study. Toremifene caused a chronic reduction in body weight that resulted in a 10% decrease in final body weight at the end of the study. While toremifene-treated rats exhibited a 67% decrease in the number of mammary cancers, the 'matched body weight reduction' rats which similarly exhibited a 10% decrease in final body weight showed only a 14% decrease in cancer number. Thus, the weight effects observed with toremifene, similar estrogens/anti-estrogens, and other classes of chemopreventive compounds (where chronic body weight reductions are 10% or less) imply that the body weight reduction has a limited effect on overall chemopreventive activity. A third study examined the effect of chronic body weight gain reduction on mammary cancers induced in older rats (MNU given at 100 days of age). This model more closely resembles the status of the breast tissue of mature women currently enrolled in clinical trials of chemopreventive agents. Under these conditions chronic reductions in body weight up to 15% had minimal effects on mammary carcinogenesis. These data further demonstrated that acute body weight reductions in young rats at the time of carcinogen treatment can be a concern in interpretation of the chemopreventive activity of an agent, but that moderate chronic depressions of body weight gain probably do not play a significant role. C1 Univ Alabama, Dept Surg, Chemoprevent Ctr, Birmingham, AL 35294 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Florida, Dept Comparat & Expt Pathol, Gainesville, FL 32610 USA. RP Crubbs, CJ (reprint author), Univ Alabama, Dept Surg, Chemoprevent Ctr, 1675 Univ Blvd, Birmingham, AL 35294 USA. FU NCI NIH HHS [N01-CN-75101-MAO, N01-CN-65025-MAO] NR 27 TC 7 Z9 7 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD MAR-APR PY 2001 VL 8 IS 2 BP 373 EP 379 PG 7 WC Oncology SC Oncology GA 403KD UT WOS:000167040300030 PM 11182059 ER PT J AU Benoliel, R Eliav, E Iadarola, MJ AF Benoliel, R Eliav, E Iadarola, MJ TI Neuropeptide Y in trigeminal ganglion following chronic constriction injury of the rat infraorbital nerve: is there correlation to somatosensory parameters? SO PAIN LA English DT Article DE neuropeptide Y; trigeminal ganglia; infraorbital nerve; orofacial pain ID PERIPHERAL AXOTOMY; SENSORY NEURONS; GROOMING PATTERNS; CA-2+ CURRENTS; MESSENGER-RNA; SUBSTANCE-P; DORSAL HORN; PAIN; HYPERALGESIA; RECEPTORS AB The aim of this study was to investigate neuropeptide Y (NPY) levels in trigeminal ganglia following infraorbital nerve injury. Two experimental procedures were performed in three groups of rats: a unilateral chronic constriction injury (CCI) to the infraorbital nerve (n = 13), nerve manipulation without CCI (n = 13) and unoperated controls (n = 8), All rats underwent baseline and regular assessment of mechanical withdrawal threshold (Von Frey) and reaction to pin prick as well as free behavior evaluations. CCI to the infraorbital nerve induced significant hyperalgesia and allodynia within 9-12 days. At 6 days seven rats were euthanized and trigeminal ganglia harvested for immunocytochemical (ICC) studies. The study was ended at 14 days when all rats were euthanized and their ganglia harvested for ICC and radioimmunoassay (RIA) studies. An increase in NPY levels was seen in the ipsilateral ganglia of manipulated and CCI rats at 6 days, when rats displayed no pain-related behavior. At 14 days, ICC and RIA both detected significant increases in NPY levels in the ipsilateral ganglia of CCI and manipulated rats but not in unoperated controls. The possible roles of NPY in pain modulation and nerve injury are discussed in light of these findings, (C) 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Neuronal Gene Express Unit, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Dept Oral Diag, Jerusalem, Israel. RP Benoliel, R (reprint author), Natl Inst Dent & Craniofacial Res, Neuronal Gene Express Unit, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. NR 49 TC 23 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD MAR PY 2001 VL 91 IS 1-2 BP 111 EP 121 DI 10.1016/S0304-3959(00)00417-6 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 417BU UT WOS:000167816200012 PM 11240083 ER PT J AU Kazzi, SNJ Romero, R McLaughlin, K Ager, J Janisse, J AF Kazzi, SNJ Romero, R McLaughlin, K Ager, J Janisse, J TI Serial changes in levels of IL-6 and IL-1 beta in premature infants at risk for bronchopulmonary dysplasia SO PEDIATRIC PULMONOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-Research CY MAY 01-05, 1999 CL SAN FRANCISCO, CALIFORNIA SP Soc Pediat Res DE bronchopulmonary dysplasia; inflammatory mediators; cytokines; neonatal lung inflammation; prematurity; neonatology; chronic lung disease ID CHRONIC LUNG-DISEASE; RESPIRATORY-DISTRESS SYNDROME; BRONCHOALVEOLAR LAVAGE FLUID; TUMOR-NECROSIS-FACTOR; PRETERM INFANTS; INFLAMMATORY MEDIATORS; DEXAMETHASONE THERAPY; SECRETORY COMPONENT; CONTROLLED TRIAL; CYTOKINE LEVELS AB The aim of this study was to define the inflammatory changes occurring in the lungs of infants at risk for bronchopulmonary dysplasia (BPD) over the first 28 days of life, and to define an optimal strategy for steroids therapy in the prevention of BPD. We measured levels of interleukin-6 (IL-6) and interleukin-l beta (IL-1 beta) in tracheal aspirate (TA) samples and blood of premature infants with severe respiratory distress syndrome RDS (n=45) on the first day of life prior to initiation of surfactant therapy and on days 5-7, 12-14, 19-21, and 26-28. Levels of IL-6 and IL-1 beta were determined with a commercially available enzyme-linked immunoassay. Logistic regression analyses were performed in order to examine differences in trends in levels of IL-6 and IL-1 beta between groups of infants. Infants were divided into group I (n = 30, FiO(2) less than or equal to 0.35 at 28 days) and group II (n=15, FiO(2)>0.35 based on their likelihood of developing BPD at 36 weeks postconceptional age (PCA). The infants were comparable with respect to mean (+/-SEM) birth weight (895+/-33 g vs. 900 +/- 40 g), gestational age (27 +/- 0.38 weeks vs. 27 +/- 0.54 weeks), and severity of respiratory illness at entry into the study (mean airway pressure: 12 +/- 1 cmH(2)O vs, 12 +/- 1 cmH(2)O, and oxygen index: 15 +/- 2 vs. 19 +/- 4) (group I vs. group II, respectively), Logistic regression analyses failed to reveal any significant differences in linear trends of levels of IL-6 and IL-1 beta in TA samples between both groups of infants. No particular pattern of change in levels of IL-6 or IL-1 beta could be identified among groups of infants. Levels of IL-6 and IL-1 beta in TA samples on the first day of life failed to predict the need for FiO(2) > 0.35 at 28 days of age. We could not identity an increasing trend or a specific pattern of changes in postnatal levels of IL-6 or IL-1 beta in TA samples of infants who were at greater risk of developing BPD at 36 weeks PCA compared to infants who were not. C1 Wayne State Univ, Sch Med, Dept Pediat, Hutzel Hosp, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Hutzel Hosp, Ctr Hlth Effectiveness Res, Detroit, MI USA. RP Kazzi, SNJ (reprint author), Wayne State Univ, Sch Med, Dept Pediat, Hutzel Hosp, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 39 TC 17 Z9 20 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-6863 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD MAR PY 2001 VL 31 IS 3 BP 220 EP 226 DI 10.1002/ppul.1032 PG 7 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 412UX UT WOS:000167573700006 PM 11276135 ER PT J AU Merke, DP Pathomvanich, A Chrousos, GP AF Merke, DP Pathomvanich, A Chrousos, GP TI Early puberty: A cautionary tale - Reply SO PEDIATRICS LA English DT Letter ID GIRLS C1 NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 1 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2001 VL 107 IS 3 BP 609 EP 610 PG 2 WC Pediatrics SC Pediatrics GA 406KW UT WOS:000167216200047 ER PT J AU Kimm, SYS Barton, BA Obarzanek, E McMahon, RP Sabry, ZI Waclawiw, MA Schreiber, GB Morrison, JA Similo, S Daniels, SR AF Kimm, SYS Barton, BA Obarzanek, E McMahon, RP Sabry, ZI Waclawiw, MA Schreiber, GB Morrison, JA Similo, S Daniels, SR TI Racial divergence in adiposity during adolescence: The NHLBI growth and health study SO PEDIATRICS LA English DT Article DE race; adolescence; adiposity; body mass index; obesity; pubertal maturation; energy intake; physical activity ID DEPENDENT DIABETES-MELLITUS; NUTRITION EXAMINATION SURVEYS; BODY-MASS INDEX; NATIONAL-HEALTH; ENERGY-INTAKE; YOUNG-ADULTS; WHITE GIRLS; OBESITY; OVERWEIGHT; TRENDS AB Background. Black women are particularly vulnerable to obesity, with a prevalence rate of >50%. The higher mortality and morbidity from cardiovascular disease, stroke, and diabetes have been attributed, in part, to their obesity. In recent years, a particular public health concern is the increasing secular trend in obesity with an even greater racial disparity, especially in girls and women. Between the early 1960s and late 1980s, the prevalence of obesity tripled in young black girls 6 to 11 years of age, while it doubled in white girls. Similarly, both overweight and obesity in adolescent girls 12 to 17 years of age also increased, with a greater increase again seen in adolescent black girls. This secular trend in obesity with a greater increase in black girls signals a potentially grave future chronic disease burden on black women, which is already higher than in white women. The increasing occurrence in children and adolescents of noninsulin-dependent diabetes, traditionally viewed as an adult-onset condition, may be a consequence of the currently high prevalence of obesity in American youth. Not surprisingly, this condition is seen more frequently among black youths. Prepubescent black girls are generally leaner than age-comparable white girls, but by 20 years of age, black women are considerably heavier than are white women. Thus, it is assumed that the racial disparity in adiposity evolves during adolescence. However, the specific age at which this occurs and underlying factors are yet to be identified because of the current paucity of longitudinal cohort data. Objectives. In 1985, the National Heart, Lung, and Blood Institute (NHLBI) initiated a 10-year longitudinal multicenter study (the NHLBI Growth and Health Study [NGHS]) to investigate the development of obesity in black and white girls during adolescence and its environmental, psychosocial, and cardiovascular disease risk factor correlates. The purpose of this report is to examine the natural history of adiposity and weight accretion during adolescence in a biracial cohort of girls to investigate the evolution of the racial divergence in adiposity and to examine the relationships between increases in adiposity and pubertal maturation, energy intake, and physical activity. Participants and Setting. A total of 2379 black (51%) and white (49%) girls, 9 to 10 years of age, were recruited from public and parochial schools in Richmond, California, and Cincinnati, Ohio, and from families enrolled in a large health maintenance organization in the Washington, DC area. Participant eligibility was limited to girls and their parents who declared themselves as being either black or white and who lived in racially concordant households. Design and Statistical Analysis. The NGHS is a multicenter prospective study of black and white girls with annual visits from 9 to 10 years of age through 18 to 19 years of age. The follow-up rate was 89% at the 10th annual visit. Skinfold measurements were obtained at the triceps, suprailiac, and subscapular sites with Holtain calipers. Sexual maturation was assessed by trained registered nurses. The onset of menarche was ascertained annually by questionnaire. All clinical assessments were conducted using a common protocol by centrally trained staff. Longitudinal regression (generalized estimating equations) models were used to examine the relationship between adiposity and race, age, pubertal maturation, daily energy intake, and physical activity. Main Outcome Measures. The main outcome measure was the sum of skinfolds (SSF) at the triceps, subscapular, and suprailiac sites as an index of adiposity for comparison between the 2 racial groups. Body mass index (BMI; weight in kilograms divided by height in meters, squared) distributions were examined by age and race. Results. Racial differences in SSF, unadjusted for maturation, were evident at 10 years of age. For each chronological age, there was a higher proportion of black girls with more advanced pubertal maturation than white girls. The 15th percentiles for SSF were similar and remained thus throughout the study. The median for SSF for black girls, although similar to the median SSF of white girls at 9 years of age, became greater for black girls at 12 years of age (36 mm vs 32.5 mm) and at age 19 years the difference was 6 mm (49.5 mm vs 43.5 mm). In contrast, the difference in the 85th as well as the 95th percentile values for SSF were substantially higher in black girls at all ages (9 mm and 10 mm, or 18% and 15%, respectively, at age 9 years) and these racial differences widened with age (20 mm and 26 mm, or 25% and 24%, respectively, by age 19 years). The racial difference in the median BMI increased from 0.4 to 2.3 kg/m(2) between ages 9 and 19 years. Unlike SSF at the 15th percentile, the BMI for lean 9-year-old black girls was similar to3% higher than whites. As with SSF, for heavier girls, BMI at the 85th percentile even at age 9 years was 11% greater in black girls and became 23% greater by age 19 years. Differences in BMI at the 95th percentile also increased from 3.6 to 8.1 kg/m(2) between ages 10 and 18 years. After adjusting for stages of maturation in multivariate longitudinal regression models, adiposity for black girls became significantly greater at age 12 years compared with white girls. The largest gain in adiposity for both groups was seen at the time of pubescence, an approximate increase of 8.0 mm in SSF for white girls and 10.8 mm for black girls. The next milestone for a gain in adiposity occurred around menarche with an increase in SSF of 5.0 mm for white girls and 3.4 mm for black girls. Additionally, there was a significantly greater accrual of adiposity with earlier achievement of menarche, ie, a gain of 3.7 mm for white girls and 3.0 mm for black girls for each year. Although the effect of puberty on the gain in adiposity was similar for both races, for each chronological age, there was a greater accrual of adiposity in black girls because they matured earlier than white girls. Energy intake was significantly and inversely associated with increasing adiposity but not with levels of physical activity. Conclusion. The time of the largest accrual of body fat occurred around the 2 major pubertal milestones, the onsets of puberty and menarche. Even after adjusting for pubertal maturation, after age 12 years, black girls were significantly fatter than were white girls. Earlier menarche conferred an additional risk for greater gain in adiposity for both racial groups. Primary prevention of obesity, therefore, should commence with fostering the maintenance of normal growth in young girls before the initiation of pubertal maturation because increased adiposity is associated with earlier menarche. Next, and more importantly, pediatricians should be particularly vigilant with growth monitoring during the critical milestones of pubertal development, a vulnerable time for a large accrual of adiposity. Greater emphasis needs to be placed on preventive efforts in black girls to minimize their risk for developing obesity during adolescence. C1 Univ Pittsburgh, Sch Med, Dept Family Med & Clin Epidemiol, Pittsburgh, PA 15261 USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Maryland, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD USA. Univ Calif Berkeley, Sch Publ Hlth, Dept Nutr, Berkeley, CA 94720 USA. Westat, Rockville, MD USA. Cincinnati Childrens Hosp, Div Cardiol, Cincinnati, OH USA. RP Kimm, SYS (reprint author), Univ Pittsburgh, Sch Med, Dept Family Med & Clin Epidemiol, M-200 Scaife, Pittsburgh, PA 15261 USA. RI McMahon, Robert/C-5462-2009 FU NHLBI NIH HHS [N0-HC-55023-26, UO1-HL48941-44] NR 33 TC 118 Z9 122 U1 2 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2001 VL 107 IS 3 AR e34 DI 10.1542/peds.107.3.e34 PG 7 WC Pediatrics SC Pediatrics GA 406KW UT WOS:000167216200006 PM 11230615 ER PT J AU Fredrickson, DS AF Fredrickson, DS TI The first twenty-five years after Asilomar SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Editorial Material C1 NIH, Natl Lib Med, Bethesda, MD 20817 USA. RP Fredrickson, DS (reprint author), NIH, Natl Lib Med, 6615 Bradley Blvd, Bethesda, MD 20817 USA. NR 11 TC 3 Z9 3 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD SPR PY 2001 VL 44 IS 2 BP 170 EP 182 DI 10.1353/pbm.2001.0025 PG 13 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 428ZH UT WOS:000168491200003 PM 11370150 ER PT J AU Bungay, PM Dedrick, RL Fox, E Balis, FM AF Bungay, PM Dedrick, RL Fox, E Balis, FM TI Probe calibration in transient microdialysis in vivo SO PHARMACEUTICAL RESEARCH LA English DT Article DE microdialysis; calibration; pharmacokinetics; area-under-the-curve; diffusion ID QUANTITATIVE MICRODIALYSIS; PHARMACOKINETICS; BRAIN; AZT AB Purpose. We examine the theoretical basis for calibrating microdialysis probes in vivo for pharmacokinetic experiments in which the extracellular analyte concentrations vary in time. Methods. A software package, MICRODIAL, was used to simulate microdialysis for illustrative transient situations with linear concentration dependence. Results. For a constant distant extracellular analyte concentration, the calibration factor (extraction fraction, E-d) exhibits a mass transfer transient associated with the development of spatial concentration profiles within the tissue and the probe. Processes clearing the analyte from the extracellular fluid (ECF) strongly influence the rapidity of approach to steady-state and affect the magnitude of the steady-state calibration factor, E-d(ss). For situations in which the distant ECF concentration varies in time as a result of exchange with the plasma compartment, different time profiles of the distant ECF and plasma concentrations yield different transient E-d. For the linear, transient cases examined, the area-under-the-curve (AUC(0-infinity)) time integral of the distant ECF concentration was found to be proportional to the outflow dialysate concentration-lime integral with E-d(ss) being the proportionality constant. Conclusions. The options for calibrating microdialysis probes in solid tissues appear limited under non-steady state conditions; however, AUC integrals for linear systems may be determined by continuous microdialysis sampling and steady-state probe calibration approaches. C1 NIH, DBEPS, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Bungay, PM (reprint author), NIH, DBEPS, Div Bioengn & Phys Sci, Off Res Serv, 13-3N17,MSC 5766, Bethesda, MD 20892 USA. NR 10 TC 25 Z9 25 U1 0 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD MAR PY 2001 VL 18 IS 3 BP 361 EP 366 DI 10.1023/A:1011015316327 PG 6 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 446NL UT WOS:000169519300018 PM 11442277 ER PT J AU Dixon, SC Knopf, KB Figg, WD AF Dixon, SC Knopf, KB Figg, WD TI The control of prostate-specific antigen expression and gene regulation by pharmacological agents SO PHARMACOLOGICAL REVIEWS LA English DT Review ID CANCER CELL-LINE; ACTIVATED RECEPTOR-GAMMA; 9-CIS RETINOIC ACID; CHINESE HERBAL PREPARATION; COLONY-STIMULATING FACTOR; FIBROBLAST GROWTH-FACTOR; HUMAN BREAST-CANCER; VITAMIN-D ANALOGS; PHASE-II TRIAL; ANDROGEN RECEPTOR AB Prostate-specific antigen is a serine protease that is a member of the kallikrein family. It is widely used as an indicator of tumor burden and as a surrogate marker for disease progression in men with androgen-independent prostate cancer. It has been shown that the expression and/or secretion of this glycoprotein can be regulated by pharmacological agents. The effects of these agents on PSA may be independent of their effects on cell growth. For example, a pharmacological agent may down-regulate PSA expression/secretion but have no effect on tumor cell growth. In this case, a patient receiving this therapeutic agent might be falsely considered as having a clinical response. Alternatively, an agent might up-regulate PSA expression/secretion and have an inhibitory effect on cell growth. A patient receiving this therapeutic agent might be diagnosed with progressive disease unless an alternative method for assessing tumor burden is used. Thus, when an agent is to be evaluated in a clinical trial utilizing PSA as a marker for disease progression, it is important to prospectively test whether the agent has an effect on PSA expression and/or secretion. In addition, it is equally important to understand how these regulatory effects relate to cell growth. The purpose of this review is to describe several agents that have been tested for their regulatory effects on PSA and to discuss potential mechanisms of by which this regulation may occur. The implications of these findings in the evaluation of new agents in androgen-independent prostate cancer will be considered. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, 10 Center Dr,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 225 TC 49 Z9 49 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD MAR PY 2001 VL 53 IS 1 BP 73 EP 91 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 402BM UT WOS:000166966200003 PM 11171939 ER PT J AU Burstein, AH Reed, E Tompkins, AC Venzon, D Figg, WD AF Burstein, AH Reed, E Tompkins, AC Venzon, D Figg, WD TI Phenylacetate pharmacokinetics based on iterative two-stage population analysis SO PHARMACOTHERAPY LA English DT Article ID PHASE-I; DIFFERENTIATION; CELLS; ACID; CANCER; HYPERAMMONEMIA; PERFORMANCE AB Study Objective. To determine the population pharmacokinetics of phenylacetate using iterative two-stage analysis implemented with ADAPT II software. Setting. United States government research hospital. Design. Retrospective pharmacokinetic analysis. Subjects. Sixty-seven patients with refractory solid tumors. Intervention. Subjects received from 1-10 courses/individual (total 141 courses) of therapy with either twice-daily administration or continuous infusions of phenylacetate. Measurements and Main Results. Extensive plasma concentration measurements were performed after the initial dose or start of infusion, with sparse sampling during subsequent courses of therapy Phenylacetate plasma concentration-time profiles were described by a one-compartment, capacity-limited clearance model with incorporation of parameters to describe extent of induction of clearance and the rate of induction. Median estimates for volume of distribution, maximum rate of drug elimination, Michaelis-Menten constant, and induction factor, and rate of onset of induction of drug clearance were 0.33 (0.26, 0.48) L/kg, 21.8 (16.3, 28.0) mg/kg/hour, 94.6 (48.8, 153.0) mg/L, 1.28 (1.06, 1.66), and 0.0038 (0.0019, 0.0058) hour(-1), respectively. Conclusion. The results of this study are similar to previous pharmacokinetic evaluations using the Abbottbase PKS system but suggest that earlier analyses were suboptimal. C1 NCI, Clin Pharmacokinet Sect, Med Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NIH, Clin Pharmacokinet Res Lab, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacokinet Sect, Med Branch, Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008; Figg Sr, William/M-2411-2016 NR 19 TC 1 Z9 1 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER BOX 806 171 HARRISON AVE, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD MAR PY 2001 VL 21 IS 3 BP 281 EP 286 DI 10.1592/phco.21.3.281.34207 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 415CF UT WOS:000167702400004 PM 11253852 ER PT J AU Hall, MC Kunkel, TA AF Hall, MC Kunkel, TA TI Purification of eukaryotic MutL homologs from Saccharomyces cerevisiae using self-cleaving affinity technology SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID DNA MISMATCH REPAIR; YEAST MSH2-MSH6; GENE; MUTATIONS; PROTEINS; COMPLEX; MLH1; MEIOSIS; ATPASE; SYSTEM AB Self-cleaving affinity technology is an effective tool for rapid purification of native sequence recombinant proteins overproduced in Escherichia coli. In this report, we describe the adaptation of this technology to purify DNA mismatch repair proteins overproduced in the eukaryote Saccharomyces cerevisiae. Mlh1 and Pms1 are homologs of the E. coli MutL protein that participate in a variety of DNA transactions in cells, including correction of DNA replication errors, recombination, excision repair, and checkpoint control. Difficulties in preparing substantial quantities of highly purified MutL homologs have impeded descriptions of their biophysical and biochemical properties and mechanisms of action. To overcome this limitation, here we use self-cleaving affinity technology to purify to apparent homogeneity the yeast Mlh1-Pms1 heterodimer and the individual yeast and human Mlh1 subunit. The availability of these proteins should accelerate an understanding of their multiple functions in mismatch repair and other DNA transactions. The general approach is a valid alternative for simple, rapid purification of recombinant proteins in yeast when expression in bacteria is unsuitable. (C) 2001 Academic Press. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP NIEHS, Mol Genet Lab, 111 Alexander Dr,MD E3-01, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 32 TC 18 Z9 19 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2001 VL 21 IS 2 BP 333 EP 342 DI 10.1006/prep.2000.1379 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 413TE UT WOS:000167627400011 PM 11237696 ER PT J AU Fox, JD Kapust, RB Waugh, DS AF Fox, JD Kapust, RB Waugh, DS TI Single amino acid substitutions on the surface of Escherichia coli maltose-binding protein can have a profound impact on the solubility of fusion proteins SO PROTEIN SCIENCE LA English DT Article DE fusion protein; inclusion bodies; maltose-binding protein; protein folding; solubility; aggregation ID GREEN FLUORESCENT PROTEIN; SUBSTRATE-BINDING; IN-VIVO; RECOMBINANT PROTEINS; POLYPEPTIDE BINDING; ACTIVE-TRANSPORT; GROEL; EXPRESSION; BACTERIAL; CHAPERONE AB Proteins are commonly fused to Escherichia coli maltose-binding protein (MBP) to enhance their yield and facilitate their purification. In addition, the stability and solubility of a passenger protein can often be improved by fusing it to MBP. In a previous comparison with two other highly soluble fusion partners, MBP was decidedly superior at promoting the solubility of a range of aggregation-prone proteins. To explain this observation, we proposed that MBP could function as a general molecular chaperone in the context of a fusion protein by binding to aggregation-prone folding intermediates of passenger proteins and preventing their self-association. The ligand-binding cleft in MBP was considered a likely site for peptide binding because of its hydrophobic nature. We tested this hypothesis by systematically replacing hydrophobic amino acid side chains in and around the cleft with glutamic acid. None of these mutations affected the yield or solubility of MBP in its unfused state. Each MBP was then tested for its ability to promote solubility when fused to three passenger proteins: green fluorescent protein, p16, and E6, Mutations within the maltose-binding cleft (W62E, A63E, Y155E, W230E, and W340E) had little or no effect on the solubility of the fusion proteins. In contrast, three mutations near one end of the cleft (W232E, Y242E, and I317E) dramatically reduced the solubility of the same fusion proteins. The mutations with the most profound effect on solubility were shown to reduce the global stability of MBP. C1 NCI, Prot Engn Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Prot Engn Sect, Macromol Crystallog Lab, POB B, Frederick, MD 21702 USA. NR 55 TC 89 Z9 90 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2001 VL 10 IS 3 BP 622 EP 630 DI 10.1110/ps.45201 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419AA UT WOS:000167926100016 PM 11344330 ER PT J AU Moll, JR Ruvinov, SB Pastan, I Vinson, C AF Moll, JR Ruvinov, SB Pastan, I Vinson, C TI Designed heterodimerizing leucine zippers with a range of pIs and stabilities up to 10(-15) M SO PROTEIN SCIENCE LA English DT Article DE leucine zipper; dimerization; electrostatic interactions; radioimmunotherapy; salt bridges; heterodimer ID COILED-COIL; AMINO-ACID; PRETARGETED RADIOIMMUNOTHERAPY; OLIGOMERIZATION STATE; POSITION; SPECIFICITY; PROTEINS; Y-90 AB We have designed a heterodimerizing leucine zipper system to target a radionuclide to prelocalized non-internalizing tumor-specific antibodies. The modular nature of the leucine zipper allows us to iteratively use design rules to achieve specific homodimer and heterodimer affinities. We present circular-dichroism thermal denaturation measurements on four pairs of heterodimerizing leucine zippers. These peptides are 47 amino acids long and contain four or five pairs of electrostatically attractive g <----> e ' (i, i ' +5) interhelical heterodimeric interactions. The most stable heterodimer consists of an acidic leucine zipper and a basic leucine zipper that melt as homodimers in the micro (T-m = 28 degreesC) or nanomolar (T-m = 40 degreesC) range, respectively, but heterodimerize with a T-m >90 degreesC, calculated to represent femtamolar affinities. Modifications to this pair of acidic and basic zippers, designed to destabilize homodimerization, resulted in peptides that are unstructured monomers at 4 muM and 6 degreesC but that heterodimerize with a T-m = 74 degreesC or K-d(37) = 1.1 x 10(-11) M. A third heterodimerizing pair was designed to have a more neutral isoelectric focusing point (pI) and formed a heterodimer with T-m = 73 degreesC. We can tailor this heterodimerizing system to achieve pharmacokinetics aimed at optimizing targeted killing of cancer cells. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 4D06, Bethesda, MD 20892 USA. NR 24 TC 61 Z9 64 U1 4 U2 19 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2001 VL 10 IS 3 BP 649 EP 655 DI 10.1110/ps.39401 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419AA UT WOS:000167926100019 PM 11344333 ER PT J AU Jetty, PV Charney, DS Goddard, AW AF Jetty, PV Charney, DS Goddard, AW TI Neurobiology of generalized anxiety disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID CORTICOTROPIN-RELEASING FACTOR; SEROTONIN TRANSPORTER GENE; PARTLY DIFFERENT ENVIRONMENTS; PANIC DISORDER; MAJOR DEPRESSION; NEUROPEPTIDE-Y; BENZODIAZEPINE RECEPTORS; NORADRENERGIC FUNCTION; HEALTHY-SUBJECTS; CCKB ANTAGONIST AB Generalized anxiety disorder is neither an infrequent nor mild condition but an important public health problem that merits further research on treatment and mechanism of illness. This article provides a concise picture of preclinical and clinical research pertinent to the neurobiology of generalized anxiety disorder. The authors cover research on functional neuroanatomy and fear circuitry; animal models relevant to generalized anxiety disorder; research on the genetics of generalized anxiety disorder; and the neurochemistry, neurophysiology, and functional imaging studies relevant to generalized anxiety disorder. Finally, the authors present a critical discussion of several biological models of generalized anxiety disorder and suggest paths for future research. C1 Hlth S Metr W Hosp, Subst Abuse Program, Fairfield, AL 35064 USA. NIMH, Anxiety Disorders Res Program, Bethesda, MD 20892 USA. NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, Anxiety Disorders Program, New Haven, CT USA. Connecticut Mental Hlth Ctr, New Haven, CT USA. RP Jetty, PV (reprint author), Hlth S Metr W Hosp, Subst Abuse Program, Fairfield, AL 35064 USA. NR 126 TC 35 Z9 40 U1 7 U2 19 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD MAR PY 2001 VL 24 IS 1 BP 75 EP + DI 10.1016/S0193-953X(05)70207-0 PG 25 WC Psychiatry SC Psychiatry GA 400MJ UT WOS:000166875200006 PM 11225510 ER PT J AU Schmidt, LA Fox, NA Perez-Edgar, K Hu, S Hamer, DH AF Schmidt, LA Fox, NA Perez-Edgar, K Hu, S Hamer, DH TI Association of DRD4 with attention problems in normal childhood development SO PSYCHIATRIC GENETICS LA English DT Article DE attention deficit hyperactivity disorder; dopamine; genetics ID DEFICIT HYPERACTIVITY DISORDER; DOPAMINE-D4 RECEPTOR D4DR; EXON-III POLYMORPHISM; SEROTONIN TRANSPORTER PROMOTER; OPIOID-DEPENDENT SUBJECTS; HUMAN PERSONALITY-TRAIT; NOVELTY SEEKING; REPEAT POLYMORPHISM; 7-REPEAT ALLELE; ADDITIONAL EVIDENCE AB Several previous studies found an association of clinically diagnosed attention deficit hyperactivity disorder with long alleles of a variation in the DRD4 dopamine receptor gene exon III coding sequence. We evaluated the DRD4 polymorphism in a non-clinically selected sample of children for whom maternal reports of attention problems were available at 4 and 7 years of age. There was a significant elevation in attention problem scores in children carrying DRD4 long alleles that accounted for 3-4% of total variation at each age and for 5-7% of the temporally stable component of the phenotype, Our results show that the DRD4 gene influences normal as well as pathological attention processes, and the results highlight the utility of longitudinal measurements in psychiatric genetics. Psychiatr Genet 11:25-29 (C) 2001 Lippincott Williams & Wilkins. C1 McMaster Univ, Dept Psychol, Hamilton, ON, Canada. Univ Maryland, Inst Child Study, College Pk, MD USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RI Perez-Edgar, Koraly/B-8463-2008 FU NICHD NIH HHS [HD 17899] NR 38 TC 44 Z9 46 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIATR GENET JI Psychiatr. Genet. PD MAR PY 2001 VL 11 IS 1 BP 25 EP 29 DI 10.1097/00041444-200103000-00005 PG 5 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 437YP UT WOS:000169027200004 PM 11409696 ER PT J AU Feng, J Craddock, N Jones, LR Cook, EH Goldman, D Heston, LL Peltonen, L DeLisi, LE Sommer, SS AF Feng, J Craddock, N Jones, LR Cook, EH Goldman, D Heston, LL Peltonen, L DeLisi, LE Sommer, SS TI Systematic screening for mutations in the glycine receptor alpha 2 subunit gene (GLRA2) in patients with schizophrenia and other psychiatric diseases SO PSYCHIATRIC GENETICS LA English DT Article DE GLRA2; schizophrenia; detection of virtually all mutations-SSCP ID PUERPERAL PSYCHOSIS; SEQUENCE CHANGES; DOVAM-S; ASSOCIATION; DISORDER; VARIANTS; IDENTIFICATION; POLYMORPHISMS; CANDIDATE; LINKAGE AB The glycine receptor, which is a member of the ligand-gated ion channel superfamily, mediates synaptic inhibition in the spinal cord and other brain regions, This superfamily has been implicated in the pathogenesis of schizophrenia and other psychiatric diseases, The complete coding sequence and splice junctions of the GLRA2 gene were scanned by DOVAM-S, a form of SSCP analysis with sufficient redundancy to detect virtually all mutations. Those analyses were performed in 113 patients with schizophrenia, and in pilot studies of patients with bipolar illness, alcoholism, puerperal psychosis, autism, and attention-deficit hyperactivity disorder (533 kb total scanned sequences). We detected three sequence changes in the coding region, all resulting in silent mutations: C894T in exon 5, C1134T in exon 7, and C1476T in exon 9. These do not alter the structure or the expression of the protein, It is unlikely that mutations in the coding region and splice junction of GLRA2 gene are associated with schizophrenia and other psychiatric diseases, Psychiatr Genet 11:45-48 (C) 2001 Lippincott Williams & Wilkins. C1 City Hope Natl Med Ctr, Dept Mol Genet, Beckman Res Inst, Duarte, CA 91010 USA. Univ Birmingham, Queen Elizabeth Psychiat Hosp, Div Neurosci, Birmingham, W Midlands, England. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIAAA, Dept Psychiat, NIH, Bethesda, MD USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. SUNY Stony Brook, Hlth Sci Ctr, Dept Psychiat, Stony Brook, NY 11794 USA. RI turton, miranda/F-4682-2011; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 20 TC 4 Z9 4 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIATR GENET JI Psychiatr. Genet. PD MAR PY 2001 VL 11 IS 1 BP 45 EP 48 DI 10.1097/00041444-200103000-00009 PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 437YP UT WOS:000169027200008 PM 11409700 ER PT J AU Fleck, DE Berch, DB Shear, PK Strakowski, SM AF Fleck, DE Berch, DB Shear, PK Strakowski, SM TI Directed forgetting in explicit and implicit memory: The role of encoding and retrieval mechanisms SO PSYCHOLOGICAL RECORD LA English DT Article ID INHIBITION; TESTS; DISORDER; ADULTS AB Despite the fact that directed-forgetting effects have been attributed to either retrieval inhibition or selective encoding, there has been no compelling evidence to suggest that either mechanism regulates performance in both implicit and explicit memory. Therefore, in two experiments we sought (a) to determine whether directed forgetting influences tests of implicit (lexical decision) and explicit (recognition) memory and (b) to examine the relative contributions of the encoding and retrieval mechanisms thought to mediate directed forgetting by having participants perform an external interference task (i.e., sequential finger tapping) at either encoding or retrieval. In Experiment 1, directed-forgetting effects were demonstrated by better performance on remember-cued than on forget-cued words for both lexical decision and recognition. In Experiment 2, external interference disrupted directed forgetting in lexical decision when it occurred at retrieval and in recognition at encoding. These results demonstrate that although directed forgetting occurs on both implicit and explicit tests, it may be independently regulated by differential retrieval on the former and selective encoding on the latter. The discussion focuses on the differential excitation of remember- and forget-cued word representations, as inhibitory processing seemed not to account for directed-forgetting effects in either implicit or explicit memory. C1 Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45267 USA. NIH, Bethesda, MD USA. RP Fleck, DE (reprint author), Univ Cincinnati, Dept Psychiat, POB 670559, Cincinnati, OH 45267 USA. NR 32 TC 8 Z9 12 U1 0 U2 3 PU PSYCHOLOGICAL RECORD PI GAMBIER PA KENYON COLLEGE, GAMBIER, OH 43022 USA SN 0033-2933 J9 PSYCHOL REC JI Psychol. Rec. PD SPR PY 2001 VL 51 IS 2 BP 207 EP 221 PG 15 WC Psychology, Multidisciplinary SC Psychology GA 438LY UT WOS:000169056300003 ER PT J AU Squire, LR Schmolck, H Buffalo, EA AF Squire, LR Schmolck, H Buffalo, EA TI Memory distortions develop over time: A reply to Horn SO PSYCHOLOGICAL SCIENCE LA English DT Editorial Material C1 Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Squire, LR (reprint author), VAMC, 116A,3350 La Jolla Village Dr, San Diego, CA 92161 USA. EM lsquire@ucsd.edu NR 2 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD MAR PY 2001 VL 12 IS 2 BP 182 EP 182 DI 10.1111/1467-9280.00332 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 424NG UT WOS:000168237900015 ER PT J AU See, RE Kruzich, PJ Grimm, JW AF See, RE Kruzich, PJ Grimm, JW TI Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior SO PSYCHOPHARMACOLOGY LA English DT Article DE basolateral amygdala; cocaine; dopamine; relapse; reward; self-administration ID LONG-TERM POTENTIATION; SELF-ADMINISTERED COCAINE; NUCLEUS-ACCUMBENS; IN-VIVO; AUTORADIOGRAPHIC DISTRIBUTION; ANTAGONIST SCH-23390; EXCITOTOXIC LESIONS; SYNAPTIC PLASTICITY; PLACE PREFERENCE; HUMAN-BRAIN AB Rationale: Following chronic cocaine self-administration and extinction, lesions of the basolateral amygdala (BLA) will significantly attenuate responding for secondary reward (tone + light previously paired with cocaine), without disrupting lever responding for primary reward. However, the specific neurotransmitters involved in conditioned reinstatement remain to be determined. Objective: In the present study, we examined possible receptor substrates of amygdalar regulation of conditioned reinstatement after chronic cocaine self-administration. Methods: Rats were allowed 2 weeks of 3-h daily sessions of cocaine self-administration along a fixed ratio (FR) 1 schedule. After 1 week of daily 3-h extinction sessions in which no programmed consequences occurred, selective antagonists of glutamate or dopamine (DA) receptors were bilaterally infused at single doses into the BLA prior to testing for a cocaine-conditioned reward (tone + light). Following three more days of extinction trials, receptor antagonist effects on reinstatement of cocaine self-administration in the absence of the conditioned stimulus were determined. Results: Infusion of an NMDA receptor antagonist (AP-5, 1.97 mug/side), a kainate/alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (CNQX, 0.83 mug/side), or both drugs together had no significant effects on conditioned reward or reinstatement of cocaine self-administration. In contrast, infusion of a DA D, receptor antagonist (SCH-23390, 2 mug/side) or a combination of SCH-23390 and a DA D-2/D-3 receptor antagonist (raclopride, 5 mug/side) significantly reduced responding for conditioned reward, but did not affect cocaine self-administration. Raclopride alone was without effect on either test day. Conclusions: These results sugdgest that conditioned reinstatement of drug-seeking behavior is dependent on amygdalar D-1 receptors. C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP See, RE (reprint author), Med Univ S Carolina, Dept Physiol & Neurosci, 173 Ashley Ave, Charleston, SC 29425 USA. FU NIDA NIH HHS [DA-10462] NR 68 TC 156 Z9 166 U1 1 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2001 VL 154 IS 3 BP 301 EP 310 DI 10.1007/s002130000636 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 421HM UT WOS:000168059000009 PM 11351937 ER PT J AU McManis, MH Bradley, MM Berg, WK Cuthbert, BN Lang, PJ AF McManis, MH Bradley, MM Berg, WK Cuthbert, BN Lang, PJ TI Emotional reactions in children: Verbal, physiological, and behavioral responses to affective pictures SO PSYCHOPHYSIOLOGY LA English DT Article DE children; startle; emotion; pictures; ratings ID STARTLE REFLEX MODULATION; DEFENSIVE BEHAVIOR; FEAR; ATTENTION; MOTIVATION; GENDER; SYSTEM; PROBE AB Many studies have shown a consistent pattern in adults' responses to affective pictures and there is growing evidence of gender differences, as well. Little is known, though, about children's verbal, behavioral, and physiological responses to affective pictures. Two experiments investigated children's responses to pictures. In Experiment I, children. adolescents, and adults viewed pictures varying in affective content and rated them for pleasure. arousal. and dominance. Results indicated that children and adolescents rated the pictures similarly to adults. In Experiment 2, physiological responses, self-report, and viewing time were measured while children viewed affective pictures. As with adults, children's responses reflected the affective content of the pictures. Gender differences in affective evaluations, corrugator activity, skin conductance, startle modulation, and viewing time indicated that girls were generally mon reactive to unpleasant materials. C1 Univ Florida, Hlth Sci Ctr, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32610 USA. RP McManis, MH (reprint author), Univ Florida, Hlth Sci Ctr, NIMH, Ctr Study Emot & Attent, Box 100165, Gainesville, FL 32610 USA. FU NIA NIH HHS [AG 09779]; NIMH NIH HHS [MH37757, MH43975] NR 40 TC 145 Z9 151 U1 5 U2 27 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-4930 USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2001 VL 38 IS 2 BP 222 EP 231 DI 10.1017/S0048577201991140 PG 10 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 406RJ UT WOS:000167228700008 PM 11347868 ER PT J AU Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Merz, CNB Sopko, G Cornell, CE Matthews, KA AF Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Merz, CNB Sopko, G Cornell, CE Matthews, KA TI Psychosocial variables are associated with atherosclerosis risk factors among women with chest pain: The WISE study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE coronary artery disease; women; psychosocial risk factors ID CORONARY HEART-DISEASE; MIDDLE-AGED WOMEN; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; MAJOR DEPRESSION; CARDIAC EVENTS; ARTERY DISEASE; YOUNG-ADULTS; MORTALITY; HOSTILITY AB Objective: We investigated associations between atherosclerosis risk factors (smoking behavior, serum cholesterol, hypertension, body mass index, and functional capacity) and psychological characteristics with suspected linkages to coronary disease (depression, hostility, and anger expression) in an exclusively female cohort. Methods: Six hundred eighty-eight middle-aged women with chest pain warranting clinical investigation completed a comprehensive diagnostic protocol that included quantitative coronary angiography to assess coronary artery disease (CAD). Primary analyses controlled for menopausal status, age, and socioeconomic status variables (income and education). Results: High depression scores were associated with a nearly three-fold risk of smoking (odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.4-5.7) after covariate adjustment, and women reporting higher depression symptoms were approximately four times more likely to describe themselves in the lowest category of functional capacity (OR = 3.7, 95% CI = 1.7-7.8). High anger-out scores were associated with a four-fold or greater risk of low high-density lipoprotein cholesterol concentration (<50 mg/dl; OR = 4.0, 95% CI = 1.4-11.1) and high Low-density lipoprotein cholesterol concentration (<160 mg/dl; OR = 4.8, 95% CI = 1.5-15.7) and a larger body mass index (OR = 3.5, 95% CI = 1.1-10.8) after covariate adjustment. Conclusions: These results demonstrate consistent and clinically relevant relationships between psychosocial factors and atherosclerosis risk factors among women and may aid our understanding of the increased mortality risk among women reporting high levels of psychological distress. C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Florida, Gainesville, FL USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Alabama, Birmingham, AL USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NHLBI, Bethesda, MD 20892 USA. RP Rutledge, T (reprint author), WISE Coordinating Ctr, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [N01-HV-68163, N01-HV-68161, N01-HV-68162] NR 37 TC 36 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD MAR-APR PY 2001 VL 63 IS 2 BP 282 EP 288 PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 415ZE UT WOS:000167752800013 PM 11292277 ER PT J AU Liakopoulou, M Alifieraki, T Katideniou, A Peppa, M Maniati, M Tzikas, D Hibbs, ED Dacou-Voutetakis, C AF Liakopoulou, M Alifieraki, T Katideniou, A Peppa, M Maniati, M Tzikas, D Hibbs, ED Dacou-Voutetakis, C TI Maternal expressed emotion and metabolic control of children and adolescents with diabetes mellitus SO PSYCHOTHERAPY AND PSYCHOSOMATICS LA English DT Article DE adolescents; children; critical comments; diabetic control; emotional overinvolvement; maternal expressed emotion ID GLUCOSE CONTROL; PSYCHIATRIC-ILLNESS; FAMILY ENVIRONMENT; GLYCEMIC CONTROL; DISORDERS; BEHAVIOR; NONCOMPLIANCE; RELIABILITY; SYMPTOMS; AGE AB Background: The objectives of this study of children and adolescents with diabetes were to: (1) examine whether maternal expressed emotion (EE), in the form of critical comments (CC), hostility and emotional over-involvement (EOI), is related to metabolic control; (2) determine if CC and EOI are separately related to poor metabolic control, and (3) ascertain whether high EE is related to psychopathology in these children. Methods: The Present Episode version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS-P/K-SADS-P) interview was administered to 55 children and adolescents with diabetes and the parental EE instrument, the 5-min speech sample, to 55 mothers. The same instruments were utilized with the 54 controls and their mothers. Glycosylated hemoglobin A1 values were used as a measure of metabolic control. Results: More than half of the children with diabetes (58.2%) had mild to moderate symptoms of anxiety depression as compared to 9.3% of the controls. High EE was exhibited by 70.9% of the index group mothers in contrast to only 29.6% of the control group mothers. High maternal EE was not related to the psychopathology of children with diabetes. High maternal EE and in particular its EOI component and excessive detail (a subcategory of EOI) were related to poor metabolic control of the index children. Conclusions: Maternal EE is related to metabolic control in childhood diabetes; maternal EOI in particular is related to poor metabolic control. Mental health professionals should work with mothers of children with diabetes in an effort to modify such attitudes and emotions. Copyright (C) 2001 S. Karger AG, Basel. C1 Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Child Psychiat, GR-11527 Athens, Greece. Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Child Endocrinol Dept, GR-11527 Athens, Greece. NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. RP Liakopoulou, M (reprint author), Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Child Psychiat, GR-11527 Athens, Greece. NR 38 TC 21 Z9 21 U1 3 U2 6 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0033-3190 J9 PSYCHOTHER PSYCHOSOM JI Psychother. Psychosom. PD MAR-APR PY 2001 VL 70 IS 2 BP 78 EP 85 DI 10.1159/000056230 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 410TQ UT WOS:000167455600003 PM 11244388 ER PT J AU Knopp, MV Lodemann, M Kage, U Runge, VM AF Knopp, MV Lodemann, M Kage, U Runge, VM TI Use of MR-contrast agents outside of their labeled indication SO RADIOLOGE LA German DT Article DE contrast agents; MRI; off-label use ID ARTHROGRAPHY; SHOULDER AB Purpose. The use of MRI contrast agents outside their labeled indications is routine in radiology. However, physicians feel frequently at unease. It is the aim of this paper to introduce the medical, juridicial and billing relevant issues in order to improve the knowledge on this topic. Methods. The basis for off-label use is the physician's prerogative, which finds its basis in the "declaration of Helsinki". Results. Off-label use is allowed under special conditions and might be even the medical state of the art. Conclusion. The necessity for off-label use will continue to increase for MR-contrast agents, as clinical trials for registration purpose are quite costly and manufactures continuously will concentrate on the essential indications. C1 Deutsch Krebsforschungszentrum, Abt Onkol Diagnost & Therapie, Forschungsschwerpunkt Radiol Diagnost & Therapie, D-69120 Heidelberg, Germany. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Univ Kentucky, Dept Radiol, Lexington, KY 40506 USA. RP Knopp, MV (reprint author), Deutsch Krebsforschungszentrum, Abt Onkol Diagnost & Therapie, Forschungsschwerpunkt Radiol Diagnost & Therapie, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. NR 31 TC 4 Z9 5 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-832X J9 RADIOLOGE JI Radiologe PD MAR PY 2001 VL 41 IS 3 BP 296 EP 302 DI 10.1007/s001170050990 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 421JZ UT WOS:000168062400010 PM 11322076 ER PT J AU Doerge, DR Churchwell, MI Chang, HC Newbold, RR Delclos, KB AF Doerge, DR Churchwell, MI Chang, HC Newbold, RR Delclos, KB TI Placental transfer of the soy isoflavone genistein following dietary and gavage administration to Sprague Dawley rats SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE soy; isoflavones; genistein; placental transfer; mass spectrometry ID CHROMATOGRAPHY-MASS-SPECTROMETRY; IN-VITRO; BREAST-CANCER; MAMMARY-GLAND; HUMAN HEALTH; EXPOSURE; PHYTOESTROGENS; ESTROGEN; MECHANISMS; CELLS AB Genistein, the principal soy isoflavone, has estrogenic activity and is widely consumed for putative beneficial health effects. The goal of the present study was to measure placental transfer of genistein in rats as a possible route of developmental exposure. Pregnant Sprague-Dawley rats were administered genistein orally, either by diet or by gavage. Concentrations of genistein aglycone and conjugates were measured in maternal and offspring serum and brain using HPLC with isotope dilution electrospray tandem mass spectrometry. Although fetal or neonatal serum concentrations of total genistein were approximately 20-fold lower than maternal serum concentrations, the biologically active genistein aglycone concentration was only 5-fold lower. Fetal brain contained predominately genistein aglycone at levels similar to those in the maternal brain. These studies show that genistein aglycone crosses the rat placenta and can reach fetal brain from maternal serum genistein levels that are relevant to those observed in humans. (C) 2001 Elsevier Science Inc. All rights reserved. C1 US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NIEHS, Dev Endocrinol Sect, Reprod Toxicol Grp, Lab Toxicol,Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Doerge, DR (reprint author), US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. FU PHS HHS [224-93-0001] NR 24 TC 81 Z9 82 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD MAR-APR PY 2001 VL 15 IS 2 BP 105 EP 110 DI 10.1016/S0890-6238(01)00108-3 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 424ET UT WOS:000168219700001 PM 11297868 ER PT J AU Lacroix, EM AF Lacroix, EM TI How consumers are gathering information from MEDLINEplus SO SCIENCE COMMUNICATION LA English DT Article AB The National Library of Medicine (NLM) introduced MEDLINEplus in October 1998 to help consumers and those who serve them find authoritative, understandable health information on the Internet. MEDLINEplus was designed to be a well-organized, selective Web resource that directs consumers to full-text health information available from NLM, the National Institutes of Health (NIH), and other reliable sources. From the beginning is has been consumer driven; that is, information obtained from studying actual searches done by the public using other NLM Internat resources was used to set priorities for MEDLINEplus. This article summarizes findings from NLM's studies of use data, Web log files, and formal evaluation that help characterize consumers' needs for information. How these findings have been used to improve the interface, functionality, and content of MEDLINEplus will also be described. C1 Natl Lib Med, Publ Serv Div, Bethesda, MD 20894 USA. RP Lacroix, EM (reprint author), Natl Lib Med, Publ Serv Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 3 TC 4 Z9 4 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1075-5470 J9 SCI COMMUN JI Sci. Commun. PD MAR PY 2001 VL 22 IS 3 BP 283 EP 291 DI 10.1177/1075547001022003005 PG 9 WC Communication SC Communication GA 412WE UT WOS:000167576700005 ER PT J AU Wang, Y Hayashi, T Chang, CF Chiang, YH Tsao, LI Su, TP Borlongan, C Lin, SZ AF Wang, Y Hayashi, T Chang, CF Chiang, YH Tsao, LI Su, TP Borlongan, C Lin, SZ TI Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation SO STROKE LA English DT Article DE amphetamines; apoptosis; cerebral ischemia, focal; transforming growth factors ID ISCHEMIC STROKE; RAT-BRAIN; INVOLVEMENT; INFARCTION; RECEPTORS; GDNF; INTOXICATION; INHALATION; APOPTOSIS; OCCLUSION AB Background and Purpose-Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen species formation and activation of apoptotic mechanism. That MA could have a synergistic or additive effect with stroke-induced brain damage is possible. The purpose of the present study was to investigate whether administration of MA in vivo would potentiate ischemic brain injury. Methods-Adult CD-1 mice were pretreated with MA or saline. Each animal later was anesthetized with chloral hydrate and placed in a stereotaxic frame. A subset of animals received intracerebral administration of glial cell line-derived neurotrophic factor (GDNF). The right middle cerebral artery and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by laser Doppler. Animals were sacrificed for triphenyltetrazolium chloride staining and p53 mRNA Northern blot assay after 24 hours of reperfusion, Cortical and striatal GDNF levels were assayed by ELISA. Results-We Found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 mRNA expression. Moreover, MA potentiated expression of p53 mRNA in the ischemic mouse brain. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA-facilitated infarction, Conclusions-Our data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of GDNF-mediated pathways and suggest that MA may antagonize endogenous neuroprotective pathways: as part of its mechanism of action. C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. Tri Serv Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. RP Wang, Y (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 26 TC 41 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2001 VL 32 IS 3 BP 775 EP 782 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 408YK UT WOS:000167354500030 PM 11239201 ER PT J AU Rao, GN AF Rao, GN TI Untitled SO TOXICOLOGIC PATHOLOGY LA English DT Letter ID DIETARY RESTRICTION C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Rao, GN (reprint author), NIEHS, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD MAR-APR PY 2001 VL 29 IS 2 BP 274 EP 275 PG 2 WC Pathology; Toxicology SC Pathology; Toxicology GA 467KC UT WOS:000170700100015 PM 11421497 ER PT J AU Chhabra, RS Herbert, RA Bucher, JR Travlos, GS Johnson, JD Hejtmancik, MR AF Chhabra, RS Herbert, RA Bucher, JR Travlos, GS Johnson, JD Hejtmancik, MR TI Toxicology and carcinogenesis studies of p,p '-dichlorodiphenyl sulfone in rats and mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE p,p '-dichlorodiphenyl sulfone; liver toxicity; kidney toxicity; centrilobular hepatic hypertrophy; p,p '-dichlorodiphenyl sulfone carcinogenicity ID ENZYME-INDUCTION; LIVER; SAMPLES; PROMOTION; TESTS AB p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Battelle Labs, Columbus, OH 43201 USA. RP Chhabra, RS (reprint author), Natl Inst Environm Hlth Sci, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 33 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2001 VL 60 IS 1 BP 28 EP 37 DI 10.1093/toxsci/60.1.28 PG 10 WC Toxicology SC Toxicology GA 407HY UT WOS:000167267200007 PM 11222870 ER PT J AU George, JD Price, CJ Marr, MC Myers, CB Jahnke, GD AF George, JD Price, CJ Marr, MC Myers, CB Jahnke, GD TI Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats SO TOXICOLOGICAL SCIENCES LA English DT Article DE isoeugenol; developmental toxicity; teratogenicity; rats; morphological development ID EUGENOL DERIVATIVES; CONSTITUENTS; FRAGRANCES; COMPONENTS; COSMETICS; ALLERGY; MICE AB Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and similar to 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at greater than or equal to 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Toxicol Program, Dev & Reprod Toxicol Grp, Res Triangle Pk, NC 27709 USA. RP George, JD (reprint author), Res Triangle Inst, Hermann Lab Bldg,3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES-65405] NR 63 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAR PY 2001 VL 60 IS 1 BP 112 EP 120 DI 10.1093/toxsci/60.1.112 PG 9 WC Toxicology SC Toxicology GA 407HY UT WOS:000167267200015 PM 11222878 ER PT J AU Dykstra, ML Cherukuri, A Pierce, SK AF Dykstra, ML Cherukuri, A Pierce, SK TI Floating the raft hypothesis for immune receptors: Access to rafts controls receptor signaling and trafficking SO TRAFFIC LA English DT Review DE B lymphocyte; lipid rafts; multichain immune recognition receptors; signaling; trafficking ID CELL ANTIGEN RECEPTOR; IMMATURE B-CELLS; LIPID RAFTS; LYMPHOCYTE ACTIVATION; MEMBRANE RAFTS; COMPLEX; TRANSDUCTION; MOLECULES; ENTRY AB The B cell antigen receptor (BCR) is a member of an important family Of multichain immune recognition receptors, which are complexes composed of ligand-binding domains associated with signal-transduction complexes. The signaling components of these receptors have no inherent kinase activity but become tyrosine phosphorylated in their cytoplasmic domains by Src-family kinases upon oligomerization, thus initiating signaling cascades. The BCR is unique in this family in that, in addition to its signaling function, it also serves to deliver antigen to intracellular compartments where the antigen is processed and presented bound to major histocompatibility complex (MHC) class II molecules. Recent evidence indicates that both the signaling and antigen-trafficking functions of the BCR are regulated by cholesterol- and sphingolipid-rich plasma membrane microdomains termed rafts. Indeed, upon oligomerization, the BCR translocates into rafts that concentrate the Src-family kinase Lyn and is subsequently internalized directly from the rafts. Thus, translocation into rafts allows the association of the oligomerized BCR with Lyn and the initiation of both signaling and trafficking. Significantly, the access of the BCR to rafts appears to be controlled by a variety of B lymphocyte co-receptors, as well as factors including the developmental state of the B cell and viral infection. Thus, the translocation of the immune receptors into signaling-competent microdomains may represent a novel mechanism to initiate and regulate immune-cell activation. C1 NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. NR 35 TC 49 Z9 50 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD MAR PY 2001 VL 2 IS 3 BP 160 EP 166 DI 10.1034/j.1600-0854.2001.020302.x PG 7 WC Cell Biology SC Cell Biology GA 465TG UT WOS:000170605600002 PM 11260521 ER PT J AU Ghedin, E Debrabant, A Engel, JC Dwyer, DM AF Ghedin, E Debrabant, A Engel, JC Dwyer, DM TI Secretory and endocytic pathways converge in a dynamic endosomal system in a primitive protozoan SO TRAFFIC LA English DT Article DE endocytic pathway; GFP chimeras; Leishmania; secretory pathway; trafficking ID LEISHMANIA-DONOVANI; MEMBRANE; GOLGI; SURFACE; PARASITES; TRYPANOSOMATIDS; ORGANIZATION; AMASTIGOTE; LYSOSOMES; TRANSPORT AB Leishmania are a group of primitive eukaryotic trypanosomatid protozoa that are apically polarized with a flagellum at their anterior end. Surrounding the base of the flagellum is the flagellar reservoir that constitutes the site for endocytosis and exocytosis in these organisms. In the present study, we define a novel multivesicular tubular compartment involved in the intracellular trafficking of macromolecules in Leishmania. This dynamic structure appears to subtend the flagellar reservoir and extends towards the posterior end of the cell. Functional domains of several surface-expressed proteins, such as the gp63 glycosyl phosphatidyl inositol anchor and the 3' nucleotidase/nuclease transmembrane domain were fused to green fluorescent protein. These chimeric proteins were found to traffic through the secretory pathway and, while reaching their intended destinations, also accumulated within the intracellular tubular compartment. Using various compounds that are efficient fluid-phase markers used to track endocytosis in higher eukaryotes, we showed that this tubular compartment constitutes an important station in the endocytic pathway of these cells. Based on our functional observations of its role in the trafficking of expressed proteins and endocytosed markers, this compartment appears to have properties similar to endosomes of higher eukaryotes. C1 NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, Bethesda, MD 20892 USA. US FDA, Lab Parasite Biol & Biochem, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Univ Calif San Francisco, Vet Adm Med Ctr, Dept Pathol, San Francisco, CA 94121 USA. RP Dwyer, DM (reprint author), NIAID, Cell Biol Sect, Parasit Dis Lab, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 54 Z9 54 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD MAR PY 2001 VL 2 IS 3 BP 175 EP 188 DI 10.1034/j.1600-0854.2001.020304.x PG 14 WC Cell Biology SC Cell Biology GA 465TG UT WOS:000170605600004 PM 11260523 ER PT J AU Bustin, M AF Bustin, M TI Revised nomenclature for high mobility group (HMG) chromosomal proteins SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Letter C1 NCI, NIH, Bethesda, MD 20892 USA. RP Bustin, M (reprint author), NCI, NIH, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 NR 0 TC 248 Z9 277 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2001 VL 26 IS 3 BP 152 EP 153 DI 10.1016/S0968-0004(00)01777-1 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432WY UT WOS:000168719800007 PM 11246012 ER PT J AU Wolfsberg, TG Schafer, S Tatusov, RL Tatusova, TA AF Wolfsberg, TG Schafer, S Tatusov, RL Tatusova, TA TI Organelle genome resources at NCBI SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Editorial Material ID MITOCHONDRIAL-DNA; DATABASE; EVOLUTION; UPDATE C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wolfsberg, TG (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 14 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD MAR PY 2001 VL 26 IS 3 BP 199 EP 203 DI 10.1016/S0968-0004(00)01773-4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 432WY UT WOS:000168719800023 PM 11339208 ER PT J AU Le Roith, D Scavo, L Butler, A AF Le Roith, D Scavo, L Butler, A TI What is the role of circulating IGF-I? SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID GROWTH-FACTOR-I; MESSENGER RIBONUCLEIC-ACID; HORMONE-RELEASING HORMONE; LONGITUDINAL BONE-GROWTH; FACTOR BINDING PROTEIN-3; STEM-CELLS; TISSUE CONCENTRATIONS; TRANSGENIC MICE; INSULIN; GENE AB Postnatal growth and development are coordinated by genetic and environmental influences and numerous growth factors. The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays an essential role in these processes. Although the GH-IGF-I axis is a closely coordinated system, both GH and IGF-I have independent actions, many of which have become apparent more recently following the characterization of clinical syndromes and the development of mouse models. Genetic manipulation of mice has enabled investigators to re-examine many of the established hypotheses regarding the GH-IGF-I axis. Results gleaned from a mouse model created by tissue-specific gene deletion of liver IGF-I has enabled investigators to re-evaluate the original 'somatomedin hypothesis'. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Le Roith, D (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 48 TC 105 Z9 108 U1 1 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2001 VL 12 IS 2 BP 48 EP 52 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432XG UT WOS:000168720600001 PM 11167121 ER PT J AU Lichten, M AF Lichten, M TI Describing recombination SO TRENDS IN GENETICS LA English DT Letter C1 NCI, DBS, LB, Bethesda, MD 20892 USA. RP Lichten, M (reprint author), NCI, DBS, LB, Bldg 37,Room 4C03,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD MAR PY 2001 VL 17 IS 3 BP 135 EP 135 DI 10.1016/S0168-9525(00)02182-X PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 432WF UT WOS:000168718200006 PM 11314655 ER PT J AU Dalgaard, JZ Klar, AJS AF Dalgaard, JZ Klar, AJS TI Does S. pombe exploit the intrinsic asymmetry of DNA synthesis to imprint daughter cells for mating-type switching? SO TRENDS IN GENETICS LA English DT Review ID FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; REPLICATION; GENES; STRANDS; FATE; RECOMBINATION; INHERITANCE; INITIATION; FREQUENCY AB Typically cell division is envisaged to be symmetrical, with both daughter cells being identical. However, during development and cellular differentiation, asymmetrical cell divisions have a crucial role. In this article, we describe a model of how Schizosaccharomyces pombe exploits the intrinsic asymmetry of DNA replication machinery-the difference between the replication of the leading strand and the lagging strand-to establish an asymmetrical mating-type switching pattern. This is the first system where the direction of DNA replication is involved in the formation of differentiated chromosomes. The discovery raises the possibility that DNA replication might be more generally involved in the establishment of asymmetric cellular differentiation. C1 Marie Curie Res Inst, Surrey RH8 0TL, England. NCI, DHHS, DBS, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Dalgaard, JZ (reprint author), Marie Curie Res Inst, Chart, Surrey RH8 0TL, England. NR 35 TC 35 Z9 35 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD MAR PY 2001 VL 17 IS 3 BP 153 EP 157 DI 10.1016/S0168-9525(00)02203-4 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 432WF UT WOS:000168718200011 PM 11226610 ER PT J AU Pedersen, LC Darden, TA Kakuta, Y Negishi, M AF Pedersen, LC Darden, TA Kakuta, Y Negishi, M TI Crystal structure-based analysis of human glucuronyltransferase 1 SO TRENDS IN GLYCOSCIENCE AND GLYCOTECHNOLOGY LA English DT Review DE glucuronyltransferase I; heparan/chondroitin biosynthesis; X-ray crystallography; substrate specificity; catalytic mechanism ID HEPARAN-SULFATE; BIOSYNTHESIS; DOMAIN; N-DEACETYLASE/N-SULFOTRANSFERASE-1; MECHANISM; EXT1 AB Glucuronyltransferase I (GlcAT-I) is a key enzyme in heparan/chondroitin biosynthesis (1). The X-ray crystal structure of human GlcAT-1 has been solved in the presence of both UDP and substrate analog. The structure reveals a two subdomain structure known as the SGC domain. Donor substrate-binding site resides in the N-terminal sub-domain, while acceptor substrate-binding site is located in the C-terminal sub-domain. In addition to conserved residues responsible for the donor binding, various residues that interact with the acceptor molecule have now been identified. The GlcAT-1 provides the structural basis for understanding the structure and function of glycosyltransferases. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Osaka Univ, Dept Biol, Grad Sch Sci, Toyonaka, Osaka 560, Japan. EM negishi@niehs.nih.gov NR 16 TC 1 Z9 1 U1 0 U2 0 PU GAKUSHIN PUBL CO PI TOKYO PA YUSHOKAIN7F, 1-38-12 NIHONBASHIKAKIGARACHO, CHUO-KU, TOKYO, 103-0014, JAPAN SN 0915-7352 J9 TRENDS GLYCOSCI GLYC JI Trends Glycosci. Glycotechnol. PD MAR PY 2001 VL 13 IS 70 BP 121 EP 129 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 440RF UT WOS:000169187500002 ER PT J AU Adams, SD Barracchini, KC Simonis, TB Stroncek, D Marincola, FM AF Adams, SD Barracchini, KC Simonis, TB Stroncek, D Marincola, FM TI High throughput HLA sequence-based typing (SBT) utilizing the ABI Prism (R) 3700 DNA analyzer SO TUMORI LA English DT Article; Proceedings Paper CT International Symposium on Blood Transfusion in Oncology CY OCT 19-21, 2000 CL MILAN, ITALY SP Assoc Donatori Sangue Ist Nazl Tumori DE sequenced based typing (SBT); polymerase chain reaction (PCR); sequence specific primers (SSP) ID PRIMERS PCR-SSP; ALLELES; IDENTIFICATION; POLYMORPHISM AB Aims and background: The genetic complexity of the human major histocompatibility complex (MHC) has required the development of various molecular typing methods. The purpose of this paper is to compare the results of two of these molecular methods: sequenced based typing (SBT) and polymerase chain reaction (PCR) using sequence specific primers (PCR-SSP). Methods: The SET method described utilizes an ABI Prism (R) 3700 DNA Analyzer, which has been designed fro high throughput production of sequence data through highly automated operation with significant walk-away time. The ABI Prism (R) 3700 DNA Analyzer is a 96-capillary electrophoresis instrument with the capability of running four 96-well plates black to back in a sixteen-hour period. Potentially, data from this machine can produce Class I sequences for A or B loci for 64 samples in this time frame. The SET method encompassed exons 2, 3, and 4 with forward and reverse sequence orientation reactions using the PE Biosystems HLA-A and HLA-B Sequenced Based Typing Kits (PE Applied Biopsystems/Perkin-Elmer, Foster City, CA, USA). Most SET methods previously employed only gather data from exons 2 and 3 which distinguishes most of the polymorphism necessary to identify the majority of alleles in the HLA region. However, in an effort to discern numerous null alleles in the HLA region, exon 4 data is also included. The PCR-SSP method utilized consists of one 96 well tray, with 95 primer mixes and one negative control, per sample designed to produce an intermediate/high resolution HLA-A, B typing. Results: Data from one 96-well capillary run on the ABI Prism (R) 3700 DNA Analyzer, which consists of results from 16 samples for HLA-A or HLA-B loci. was compared to data derived sixteen HLA-A and HLA-B PCR-SSP typings. 75% of loci tested achieved a higher resolution HLA typing by the SET method. Discussion: The ability to provide allele level HLA typing results can have significant functional implications for the bone marrow transplant community and numerous vaccine studies. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, HLA Lab, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Adams, SD (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, HLA Lab, 10 Ctr Dr,MSC 1184,Bldg 10,Room 1C744, Bethesda, MD 20892 USA. NR 8 TC 8 Z9 10 U1 0 U2 0 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA BRADANO 3/C, 00199 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD MAR-APR PY 2001 VL 87 IS 2 BP S40 EP S43 PG 4 WC Oncology SC Oncology GA 435NC UT WOS:000168886700024 PM 11401225 ER PT J AU Klein, HG AF Klein, HG TI The immunomodulatory effects of blood transfusion SO TUMORI LA English DT Article; Proceedings Paper CT International Symposium on Blood Transfusion in Oncology CY OCT 19-21, 2000 CL MILAN, ITALY SP Assoc Donatori Sangue Ist Nazl Tumori ID DISEASE; CELLS; MICROCHIMERISM; RECIPIENTS; RECURRENCE; INFECTION; SURVIVAL; SURGERY; WOMEN C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Klein, HG (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Rm 1C-711, Bethesda, MD 20892 USA. NR 19 TC 3 Z9 3 U1 0 U2 1 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA BRADANO 3/C, 00199 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD MAR-APR PY 2001 VL 87 IS 2 BP S17 EP S19 PG 3 WC Oncology SC Oncology GA 435NC UT WOS:000168886700017 PM 11401217 ER PT J AU Hunt, KJ Sharrett, AR Chambless, LE Folsom, AR Evans, GW Heiss, G AF Hunt, KJ Sharrett, AR Chambless, LE Folsom, AR Evans, GW Heiss, G TI Acoustic shadowing on B-mode ultrasound of the carotid artery predicts CHD SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE carotid arteries; coronary disease; incidence; risk factors; ultrasonography; acoustic shadowing ID CORONARY HEART-DISEASE; HUMAN ATHEROSCLEROTIC PLAQUES; OSTEOPONTIN MESSENGER-RNA; BEAM COMPUTED-TOMOGRAPHY; RISK-FACTORS; TISSUE CHARACTERIZATION; ATHEROMATOUS PLAQUES; MEDIAL THICKNESS; SMOOTH-MUSCLE; CALCIFICATION AB The relationship between carotid artery lesions (CALs), with and without acoustic shadowing (AS) as an index of arterial mineralization, and incident coronary heart disease (CHD) was examined in the Atherosclerosis Risk in Communities study cohort. Among 12,375 individuals, ages 45-64 years, free of CHD at baseline, 399 CHD events occurred between 1987-1995, In a 3-cm segment centered at the carotid bifurcation, CALs with and without AS mere identified by B-mode ultrasound (US), After adjustment for the major CHD risk factors, the CHD hazard ratio (HR) for women with CAL without AS compared to women without CAL was 1.78 (95% CI: 1.22, 2.60) and the HR comparing women with CAL with AS to women with CAL without AS was 1.73 (95% CI: 1.07, 2.80), Corresponding HRs for men were 1.59 (95% CI: 1.22, 2.07) and 1.04 (95% CI: 0.72, 1.51), CALs predicted CHD events; this association was stronger for mineralized CALs in women, but not men. (C) 2001 World Federation for Ultrasound in Medicine & Biology. C1 Univ N Carolina, Dept Epidemiol, CVD Program, Bank Amer, Chapel Hill, NC 27514 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Wake Forest Univ, Baptist Med Ctr, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP Heiss, G (reprint author), Univ N Carolina, Dept Epidemiol, CVD Program, Bank Amer, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55019, 5T32-HL07055, N01-HC-55015, N01-HC-55020, N01-HC-55016, N01-HC-55018, N01-HC-55021] NR 37 TC 31 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD MAR PY 2001 VL 27 IS 3 BP 357 EP 365 DI 10.1016/S0301-5629(00)00353-7 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 428ZB UT WOS:000168490600005 PM 11369121 ER PT J AU Watson, RP Blanchard, TW Mense, MG Gasper, PW AF Watson, RP Blanchard, TW Mense, MG Gasper, PW TI Histopathology of experimental plague in cats SO VETERINARY PATHOLOGY LA English DT Article DE bubonic plague; cats; histopathology; immunohistochemistry; lymph node; pneumonic plague; sylvatic plague; Yersinia pestis; zoonoses ID YERSINIA-PESTIS INFECTION; PNEUMONIC PLAGUE; DOMESTIC CAT; CALIFORNIA; DOGS; SURVEILLANCE; DISEASE AB Formalin-fixed paraffin-embedded archival tissues of seven adult cats of both sexes that died after being experimentally infected with Yersinia pestis were examined light microscopically to characterize the lesions. The cats were exposed in two groups using two routes of infection: ingestion of Y. pestis-infected rodent or a subcutaneous injection of Y. pestis to simulate a flea bite. Immunohistochemistry was performed on tissues from all organ systems from a representative cat from each group to determine the distribution of Y. pestis bacilli during infection. In all seven cats, bubonic plague lesions were seen. The lesions of pneumonic plague were present in two cats. Septicemic plague was confirmed in all seven cats by bacteriologic culture. Aggregations of bacteria were seen in lymphoid tissue in all cats and in lung tissues from the two cats with pneumonic plague. The most consistent histologic finding was necrosuppurative inflammation in the lymph nodes. Invariably, Y. pestis bacteria were present in large numbers at affected sites. Orally infected cats had more numerous lesions in the lymph nodes of the head and neck regions. These experimentally induced cases of feline plague document that cats are unique among carnivores in exhibiting bubonic, pneumonic, and septicemic plague following exposure to Y. pestis. The lesions of the orally infected cats were consistent with those previously described for naturally occurring Y. pestis infections in cats and corroborate the contention that cats most commonly contract plague by eating Y. pestis-infected rodents and not via flea bite. The histopathology of Y, pestis disease in these cats is comparable to that described for human plague. C1 Univ Maryland, Avrum Gudelsky Ctr Vet Med, Dept Pathol, College Pk, MD 20742 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. RP Gasper, PW (reprint author), NIA, Gerontol Res Ctr, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 14 Z9 15 U1 0 U2 2 PU AMER COLL VET PATHOLOGIST PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2001 VL 38 IS 2 BP 165 EP 172 DI 10.1354/vp.38-2-165 PG 8 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 410LH UT WOS:000167441100004 PM 11280372 ER PT J AU Chernyak, A Karavanov, A Ogawa, Y Kovac, P AF Chernyak, A Karavanov, A Ogawa, Y Kovac, P TI Conjugating oligosaccharides to proteins by squaric acid diester chemistry: rapid monitoring of the progress of conjugation, and recovery of the unused ligand SO CARBOHYDRATE RESEARCH LA English DT Article DE neoglycoconjugate; molecular mass determination; squaric acid derivatives; Vibrio cholerae O : 1; SELDI-TOF MS/ProteinChip((R)) ID VIBRIO-CHOLERAE O-1; MASS-SPECTROMETRY; COUPLING REAGENT; DIETHYL SQUARATE; SEROTYPE OGAWA; POLYSACCHARIDE; MS; DETERMINANT; GLYCOSIDES; VACCINES AB Samples that are periodically withdrawn from the mixture of a conjugation reaction can be analyzed on a picomolar scale without any work-up or pre-purification using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) in combination with the ProteinChipo(R) System. The technique provides rapid information about the increasing molecular mass of the glycoconjugate formed, thereby allowing termination of the process when the desired incorporation of the ligand onto the carrier protein is achieved. The excess oligosaccharide used at the onset of conjugation can be recovered and used in preparation of a similar neoglycoconjugate. The overall economy of conjugations, which often involve labor-intensive linker-equipped oligosaccharides, can be markedly increased in this way. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Ciphergen Biosyst Inc, Fremont, CA 94555 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Karavanov, A (reprint author), Ciphergen Biosyst Inc, 6611 Dumbarton Circle, Fremont, CA 94555 USA. NR 24 TC 62 Z9 66 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD FEB 28 PY 2001 VL 330 IS 4 BP 479 EP 486 DI 10.1016/S0008-6215(01)00018-0 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 407AB UT WOS:000167248300005 PM 11269399 ER PT J AU Engle, MR Singh, SP Nanduri, B Ji, XH Zimniak, P AF Engle, MR Singh, SP Nanduri, B Ji, XH Zimniak, P TI Invertebrate glutathione transferases conjugating 4-hydroxynonenal: CeGST 5.4 from Caenorhabditis elegans SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT International Conference on Glutathione Transferases CY MAY 19-23, 2000 CL UPPSALA, SWEDEN SP Uppsala Univ, Swedish Chem Soc, Swedish Natl Comm Chem, Royal Swedish Acad Sci, Wenner Gren Ctr Fdn, Swedish Res Council Engn Sci, Swedish Nat Sci Res Council, Swedish Med Res Council, Swedish Canc Soc, Schering Plough Res Inst, F Hoffman La Roche, Astra Zeneca, Elsevier Sci BV, Telik Inc, Pharmacia Corp DE glutathione transferase; 4-hydroxynonenal; oxidative stress; Caenorhabditis elegans ID HETEROLOGOUS EXPRESSION; ENZYME; CDNA; 4-HYDROXYALK-2-ENALS; IDENTIFICATION; CLONING; GST-5.7 AB Formation of 4-hydroxyalkenals appears to be an obligatory consequence of aerobic metabolism, especially respiration. Mammals have evolved a special group of alpha -class GSTs with high catalytic activity towards 4-hydroxyalkenals, We now identified an invertebrate (Caenorhabditis elegans) GST with the same activity, named CeGST 5.4. The enzyme is closely related to the pi class of GSTs. This finding demonstrates that conjugation of 4-hydroxyalkenals is phylogenetically widespread and thus probably physiologically essential, at least in aerobes. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Internal Med, Little Rock, AR 72205 USA. NCI, Biomol Struct Sect, Macromol Crystallog Lab, FCRDC, Frederick, MD 21702 USA. RP John L McClellan Mem Vet Adm Med Ctr, 4300 W 7th St, Little Rock, AR 72205 USA. EM zimniakpiotr@exchange.uams.edu RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 NR 17 TC 7 Z9 9 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD FEB 28 PY 2001 VL 133 IS 1-3 SI SI BP 244 EP 248 PG 5 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 424QY UT WOS:000168244000070 ER PT J AU Caughey, B AF Caughey, B TI Prion protein interconversions SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Discussion Meeting on Protein Misfolding and Disease CY FEB 23-24, 2000 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE prion; transmissible spongiform encephalopathies; structure; conversion; Creutzfeldt-Jakob disease; bovine spongiform encephalopathy ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE-ASSOCIATED FORM; CELL-FREE CONVERSION; RESISTANT STATE; NEUROBLASTOMA-CELLS; CULTURED-CELLS; PRP; INHIBITION; PHTHALOCYANINES; SUSCEPTIBILITY AB The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neuro-degenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease-associated, protease-resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti-TSE drugs. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. NR 41 TC 15 Z9 17 U1 0 U2 2 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD FEB 28 PY 2001 VL 356 IS 1406 BP 197 EP 200 DI 10.1098/rstb.2000.0765 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 406XL UT WOS:000167241400016 PM 11260800 ER PT J AU Katakai, K Liu, J Nakajima, K Keefer, LK Waalkes, MP AF Katakai, K Liu, J Nakajima, K Keefer, LK Waalkes, MP TI Nitric oxide induces metallothionein (MT) gene expression apparently by displacing zinc bound to MIT SO TOXICOLOGY LETTERS LA English DT Article DE diethylenetriamine nitric oxide adduct; DETA/NO; zinc; metallothionein; TRL1215 cells; G-75 gel-filtration ID SULFUR CLUSTERS; RELEASE; METAL AB The metal binding protein metallothionein (MT) is involved in zinc homeostasis since it typically binds large amounts of zinc. Free zinc can control MT gene expression by interacting with metal-sensitive transcription factors. However, the precise factors governing intracellular release of metal ions from MT remain unknown. Aerobic nitric oxide (NO) can nitrosate thiol groups in proteins, and MT-bound cadmium is released by NO exposure. Thus, we hypothesized that NO may also be effective at displacing zinc from MT in cultured cells and that this could be an important physiological control mechanism in zinc homeostasis and utilization. In this study, DETA/NO, an agent that spontaneously generates NO with a 20-h half life in physiological media, was used to study the release of zinc from MT and the induction of MT in TRL1215 cells (a normal rat liver cell line). Zinc or cadmium was given at levels inducing MT production, followed by DETA/NO (20-200 muM) to produce controlled NO exposure in both cell lines. Although both metals activated MT gene expression, MT-I mRNA and MT protein were further increased when DETA/NO was given after zinc or cadmium treatment. Additionally. NO from DETA/NO clearly displaced MT-bound zinc, as evidenced by G-75 gel-filtration chromatography. The released zinc or cadmium probably then stimulates Further MT gene expression These results suggest that NO may play an important role in regulation of cellular zinc homeostasis by providing a controlled release mechanism for metal ions stored in MT, and NO-mediated release of MT-bound zinc could in turn activate gene expression, such as with the MT gene. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. Otsuka Amer Pharmaceut Inc, Rockville, MD USA. NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Comparat Carcinogenesis Lab, NCI, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 16 TC 41 Z9 43 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD FEB 28 PY 2001 VL 119 IS 2 BP 103 EP 108 DI 10.1016/S0378-4274(00)00301-5 PG 6 WC Toxicology SC Toxicology GA 412VZ UT WOS:000167576200003 PM 11311571 ER PT J AU Evans, TG McElrath, MJ Matthews, T Montefiori, D Weinhold, K Wolff, M Keefer, MC Kallas, EG Corey, L Gorse, GJ Belshe, R Graham, BS Spearman, PW Schwartz, D Mulligan, MJ Goepfert, P Fast, P Berman, P Powell, M Francis, D AF Evans, TG McElrath, MJ Matthews, T Montefiori, D Weinhold, K Wolff, M Keefer, MC Kallas, EG Corey, L Gorse, GJ Belshe, R Graham, BS Spearman, PW Schwartz, D Mulligan, MJ Goepfert, P Fast, P Berman, P Powell, M Francis, D CA NIAID AIDS Vaccine Evaluation Grp TI QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immmunization in humans SO VACCINE LA English DT Article; Proceedings Paper CT 5th Conference on Retroviruses and Opportunistic Infections CY FEB 01-05, 1998 CL CHICAGO, ILLINOIS DE QS-21; gp120 HIV-1MN protein; immunization ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE RESPONSES; SAPONIN ADJUVANT; IMMUNE-RESPONSES; RECOMBINANT GLYCOPROTEIN-120; NEUTRALIZING ANTIBODIES; SERONEGATIVE VOLUNTEERS; CONJUGATE VACCINE; HEPATITIS-B; IMMUNOGENICITY AB Three separate studies were undertaken in HIV-1 uninfected persons to determine if the adjuvant QS-21 improves the magnitude or kinetics of immune responses induced by recombinant soluble gp120 HIV-1(MN) protein (rsgp120) immunization. The QS-21 was administered at two doses (50 and 100 mug), either alone or in combination with aluminum hydroxide (600 mug). At the highest doses of rsgp120 (100, 300, and 600 mug). QS-21 exerted no significant effect on either binding or neutralizing antibody titers. Antibody binding and neutralizing responses fell dramatically when rsgp120, formulated with alum alone, was given at low doses (3 and 30 mug). In contrast, antibody responses similar in titer to those in the high dose antigen groups were induced with the low dose rsgp120 formulated with QS-21. In addition, the lymphocyte proliferation and delayed type hypersensitivity skin testing were superior in the QS-21 recipients compared with the alum recipients at the low antigen doses. Moderate to severe pain was observed in majority of the volunteers receiving QS-21 formulations, and vasovagal episodes and hypertension were not infrequent. Thus, the use of QS-21 may provide a means to reduce the dose of a soluble protein immunogen. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Rochester, Sch Med & Dent, Rochester, NY USA. Univ Washington, Sch Med, Seattle, WA USA. Duke Univ, Med Ctr, Durham, NC USA. EMMES Corp, Potomac, MD USA. St Louis VA Med Ctr, St Louis, MO USA. St Louis Univ, Sch Med, St Louis, MO USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Alabama, Birmingham, AL USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. VaxGen Corp, San Francisco, CA USA. RP Evans, TG (reprint author), Div Infect Dis, PSSB Suite 500,4150 V St, Sacramento, CA 95817 USA. RI Kallas, Esper/C-9539-2012 FU NIAID NIH HHS [AI-82500, N01 AI-45208, N01 AI-45209, N01 AI-45210, N01 AI-45211, N01 AI-45212, N01 AI-65305] NR 48 TC 90 Z9 95 U1 2 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 28 PY 2001 VL 19 IS 15-16 BP 2080 EP 2091 DI 10.1016/S0264-410X(00)00415-1 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 412DF UT WOS:000167538200029 PM 11228380 ER PT J AU Wojtuszewski, K Hawkins, ME Cole, JL Mukerji, I AF Wojtuszewski, K Hawkins, ME Cole, JL Mukerji, I TI HU binding to DNA: Evidence for multiple complex formation and DNA bending SO BIOCHEMISTRY LA English DT Article ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; SITE-SPECIFIC BINDING; HISTONE-LIKE PROTEINS; ESCHERICHIA-COLI HU; CRUCIFORM DNA; BACILLUS-STEAROTHERMOPHILUS; FLUORESCENCE ANISOTROPY; RESOLUTION STRUCTURE; ENERGY-TRANSFER; IHF AB HU, a nonspecific histone-like DNA binding protein, participates in a number of genomic events as an accessory protein and forms multiple complexes with DNA. The HU-DNA binding interaction was characterized by fluorescence, generated with the guanosine analogue 3-methyl-8-(2-deoxy-beta -D-ribofuranosyl)isoxanthopterin (3-MI) directly incorporated into DNA duplexes. The stoichiometry and equilibrium binding constants of complexes formed between HU and 13 and 34 bp DNA duplexes were determined using fluorescence anisotropy and analytical ultracentrifugation. These measurements reveal that three HU molecules bind to the 34 bp duplexes, while two HU molecules bind to the 13 bp duplex. The data are well described by an independent binding site model, and the association constants for the first binding event for both duplexes are similar(similar to1 x 10(6) M-1), indicating that HU binding affinity is independent of duplex length. Further analysis of the binding curves in terms of a nonspecific binding model is indicative that HU binding to DNA exhibits little to no cooperativity. The fluorescence intensity also increases upon HU binding, consistent with decreased base stacking and increased solvent exposure of the 3-MI fluorescence probe. These results are suggestive of a local bending or unwinding of the DNA. On the basis of these results we propose a model in which bending of DNA accompanies HU binding. Up to five complex bands are observed in gel mobility shift assays of HU binding to the 34 bp duplexes. We suggest that protein-induced bending of the DNA leads to the observation of complexes in the gel, which have the same molecular weight but different relative mobilities. C1 Wesleyan Univ, Dept Mol Biol & Biochem, Mol Biophys Program, Middletown, CT 06459 USA. NCI, Pediat Branch, Bethesda, MD 20892 USA. Merck Res Labs, Dept Antiviral Res, W Point, PA 19486 USA. RP Mukerji, I (reprint author), Wesleyan Univ, Dept Mol Biol & Biochem, Mol Biophys Program, Middletown, CT 06459 USA. RI Cole, James/G-2586-2011 FU NIGMS NIH HHS [IT32-GM08271] NR 42 TC 69 Z9 70 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 27 PY 2001 VL 40 IS 8 BP 2588 EP 2598 DI 10.1021/bi002382r PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404VA UT WOS:000167121500032 PM 11327882 ER PT J AU Zhu, JH Quyyumi, AA Rott, D Csako, G Wu, HS Halcox, J Epstein, SE AF Zhu, JH Quyyumi, AA Rott, D Csako, G Wu, HS Halcox, J Epstein, SE TI Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease - Evidence for an autoimmune component of atherogenesis SO CIRCULATION LA English DT Article DE coronary disease; proteins; immunology ID SERUM ANTIBODIES; ENDOTHELIAL CYTOTOXICITY; CAROTID ATHEROSCLEROSIS; ESCHERICHIA-COLI; HEAT-SHOCK-PROTEIN-65; IMMUNIZATION; AUTOANTIBODIES; MACROPHAGES; LESIONS; RABBITS AB Background-Antibodies to mycobacterial heat-shock protein (HSP) 65 have been reported to be associated with carotid artery thickening. We examined whether antibodies to human HSP60 are associated with the risk of coronary artery disease (CAD). Methods and Results-Blood samples from 391 patients (62% men, mean age 57 years) being evaluated for CAD by coronary angiography were tested for IgG antibodies to human HSP60 by ELISA. We found that 75% of the study subjects had anti-HSP60 antibodies. The prevalence of CAD was increased in seropositive compared with seronegative patients (68% versus 49%, P=0.0009). Mean titers of HSP60 antibodies were higher in CAD patients than in non-CAD patients (P=0.008). No association between HSP60 antibodies and infection or inflammation was found. Importantly, HSP60 antibodies were related to disease severity. The prevalence of HSP60 antibodies was 76%, 80%, and 85% in patients with 1-, 2-, and 3-vessel disease, compared with 64% in patients without CAD (P for trend=0.003). A similar association between increasing antibody titers and number of diseased vessels was also found (P=0.03). Significant associations between antibodies to HSP60 and CAD severity persisted after adjustment for traditional risk factors by age, race, sex, smoking, diabetes, hypercholesterolemia, hypertension, and C-reactive protein levels. Adjusted OR for number of vessels diseased was 1.86 (95% CI 1.13 to 3.04). Conclusions-This is the first study demonstrating a significant association between human HSP60 antibodies and both the presence and severity of CAD. C1 Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. NHLBI, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Zhu, JH (reprint author), Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, 110 Irving St NW,Suite 4B-1, Washington, DC 20010 USA. OI Halcox, Julian/0000-0001-6926-2947 NR 23 TC 151 Z9 161 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 27 PY 2001 VL 103 IS 8 BP 1071 EP 1075 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NW UT WOS:000167562100017 PM 11222468 ER PT J AU Chalela, JA Wolf, RL Maldjian, JA Kasner, SE AF Chalela, JA Wolf, RL Maldjian, JA Kasner, SE TI MRI identification of early white matter injury in anoxic-ischemic encephalopathy SO NEUROLOGY LA English DT Article ID DIFFUSION; STROKE AB Background: Anoxic-ischemic encephalopathy (AIE) affects the gray matter more than the white matter. Recent animal experiments suggest that the white matter is more sensitive to ischemia than previously thought. The authors describe the MRI findings in seven patients with AIE who demonstrate early preferential involvement of the white matter. Materials and methods: A retrospective case series study was performed, including seven patients with AIE who underwent MRI of the brain within 7 days of insult. Demographic information, type of insult, clinical. examination findings, EEG findings, and clinical outcome were obtained. MRI studies were reviewed with specific attention to the cortex, deep gray matter, and the white matter structures. Mean apparent diffusion coefficient (ADC) was calculated in regions of interest placed in the cerebellar hemispheres, putamen, thalamus, splenium of corpus callosum, centrum semiovale, and medial frontal cortex. Results: The causes of AIE were cardiac arrhythmias in two patients, myocardial infarction in one, drug overdose in two, carbon monoxide poisoning in one, and respiratory failure and sepsis in one. The median time to MRT was 2.5 days. Symmetric areas of restricted diffusion were found in the periventricular white matter tracts (7/7 patients), the corpus callosum (6/7 patients), internal capsule (5/7 patients), and the subcortical association fibers (3/7 patients). ADC maps confirmed the restricted diffusion. Gray matter involvement was seen in three patients, and was more prominent on conventional imaging sequences compared with diffusion-weighted imaging. A subtle decrease in mean ADC was seen in cortex. Conclusions: Prominent, symmetric restricted diffusion can occur early after AIE in white matter, whereas gray matter involvement may be less prominent. Further studies involving a larger sample and serial imaging are required to confirm these preliminary findings. C1 Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. RP Chalela, JA (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 36 Convent Dr,Room 4A03,MSC 4129, Bethesda, MD 20892 USA. RI Kasner, Scott/C-6109-2011 NR 11 TC 87 Z9 92 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 27 PY 2001 VL 56 IS 4 BP 481 EP 485 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 405HT UT WOS:000167154500012 PM 11222791 ER PT J AU Boroojerdi, B Phipps, M Kopylev, L Wharton, CM Cohen, LG Grafman, J AF Boroojerdi, B Phipps, M Kopylev, L Wharton, CM Cohen, LG Grafman, J TI Enhancing analogic reasoning with rTMS over the left prefrontal cortex SO NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; FACILITATION AB The authors utilized repetitive transcranial magnetic stimulation (rTMS) in 16 normal volunteers to investigate the role of the left dorsolateral prefrontal cortex (PFC) in analogic reasoning, rTMS over the left and right PFC, over the left motor cortex, and sham stimulation over the left PFC were administered during memory and analogic reasoning conditions. rTMS over the left PFC led to a significant reduction in response times only in the analogy condition without affecting accuracy. These results indicate that the left PFC is relevant for analogic reasoning and that rTMS applied to the PFC can speed up solution time. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,MSC 1440, Bethesda, MD 20892 USA. OI Phipps, Michael/0000-0001-8398-5404; Grafman, Jordan H./0000-0001-8645-4457 NR 10 TC 102 Z9 107 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 27 PY 2001 VL 56 IS 4 BP 526 EP 528 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 405HT UT WOS:000167154500020 PM 11222799 ER PT J AU Someya, A Sata, M Takeda, K Pacheco-Rodriguez, G Ferrans, VJ Moss, J Vaughan, M AF Someya, A Sata, M Takeda, K Pacheco-Rodriguez, G Ferrans, VJ Moss, J Vaughan, M TI ARF-GEP(100), a guanine nucleotide-exchange protein for ADP-ribosylation factor 6 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PLECKSTRIN-HOMOLOGY DOMAINS; YEAST GOLGI-APPARATUS; SEC7 DOMAIN; BREFELDIN-A; STRUCTURAL BASIS; PHOSPHOLIPASE-D; DOWNSTREAM EFFECTOR; FACTOR ARNO; ARF GTPASE; MEMBRANE AB A human cDNA encoding an 841-aa guanine nucleotide-exchange protein (GEP) for ADP-ribosylation factors (ARFs), named ARF-GEP(100), which contains a Sec7 domain, a pleckstrin homology (PH)-like domain, and an incomplete IQ-motif, was identified. On Northern blot analysis of human tissues, a approximate to8-kb mRNA that hybridized with an ARF-GEP(100) cDNA was abundant in peripheral blood leukocytes, brain, and spleen. ARF-GEP(100) accelerated [S-35]GTP gammaS binding to ARF1 (class I) and ARF5 (class II) 2-to 3-fold, and to ARF6 (class III) ca. 12-fold. The ARF-GEP(100) Sec7 domain contains Asp(543) and Met(555), corresponding to residues associated with sensitivity to the inhibitory effect of the fungal metabolite brefeldin A (BFA) in yeast Sec7, but also Phe(535) and Ala(536), associated with BFA-insensitivity, The PH-like domain differs greatly from those of other ARF GEPs in regions involved in phospholipid binding. Consistent with its structure, ARF-GEP(100) activity was not affected by BFA or phospholipids. After subcellular fractionation of cultured T98G human glioblastoma cells, ARF6 was almost entirely in the crude membrane fraction, whereas ARF-GEP(100), a 100-kDa protein detected with antipeptide antibodies, was cytosolic. On immunofluorescence microscopy, both proteins had a punctate pattern of distribution throughout the cells, with apparent colocalization only in peripheral areas. The coarse punctate distribution of EEA-1 in regions nearer the nucleus appeared to coincide with that of ARF-GEP(100) in those areas. No similar coincidence of ARF-GEP(100) with AP-1, AP-2, catenin, LAMP-1, or 58K was observed. The new human BFA-insensitive GEP may function with ARF6 in specific endocytic processes. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Someya, A (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 43 TC 79 Z9 82 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 27 PY 2001 VL 98 IS 5 BP 2413 EP 2418 DI 10.1073/pnas.051634798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900057 PM 11226253 ER PT J AU Casimiro, MC Knollmann, BC Ebert, SN Vary, JC Greene, AE Franz, MR Grinberg, A Huang, SP Pfeifer, K AF Casimiro, MC Knollmann, BC Ebert, SN Vary, JC Greene, AE Franz, MR Grinberg, A Huang, SP Pfeifer, K TI Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG-QT SYNDROME; POTASSIUM CHANNEL GENE; RECTIFIER K+ CURRENTS; CARDIAC-ARRHYTHMIA; INNER-EAR; MUTATIONS; MICE; COTRANSPORTER; PROTEIN; KVLQT1 AB KCNQ1 encodes KCNQ1, which belongs to a family of voltage-dependent K+ ion channel proteins, KCNQ1 associates with a regulatory subunit, KCNE1, to produce the cardiac repolarizing current, I-Ks. Loss-of-function mutations in the human KCNQ1 gene have been linked to Jervell and Lange-Nielsen Syndrome (JLNS), a disorder characterized by profound bilateral deafness and a cardiac phenotype. To generate a mouse model for JLNS, we created a line of transgenic mice that have a targeted disruption in the Kcnq1 gene. Behavioral analysis revealed that the Kcnq1(-/-) mice are deaf and exhibit a shaker/waltzer phenotype. Histological analysis of the inner ear structures of Kcnq1(-/-) mice revealed gross morphological anomalies because of the drastic reduction in the volume of endolymph. ECGs recorded from Kcnq1(-/-) mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes are indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. Together, these data suggest that Kcnq1(-/-) mice are a potentially valuable animal model of JLNS. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Med, Div Clin Pharmacol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. NIH, Howard Hughes Med Inst, Res Scholar Program, Bethesda, MD 20872 USA. Childrens Natl Med Ctr, Dept Cardiol, Washington, DC 20111 USA. RP Pfeifer, K (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. OI Knollmann, Bjorn/0000-0003-4956-9735; Pfeifer, Karl/0000-0002-0254-682X NR 44 TC 148 Z9 157 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 FEB 27 PY 2001 VL 98 IS 5 BP 2526 EP 2531 DI 10.1073/pnas.041398998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900076 PM 11226272 ER PT J AU Sullivan, TJ Letterio, JJ van Elsas, A Mamura, M van Amelsfort, J Sharpe, S Metzler, B Chambers, CA Allison, JP AF Sullivan, TJ Letterio, JJ van Elsas, A Mamura, M van Amelsfort, J Sharpe, S Metzler, B Chambers, CA Allison, JP TI Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-CHAIN ANTIBODY; TGF-BETA; CTLA-4-DEFICIENT MICE; TARGETED DISRUPTION; CTLA-4; FACTOR-BETA-1; ANTIGEN; RESPONSIVENESS; EXPRESSION; RECEPTOR AB Similarities in the phenotypes of mice deficient for cytotoxic T lymphocyte antigen-4 (CTLA-4) or transforming growth factor-beta1 (TGF-beta1) and other observations have led to speculation that CTLA-4 mediates its inhibitory effect on T cell activation via costimulation of TGF-beta production, Here, we examine the role of TGF-beta in CTLA-4-mediated inhibition of T cell activation and of CTLA-4 in the regulation of TGF-beta production, Activation of AND TCR transgenic mouse T cells with costimulatory receptor-specific antigen presenting cells results in efficient costimulation of proliferation by CD28 ligation and inhibition by CTLA-4 ligation. Neutralizing antibody to TGF-beta does not reverse CTLA-4-mediated inhibition. Also, CTLA-4 ligation equally inhibits proliferation of wild-type, TGF-beta1(-/-), and Smad3(-/-) T cells, Further, CTLA-4 engagement does not result in the increased production of either latent or active TGF-beta by CD4(+) T cells. These results indicate that CTLA-4 ligation does not regulate TGF-beta production and that CTLA-4-mediated inhibition can occur independently of TGF-beta, Collectively, these data demonstrate that CTLA-4 and TGF-beta represent distinct mechanisms for regulation of T cell responses. C1 Univ Calif Berkeley, Dept Mol & Cell Biol, Canc Res Lab, Howard Hughes Med Inst, Berkeley, CA 94720 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NV Organon, Dept Pharmacol, NL-5340 BH Oss, Netherlands. Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01655 USA. RP Allison, JP (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Canc Res Lab, Howard Hughes Med Inst, 401 LSA, Berkeley, CA 94720 USA. OI Mamura, Mizuko/0000-0003-4531-0144 FU NCI NIH HHS [CA09041, CA40041, T32 CA009041, R01 CA040041] NR 34 TC 41 Z9 43 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 FEB 27 PY 2001 VL 98 IS 5 BP 2587 EP 2592 DI 10.1073/pnas.051632398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900087 PM 11226283 ER PT J AU Gamain, B Miller, LH Baruch, DI AF Gamain, B Miller, LH Baruch, DI TI The surface variant antigens of Plasmodium falciparum contain cross-reactive epitopes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ERYTHROCYTE-MEMBRANE PROTEIN-1; INTERCELLULAR-ADHESION MOLECULE-1; RED-CELL SURFACE; INFECTED ERYTHROCYTES; CEREBRAL MALARIA; BINDING DOMAIN; VAR GENES; AGGLUTINATION; EXPRESSION; ADHERENCE AB Plasmodium falciparum parasites evade the host immune system by clonal expression of the variant antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1). Antibodies to PfEMP1 correlate with development of clinical immunity but are predominantly variant-specific. To overcome this major limitation for vaccine development, we set out to identify cross-reactive epitopes on the surface of parasitized erythrocytes (PEs). We prepared mAbs to the cysteine-rich interdomain region 1 (CIDR1) of PfEMP1 that is functionally conserved for binding to CD36. Two mAbs, targeting different regions of CIDR1, reacted with multiple P. falciparum strains expressing variant PfEMP1s. One of these mAbs, mAb 6A2-B1, recognized nine of 10 strains tested, failing to react with only one strain that does not bind CD36. Flow cytometry with Chinese hamster ovary cells expressing variant CIDR1s demonstrated that both mAbs recognized the CIDR1 of various CD36-binding PfEMP1s and are truly cross-reactive. The demonstration of cross-reactive epitopes on the PE surface provides further credence for development of effective vaccines against the variant antigen on the surface of P. falciparum-infected erythrocytes. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Baruch, DI (reprint author), NIAID, Parasit Dis Lab, NIH, Room B1-37,4 Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. NR 30 TC 44 Z9 44 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 FEB 27 PY 2001 VL 98 IS 5 BP 2664 EP 2669 DI 10.1073/pnas.041602598 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900100 PM 11226296 ER PT J AU Jung, SC Han, IP Limaye, A Xu, R Gelderman, MP Zerfas, P Tirumalai, K Murray, GJ During, MJ Brady, RO Qasba, P AF Jung, SC Han, IP Limaye, A Xu, R Gelderman, MP Zerfas, P Tirumalai, K Murray, GJ During, MJ Brady, RO Qasba, P TI Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ALPHA-GALACTOSIDASE-A; ADENOASSOCIATED VIRUS VECTOR; MUCOPOLYSACCHARIDOSIS TYPE-VII; BONE-MARROW CELLS; STRUCTURAL ORGANIZATION; SUSTAINED EXPRESSION; DISEASE MICE; FACTOR-IX; THERAPY; LIVER AB Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha -galactosidase A (alpha -gal A). This enzyme deficiency leads to impaired catabolism of alpha -galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha -gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha -gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha -gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha -gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha -gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Electron Microscopy Facil, NIH, Bethesda, MD 20892 USA. NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Auckland, Sch Med, Dept Mol Med, Auckland, New Zealand. Thomas Jefferson Univ, Dept Neurosurg, Philadelphia, PA 19107 USA. RP Qasba, P (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D04,10 Ctr Dr, Bethesda, MD 20892 USA. OI Jung, Sung-Chul/0000-0002-3174-8965 NR 41 TC 100 Z9 108 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 FEB 27 PY 2001 VL 98 IS 5 BP 2676 EP 2681 DI 10.1073/pnas.051634498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900102 PM 11226298 ER PT J AU Ohshima, T Ogawa, M Veeranna Hirasawa, M Longenecker, G Ishiguro, K Pant, HC Brady, RO Kulkarni, AB Mikoshiba, K AF Ohshima, T Ogawa, M Veeranna Hirasawa, M Longenecker, G Ishiguro, K Pant, HC Brady, RO Kulkarni, AB Mikoshiba, K TI Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DIRECTED PROTEIN-KINASE; MICROTUBULE-ASSOCIATED PROTEIN; REELER-LIKE PHENOTYPE; MOLECULAR-CLONING; CDK5 ACTIVATOR; TAU-PROTEIN; TYROSINE PHOSPHORYLATION; LAMINAR ORGANIZATION; REGULATORY SUBUNIT; CDC2-LIKE KINASE AB Cyclin-dependent kinase (Cdk) 5 is a unique member of the Cdk family, because Cdk5 kinase activity is detected only in the nervous tissue. Two neuron-specific activating subunits of tdk5, p35 and p39, have been identified. Overlapping expression pattern of these isoforms in the embryonic mouse brain and the significant residual Cdk5 kinase activity in brain homogenate of the p35-/- mice indicate the redundant functions of the Cdk5 activators in vivo. Severe neuronal migration defects in p35-/-Cdk5 +/- mice further support the idea that the redundant expression of the Cdk5 activators may cause a milder phenotype in p35-/- mice compared with Cdk5-/- mice. Mutant mice lacking either Cdk5 or p35 exhibit certain similarities with Reelin/Dab1-mutant mice in the disorganization of cortical laminar structure in the brain. To elucidate the relationship between Cdk5/p35 and Reelin/Dab1 signaling, we generated mouse lines that have combined defects of these genes. The addition of heterozygosity of either Dab1 or Reelin mutation to p35-/- causes the extensive migration defects of cortical neurons in the cerebellum. In the double-null mice of p35 and either Dab1 or Reelin, additional migration defects occur in the Purkinje cells in the cerebellum and in the pyramidal neurons in the hippocampus. These additional defects in neuronal migration in mice lacking both Cdk5/p35 and Reelin/Dab1 indicate that Cdk5/p35 may contribute synergistically to the positioning of the cortical neurons in the developing mouse brain. C1 RIKEN, Inst Phys & Chem Res, Dev Neurobiol Lab, Wako, Saitama 3510198, Japan. RIKEN, Inst Phys & Chem Res, Brain Sci Inst, Wako, Saitama 3510198, Japan. Natl Inst Dent & Craniofacial Res, Funct Genom Unit, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Mitsubishi Kasei Inst Life Sci, Tokyo 1948511, Japan. Univ Tokyo, Inst Med Sci, Dept Mol Neurobiol, Minato Ku, Tokyo 1088639, Japan. RP Ohshima, T (reprint author), RIKEN, Inst Phys & Chem Res, Dev Neurobiol Lab, Wako, Saitama 3510198, Japan. RI Mikoshiba, Katsuhiko/N-7943-2015 NR 50 TC 95 Z9 104 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 FEB 27 PY 2001 VL 98 IS 5 BP 2764 EP 2769 DI 10.1073/pnas.051628498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 407EH UT WOS:000167258900118 PM 11226314 ER PT J AU Li, AG Hou, YS Trent, A AF Li, AG Hou, YS Trent, A TI Effects of elevated atmospheric CO2 and drought stress on individual grain filling rates and durations of the main stem in spring wheat SO AGRICULTURAL AND FOREST METEOROLOGY LA English DT Article DE elevated CO2; drought stress; wheat; grain filling rate; grain filling duration; yield ID TRITICUM-AESTIVUM-L; DRY-MATTER ACCUMULATION; TEMPERATURE; WEIGHT; ENRICHMENT; GENOTYPES; CULTIVARS; GROWTH AB Rate and duration of individual grain growth determine final kernel weight and are influenced by environmental factors. The objectives of this research were to assess the effects of elevated CO2 and drought stress on the grain filling rate and duration, and the weight of individual kernels. Spring wheat (Triticum aestivum L.) was grown in a free air CO2 enrichment (FACE) system on the demonstration farm at the University of Arizona Maricopa Agricultural Center with a split-block design of four replications. Mainplots were 550 or 370 mu mol mol(-1) of atmospheric CO2 concentrations and subplots were two irrigation treatments. The weights of individual kernels from upper. middle, and lower spikelets of the main stem spike were fitted into nonlinear cumulative logistic curves as a function of accumulated thermal units using SAS proc NLIN. Rate and duration of individual grain filling varied greatly depending on floret positions and environmental factors. The combination of these changes determined the final weight of individual kernels. The rank order of kernel weights among kernel positions within a middle and lower spikelet was not affected by either elevated CO2 or water stress treatments in this study. Elevated CO2 often stimulated the rate of individual grain filling, whereas the well-watered condition extended duration of individual grain filling. Furthermore, kernels further from the rachis or nearest to the rachis were affected proportionately more than those towards the center of a spikelet. The information from this research will be used to model wheat grain growth as a function of climate. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NEI, NIH, Bethesda, MD 20892 USA. Washington State Univ, USDA ARS, Weed Sci Lab, Pullman, WA 99164 USA. Univ Idaho, Dept Plant Soil & Entomol Sci, Moscow, ID 83844 USA. RP Li, AG (reprint author), NEI, NIH, Bldg 6,Rm 313,6 Ctr Dr,MSC 2740, Bethesda, MD 20892 USA. NR 24 TC 17 Z9 20 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1923 J9 AGR FOREST METEOROL JI Agric. For. Meteorol. PD FEB 26 PY 2001 VL 106 IS 4 BP 289 EP 301 DI 10.1016/S0168-1923(00)00221-5 PG 13 WC Agronomy; Forestry; Meteorology & Atmospheric Sciences SC Agriculture; Forestry; Meteorology & Atmospheric Sciences GA 396FL UT WOS:000166625600003 ER PT J AU Ehrenfeld, E AF Ehrenfeld, E TI Chemistry at NIH SO CHEMICAL & ENGINEERING NEWS LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Ehrenfeld, E (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2347 J9 CHEM ENG NEWS JI Chem. Eng. News PD FEB 26 PY 2001 VL 79 IS 9 BP 8 EP 8 DI 10.1021/cen-v079n009.p008 PG 1 WC Chemistry, Multidisciplinary; Engineering, Chemical SC Chemistry; Engineering GA 405VJ UT WOS:000167181000002 ER PT J AU Rashid, MA Gustafson, KR Boyd, MR AF Rashid, MA Gustafson, KR Boyd, MR TI New chondropsin macrolide lactams from marine sponges in the genus Ircinia SO TETRAHEDRON LETTERS LA English DT Article DE macrolide lactams; polyketide; chondropsins; Ircinia ramosa AB Two new polyketide-derived macrolide lactams, identified as 73-deoxychondropsin A (2) and chondropsin C (3), have been isolated from two different collections of marine sponges which belong to the genus 6 Ircinia. An Australian collection of Ircinia ramosa provided 73-deoxychondropsin A (2), while samples of Ircinia sp. collected in the Philippines yielded chondropsin C (3). The structures of 2 and 3 were assigned by interpretation of their spectral data. Published by Elsevier Science Ltd. C1 NCI, Div Basic Sci, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. SAIC Frederick, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Div Basic Sci, Lab Drug Discovery Res & Dev, Room 121, Frederick, MD 21702 USA. NR 5 TC 16 Z9 17 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD FEB 26 PY 2001 VL 42 IS 9 BP 1623 EP 1626 DI 10.1016/S0040-4039(00)02348-0 PG 4 WC Chemistry, Organic SC Chemistry GA 406FW UT WOS:000167205100008 ER PT J AU Woodgate, R AF Woodgate, R TI Evolution of the two-step model for UV-mutagenesis SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE DNA polymerase; Rad30; Rad30B; SOS mutagenesis; UmuC; UmuD ID DNA-POLYMERASE-III; ESCHERICHIA-COLI DINB; THYMINE-THYMINE DIMER; SINGLE-STRANDED-DNA; UMUC GENE-PRODUCT; SACCHAROMYCES-CEREVISIAE; ULTRAVIOLET-LIGHT; SOS MUTAGENESIS; XERODERMA-PIGMENTOSUM; TRANSLESION REPLICATION AB It is quite remarkable how our understanding of translesion DNA synthesis (TLS) has changed so dramatically in the past 2 years. Until very recently, little was known about the molecular mechanisms of TLS in higher eukaryotes and what we did know, was largely based upon Escherichia coli and Saccharomyces cerevisiae model systems. The paradigm, proposed by Bryn Bridges and I [Mutat. Res. 150 (1985) 133] in 1985, was that error-prone TLS occurred in two steps; namely a misinsertion event opposite a lesion, followed by extension of the mispair so as to facilitate complete bypass of the lesion. The initial concept was that at least for E. coli, the misinsertion event was performed by the cell's main replicase, DNA polymerase III holoenzyme, and that elongation was achieved through the actions of specialized polymerase accessory proteins, such as UmuD and UmuC. Some 15 years later, we now know that this view is likely to be incorrect in that both misinsertion and bypass are performed by the Umu proteins (now called pol V). As pol V is normally a distributive enzyme, pol III may only be required to "fix" the misincorporation as a mutation by completing chromosome duplication. However, while the role of the E. coli proteins involved in TLS have changed, the initial concept of misincorporation followed by extension/bypass remains valid. Indeed, recent evidence suggests that it can equally be applied to TLS in eukaryotic cells where there are many more DNA polymerases to choose from. The aim of this review is, therefore, to provide a historical perspective to the "two-step" model for UV-mutagenesis, how it has recently evolved, and in particular, to highlight the seminal contributions made to it by Bryn Bridges. Published by Elsevier Science B.V. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. NR 91 TC 39 Z9 39 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8777 J9 MUTAT RES-DNA REPAIR JI Mutat. Res.-DNA Repair PD FEB 25 PY 2001 VL 485 IS 1 SI SI BP 83 EP 92 DI 10.1016/S0921-8777(00)00076-8 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 403BW UT WOS:000167023500009 PM 11341996 ER PT J AU Biesecker, B AF Biesecker, B TI Prenatal diagnoses of sex chromosome conditions - Parents need more than just accurate information SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, B (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. NR 11 TC 7 Z9 7 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8138 J9 BRIT MED J JI Br. Med. J. PD FEB 24 PY 2001 VL 322 IS 7284 BP 441 EP 442 DI 10.1136/bmj.322.7284.441 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 406YD UT WOS:000167243000001 PM 11222404 ER PT J AU Futaki, M Watanabe, S Kajigaya, S Liu, JM AF Futaki, M Watanabe, S Kajigaya, S Liu, JM TI Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Fanconi anemia; phosphorylation; TNF-alpha; protein complex; protein regulation; NF-kappa B ID NECROSIS-FACTOR-ALPHA; NUCLEAR ACCUMULATION; KAPPA-B; COMPLEX; FANCG/XRCC9; APOPTOSIS; DISEASE; THERAPY; MICE AB Fanconi anemia (FA) is a genetic syndrome characterized by bone marrow failure, birth defects, and a predisposition to malignancy. At this time, six FA genes have been identified, and several gene products have been found to interact in a protein complex. FA cells appear to overexpress the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-cu), We therefore examined the effects of TNF-alpha on the regulation of FA complementation group proteins, FANCG and FANCA, We found that treatment with TNF-alpha induced FANCG; protein expression. FANCA was induced concurrently with FANCG;, and the FANCA/FANCG complex was increased in the nucleus following TNF-alpha treatment. Inactivation of inhibitory kappa B kinase-2 modulated the expression of FANCG. We also found that both nuclear and cytoplasmic FANCG fractions were phosphorylated. These results show that FANCG is a phosphoprotein and suggest that the cellular accumulation of FA proteins is subject to regulation by TNF-alpha signaling. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, JM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C103, Bethesda, MD 20892 USA. NR 22 TC 17 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 23 PY 2001 VL 281 IS 2 BP 347 EP 351 DI 10.1006/bbrc.2001.4359 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 407FR UT WOS:000167262000015 PM 11181053 ER PT J AU Locksley, RM Killeen, N Lenardo, MJ AF Locksley, RM Killeen, N Lenardo, MJ TI The TNF and TNF receptor superfamilies: Integrating mammalian biology SO CELL LA English DT Review ID TUMOR-NECROSIS-FACTOR; SECONDARY LYMPHOID-TISSUES; P75 NEUROTROPHIN RECEPTOR; ALPHA-DEFICIENT MICE; FAMILY MEMBER TRANCE; CELL-DEATH; OSTEOPROTEGERIN-LIGAND; LYMPHOTOXIN-ALPHA; CRYSTAL-STRUCTURE; NODE DEVELOPMENT C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Locksley, RM (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. NR 109 TC 2077 Z9 2161 U1 17 U2 149 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 23 PY 2001 VL 104 IS 4 BP 487 EP 501 DI 10.1016/S0092-8674(01)00237-9 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 405VP UT WOS:000167181500005 PM 11239407 ER PT J AU Rashin, AA Topol, IA Tawa, GJ Burt, SK AF Rashin, AA Topol, IA Tawa, GJ Burt, SK TI Charge distributions in water and ion-water clusters SO CHEMICAL PHYSICS LETTERS LA English DT Article ID ATOMIC MULTIPOLE MOMENTS; VANDERWAALS MOLECULES; SOLVATION; HYDRATION; MODEL; THERMODYNAMICS; CONTINUUM AB We applied sequential atomic multipole fitting and the Gauss electric field flux theorem to calculate total molecular charge, charge distribution and charge transfer in a number of water, ion, and ion-water clusters. We have found that: (a) charge redistribution upon formation of ionic and of hydrogen bonds are similar and they are drastically different in covalent bonding; (b) polarization accounts for charge re-distribution upon formation of ionic or hydrogen bonds without invoking a charge transfer; (c) the 'charge leak' from molecular cavities, encountered in the hydration theories, is usually compensated by the electron density of the surrounding water; (d) the flux theorem provides alternative means of defining atomic radii in molecules in solution or clusters. (C) 2001 Elsevier Science B.V. All rights reserved. C1 BioChemComp Inc, Teaneck, NJ 07666 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Adv Biochem Comp Ctr, Frederick, MD 21702 USA. RP Rashin, AA (reprint author), BioChemComp Inc, 543 Sagamore Ave, Teaneck, NJ 07666 USA. NR 28 TC 17 Z9 17 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD FEB 23 PY 2001 VL 335 IS 3-4 BP 327 EP 333 DI 10.1016/S0009-2614(00)01330-0 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 406CR UT WOS:000167197800027 ER PT J AU Deitsch, KW Carlton, JMR Wootton, JC Wellems, TE AF Deitsch, KW Carlton, JMR Wootton, JC Wellems, TE TI Host sequences in Plasmodium falciparum and Plasmodium vivax genomic DNA: horizontal transfer or contamination artifact? SO FEBS LETTERS LA English DT Letter ID HUMAN MALARIA PARASITE; GENE C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. NR 7 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 23 PY 2001 VL 491 IS 1-2 BP 164 EP 165 DI 10.1016/S0014-5793(01)02154-8 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 407AC UT WOS:000167248400035 PM 11245166 ER PT J AU Luo, D Broad, LM Bird, GSJ Putney, JW AF Luo, D Broad, LM Bird, GSJ Putney, JW TI Signaling pathways underlying muscarinic receptor-induced [Ca2+](i) oscillations in HEK293 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; LACRIMAL ACINAR-CELLS; SMOOTH-MUSCLE CELLS; ARACHIDONIC-ACID; CA2+ ENTRY; INOSITOL TRISPHOSPHATE; HUMAN-NEUTROPHILS; PLASMA-MEMBRANE; FATTY-ACIDS; ACTIVATION AB We have investigated the signaling pathways underlying muscarinic receptor-induced calcium oscillations in human embryonic kidney (HEK293) cells. Activation of muscarinic receptors with a maximal concentration of carbachol (100 muM) induced a biphasic rise in cytoplasmic calcium ([Ca2+](i)) comprised of release of Ca2+ from intracellular stores and influx of Ca2+ from the extracellular space. A lower concentration of carbachol (5 muM) induced repetitive [Ca2+](i) spikes or oscillations, the continuation of which was dependent on extracellular Ca2+. The entry of Ca2+ with 100 muM carbachol and with the sarcoplasmic-endoplasmic reticulum calcium ATPase inhibitor, thapsigargin, was completely blocked by 1 muM Gd3+, as well as 30-100 muM concentrations of the membrane-permeant inositol 1,4,5-trisphosphate receptor inhibitor, 2-aminoethyoxydiphenyl borane (8-APE). Sensitivity to these inhibitors is indicative of capacitative calcium entry. Arachidonic acid, a candidate signal for Ca2+ entry associated with [Ca2+](i) oscillations in HEK293 cells, induced entry that was inhibited only by much higher concentrations of Gd3+ and was unaffected by 100 muM 2-APB. Like arachidonic acid-induced entry, the entry associated with [Ca2+](i) oscillations was insensitive to inhibition by Gd3+ but was completely blocked by 100 muM 8-APE. These findings indicate that the signaling pathway responsible for the Ca2+ entry driving [Ca2+](i) oscillations in HEK293 cells is more complex than originally thought, and may involve neither capacitative calcium entry nor a role for PLA(2) and arachidonic acid. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 104 Z9 107 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 23 PY 2001 VL 276 IS 8 BP 5613 EP 5621 DI 10.1074/jbc.M007524200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404RU UT WOS:000167115100030 PM 11096083 ER PT J AU Malek, RL Toman, RE Edsall, LC Wong, S Chiu, J Letterle, CA Van Brocklyn, JR Milstien, S Spiegel, S Lee, NH AF Malek, RL Toman, RE Edsall, LC Wong, S Chiu, J Letterle, CA Van Brocklyn, JR Milstien, S Spiegel, S Lee, NH TI Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosime-1-phosphate receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; NERVE GROWTH-FACTOR; MULTIPLE SIGNALING PATHWAYS; M1 MUSCARINIC ACETYLCHOLINE; JUN NH2-TERMINAL KINASE; II TYPE-2 RECEPTORS; LYSOPHOSPHATIDIC ACID; MOLECULAR-CLONING; REGULATED KINASE; CELL-MIGRATION AB The previously cloned rat nerve growth factor-regulated G protein-coupled receptor NRG-1 (Glickman, M., Malek, R. L., Kwitek-Black, A. E., Jacob, H. J., and Lee N. H. (1999) Mot Cell. Neurosci. 14, 141-52), also known as EDG-8, binds sphingosine-l-phosphate (S1P) with high affinity and specificity, In this paper we examined the signal transduction pathways regulated by the binding of SIP to EDG-8. In Chinese hamster ovary cells heterologously expressing EDG-8, SIP inhibited forskolin-induced cAMP accumulation and activated c-Jun NH2-terminal kinase. Surprisingly, S1P inhibited serum-induced activation of extracellular regulated protein kinase 1 and 2 (ERK1/2). Treatment with pertussis toxin, which ADP-ribosylates and inactivates G(i), blacked S1P-mediated inhibition of cAMP accumulation, but had no effect on c-Jun NH2-terminal kinase activation or inhibition of ERK1/2. The inhibitory effect of SIP on ERK1/2 activity was abolished by treatment with orthovanadate, suggesting the involvement of a tyrosine phosphatase. A subunit selective [S-35] guanosine 5'-3-O-(thio)triphosphate binding assay demonstrates that; EDG-8 activated G(i/o) and G(12) but not G(s) and G(q/11) in response to S1P. In agreement, EDG-8 did not stimulate phosphoinositide turnover or cAMP accumulation. The ability of S1P to induce mitogenesis in cells expressing the EDG-1 subfamily of G protein-coupled receptors is well characterized. In contrast, SIP inhibited proliferation in Chinese hamster ovary cells expressing EDG-8 but not empty vector. The antiproliferative effect, like SIP-mediated ERK1/2 inhibition, was orthovanadate-sensitive and pertussis toxin-insensitive. Our results indicate that EDG-8, a member of the EDG-1 subfamily, couples to unique signaling pathways. C1 Inst Genome Res, Dept Mol & Cellular Biol, Rockville, MD 20850 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. Georgetown Univ, Med Ctr, Interdisciplinary Program Neurosci, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Lee, NH (reprint author), Inst Genome Res, Dept Mol & Cellular Biol, 9712 Med Ctr Dr, Rockville, MD 20850 USA. RI Van Brocklyn, Jim/A-9733-2010 FU NCI NIH HHS [CA61774]; NINDS NIH HHS [NS352321] NR 62 TC 99 Z9 101 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 23 PY 2001 VL 276 IS 8 BP 5692 EP 5699 DI 10.1074/jbc.M003964200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404RU UT WOS:000167115100040 PM 11069896 ER PT J AU Guo, CH Yu, SH Davis, AT Wang, HM Green, JE Ahmed, K AF Guo, CH Yu, SH Davis, AT Wang, HM Green, JE Ahmed, K TI A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CASEIN KINASE-2; TRANSCRIPTIONAL ACTIVITY; ANDROGENIC REGULATION; BETA-SUBUNIT; PROSTATE; PHOSPHORYLATION; INDUCTION; PROLIFERATION; STIMULATION; GROWTH AB Protein kinase CK2 (CK2) has long been implicated in the regulation of cell growth and proliferation. Its activity is generally elevated in rapidly proliferating tissues, and nuclear matrix (NM) is an important subnuclear locale of its functional signaling. In the prostate, nuclear CK2 is rapidly lost commensurate with induction of receptor-mediated apoptosis after growth stimulus withdrawal. Ey contrast, chemical-induced apoptosis in prostate cancer and other cells (by etoposide and diethylstilbestrol) evokes an enhancement in CK2 associated with the NM that appears to be because of translocation of CK2 from the cytoplasmic to the nuclear compartment. This shuttling of CK2 to the NM may reflect a protective response to chemical-mediated apoptosis. Supporting evidence for this was obtained by employing cells that were transiently transfected with various expression plasmids of CK2 (thereby expressing additional CK2) prior to treatment with etoposide or diethylstilbestrol. Cells transfected with the CK2 alpha or CK2 alpha beta showed significant resistance to chemical-mediated apoptosis commensurate with the corresponding elevation in CK2 in the NM. Transfection with CK2 beta did not demonstrate this effect. These results suggest, for the first time, that besides the commonly appreciated function of CK2 in cell growth, it may also have a role in protecting cells against apoptosis. C1 Dept Vet Affairs Med Ctr, Minneapolis, MN 55417 USA. Univ Minnesota, Dept Lab Med & Pathol, Cellular & Mol Biochem Res Lab 151, Minneapolis, MN 55417 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55417 USA. NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Vet Affairs Med Ctr, Cellular & Mol Biochem Res Lab 151, 1 Vet Dr, Minneapolis, MN 55417 USA. EM ahmedk@tc.umn.edu FU NCI NIH HHS [CA-15062] NR 41 TC 119 Z9 130 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 23 PY 2001 VL 276 IS 8 BP 5992 EP 5999 DI 10.1074/jbc.M004862200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404RU UT WOS:000167115100078 PM 11069898 ER PT J AU Bernardini, R Johnson, EO Kamilaris, T Chiarenza, A Cantarella, G Calogero, AE Lempereur, L Chrousos, GP Giuffrida, R Gold, PW AF Bernardini, R Johnson, EO Kamilaris, T Chiarenza, A Cantarella, G Calogero, AE Lempereur, L Chrousos, GP Giuffrida, R Gold, PW TI Increased ACTH and cortisol secretion after interleukin-1 alpha injection in the common marmoset (Callithrix jacchus jacchus) SO LIFE SCIENCES LA English DT Article DE hyperimmunity; primate; interleukin-1; immune-adrenal feedback ID CORTICOTROPIN-RELEASING HORMONE; PITUITARY-ADRENAL AXIS; ENDOCRINE INTERACTIONS; LEWIS RATS; PRIMATE; CORTEX; ARTHRITIS; RECEPTOR; STRESS; HYPOTHESES AB We have studied the effect of intravenous injection of interleukin-1 (dose range: from 0.25 to 4.5 mug/kg of body weight) on plasma ACTH and cortisol levels in the marmoset, a primate paradygm of peripheral glucocorticoid resistance. Blood sampling were collected and body temperature recorded 0, 15, 30, 60, 120, 180, 240 and 300 min after injection. Interleukin-1 stimulated secretion of ACTH in a dose-dependent fashion. Maximal secretion occurred 120 min after injection, and lasted up to 240 min. Plasma ACTH levels returned to baseline 300 min after interleukin-1 injection. Plasma cortisol levels were related to ACTH levels. Body temperature elevation, which occurred 10-15 min after injection was dose-dependent, and lasted 3 h. Results suggest that the pyrogenic effect of interleukin is associated, in the marmoset, with integrated activation of the hypothalamic-pituitary-adrenal axis. In light of the proneness of marmosets to hyperimmune disorders, our data are consistent with the hypothesized central biological role of IL-1, as well as the pathophysiological relevance of the neuro-endocrine-immune cross-talk during the acute phase response. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Univ Catania, Sch Med, Dept Expt & Clin Pharmacol, I-95125 Catania, Italy. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Catania, Sch Med, Dept Physiol Sci, I-95125 Catania, Italy. Univ Catania, Sch Med, Dept Internal Med, I-95125 Catania, Italy. RP Bernardini, R (reprint author), Univ Catania, Sch Med, Dept Expt & Clin Pharmacol, Viale Andrea Doria 6, I-95125 Catania, Italy. OI Giuffrida, Rosario/0000-0001-7494-3675; bernardini, renato/0000-0002-4765-0663 NR 33 TC 2 Z9 2 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD FEB 23 PY 2001 VL 68 IS 14 BP 1657 EP 1665 DI 10.1016/S0024-3205(01)00961-4 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 406NQ UT WOS:000167222400009 PM 11263678 ER PT J AU Fries, P Reynolds, JH Rorie, AE Desimone, R AF Fries, P Reynolds, JH Rorie, AE Desimone, R TI Modulation of oscillatory neuronal synchronization by selective visual attention SO SCIENCE LA English DT Article ID FIELD POTENTIAL OSCILLATIONS; CORTICAL AREAS; NEURAL MECHANISMS; CORTEX; RESPONSES; V4; MODEL; V2; ACTIVATION; STIMULUS AB In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons activated by the attended stimulus showed increased gamma-frequency (35 to 90 hertz) synchronization but reduced low-frequency (<17 hertz) synchronization compared with neurons at nearby V4 sites activated by distracters. Because postsynaptic integration times;are short, these Localized changes in synchronization may serve to amplify behaviorally relevant signals in the cortex. C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, Syst Neurobiol Lab, La Jolla, CA 92037 USA. RP Fries, P (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,9000 Rpckville Pike, Bethesda, MD 20892 USA. RI Fries, Pascal/E-3196-2010 OI Fries, Pascal/0000-0002-4270-1468 NR 34 TC 1377 Z9 1401 U1 10 U2 90 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 23 PY 2001 VL 291 IS 5508 BP 1560 EP 1563 DI 10.1126/science.1055465 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405HF UT WOS:000167153400049 PM 11222864 ER PT J AU Sinnarajah, S Dessauer, CW Srikumar, D Chen, J Yuen, J Yilma, S Dennis, JC Morrison, EE Vodyanoy, V Kehrl, JH AF Sinnarajah, S Dessauer, CW Srikumar, D Chen, J Yuen, J Yilma, S Dennis, JC Morrison, EE Vodyanoy, V Kehrl, JH TI RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III SO NATURE LA English DT Article ID RECEPTOR-CELLS; ODORANT DETECTION; IDENTIFICATION; STIMULATION; INHIBITION; MECHANISM; PROTEINS; ROLES; CAMP AB The heterotrimeric G-protein G(s) couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein alpha -subunits alpha (i) and alpha (q), lack such activity for alpha (s) (refs 3-6). But several RGS proteins inhibit cAMP production by G(s)-linked receptors(7,8). Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the alpha (s) family member alpha (olf) links odorant receptors to adenylyl cyclase activation(9,10). Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha (olf) but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours. C1 NIAID, Cell Mol Biol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77225 USA. Auburn Univ, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA. RP Kehrl, JH (reprint author), NIAID, Cell Mol Biol Sect B, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Kehrl, John/0000-0002-6526-159X FU NIGMS NIH HHS [R01 GM060419, R01 GM060419-01A1] NR 25 TC 185 Z9 190 U1 2 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 22 PY 2001 VL 409 IS 6823 BP 1051 EP 1055 DI 10.1038/35059104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405FT UT WOS:000167148800048 PM 11234015 ER PT J AU Mandelboim, O Lieberman, N Lev, M Paul, L Arnon, TI Bushkin, Y Davis, DM Strominger, JL Yewdell, JW Porgador, A AF Mandelboim, O Lieberman, N Lev, M Paul, L Arnon, TI Bushkin, Y Davis, DM Strominger, JL Yewdell, JW Porgador, A TI Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells SO NATURE LA English DT Article ID NATURAL-KILLER-CELLS; IMMUNOGLOBULIN-SUPERFAMILY; MOLECULAR-CLONING; RECEPTOR; CYTOTOXICITY; ANTIGEN; MEMBER; ACID AB Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation(1). In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface(2-8). NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined(9-14). NKp46 is thought to be the main activating receptor for human NK cells(9,15). Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein. C1 Ben Gurion Univ Negev, Fac Hlth Sci, Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Ctr Canc Res, IL-84105 Beer Sheva, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel. Publ Hlth Res Inst City New York Inc, Lab Mol Immunol, New York, NY 10016 USA. Univ London Imperial Coll Sci Technol & Med, Dept Biol, London SW7 2AZ, England. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Porgador, A (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 29 TC 550 Z9 563 U1 4 U2 22 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 22 PY 2001 VL 409 IS 6823 BP 1055 EP 1060 DI 10.1038/35059110 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 405FT UT WOS:000167148800049 PM 11234016 ER PT J AU Hedenfalk, I Duggan, D Chen, YD Radmacher, M Bittner, M Simon, R Meltzer, P Gusterson, B Esteller, M Kallioniemi, OP Wilfond, B Borg, A Trent, J Raffeld, M Yakhini, Z Ben-Dor, A Dougherty, E Kononen, J Bubendorf, L Fehrle, W Pittaluga, S Gruvberger, S Loman, N Johannsoson, O Olsson, H Sauter, G AF Hedenfalk, I Duggan, D Chen, YD Radmacher, M Bittner, M Simon, R Meltzer, P Gusterson, B Esteller, M Kallioniemi, OP Wilfond, B Borg, A Trent, J Raffeld, M Yakhini, Z Ben-Dor, A Dougherty, E Kononen, J Bubendorf, L Fehrle, W Pittaluga, S Gruvberger, S Loman, N Johannsoson, O Olsson, H Sauter, G TI Gene-expression profiles in hereditary breast cancer. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GERM-LINE MUTATIONS; OVARIAN-CANCER; SUSCEPTIBILITY GENE; SPORADIC BREAST; BRCA2 MUTATIONS; FOLLOW-UP; CARRIERS; GRADE; FAMILIES; LINKAGE AB Background: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. Methods: RNA from samples of primary tumors from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. Results: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations. Conclusions: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer. (N Engl J Med 2001;344:539-48.) Copyright (C) 2001 Massachusetts Medical Society. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Oncol, Lund, Sweden. Univ Glasgow, Western Infirm, Dept Pathol, Glasgow G11 6NT, Lanark, Scotland. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Div Tumor Biol, Baltimore, MD 21205 USA. NCI, Dept Pathol, Bethesda, MD USA. Agilent Labs, Dept Chem & Biol Syst, Palo Alto, CA USA. Texas A&M Univ, Dept Elect Engn, College Stn, TX USA. NIH, Natl Human Genome Inst, Canc Genet Branch, Bethesda, MD USA. Univ Basel, Inst Pathol, Basel, Switzerland. Lund Univ, Dept Oncol, Lund, Sweden. RP Trent, J (reprint author), NHGRI, Canc Genet Branch, NIH, Bldg 49,Rm 4A22, Bethesda, MD 20892 USA. EM jtrent@nih.gov RI gusterson, barry/D-3752-2009; Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012; Esteller, Manel/L-5956-2014 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Esteller, Manel/0000-0003-4490-6093 NR 41 TC 1087 Z9 1122 U1 5 U2 45 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 22 PY 2001 VL 344 IS 8 BP 539 EP 548 DI 10.1056/NEJM200102223440801 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 403LU UT WOS:000167044600001 PM 11207349 ER PT J AU Markovitz, JH Iribarren, C Bild, DE AF Markovitz, JH Iribarren, C Bild, DE TI Psychological factors and coronary artery disease. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Alabama, Birmingham, AL 35205 USA. Kaiser Permanente, Div Res, Oakland, CA 94611 USA. NHLBI, Bethesda, MD 20892 USA. RP Markovitz, JH (reprint author), Univ Alabama, Birmingham, AL 35205 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 22 PY 2001 VL 344 IS 8 BP 610 EP 610 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 403LU UT WOS:000167044600019 PM 11221629 ER PT J AU Ramesha, AR Kroth, H Jerina, DM AF Ramesha, AR Kroth, H Jerina, DM TI Solvent-free synthesis of benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the N-2-position of deoxyguanosine SO ORGANIC LETTERS LA English DT Article ID DNA ADDUCTS; EPOXIDE; ENANTIOMERS; REPAIR AB [GRAPHICS] The first solid state (or solvent-free) synthesis of protected deoxyguanosine (dG) adducts of benzo[a]pyrene diol epoxides at room temperature is reported. Whereas dG adducts derived from cis- and trans-opening of (+/-)-7 beta ,8 alpha -dihydroxy-9 beta ,10 beta -epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (DE-1 1) are formed as a 1:1 mixture, the direct opening of the diastereomeric (+/-)-7 beta ,8 alpha -dihydroxy-9 alpha ,10 alpha -epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene (DE-2, 2) produced a 15:85 ratio favoring the trans opened dG adduct 7. C1 NIDDK, Sect Oxidat Mechanisms, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDK, Sect Oxidat Mechanisms, Lab Bioorgan Chem, NIH, Bldg 8A,Room 1A15, Bethesda, MD 20892 USA. NR 20 TC 4 Z9 4 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD FEB 22 PY 2001 VL 3 IS 4 BP 531 EP 533 DI 10.1021/ol0003580 PG 3 WC Chemistry, Organic SC Chemistry GA 403MD UT WOS:000167046300010 PM 11178817 ER PT J AU Lee, K Cass, C Jacobson, KA AF Lee, K Cass, C Jacobson, KA TI Synthesis using ring closure metathesis and effect on nucleoside transport of a (N)-methanocarba S-(4-nitrobenzyl)thioinosine derivative SO ORGANIC LETTERS LA English DT Article ID ORGANIC-SYNTHESIS; BIOLOGICAL-ACTIVITY; CLOSING METATHESIS; LEUKEMIA-CELLS; (-)-NEPLANOCIN-A; ANALOGS; NITROBENZYLTHIOINOSINE; OLIGONUCLEOTIDES AB [GRAPHICS] A new synthetic route to ring constrained (N) methanocarba nucleosides and nucleotides is presented. Ring closure of a diene intermediate using Grubbs catalyst provides a new avenue far the preparation of the cyclopentenone derivative 6, which is a versatile intermediate for various carbocycles. The product was almost as potent an inhibitor of es mediated nucleoside transport as the parent compound, inhibiting initial rates of uptake of uridine into cultured CCRF CEM cells by 50% at approximately 30-50 nM. C1 NIDDKD, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 26 TC 48 Z9 48 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD FEB 22 PY 2001 VL 3 IS 4 BP 597 EP 599 DI 10.1021/ol006999c PG 3 WC Chemistry, Organic SC Chemistry GA 403MD UT WOS:000167046300027 PM 11178834 ER PT J AU Dammann, O Phillips, TM Allred, EN O'Shea, TM Paneth, N Van Marter, LJ Bose, C Ehrenkranz, RA Bednarek, FJ Naples, M Leviton, A AF Dammann, O Phillips, TM Allred, EN O'Shea, TM Paneth, N Van Marter, LJ Bose, C Ehrenkranz, RA Bednarek, FJ Naples, M Leviton, A CA Elgan Study Investigators TI Mediators of fetal inflammation in extremely low gestational age newborns SO CYTOKINE LA English DT Article DE cytokines; growth factors; infant; premature; inflammation ID NECROSIS-FACTOR-ALPHA; COLONY-STIMULATING FACTOR; AMNIOTIC-FLUID; ENDOTHELIAL-CELLS; CEREBRAL-PALSY; PRETERM LABOR; BRONCHOPULMONARY DYSPLASIA; CYTOKINES INTERLEUKIN-6; INTRAUTERINE INFECTION; BRAIN-DAMAGE AB To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, less than or equal to 28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-alpha, G-CSF, M-CSF, GM-CSF, MTP-1 alpha, and RANTES mere considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-alpha, G-CSF, and MIP-1 alpha declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-beta1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed, We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity. (C) 2001 Academic Press. C1 Childrens Hosp, Neuroepidemiol Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. William Beaumont Hosp, Royal Oak, MI 48073 USA. DeVos Childrens Hosp, Grand Rapids, MI 49503 USA. Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. New England Med Ctr, Boston, MA 02111 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. E Carolina Univ, Sch Med, Greenville, NC 27858 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Michigan State Univ, Sparrow Hosp, E Lansing, MI 48823 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. NIH, DBEPS, ORS, Bethesda, MD 20892 USA. Univ Chicago, Chicago, IL 60637 USA. Childrens Hosp, Baystate Med Ctr, Springfield, MA 01199 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Dammann, O (reprint author), Childrens Hosp, Neuroepidemiol Unit, CA505,300 Longwood Ave, Boston, MA 02115 USA. NR 30 TC 61 Z9 63 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 1043-4666 J9 CYTOKINE JI Cytokine PD FEB 21 PY 2001 VL 13 IS 4 BP 234 EP 239 DI 10.1006/cyto.2000.0820 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 410CB UT WOS:000167421500006 PM 11237431 ER PT J AU Huizing, M Didier, A Walenta, J Anikster, Y Gahl, WA Kramer, H AF Huizing, M Didier, A Walenta, J Anikster, Y Gahl, WA Kramer, H TI Molecular cloning and characterization of human VPS18, VPS 11, VPS16, and VPS33 SO GENE LA English DT Article DE Hermansky-Pudlak syndrome; lysosomal delivery; pigmentation ID HERMANSKY-PUDLAK-SYNDROME; PROTEIN COMPLEX; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; LYSOSOMAL DELIVERY; DEEP ORANGE; YEAST; GENE; MUTATIONS; TRAFFICKING AB In multicellular organisms, the delivery of proteins to lysosomes is essential. Many of the genes necessary for this process have first been identified by their requirement for vacuolar delivery in yeast. A subset of these genes, the four class C vps genes, is necessary for the delivery of endocytic and biosynthetic cargo in yeast, and also in Drosophila. Here, we describe the sequence and expression pattern of four human homologs of these genes. This initial molecular description of these four genes is an important step towards their evaluation as candidate genes that may be involved in the pathogenesis of Hermansky-Pudlak syndrome-related diseases. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Cell Biol, Dallas, TX 75390 USA. NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Kramer, H (reprint author), Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA. OI Kramer, Helmut/0000-0002-1167-2676 FU NEI NIH HHS [R01 EY010199, EY10199] NR 30 TC 41 Z9 46 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD FEB 21 PY 2001 VL 264 IS 2 BP 241 EP 247 DI 10.1016/S0378-1119(01)00333-X PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 414FC UT WOS:000167654500010 PM 11250079 ER PT J AU Yancik, R Wesley, MN Ries, LAG Havlik, RJ Edwards, BK Yates, JW AF Yancik, R Wesley, MN Ries, LAG Havlik, RJ Edwards, BK Yates, JW TI Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LYMPH-NODE DISSECTION; AXILLARY DISSECTION; WOMEN; CARE; SURVIVAL; PATTERNS; IMPACT AB Context Postmenopausal women aged 55 years and older have 66% of incident breast tumors and experience 77% of breast cancer mortality, but other age-related health problems may affect tumor prognosis and treatment decisions. Objective To document the comorbidity burden of postmenopausal breast cancer patients and evaluate its relationship with age on disease stage, treatment, and early mortality. Design and Setting Data were collected on breast cancer patients' comorbidities by retrospective hospital medical records review and merged with information on patients' tumor characteristics collected from 6 regional National Cancer Institute Surveillance, Epidemiology, and End Results cancer registries. Patients were followed up until death or for 30 months from breast cancer diagnosis. Participants Population-based random sample of 1800 postmenopausal breast cancer patients diagnosed in 1992 stratified by 3 age groups: 55 to 64 years, 65 to 74 years, and 75 years and older. Main Outcome Measures Extent of disease, therapy received, comorbidity, cause of death, and survival. Results Seventy-three percent (1312 of 1800) of the sample was diagnosed with stage I and II breast cancer, 10% (n=188) with stage III and IV breast cancer, and 17% (n=300) did not have a stage assignment. Of the 1017 patients with stage I and stage II node-negative breast cancer, 95% received therapy in agreement with the National Institutes of Health consensus statement recommendation for early-stage breast cancer. Patients in older age groups were less likely to:receive therapy consistent with the consensus statement (P<.001), and women aged 70 years and older were significantly less likely to receive axillary lymph node dissection as determined by logistic regression analysis (P<.01). Diabetes, renal failure, stroke, liver disease, a previous malignant tumor, and smoking were significant in predicting early mortality in a statistical model that included age and disease stage. Breast cancer was the underlying cause of death for 135 decedents (51.3%). Heart disease (n=45, 17.1%) and previous cancers (n=22, 8.4%) were the next major underlying causes. In the 30-month follow-up period, 263 patients (15%) died. Conclusion Patient care decisions occur in the context of breast cancer and other age-related conditions. Comorbidity in older patients may limit the ability to obtain prognostic information (ie, axillary lymph node dissection), tends to minimize treatment options (eg, breast-conserving therapy), and increases the risk of death from causes other than breast cancer. C1 NIA, Canc Sect, Geriatr Program, NIH, Bethesda, MD 20892 USA. NIA, Epidemiol Biometry & Demog Program, NIH, Bethesda, MD 20892 USA. NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Yancik, R (reprint author), NIA, Canc Sect, Geriatr Program, NIH, Bethesda, MD 20892 USA. NR 41 TC 488 Z9 499 U1 2 U2 13 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 FEB 21 PY 2001 VL 285 IS 7 BP 885 EP 892 DI 10.1001/jama.285.7.885 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 402BE UT WOS:000166965500025 PM 11180731 ER PT J AU Jemal, A Chu, KC Tarone, RE AF Jemal, A Chu, KC Tarone, RE TI Recent trends in lung cancer mortality in the United States SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BIRTH COHORT PATTERNS; CIGARETTE-SMOKING; MARIJUANA; RATES; TOBACCO; AGE; POPULATION; SMOKERS; COCAINE; PERIOD AB Background: Previous age-period-cohort analyses of lung cancer incidence and mortality rates in the United States have demonstrated a decrease in risk by birth cohort through 1950, consistent with declining trends in smoking prevalence. This study was conducted to examine recent lung cancer trends, including trends among the cohorts born after 1950. Methods: Lung cancer mortality rates from 1970 through 1997 for whites aged 24-83 years and for blacks aged 30-83 years were investigated. Using age-period-cohort analyses with a-year age and 2-year calendar-period intervals, we examined changes in the slope of the trends in birth-cohort and calendar-period effects. All statistical tests are two-sided. Results: There was an unexpected, statistically significant moderation in the rate of decrease of the birth-SUBJECTS AND METHODS cohort trend in lung cancer mortality for whites born after 1950, with a corresponding smaller and statistically nonsignificant moderation for blacks. These data are consistent with smoking initiation rates: Rates of both cigarette and marijuana smoking initiation increased for children aged 12-17 years from 1965 through 1977, There was a statistically significant decrease in the slope of the calendar-period trend for lung cancer mortality in 1990 for both whites and blacks that was observed primarily in people 55 years of age and older. Conclusions and Implications: The birth-cohort pattern of lung cancer mortality after 1950 appears to reflect the early impact of teenage cigarette smoking on lung cancer risk in people under the age of 45 years, although a contribution from marijuana smoking cannot be ruled out. This result provides additional support for increasing smoking cessation and prevention programs for teenagers, The calendar-period decrease in lung cancer mortality after 1990 may reflect the long-term benefits of reductions in tobacco carcinogens in cigarettes and increases in smoking cessation beginning around 1960. C1 NCI, Off Special Populat Res, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Jemal, A (reprint author), NIH, Bldg 10,6120 Execut Blvd,EPS 8049, Bethesda, MD 20892 USA. NR 40 TC 115 Z9 121 U1 1 U2 9 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 277 EP 283 DI 10.1093/jnci/93.4.277 PG 7 WC Oncology SC Oncology GA 403NK UT WOS:000167049200011 PM 11181774 ER PT J AU Harro, CD Pang, YYS Roden, RBS Hildesheim, A Wang, ZH Reynolds, MJ Mast, TC Robinson, R Murphy, BR Karron, RA Dillner, J Schiller, JT Lowy, DR AF Harro, CD Pang, YYS Roden, RBS Hildesheim, A Wang, ZH Reynolds, MJ Mast, TC Robinson, R Murphy, BR Karron, RA Dillner, J Schiller, JT Lowy, DR TI Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HEPATITIS-B VACCINE; COTTONTAIL RABBIT PAPILLOMAVIRUS; CERVICAL-CANCER; INSECT CELLS; IMMUNIZATION; ANTIBODIES; WORLDWIDE; PROTEIN; MUCOSAL; SERUM AB Background: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. Methods: Volunteers were given intramuscular injections with placebo or with 10- or 50-mug doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. Results: The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40-640), All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant, With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10240 (1499 to 69938) without adjuvant, 10 240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum, Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation = .85), confirming that ELISA titers are valid proxies for neutralizing antibodies. Conclusions: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. Novavax Inc, Columbia, MD USA. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Lab Cellular Oncol, Div Basic Sci, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Int Med, Ctr Immunizat Res, Baltimore, MD 21205 USA. RP Lowy, DR (reprint author), NIH, Bldg 36,Rm 1D-32, Bethesda, MD 20892 USA. NR 41 TC 364 Z9 386 U1 3 U2 18 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 284 EP 292 DI 10.1093/jnci/93.4.284 PG 9 WC Oncology SC Oncology GA 403NK UT WOS:000167049200012 PM 11181775 ER PT J AU Solomon, D Schiffman, M Tarone, R AF Solomon, D Schiffman, M Tarone, R CA ALTS Grp TI Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: Baseline results from a randomized trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID WOMEN AB Background: More than 2 million U.S. women receive an equivocal cervical cytologic diagnosis (atypical squamous cells of undetermined significance [ASCUS]) each year, Effective colposcopy triage strategies are needed to identify the minority of women who have clinically significant disease while avoiding excessive follow-up evaluation for others. Methods: The ASCUS/LSIL (i.e., low-grade squamous intraepithelial lesion) Triage Study (ALTS) is a multicenter, randomized trial comparing the sensitivity and specificity of the following three management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3): 1) immediate colposcopy (considered to be the reference standard), 2) triage to colposcopy based on human papillomavirus (HPV) results from Hybrid Capture 2(TM) (HC 2) and thin-layer cytology results, or 3) triage based on cytology results alone. This article summarizes the cross-sectional enrollment results for 3488 women with a referral diagnosis of ASCUS, All statistical tests are two-sided. Results: Among participants with ASCUS, the underlying prevalence of histologically confirmed CIN3 was 5.1 %. Sensitivity to detect CIN3 or above by testing for cancer-associated HPV DNA was 96.3% (95% confidence interval [CI] = 91.6% to 98.8%), with 56.1% of women referred to colposcopy, Sensitivity of a single repeat cytology specimen with a triage threshold of HSIL or above was 43.1% (95 % CI = 35.6% to 52.9 %), with 6.9% referred. Sensitivity of a lower cytology triage threshold of ASCUS or above was 85.3% (95% Ct = 78.2% to 90.8%), with 58.6% referred. Conclusions: HC 2 testing for cancer-associated HPV DNA is a viable option in the management of women with ASCUS, It has greater sensitivity to detect CIN3 or above and specificity comparable to a single additional cytologic test Indicating ASCUS or above. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. NCI, Breast & Gynecol Canc Res Grp, Div Canc Prevent, Bethesda, MD USA. RP Solomon, D (reprint author), Execut Plaza N,6130 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [CN55156, CN55105, CN55153, CN55154, CN55155, CN55157, CN55158, CN55159] NR 12 TC 665 Z9 698 U1 2 U2 12 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 293 EP 299 DI 10.1093/jnci/93.4.293 PG 7 WC Oncology SC Oncology GA 403NK UT WOS:000167049200013 PM 11181776 ER PT J AU Hildesheim, A Schiffman, M Bromley, C Wacholder, S Herrero, R Rodriguez, AC Bratti, MC Sherman, ME Scarpidis, U Lin, QQ Terai, M Bromley, RL Buetow, K Apple, RJ Burk, RD AF Hildesheim, A Schiffman, M Bromley, C Wacholder, S Herrero, R Rodriguez, AC Bratti, MC Sherman, ME Scarpidis, U Lin, QQ Terai, M Bromley, RL Buetow, K Apple, RJ Burk, RD TI Human papillomavirus type 16 variants and risk of cervical cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NONRADIOACTIVE OLIGONUCLEOTIDE PROBES; POLYMERASE CHAIN-REACTION; INTRAEPITHELIAL NEOPLASIA; SEQUENCE VARIANTS; HPV-16 E6; POLYMORPHISM; WOMEN; HPV16; GRADE; ASSOCIATIONS C1 Roche Mol Syst, Alameda, CA USA. LI COR Inc, Div Biotechnol, Lincoln, NE USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, NCI, Div Canc Epidemiol & Genet, Baltimore, MD USA. Caja Costarricense Segruo Social, San Jose, Costa Rica. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hildesheim, A (reprint author), NIH, 6120 Execut Blvd,Rm 7062, Rockville, MD 20852 USA. RI apple, raymond/I-4506-2012 OI apple, raymond/0000-0002-8007-0345 FU NCI NIH HHS [CA78527] NR 32 TC 130 Z9 133 U1 0 U2 3 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 315 EP 318 DI 10.1093/jnci/93.4.315 PG 4 WC Oncology SC Oncology GA 403NK UT WOS:000167049200016 PM 11181779 ER PT J AU Whiteman, DC Murphy, MFG Cook, LS Cramer, DW Hartge, P Marchbanks, PA Nasca, PC Ness, RB Purdie, DM Risch, HA AF Whiteman, DC Murphy, MFG Cook, LS Cramer, DW Hartge, P Marchbanks, PA Nasca, PC Ness, RB Purdie, DM Risch, HA TI Re: Multiple births and risk of epithelial ovarian cancer - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Yale Univ, Sch Med, New Haven, CT USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Massachusetts, Amherst, MA 01003 USA. Ctr Dis Control & Prevent, Fertil Epidemiol Sect, Atlanta, GA USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Calgary, Calgary, AB, Canada. Univ Oxford, Imperial Canc Res Fund, Gen Practice Res Grp, Oxford, England. Queensland Inst Med Res, Populat & Clin Sci Div, Herston, Qld 4029, Australia. RP Whiteman, DC (reprint author), Queensland Inst Med Res, Populat & Clin Sci Div, PO Royal Brisbane Hosp, Herston, Qld 4029, Australia. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 319 EP 320 PG 2 WC Oncology SC Oncology GA 403NK UT WOS:000167049200018 ER PT J AU Marcus, PM Fagerstrom, RM Prorok, PC AF Marcus, PM Fagerstrom, RM Prorok, PC TI Re: Lung cancer mortality in the Mayo Lung Project: Impact of extended follow-up - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NIH, 6130 Execut Blvd,MSC 7354,Suite 344, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 21 PY 2001 VL 93 IS 4 BP 322 EP 322 DI 10.1093/jnci/93.4.322 PG 1 WC Oncology SC Oncology GA 403NK UT WOS:000167049200021 ER PT J AU Weissman, NJ Panza, JA Tighe, JF Gwynne, JT AF Weissman, NJ Panza, JA Tighe, JF Gwynne, JT TI Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy - A randomized, double-blind, placebo-controlled trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID APPETITE-SUPPRESSANT DRUGS; HEART-DISEASE; OBESE PATIENTS; FENFLURAMINE; PHENTERMINE; PREVALENCE; ECHOCARDIOGRAPHY; INSUFFICIENCY; CESSATION; RISK AB Background: Previous studies have reported small increases in the prevalence of low-grade aortic and mitral regurgitation in patients treated with dexfenfluramine compared with placebo. However, whether valvular abnormalities develop or progress 1 year after discontinuation of dexfenfluramine therapy has not been determined. Objective: To assess change in valvular regurgitation and morphologic characteristics 1 year after discontinuation of dexfenfluramine therapy. Design: Randomized, double-blind, placebo-controlled, multicenter study. Setting: outpatient obesity centers. Patients: obese perrons who had been treated for 2 to 3 months with dexfenfluramine. sustained-release dexfenfluramine, or placebo. Blinding was maintained, and patients returned for repeated echocardiography at 1 year. Measurements: Pain of echocardiograms were evaluated with a side-by-side reading method for change in grade of valvular regurgitation, structure, and function. A standardized acquisition and reading protocol was followed, and a core laboratory was used. Results: 914 patients who had initial echocardiography returned for repeated echocardiography 11.4 +/- 1.0 months (mean +/- SD) after discontinuing study medication (10.0 +/- 1.0 months after initial echocardiography). Compared with the placebo group, a greater proportion of patients in both dexfenfluramine groups had decreased aortic regurgitation (P = 0.003 for the dexfenfluramine group, P = 0.02 for the sustained-release group). No change in mitral regurgitation or any other measure of valvular structure or function was seen in any treatment group. Conclusions: After dexfenfluramine therapy is taken for 2 to 3 months and discontinued, development or progression of any valvular regurgitation over the following year is unlikely. Echocardiographic evidence suggests that aortic regurgitation regresses in some previously treated patients. C1 Washington Hosp Ctr, Inst Cardiovasc Res, Washington, DC 20010 USA. Wyeth Ayerst Res, Philadelphia, PA USA. NHLBI, Bethesda, MD 20892 USA. RP Weissman, NJ (reprint author), Washington Hosp Ctr, Inst Cardiovasc Res, 110 Irving St NW,Suite 4B-1, Washington, DC 20010 USA. NR 17 TC 24 Z9 24 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 20 PY 2001 VL 134 IS 4 BP 267 EP 273 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 403NW UT WOS:000167050200002 PM 11182836 ER PT J AU Pacak, K Linehan, WM Eisenhofer, G Walther, MM Goldstein, DS AF Pacak, K Linehan, WM Eisenhofer, G Walther, MM Goldstein, DS TI Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID MULTIPLE ENDOCRINE NEOPLASIA; MEDULLARY-THYROID CARCINOMA; CLONIDINE-SUPPRESSION TEST; HIPPEL-LINDAU-DISEASE; POSITRON-EMISSION-TOMOGRAPHY; NEGATIVE I-131 MIBG; TERM FOLLOW-UP; RET PROTOONCOGENE; FAMILIAL PHEOCHROMOCYTOMA; CHROMOGRANIN-A AB Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as (123)l-metaiodobenzylguanidine scintigraphy and 6-[F-18]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr MSC-1583, Bethesda, MD 20892 USA. NR 138 TC 278 Z9 297 U1 0 U2 14 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 FEB 20 PY 2001 VL 134 IS 4 BP 315 EP 329 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 403NW UT WOS:000167050200008 PM 11182843 ER PT J AU Tsao, CC Wester, MR Ghanayem, B Coulter, SJ Chanas, B Johnson, EF Goldstein, JA AF Tsao, CC Wester, MR Ghanayem, B Coulter, SJ Chanas, B Johnson, EF Goldstein, JA TI Identification of human CYP2C19 residues that confer S-mephenytoin 4 '-hydroxylation activity to CYP2C9 SO BIOCHEMISTRY LA English DT Article ID POOR METABOLIZER PHENOTYPE; SITE-DIRECTED MUTAGENESIS; AMINO-ACID; SUBSTRATE-SPECIFICITY; GENETIC-DEFECT; BINDING; HYDROXYLATION; POLYMORPHISM; SUBFAMILY; DETERMINANTS AB CYP2C19 is selective for the 4 ' -hydroxylation of S-mephenytoin while the highly similar CYP2C9 has We activity toward this substrate. To identify critical amino acids determining the specificity of human CYP2C19 for S-mephenytoin 4 ' -hydroxylation, we constructed chimeras by replacing portions of CYP2C9 containing various proposed substrate recognition sites (SRSs) with those of CYP2C19 and mutating individual residues by site-directed mutagenesis. Only a chimera containing regions encompassing SRSs 1-4 was active (30% of wild-type CYP2C19), indicating that multiple regions are necessary to confer specificity for S-mephenytoin. Mutagenesis studies identified six residues in three topological components of the proteins required to convert CYP2C9 to an S-mephenytoin 4 ' hydroxylase (6% of the activity of wild-type CYP2C19). Of these, only the I99H difference located in SRS 1 between helices B and C reflects a change in a side chain that is predicted to be in the substrate-binding cavity formed above the heme prosthetic group. Two additional substitutions, S220P and P221T residing between helices F and G but not in close proximity to the substrate binding site together with five differences in the N-terminal portion of helix I conferred S-mephenytoin 4 ' -hydroxylation activity with a KM similar to that of CYP2C19 but a 3-fold lower K-cat. Three residues in helix I, S286N, V292A, and F2951, were essential for S-mephenytoin 4 ' -hydroxylation activity. On the basis of the structure of the closely related enzyme CYP2C5, these residues are unlikely to directly contact the substrate during catalysis but are positioned to influence the packing of substrate binding site residues and likely substrate access channels in the enzyme. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Goldstein, JA (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. RI Goldstein, Joyce/A-6681-2012; OI Coulter, Sherry/0000-0002-2732-3470 FU NIGMS NIH HHS [GM31001] NR 30 TC 45 Z9 46 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 20 PY 2001 VL 40 IS 7 BP 1937 EP 1944 DI 10.1021/bi001678u PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404TR UT WOS:000167117600009 PM 11329260 ER PT J AU Li, YL Lipschultz, CA Mohan, S Smith-Gill, SJ AF Li, YL Lipschultz, CA Mohan, S Smith-Gill, SJ TI Mutations of an epitope hot-spot residue alter rate limiting steps of antigen-antibody protein-protein associations SO BIOCHEMISTRY LA English DT Article ID SURFACE-PLASMON RESONANCE; EGG-WHITE LYSOZYME; SITE-DIRECTED MUTAGENESIS; TRANSFER-RNA SYNTHETASE; CRYSTAL-STRUCTURE; MONOCLONAL-ANTIBODIES; CHEMICAL RELAXATION; EXPERIMENTAL-DESIGN; CHICKEN LYSOZYME; IMMUNE-RESPONSE AB The antibodies, HyHEL-10 and HyHEL-26 (H10 and H26, respectively), share over 90% sequence homology and recognize with high affinity the same epitope on hen egg white lysozyme (HEL) but differ in degree of cross-reactivity with mutant lysozymes. The binding kinetics, as measured by BIAcore surface plasmon resonance, of monovalent Fab from both Abs (Fab10 and Fab26) to HEL and mutant lysozymes are best described by a two-step association model consistent with an encounter followed by docking that may include conformational changes. In their complexes with HEL, both Abs make the transition to the docked phase rapidly. For H10, the encounter step is rate limiting, whereas docking is also partially rate limiting for 1126. The forward rate constants of H10 are higher than those of 1126. The docking equilibrium as well as the overall equilibrium constant are also higher for H10 than for H26. Most of the free energy change of association (DeltaG degrees) occurs during the encounter phase (Delta G1) of both Abs. H10 derives a greater amount and proportion of free energy change from the docking phase (Delta G2) than does H26. In the H10-HEL(R21Q) complex, a significant slowing of docking results in lowered affinity, a loss of most of Delta G2, and apparently faster dissociation. Slower encounter and docking cause lowered affinity and a loss of free energy change primarily in the encounter step (Delta G1) of H26 with mutant HEL(R21Q). Overall, in the process of complex formation with lysozyme, the mutations HEL(R21X) affect primarily the docking phase of H10 association and both phases of H26. Our results are consistent with the interpretation that the free energy barriers to conformational rearrangement are highest in H26, especially with mutant antigen. C1 NCI, Frederick Canc Res & Dev Ctr, Program Struct Biol, Basic Res Lab, Frederick, MD 21702 USA. RP Smith-Gill, SJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Program Struct Biol, Basic Res Lab, POB B,Bldg 469,Room 206, Frederick, MD 21702 USA. EM smithgil@helix.nih.gov NR 50 TC 32 Z9 32 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 20 PY 2001 VL 40 IS 7 BP 2011 EP 2022 DI 10.1021/bi0014148 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 404TR UT WOS:000167117600017 PM 11329268 ER PT J AU Volpato, S Guralnik, JM Ferrucci, L Balfour, J Chaves, P Fried, LP Harris, TB AF Volpato, S Guralnik, JM Ferrucci, L Balfour, J Chaves, P Fried, LP Harris, TB TI Cardiovascular disease, interlenkin-6, and risk of mortality in older women - The women's health and aging study SO CIRCULATION LA English DT Article DE interleukins; cardiovascular diseases; mortality; women; aging ID C-REACTIVE PROTEIN; CONGESTIVE-HEART-FAILURE; AMYLOID-A-PROTEIN; UNSTABLE ANGINA; ATHEROSCLEROTIC PLAQUES; INTERLEUKIN-6; CYTOKINES; INFLAMMATION; ASPIRIN; INDEX AB Background--Systemic chronic inflammation has been found to be related to all-cause mortality risk in older persons. We investigated whether specific chronic conditions, particularly cardiovascular disease (CVD), affect the association between high interleukin (IL)-6 level and mortality in a sample of disabled older women. Methods and Results--IL-6 serum level was measured at baseline in 620 women greater than or equal to 65 years old. The presence and severity of medical conditions was ascertained by standard criteria that used multiple sources of information. The sample was surveyed over the 3-year follow-up. After adjustment for potential confounders, compared with those in the lowest tertile, women in the highest IL-6 tertile were at higher risk of all-cause mortality. The presence of CVD, however, strongly affected the risk of mortality associated with high IL-6. Among women with prevalent CVD, those with high IL-6 levels had >4-fold risk of death (RR 4.6; 95% CI 2.0 to 10.5) compared with women in the lowest tertile, whereas the relative risk associated with high IL-6 among those without CVD was much lower and not significant (RR 1.8; 95% CI 0.7 to 4.2), Adjustment for all chronic diseases and disease severity measures, including ankle-brachial index, forced expiratory volume, and exercise tolerance, did not change the results. Conclusions--IL-6 level is helpful in identifying a subgroup of older CVD patients with high risk of death over a period of 3 years. Systemic inflammation, as measured by IL-6, may be related to the clinical evolution of older patients with CVD. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Italian Natl Inst Res & Care Aging, I Fraticini, Dept Geriatr, Florence, Italy. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. RP Volpato, S (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Room 3C-309, Bethesda, MD 20892 USA. RI VOLPATO, STEFANO/H-2977-2014 OI VOLPATO, STEFANO/0000-0003-4335-6034 FU NIA NIH HHS [N01-AG-1-2112] NR 28 TC 250 Z9 264 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 20 PY 2001 VL 103 IS 7 BP 947 EP 953 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NV UT WOS:000167562000007 PM 11181468 ER PT J AU Hollander, MC Sheikh, MS Yu, K Zhan, QM Iglesias, M Woodworth, C Fornace, AJ AF Hollander, MC Sheikh, MS Yu, K Zhan, QM Iglesias, M Woodworth, C Fornace, AJ TI Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE apoptosis; Gadd34; ceramide; expression; GADD153; GADD45; BAX; WAF1 ID HERPES-SIMPLEX VIRUS; BCL-2 MESSENGER-RNA; CELL-DEATH; PROTEIN-SYNTHESIS; GENOTOXIC STRESS; CD95 FAS/APO-1; CERAMIDE; GENE; RADIATION; SHUTOFF AB DNA damage has many cellular consequences including, in some cases, apoptosis. Expression of Gadd34 was shown to be increased by ionizing radiation only in cells that undergo rapid apoptosis following this treatment. The effects of various other apoptosis-inducing agents as well as apoptosis-inhibiting genes on regulation of Gadd34 were investigated. In many cell types, agents which have been reported to lead to increased intracellular ceramide levels led to an increase in Gadd34 transcript levels. These included TNF alpha, the ceramide analog C-2 ceramide, dimethyl sphingosine and anti-Fas antibody as well as ionizing radiation. Induction of Gadd34 by ionizing radiation was coincident with the onset of apoptosis and increased as apoptosis progressed. In a short-term transfection assay, more than 30% of Gadd34-transfected cells exhibited nuclear fragmentation by 48 hours. Apoptosis, as well as induction of Gadd34 by apoptotic stimuli, was attenuated by the apoptosis inhibitors, Bcl-2, cowpox virus CrmA and herpes simplex virus ICP34.5. Thus, activation of Gadd34 is a downstream event in apoptotic signaling pathways and may directly contribute to the apoptotic process. 2001 Wiley-Liss, Inc. C1 NCI, Div Basic Sci, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, Biol Lab, Bethesda, MD USA. RP Hollander, MC (reprint author), NCI, Div Basic Sci, Basic Res Lab, NIH, Bldg 37,Room 6144, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 33 TC 51 Z9 54 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 20 PY 2001 VL 96 IS 1 BP 22 EP 31 DI 10.1002/1097-0215(20010220)96:1<22::AID-IJC3>3.0.CO;2-K PG 10 WC Oncology SC Oncology GA 400UA UT WOS:000166889000003 PM 11241327 ER PT J AU Kulikov, VV Derkatch, IL Noskov, VN Tarunina, OV Chernoff, YO Rogozin, IB Pavlov, YI AF Kulikov, VV Derkatch, IL Noskov, VN Tarunina, OV Chernoff, YO Rogozin, IB Pavlov, YI TI Mutagenic specificity of the base analog 6-N-hydroxylaminopurine in the LYS2 gene of yeast Saccharomyces cerevisiae SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE base analog mutagenesis; yeast; suppression; prions; mutation hotspots ID DNA-REPLICATION ERRORS; ESCHERICHIA-COLI; POLYMERASE-EPSILON; MUTATION-RATES; LAC REPRESSOR; CAN1 LOCUS; REPAIR; TRANSLATION; DELTA; TERMINATION AB We used the LYS2 gene mutational system to study mutation specificity of the base analog 6-N-hydroxylaminopurine (HAP) in yeast. We characterized phenotypes of mutations using codon-specific nonsense suppressors and the test employing inactivation of the release factor Sup35 due to overexpression and formation of prion-like derivative [PSI]. We have shown that HAP induces predominantly nonsense mutations. While the tests using codon-specific nonsense-suppressors allowed to identify only about 50% of nonsense-mutations, all the nonsense-mutations were identified in the test with defective Sup35. We determined and analyzed the spectrum of MAP-induced nucleotide changes in two regions of the gene. HAP induces predominantly GC --> AT transitions in a hotspots of a central position of trinucleotide GGA or AGG. Directionality of these transitions is consistent with the idea that initial dHAPMP incorporation in the leading strand is more genetically dangerous than in lagging DNA strand. We revealed a specific context inhibitory for HAP mutagenesis, a "T" in -1 position to mutation site. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Sankt Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Novosibirsk, Russia. RP Pavlov, YI (reprint author), NIEHS, Labs Mol Genet & Struct Biol, POB 12233, Res Triangle Pk, NC 27709 USA. RI Chernoff, Yury/J-2833-2014; OI Chernoff, Yury/0000-0002-8934-9051 FU NIGMS NIH HHS [R01GM58763] NR 41 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD FEB 20 PY 2001 VL 473 IS 2 BP 151 EP 161 DI 10.1016/S0027-5107(00)00142-1 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 403GB UT WOS:000167033200002 PM 11166033 ER PT J AU Ploski, JE Aplan, PD AF Ploski, JE Aplan, PD TI Characterization of DNA fragmentation events caused by genotoxic and non-genotoxic agents SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE DNA fragmentation; chemotherapy; apoptosis; leukemia; pulsed field gel; MLL ID BREAKPOINT CLUSTER REGION; ORDER CHROMATIN FRAGMENTATION; TOPOISOMERASE-II INHIBITORS; APOPTOTIC CELL-DEATH; DOUBLE-STRAND BREAKS; CLEAVAGE; LEUKEMIA; SITE; CONDENSATION; MECHANISMS AB Leukemic cells have been shown to generate several classes of DNA fragments after treatment with cytotoxic cancer chemotherapy agents. However, it is unclear which of these fragmentation events are a direct effect of DNA-damaging chemotherapy agents, and which fragmentation events are caused by downstream processes. such as apoptosis. We have performed a detailed analysis of DNA fragmentation events which occur following cytotoxic chemotherapy in four representative leukemic cell lines (HL-60, Jurkat, K562, and Molt-4). We used a DNA topoisomerase II inhibitor (etoposide), an alkylating agent (melphalan), a nucleoside analog (cytosine arabinoside), and a non-genotoxic agent (N-methylformamide) to induce cell death. We studied high molecular weight and low molecular weight DNA fragmentation events, as well as the specific cleavage of the MLL breakpoint cluster region (bcr). The DNA fragments produced at late time points were largely independent of the agents used. while those generated at earlier time points showed dear differences in terms of fragment size and relative abundance, depending on the agent used. In addition. there were clear differences between cell lines in terms of size, relative abundance, and rate at which DNA fragments were produced by treatment with the same agents. We think that this survey documents the importance of studying several different cell lines. time points, and assays before reaching conclusions about the types of DNA fragments produced during treatment with cytotoxic agents. and provides a useful framework for studying a wide range of DNA fragments produced by cytotoxic agents. Published by Elsevier Science B.V. C1 Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. Childrens Hosp Buffalo, Div Pediat Hematol Oncol, Buffalo, NY USA. RP NCI, Div Clin Sci, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 FU NCI NIH HHS [CA16056, CA73773] NR 34 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD FEB 20 PY 2001 VL 473 IS 2 BP 169 EP 180 DI 10.1016/S0027-5107(00)00147-0 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 403GB UT WOS:000167033200004 PM 11166035 ER PT J AU Haddad, EK Wu, XF Hammer, JA Henkart, PA AF Haddad, EK Wu, XF Hammer, JA Henkart, PA TI Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice SO JOURNAL OF CELL BIOLOGY LA English DT Article DE lymphocyte; cytotoxicity; Rab; exocytosis; myosin V ID GRISCELLI-SYNDROME; RAB GTPASES; FAS LIGAND; CELLS; TRANSPORT; SECRETION; MUTATIONS; DISEASE; CTLA-4; 15Q21 AB Because mutations in Rab27a have been linked to immune defects in humans, we have examined cytotoxic lymphocyte function in ashen mice, which contain a splicing mutation in Rab27a. Ashen cytotoxic T lymphocytes (CTLs) showed a >90% reduction in lytic activity on Fas-negative target cells compared with control C3H CTLs, and ashen natural killer cell activity was likewise diminished. Although their granule-mediated cytotoxicity pathway is profoundly defective, ashen CTLs displayed a normal FasL-Fas cytotoxicity pathway. The CD4/8 phenotype of ashen T cells and their proliferative responses were similar to controls. Ashen CTLs had normal levels of perforin and granzymes A and B and normal-appearing perforin-positive granules, which polarized upon interaction of the CTLs with anti-CD3-coated beads. However, rapid anti-CD3-induced granule secretion was drastically defective in both CD8(+) and CD4(+) T cells from ashen mice. This defect in exocytosis was not observed in the constitutive pathway, as T cell receptor-stimulated interferon-gamma secretion was normal. Based on these results and our demonstration that Rab27a colocalizes with granzyme B-positive granules and is undetectable in ashen CTLs, we conclude that Rab27a is required for a late step in granule exocytosis, compatible with current models of Rab protein function in vesicle docking and fusion. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Henkart, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. NR 20 TC 172 Z9 175 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD FEB 19 PY 2001 VL 152 IS 4 BP 835 EP 841 DI 10.1083/jcb.152.4.835 PG 7 WC Cell Biology SC Cell Biology GA 404RQ UT WOS:000167114800018 PM 11266473 ER PT J AU Basanez, G Zimmerberg, J AF Basanez, G Zimmerberg, J TI HIV and apoptosis: Death and the mitochondrion SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material ID VIRAL PROTEIN-R; ANTIRETROVIRAL THERAPY; VPR PROTEIN; VIRUS; MECHANISMS; RESERVOIRS; CHANNELS; NEURONS; CELLS; AIDS C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 10D14,10 Ctr Dr,MSC 1855, Bethesda, MD 20892 USA. RI Basanez, Gorka/L-9509-2014 OI Basanez, Gorka/0000-0002-7475-7861 NR 26 TC 14 Z9 14 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 19 PY 2001 VL 193 IS 4 BP F11 EP F14 DI 10.1084/jem.193.4.F11 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 404RR UT WOS:000167114900001 PM 11181706 ER PT J AU Guan, Z Lu, LR Zheng, ZC Liu, J Yu, FR Lu, S Xin, Y Liu, XY Hong, JY Zhang, WQ AF Guan, Z Lu, LR Zheng, ZC Liu, J Yu, FR Lu, S Xin, Y Liu, XY Hong, JY Zhang, WQ TI A spontaneous recurrent seizure-related Rattus NSF gene identified by linker capture subtraction SO MOLECULAR BRAIN RESEARCH LA English DT Article DE spontaneous recurrent seizures; kainic acid; linker capture subtraction; N-ethylmaleimide-sensitive fusion protein; epilepsy related gene 1 ID SYNAPTIC VESICLE DOCKING; KAINIC ACID INJECTION; IN-VITRO; MOSSY FIBERS; FUSION; HIPPOCAMPUS; EPILEPSY; TOOL; RATS AB Spontaneous recurrent seizures (SRS) are the major clinical characteristic of epilepsy. In this study, using a SRS-behavior test combined with linker capture subtraction (LCS) to identify genes altered in their expression in response to a single kainic acid (KA)-induced SRS at 3 weeks in the rat hippocampal formation. Dot blot analysis of the differentially expressed cDNA fragments with LCS showed the down-regulation of one cDNA related to SRS, which was designated epilepsy-related gene 1 (ERG1). Northern blot analysis showed that ERG1 mRNA was reduced by KA administration with and without SRS, but more so with SRS. This differential expression had also been confirmed by in situ hybridization, which showed that ERG1 mRNA was down-regulated in the dorsal dentate granule cells (dDGCs) of the hippocampal formation, but remarkable up-regulated in the amygdalohippocampal area (AHi), posteromedial cortical amygdaloid nucleus (PMCo) and perirhinal cortex (PRh). The complete cDNA of ERG1 was cloned, sequenced (AF142097). It encodes a Rattus homologue of N-ethylmaleimide-sensitive fusion protein (NSF), which is an ATPase that plays a key role in mediating docking and/or fusion of transport vesicles in the multi-step pathways of vesicular transport. Sequence analysis revealed that ERG1 has high sequence similarity with the cDNA of the Mus musculus suppressor of K+ transport growth defect (SKD2), N-ethylmaleimide(NEM)-sensitive fusion protein of Chinese hamster and human NEM-sensitive factor (HSU03985). (C) 2001 Elsevier Science B.V. All rights reserved. C1 Dalien Med Univ, Dept Physiol, Dalian 116023, Peoples R China. Chinese Acad Sci, Shanghai Inst Biochem, Shanghai 200031, Peoples R China. NIEHS, Toxicol Lab, Neuropharmacol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Guan, Z (reprint author), MIT, Ctr Learning & Memory, 50 Ames St,E18-605, Cambridge, MA 02139 USA. NR 30 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD FEB 19 PY 2001 VL 87 IS 1 BP 117 EP 123 DI 10.1016/S0169-328X(00)00286-2 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 406EP UT WOS:000167202200013 ER PT J AU Andiman, W Boucher, M Bulterys, MB Burns, D Bryson, Y de Martino, M Farley, J Fowler, MG Galli, L Hanson, IC Kind, C Korber, B Kovacs, A Krogstad, P Landesman, S Lapointe, N Lemay, M Mandelbrot, L Mayaux, MJ Mellins, R Minkoff, H Mofenson, L Nielsen, K Newell, ML Pardi, G Peavy, H Peckham, C Read, JS Rother, C Rudin, C Scott, G Semprini, A Shearer, W Simpson, BJ Stek, A Thompson, B Tovo, PA Tuomala, R Van Dyke, RB Weedon, J Gabiano, C Harris, DR Lindsay, M Newell, ML Nielsen, K Peavy, HH Chan, L Easley, K Khammy, A Muenz, L Nugent, RP Durako, S Goodwin, S Mitchell, R Owen, W Van Dyke, R Widmayer, S Bardeguez, A Hanson, C Wiznia, A Luzuriaga, K Viscarello, R Ho, D Koup, R Chen, I Krogstad, P Mullins, J Wolinsky, S Walker, B Ammann, A Clapp, S McDonald, D Fauvel, M Hankins, C Samson, J Newell, ML Peckham, CS Thorne, CN Giaquinto, C Ruga, E De Rossi, A Truscia, D Grosch-Worner, I Schafer, A Mok, J Johnstone, F Jiminez, J de Alba, C Rodriguez, MCG Bates, I de Jose, I Hawkins, F Zapico, RM Pena, JM Garcia, JG Lopez, JRA Asensi-Botet, F Otero, MC Perez-Tamarit, D Moya, A Galbis, MJ Scherpbier, H Boer, K Bohlin, AB Lindgren, S Anzen, B Belfrage, E Lidin-Jansson, G Levy, J Barlow, P Hainaut, M Peltier, A Ferrazin, A De Maria, A Gotta, C Mur, A Vinolas, M Paya, A Lopez-Vilchez, MA Coll, O Fortuny, C Boguna, J Caro, MC Canet, Y Pardi, G Ravizza, M Semprini, E Castagna, C Fiore, S Guerra, B Lanari, M Bianchi, S Bovicelli, L Prati, E Zanelli, S Duse, M Soresina, A Scaraveli, G Stegagno, M De Santis, M Muggiasca, ML Vigano, A Spinillo, A Probizer, FR Bucceri, A Rancilio, L Taylor, GP Lyall, H Penn, Z Blott, M Valerius, NH Martinelli, P Buffolano, W Tibaldi, C Ziarati, N Pardi, G Semprini, A Ravizza, M Castagna, C Fiore, S Della Torre, M Parazzini, F Bovicelli, L Guerra, B Dallacasa, P Bianchi, S Duse, M Prati, E Zanelli, S Soresina, A Pachi, A Scaravelli, G Stegagno, M Mancuso, S De Santis, M Villa, P Conti, M Principi, N Muggiasca, M Marchisio, P Zara, C Spinillo, A Ravagni, F Vignali, M Bucceri, A Rossi, G Rancilio, L Selvaggi, L Greco, P Vimercati, A Massi, G Innocenti, T Fiscella, A Martinelli, P Sansone, M Benedetto, C Tibaldi, C Ziarati, N Tadrist, B Thevenieau, D Gondry, J Paulard, B Alisy, C Brault, D Tordjeman, N Mamou, J Rozan, M Colombani, D Pincemaille, O Salvetti, A Chabanier, C Hernandorena, X Leroy, J Schaal, J Balde, P Faucher, P Lachassinne, E Benoit, S Douard, D Hocke, C Barjot, P Brouard, J Delattre, P Stien, L Audibert, F Labrune, P Vial, M Mazy, F Sitbon, D Crenn-Hebert, C Floch-Tudal, C Akakpo, R Daveau, C Leblanc, A Cesborn, P Duval-Arnould, D Huraux-Rendu, C Lemerle, S Touboul, C Guerin, M Maingueneau, C Reyaud, I Rousseau, T Ercoil, V Lanza, M Denavit, M Garnier, J Lahsinat, K Pia, P Allouche, C Nardou, M Grall, F May, A Dallot, M Lhuillier, P Cecile, W Mezin, R Balde, P Bech, A Lobut, J Algava, G Dermesay, AC Busuttil, R Jacquemot, M Bader-Meunier, B Fridman, S Codaccioni, X Maxingue, F Thomas, D Alain, J De Lumley, L Tabaste, J Salin, PB Seaume, H Guichard, A Kebaill, K Roussouly, C Botto, C De Lanete, A Wipff, P Cravello, L De Boisse, P Leclaire, M Michel, G Crumiere, C Lefevre, V Le Lorier, B Pauly, I Robichez, B Seguy, D Delhinger, M Rideau, F Talon, P Benos, P Huret, C Nicolas, J Heller-Roussin, B Saint-Leger, S Delaporte, M Hubert, C De Sarcus, B Karoubi, P Mechinaud, F Bertcrottiere, D Bongain, A Monpoux, F De Gennes, C Devianni, F Nisand, I Rousset, M Karoubi, P Mouchnino, G Muray, J Munzer, M Quereux, C Brossard, V Clavier, B Allemon, M Rotten, D Stephan, J Varlet, M Guyot, B Narcy, P Bardinet, F De Caunes, F Jeny, R Robin, M Boulley, AR Savey, L Berrebi, A Tricoire, J Borderon, J Fignon, A Guillot, F Maria, B Broyard, A Chitrit, Y Firtion, G Mandelbrot, L Pillet, ML Parat, S Boissinot, C Garec, N Levine, M Ottenwalter, A Schaller, F Vilmer, E Coupotin, C Brunner, C Ciraru-Vigneron, N Hatem-Gantzer, G Heller-Roussin, B Fritel, X Wallet, A Bouille, J Milliez, J Mrejen, DB Dermer, E Noseda, G Bardou, D Cressaty, J Francoual, C Moncomble, CC Cohen, H Blanche, S Bastion, H Benifla, J Benkhatar, F Berkane, N Herve, F Ronzier, M Mayaux, MJ Blanche, S Mandelbrot, L de Martino, M Tovo, PA Galli, L Gabiano, C Ferraris, G Rancilio, L Bucceri, A Garetto, S Palomba, E Riva, C Vierucci, A de Luca, M Farina, S Fundaro, C Genovese, O Mereu, G Forni, GL Casadei, A Zuccotti, GV Riva, E Cellini, M Baraldi, C Consolini, R Palla, G Ruggeri, M Ciccimarra, F Guarino, A Osimani, P Banaglia, G Romano, A Lanari, M De Mattia, D Caselli, D Boni, S Dell'Erba, G Bassanetti, F Sticca, M Timpano, C Magnani, C Salvatore, C Lipreri, R Tornaghi, R Pinzani, R Cecchi, MT Bezzi, T Battisti, L Bresciani, E Gattinara, GC Nasi, C Pellegatta, A Mazza, A Baldi, F Ruga, E Altobelli, R Deiana, M Colnaghi, C Tarallo, L Tondo, U Anastasio, E Duse, M Chiriaco, PG Ruggeri, C Scott, G Hutto, C O'Sullivan, M Malmsberry, A Willoughby, A Burns, D Goedert, J Landesman, S Minkoff, H Mendez, H Holman, S Rubinstein, A Durako, S Muenz, L Goodwin, S Nesheim, S Lindsay, M Lee, F Nahmias, A Sawyer, M Vink, P Farley, J Alger, L Abrams, E Bamji, M Lambert, G Schoenbaum, E Thomas, P Weedon, J Palumbo, P Bardeguez, A Denny, T Oleske, J Bulterys, M SImonds, R Ethier-Ives, J Rogers, M Schluchter, M Kutner, M Kaplan, S Kattan, M Lipshultz, S Mellins, R Shearer, W Peavy, H Sopko, G Sloand, E Wu, M Kind, C Nadal, D Rudin, C Siegrist, CA Wyler, CA Cheseaux, JJ Aebi, C Gnehm, H Schubiger, G Klingler, J Hunziker, U Kuchler, H Gianinazzi, M Buhlmann, U Rudin, C Biedermann, K Lauper, U Irion, O Brunelli, A Spoletini, G Schreyer, A Kind, C Hosli, I Saurenmann, E Drack, G Isenschmid, M Poorbeik, M Schupbach, J Perrin, L Erb, P Joller, H Bryson, Y Dillon, M Nielsen, K Boyer, P Liao, D Keller, M Deveikis, A Kovacs, A Stek, A Chan, L Khoury, M Diaz, C Pacheco-Acosta, E Tuomala, R Cooper, E Mesthene, D Pitt, J Higgins, A Landesman, S Mendez, H Moroso, G Rich, K Turpin, D Shearer, W Hanson, C Cooper, N Fowler, MG Nugent, RP Davenny, K Thompson, B Andiman, W Simpson, J AF Andiman, W Boucher, M Bulterys, MB Burns, D Bryson, Y de Martino, M Farley, J Fowler, MG Galli, L Hanson, IC Kind, C Korber, B Kovacs, A Krogstad, P Landesman, S Lapointe, N Lemay, M Mandelbrot, L Mayaux, MJ Mellins, R Minkoff, H Mofenson, L Nielsen, K Newell, ML Pardi, G Peavy, H Peckham, C Read, JS Rother, C Rudin, C Scott, G Semprini, A Shearer, W Simpson, BJ Stek, A Thompson, B Tovo, PA Tuomala, R Van Dyke, RB Weedon, J Gabiano, C Harris, DR Lindsay, M Newell, ML Nielsen, K Peavy, HH Chan, L Easley, K Khammy, A Muenz, L Nugent, RP Durako, S Goodwin, S Mitchell, R Owen, W Van Dyke, R Widmayer, S Bardeguez, A Hanson, C Wiznia, A Luzuriaga, K Viscarello, R Ho, D Koup, R Chen, I Krogstad, P Mullins, J Wolinsky, S Walker, B Ammann, A Clapp, S McDonald, D Fauvel, M Hankins, C Samson, J Newell, ML Peckham, CS Thorne, CN Giaquinto, C Ruga, E De Rossi, A Truscia, D Grosch-Worner, I Schafer, A Mok, J Johnstone, F Jiminez, J de Alba, C Rodriguez, MCG Bates, I de Jose, I Hawkins, F Zapico, RM Pena, JM Garcia, JG Lopez, JRA Asensi-Botet, F Otero, MC Perez-Tamarit, D Moya, A Galbis, MJ Scherpbier, H Boer, K Bohlin, AB Lindgren, S Anzen, B Belfrage, E Lidin-Jansson, G Levy, J Barlow, P Hainaut, M Peltier, A Ferrazin, A De Maria, A Gotta, C Mur, A Vinolas, M Paya, A Lopez-Vilchez, MA Coll, O Fortuny, C Boguna, J Caro, MC Canet, Y Pardi, G Ravizza, M Semprini, E Castagna, C Fiore, S Guerra, B Lanari, M Bianchi, S Bovicelli, L Prati, E Zanelli, S Duse, M Soresina, A Scaraveli, G Stegagno, M De Santis, M Muggiasca, ML Vigano, A Spinillo, A Probizer, FR Bucceri, A Rancilio, L Taylor, GP Lyall, H Penn, Z Blott, M Valerius, NH Martinelli, P Buffolano, W Tibaldi, C Ziarati, N Pardi, G Semprini, A Ravizza, M Castagna, C Fiore, S Della Torre, M Parazzini, F Bovicelli, L Guerra, B Dallacasa, P Bianchi, S Duse, M Prati, E Zanelli, S Soresina, A Pachi, A Scaravelli, G Stegagno, M Mancuso, S De Santis, M Villa, P Conti, M Principi, N Muggiasca, M Marchisio, P Zara, C Spinillo, A Ravagni, F Vignali, M Bucceri, A Rossi, G Rancilio, L Selvaggi, L Greco, P Vimercati, A Massi, G Innocenti, T Fiscella, A Martinelli, P Sansone, M Benedetto, C Tibaldi, C Ziarati, N Tadrist, B Thevenieau, D Gondry, J Paulard, B Alisy, C Brault, D Tordjeman, N Mamou, J Rozan, M Colombani, D Pincemaille, O Salvetti, A Chabanier, C Hernandorena, X Leroy, J Schaal, J Balde, P Faucher, P Lachassinne, E Benoit, S Douard, D Hocke, C Barjot, P Brouard, J Delattre, P Stien, L Audibert, F Labrune, P Vial, M Mazy, F Sitbon, D Crenn-Hebert, C Floch-Tudal, C Akakpo, R Daveau, C Leblanc, A Cesborn, P Duval-Arnould, D Huraux-Rendu, C Lemerle, S Touboul, C Guerin, M Maingueneau, C Reyaud, I Rousseau, T Ercoil, V Lanza, M Denavit, M Garnier, J Lahsinat, K Pia, P Allouche, C Nardou, M Grall, F May, A Dallot, M Lhuillier, P Cecile, W Mezin, R Balde, P Bech, A Lobut, J Algava, G Dermesay, AC Busuttil, R Jacquemot, M Bader-Meunier, B Fridman, S Codaccioni, X Maxingue, F Thomas, D Alain, J De Lumley, L Tabaste, J Salin, PB Seaume, H Guichard, A Kebaill, K Roussouly, C Botto, C De Lanete, A Wipff, P Cravello, L De Boisse, P Leclaire, M Michel, G Crumiere, C Lefevre, V Le Lorier, B Pauly, I Robichez, B Seguy, D Delhinger, M Rideau, F Talon, P Benos, P Huret, C Nicolas, J Heller-Roussin, B Saint-Leger, S Delaporte, M Hubert, C De Sarcus, B Karoubi, P Mechinaud, F Bertcrottiere, D Bongain, A Monpoux, F De Gennes, C Devianni, F Nisand, I Rousset, M Karoubi, P Mouchnino, G Muray, J Munzer, M Quereux, C Brossard, V Clavier, B Allemon, M Rotten, D Stephan, J Varlet, M Guyot, B Narcy, P Bardinet, F De Caunes, F Jeny, R Robin, M Boulley, AR Savey, L Berrebi, A Tricoire, J Borderon, J Fignon, A Guillot, F Maria, B Broyard, A Chitrit, Y Firtion, G Mandelbrot, L Pillet, ML Parat, S Boissinot, C Garec, N Levine, M Ottenwalter, A Schaller, F Vilmer, E Coupotin, C Brunner, C Ciraru-Vigneron, N Hatem-Gantzer, G Heller-Roussin, B Fritel, X Wallet, A Bouille, J Milliez, J Mrejen, DB Dermer, E Noseda, G Bardou, D Cressaty, J Francoual, C Moncomble, CC Cohen, H Blanche, S Bastion, H Benifla, J Benkhatar, F Berkane, N Herve, F Ronzier, M Mayaux, MJ Blanche, S Mandelbrot, L de Martino, M Tovo, PA Galli, L Gabiano, C Ferraris, G Rancilio, L Bucceri, A Garetto, S Palomba, E Riva, C Vierucci, A de Luca, M Farina, S Fundaro, C Genovese, O Mereu, G Forni, GL Casadei, A Zuccotti, GV Riva, E Cellini, M Baraldi, C Consolini, R Palla, G Ruggeri, M Ciccimarra, F Guarino, A Osimani, P Banaglia, G Romano, A Lanari, M De Mattia, D Caselli, D Boni, S Dell'Erba, G Bassanetti, F Sticca, M Timpano, C Magnani, C Salvatore, C Lipreri, R Tornaghi, R Pinzani, R Cecchi, MT Bezzi, T Battisti, L Bresciani, E Gattinara, GC Nasi, C Pellegatta, A Mazza, A Baldi, F Ruga, E Altobelli, R Deiana, M Colnaghi, C Tarallo, L Tondo, U Anastasio, E Duse, M Chiriaco, PG Ruggeri, C Scott, G Hutto, C O'Sullivan, M Malmsberry, A Willoughby, A Burns, D Goedert, J Landesman, S Minkoff, H Mendez, H Holman, S Rubinstein, A Durako, S Muenz, L Goodwin, S Nesheim, S Lindsay, M Lee, F Nahmias, A Sawyer, M Vink, P Farley, J Alger, L Abrams, E Bamji, M Lambert, G Schoenbaum, E Thomas, P Weedon, J Palumbo, P Bardeguez, A Denny, T Oleske, J Bulterys, M SImonds, R Ethier-Ives, J Rogers, M Schluchter, M Kutner, M Kaplan, S Kattan, M Lipshultz, S Mellins, R Shearer, W Peavy, H Sopko, G Sloand, E Wu, M Kind, C Nadal, D Rudin, C Siegrist, CA Wyler, CA Cheseaux, JJ Aebi, C Gnehm, H Schubiger, G Klingler, J Hunziker, U Kuchler, H Gianinazzi, M Buhlmann, U Rudin, C Biedermann, K Lauper, U Irion, O Brunelli, A Spoletini, G Schreyer, A Kind, C Hosli, I Saurenmann, E Drack, G Isenschmid, M Poorbeik, M Schupbach, J Perrin, L Erb, P Joller, H Bryson, Y Dillon, M Nielsen, K Boyer, P Liao, D Keller, M Deveikis, A Kovacs, A Stek, A Chan, L Khoury, M Diaz, C Pacheco-Acosta, E Tuomala, R Cooper, E Mesthene, D Pitt, J Higgins, A Landesman, S Mendez, H Moroso, G Rich, K Turpin, D Shearer, W Hanson, C Cooper, N Fowler, MG Nugent, RP Davenny, K Thompson, B Andiman, W Simpson, J CA Int Perinatal HIV Grp TI Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies SO AIDS LA English DT Article; Proceedings Paper CT 7th Conference on Retroviruses and Opportunistic Infections CY JAN 30-FEB 02, 2000 CL CHICAGO, ILLINOIS ID HUMAN-IMMUNODEFICIENCY-VIRUS; MOTHER-TO-CHILD; FRENCH PERINATAL COHORT; ZIDOVUDINE PROPHYLAXIS; RISK-FACTORS; TYPE-1; PREGNANCY; INFECTION; TRIAL; PREVENTION AB Objective: To test the a priori hypothesis that longer duration of ruptured membranes is associated with increased risk of vertical transmission of HIV. Design: The relationship between duration of ruptured membranes and vertical transmission of HIV was evaluated in an individual patient data meta-analysis. Methods: Eligible studies were prospective cohort studies including at least 100 mother-child pairs, from regions where HIV-infected women are counselled not to breastfeed. Analyses were restricted to vaginal deliveries and non-elective Cesarean sections; elective Cesarean section deliveries (those performed before onset of labour and before rupture of membranes) were excluded. Results: The primary analysis included 4721 deliveries with duration of ruptured membranes less than or equal to 24 h. After adjusting for other factors known to be associated with vertical transmission using logistic regression analysis to assess the strength of the relationship, the risk of vertical HIV transmission increased approximately 2% with an increase of 1 h in the duration of ruptured membranes [adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.04; for each 1 h increment]. There were no significant interactions of duration of ruptured membranes with study cohort or with any of the covariates, except maternal AIDS. Among women diagnosed with AIDS, the estimated probability of transmission increased from 8% to 31% with duration of ruptured membranes of 2 h and 24 h respectively (P < 0.01). Conclusions: These results support the importance of duration of ruptured membranes as a risk factor for vertical transmission of HIV and suggest that a diagnosis of AIDS in the mother at the time of delivery may potentiate the effect of duration of ruptured membranes. (C) 2001 Lippincott Williams & Wilkins. C1 NICHD, PAMA Branch, NIH, Bethesda, MD 20892 USA. Univ Miami, Infants HIH1 Seroposit Mothers, Coral Gables, FL 33124 USA. Univ Calif Los Angeles, Los Angeles Maternal Infant HIV Transmiss Study, Los Angeles, CA 90024 USA. Univ So Calif, Los Angeles Cty Perinatal Transmiss Study, Los Angeles, CA 90089 USA. Yale Univ, Prospect Longitudinal Cohort Study, New Haven, CT 06520 USA. US Publ Hlth Serv, Washington, DC USA. RP Read, JS (reprint author), NICHD, PAMA Branch, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd MSC 7510, Bethesda, MD 20892 USA. RI Wolinsky, Steven/B-2893-2012; SHCS, MoCHIV/G-4081-2011; vimercati, antonella/I-8114-2012; VILLA, PAOLA/J-1579-2012; peckham, catherine/I-6300-2013; SHCS, int. coll. B/G-4090-2011; SHCS, all/G-4072-2011; SHCS, ch/G-4077-2011; De Rossi, Anita/L-3128-2015; Thorne, Claire/C-5943-2008; de maria, andrea/F-7116-2016; FRITEL, Xavier/K-8566-2012; Easley, Kirk/K-6910-2015; Marchisio, Paola /J-7342-2016 OI Mofenson, Lynne/0000-0002-2818-9808; Wolinsky, Steven/0000-0002-9625-6697; Tovo, Pier Angelo/0000-0002-0192-3240; SEMPRINI, AUGUSTO ENRICO/0000-0002-1113-2012; Hankins, Catherine/0000-0002-1642-8592; Newell, Marie-Louise/0000-0002-1074-7699; Korber, Bette/0000-0002-2026-5757; BENEDETTO, CHIARA/0000-0003-1514-4771; parazzini, fabio/0000-0001-5624-4854; vimercati, antonella/0000-0002-9862-1619; De Rossi, Anita/0000-0001-6435-7509; Thorne, Claire/0000-0003-0389-1956; de maria, andrea/0000-0001-5782-333X; FRITEL, Xavier/0000-0002-4987-8127; Easley, Kirk/0000-0003-4419-2617; Marchisio, Paola /0000-0002-5691-3920 NR 29 TC 57 Z9 62 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 16 PY 2001 VL 15 IS 3 BP 357 EP 368 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 403BM UT WOS:000167022700009 ER PT J AU Slebos, RJC Taylor, JA AF Slebos, RJC Taylor, JA TI A novel host cell reactivation assay to assess homologous recombination capacity in human cancer cell lines SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE homologous recombination; green fluorescent protein; host cell reactivation assay ID DNA-DAMAGE RESPONSE; MAMMALIAN-CELLS; GENOMIC INSTABILITY; MISMATCH REPAIR; DIRECTED REPAIR; P53; PROTEIN; BRCA1; RAD51; GENE AB Repair of DNA double-strand breaks (DSB) is essential for cell viability and genome stability. Homologous recombination repair plays an important role in DSB repair and impairment of this repair mechanism may lead to loss of genomic integrity, which is one of the hallmarks of cancer. Recent research has shown that the tumor suppressor genes p53 and BRCA1 and -2 are involved in the proper control of homologous recombination, suggesting a role of this type of repair in human cancer. me developed a novel assay based on recombination between two Green Fluorescent Protein (GFP) sequences in transiently transfected plasmid DNA. The plasmid construct contains an intact, emission-shifted, "blue" variant of GFP (BFP), with a 300 nucleotide stretch of homology to a nonfunctional copy of GFP. In the absence of homologous recombination only BFP is present, but homologous recombination can create a functional GFP. The homologous regions in the plasmid were constructed in both the direct and the inverted orientation of transcription to detect possible differences in the recombination mechanisms involved. A panel of human tumor cell Lines was chosen on the basis of genetic background and chromosome integrity and tested for homologous recombination using this assay. The panel included cell lines with varying levels of karyotypic abnormalities, isogenic cell lines with normal and mutant p53, isogenic cell Lines with or without DNA mismatch repair, BRCA1 and -2 mutant cell lines, and the lymphoma cell line DT40. With this assay, the observed differences between cell lines with the lowest and highest levels of recombination were about 100-fold. Increased levels of recombination were associated with mutant p53, whereas a low level of recombination was found in the BRCA1 mutant cell line. In the cell line HT1080TG, a mutagenized derivative of HT1080 with two mutant alleles of p53, high levels of recombination mere found with the direct orientation but not with the inverted orientation plasmid. No difference in recombination was detected between two isogenic cell lines that only differed in DNA mismatch repair capability. We conclude that this assay can detect differences in homologous recombination capacity in cultured cell lines and that these differences follow the patterns that would be expected from the different genotypes of these cell lines. Future application in normal cells may be useful to identify genetic determinants controlling genomic integrity or to detect differences in DNA repair capacity in individuals. (C) 2001 Academic Press. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Slebos, RJC (reprint author), NIEHS, Mol Carcinogenesis Lab, Maildrop C2-01,POB 12233, Res Triangle Pk, NC 27709 USA. OI taylor, jack/0000-0001-5303-6398 NR 33 TC 27 Z9 27 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 16 PY 2001 VL 281 IS 1 BP 212 EP 219 DI 10.1006/bbrc.2001.4335 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 404TM UT WOS:000167116900032 PM 11178982 ER PT J AU Glazko, GV Rogozin, IB Glazkov, MV AF Glazko, GV Rogozin, IB Glazkov, MV TI Comparative study and prediction of DNA fragments associated with various elements of the nuclear matrix SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE nuclear matrix; scaffold/matrix-associated region; computer-based prediction; nucleotide motifs; discriminant analysis; satellite DNA ID SCAFFOLD ATTACHMENT REGIONS; CHROMOSOMAL LOOP ANCHORAGE; SYNAPTONEMAL COMPLEX; HUMAN GENOME; CHROMATIN; PROTEIN; SITES; SEQUENCE; GENE; ORGANIZATION AB Scaffold/matrix-associated region (S/MAR) sequences are DNA regions that are attached to the nuclear matrix, and participate in many cellular processes. The nuclear matrix is a complex structure consisting of various elements. In this paper we compared frequencies of simple nucleotide motifs in S/MAR sequences and in sequences extracted directly from various nuclear matrix elements, such as nuclear lamina, cores of rosette-like structures, synaptonemal complex, Multivariate linear discriminant analysis revealed significant differences between these sequences. Based on this result we have developed a program, ChrClass (Win/NT version, ftp.bionet.nsc.ru/pub/biology/chrclass/ chrclass.zip), for the prediction of the regions associated with various elements of the nuclear matrix in a query sequence. Subsequently, several test samples were analyzed by using two S/MAR prediction programs (a ChrClass and MAR-Finder) and a simple MRS criterion (S/MAR recognition signature) indicating the presence of S/MARs. Same overlap between the predictions of all MAR prediction tools has been found. Simultaneous use of the ChrClass, MRS criterion and MAR-Finder programs may help to obtain a more clearcut picture of S/MAR distribution in a query sequence. In general, our results suggest that the proportion of missed S/MARs is lower for ChrClass, whereas the proportion of wrong S/MARs is lower for MAR-Finder and MRS. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Inst Cytol & Genet, Novosibirsk 630090, Russia. Penn State Univ, Inst Mol Evolut Genet, Mueller Lab 311, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, Mueller Lab 311, University Pk, PA 16802 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Inst Gen Genet, Moscow 117809, Russia. RP Glazko, GV (reprint author), Inst Cytol & Genet, Novosibirsk 630090, Russia. EM gvg2@psu.edu RI Glazkov, Mikhail/O-9329-2015 OI Glazkov, Mikhail/0000-0001-7538-0069 NR 56 TC 28 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD FEB 16 PY 2001 VL 1517 IS 3 BP 351 EP 364 DI 10.1016/S0167-4781(00)00297-9 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 404GP UT WOS:000167089300003 PM 11342213 ER PT J AU Samuni, AM DeGraff, W Krishna, MC Mitchell, JB AF Samuni, AM DeGraff, W Krishna, MC Mitchell, JB TI Cellular sites of H(2)O(2)-induced damage and their protection by nitroxides SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE cytotoxicity; DNA; double strand break; histidine ID DOUBLE-STRAND BREAKS; HISTIDINE-MEDIATED ENHANCEMENT; PEROXIDE-INDUCED CYTOTOXICITY; GRADIENT GEL-ELECTROPHORESIS; HABER-WEISS REACTION; HYDROGEN-PEROXIDE; DNA-DAMAGE; OXIDATIVE STRESS; MAMMALIAN-CELLS; FENTON REACTION AB While the exact mechanism of H(2)O(2)-induced cytotoxicity is unknown, there is considerable evidence implicating DNA as a primary target. A recent study showed that a cell-impermeable nitroxide protected mammalian cells from H(2)O(2)-induced cell killing and suggested that the protection was mediated through cell membrane-bound or extracellular factors. To further define the protective properties of nitroxides, Chinese hamster V79 cells were exposed to H(2)O(2) with or without cell-permeable and impermeable nitroxides and selected metal chelators. EPR spectroscopy and paramagnetic line broadening agents were used to distinguish between intra- and extracellular nitroxide distribution. To study the effectiveness of nitroxide protection, in the absence of a cell membrane, H(2)O(2)-mediated damage to supercoiled plasmid DNA was evaluated. Both deferrioxamine and Tempol cross the cell membrane, and inhibited H(2)O(2)-mediated cell killing, whereas the cell-impermeable DTPA and nitroxide, CAT-1, failed to protect. Similar protective effects of the chelators and nitroxides were observed when L-histidine, which enhances intracellular injury, was added to H(2)O(2) in contrast, when damage to plasmid DNA was induced (in the absence of a cell membrane), both nitroxides were protective. Collectively, these results do not support a role for membrane-bound or extracellular factors in mediating H(2)O(2) cytotoxicity in mammalian cells. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Div Clin Sci, NIH, Bldg 10,Rm b3B69, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov NR 38 TC 35 Z9 35 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB 16 PY 2001 VL 1525 IS 1-2 BP 70 EP 76 DI 10.1016/S0304-4165(00)00172-0 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 404DE UT WOS:000167081500009 PM 11342255 ER PT J AU Zito, MA Koennecke, LA McAuliffe, MJ McNally, B van Rooijen, N Heyes, MP AF Zito, MA Koennecke, LA McAuliffe, MJ McNally, B van Rooijen, N Heyes, MP TI Depletion of systemic macrophages by liposome-encapsulated clodronate attenuates striatal macrophage invasion and neurodegeneration following local endotoxin infusion in gerbils SO BRAIN RESEARCH LA English DT Article DE inflammation; macrophage; microglia; neurodegeneration; animal model ID ACUTE INFLAMMATORY RESPONSE; NEUROTOXIN QUINOLINIC ACID; CONVERT L-TRYPTOPHAN; RAT-BRAIN; IMMUNE ACTIVATION; LIPOPOLYSACCHARIDE; MICROGLIA; ENCEPHALOMYELITIS; ELIMINATION; INJECTION AB CNS-localized inflammation with microglial activation and macrophage infiltration contributes to the pathogenesis of a broad spectrum of neurologic diseases. A direct injection of lipopolysaccharide (LPS) into the striatum of gerbils induced lectin-positive macrophage parenchymal invasion, minimal local microglial staining but extensive neurodegeneration (cresyl violet and silver staining) when evaluated 4 days later. In mice, LPS activated microglia (increased lectin staining of morphologically identified cells) with substantially less macrophage invasion but no neurodegeneration was seen at 4 days post LPS infusion. To evaluate the role of infiltrating macrophages in the neurodegenerative response in gerbils, peripheral macrophages were depleted by an intravenous injection of liposome-encapsulated clodronate. This preparation depleted spleen and liver macrophages (>95%), decreased blood monocytes by 55% and attenuated striatal macrophage infiltration (32 to 73% in five representative sections). Notably, the liposome-encapsulated clodronate reduced the severity of LPS-induced neurodegeneration, as visualized by cresyl violet staining and quantified in 20 serially stained silver sections (total volume, 1.32+/-0.41 mm(3) in liposome-encapsulated clodronate-treated versus 3.04+/-0.72 mm(3) in saline-treated controls). These results indicate that a local LPS infusion in gerbil brain may be a useful model in which to investigate the role of invading macrophages and other inflammatory responses in neurodegeneration in inflammatory neurological disease. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. Free Univ Amsterdam, Fac Med, Dept Cell Biol & Immunol, Amsterdam, Netherlands. RP Heyes, MP (reprint author), NIMH, Lab Neurotoxicol, Bldg 10,Room 3D42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 16 PY 2001 VL 892 IS 1 BP 13 EP 26 DI 10.1016/S0006-8993(00)03135-8 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 402RC UT WOS:000167001100002 PM 11172745 ER PT J AU Lenfant, C AF Lenfant, C TI Cardiovascular research - A look into tomorrow SO CIRCULATION RESEARCH LA English DT Editorial Material DE genomics; cardiovascular genetics; cell biology; molecular imaging; imaging ID HUMAN-GENOME-PROJECT; GENE-THERAPY; ANGIOGENESIS; CELLS C1 NHLBI, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Bldg 31,Room 5A5231,Ctr Dr,MSC 2486, Bethesda, MD 20892 USA. NR 15 TC 2 Z9 4 U1 0 U2 1 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 FEB 16 PY 2001 VL 88 IS 3 BP 253 EP 255 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 412PC UT WOS:000167562700001 PM 11179188 ER PT J AU Balaban, RS Arai, A AF Balaban, RS Arai, A TI Function, metabolic, and flow heterogeneity of the heart - The view is getting better SO CIRCULATION RESEARCH LA English DT Editorial Material DE capillary; magnetic resonance imaging; perfusion; oxygen ID MYOCARDIAL MOTION TRACKING; CORONARY BLOOD-FLOW; RAT-HEART; PERFUSION; MRI; MICROCIRCULATION; DENSE C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Room BID-416,Mail Stop 1061, Bethesda, MD 20892 USA. EM rsb@nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 34 TC 19 Z9 19 U1 0 U2 0 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 FEB 16 PY 2001 VL 88 IS 3 BP 265 EP 267 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 412PC UT WOS:000167562700005 PM 11179192 ER PT J AU Wei, Q Paterson, BM AF Wei, Q Paterson, BM TI Regulation of MyoD function in the dividing myoblast SO FEBS LETTERS LA English DT Review DE cell cycle; myogenesis; MyoD; cyclin D1; G1 cyclin-dependent kinase; Rb ID FIBROBLAST GROWTH-FACTOR; DEPENDENT KINASE-4 CDK4; MUSCLE-SPECIFIC GENES; CELL-CYCLE ARREST; MYOGENIC DIFFERENTIATION; C-JUN; DNA-BINDING; RETINOBLASTOMA PROTEIN; SKELETAL-MUSCLE; D1 GENE AB Proliferating myoblasts express MyoD, yet no phenotypic markers are activated as long as mitogen levels are sufficient to keep the cells dividing. Depending upon mitogen levels, a decision is made in ct that commits the myoblast to either continue to divide or to exit from the cell cycle and activate terminal differentiation. Ectopic expression of MyoD under the control of the RSV or CMV promoters causes 10T1/2 cells to rapidly exit the cell cycle and differentiate as single myocytes, even in growth medium, whereas expression of MgoD under the weaker SV40 promoter is compatible with proliferation. Coexpression of MyoD and cyclin D1, but not cyclins A, B, E or D3, blocks transactivation of a MyoD responsive reporter. Similarly, transfection of myoblasts with the cyclin-dependent kinase (cdk) inhibitors p16 and p21 supports some muscle-specific gene expression even in growth medium. Taken altogether, these results suggest cell cycle progression negatively regulates myocyte differentiation, possibly through a mechanism involving the D1 responsive cdks. We review evidence coupling growth status, the cell cycle and myogenesis. We describe a novel mitogen-sensitive mechanism that involves the cyclin D1-dependent direct interaction between the G1 cdks and MyoD in the dividing myoblast, which regulates MyoD function in a mitogen-sensitive manner. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NR 100 TC 83 Z9 87 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 16 PY 2001 VL 490 IS 3 BP 171 EP 178 DI 10.1016/S0014-5793(01)02120-2 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 407MH UT WOS:000167275000009 PM 11223032 ER PT J AU Dallongeville, J Bauge, E Tailleux, A Peters, JM Gonzalez, FJ Fruchart, JC Staels, B AF Dallongeville, J Bauge, E Tailleux, A Peters, JM Gonzalez, FJ Fruchart, JC Staels, B TI Peroxisome proliferator-activated receptor alpha is not rate-limiting for the lipoprotein-lowering action of fish oil SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APOLIPOPROTEIN-A-I; POLYUNSATURATED FATTY-ACIDS; HIGH-DENSITY-LIPOPROTEINS; MESSENGER-RNA ABUNDANCE; ELEMENT-BINDING PROTEIN; S14 GENE-TRANSCRIPTION; EICOSAPENTAENOIC ACID; ACYL-COENZYME; DIETARY-FAT; C-III AB Similar to fibrate hypolipidemic drugs, long chain polyunsaturated fatty acids contained in fish oil are activators of peroxisome proliferator-activated receptor alpha (PPAR alpha), The goal of this study was to assess the contribution of PPAR alpha in mediating the effect of fish oil on plasma lipid, lipoprotein, and apolipoprotein levels. To this end, PPAR alpha -deficient mice and wild-type littermates were fed isocaloric fish oil or coconut oil diets, the content of which varied reciprocally between 0, 3, 7, and 10% for 1 week. In both wild-type and PPAR alpha -deficient mice, fish oil feeding was associated with a dose-dependent decrease in triglycerides, cholesterol, and phospholipids associated with lower levels of very low density lipoprotein (VLDL) triglycerides and high density lipoprotein (HDL) cholesterol, The lowering of triglycerides and VLDL triglycerides was associated with a significant decrease of plasma apoC-III in both genotypes, Fish oil treatment did not influence hepatic apoC-III mRNA levels in either genotype indicating that apoC-III is not under transcriptional control by fish oil. The lowering of HDL cholesterol observed in both genotypes was associated with reduced plasma apoA-II without changes in liver apoA-II mRNA levels. In contrast, plasma apoA-I and liver apoA-I mRNA levels were decreased in wild-type but not in PPAR alpha -deficient mice after fish oil feeding indicating that PPAR alpha contributes to the effect of fish oil on apoA-I gene expression. In conclusion, PPAR alpha is not rate-limiting for fish oil to exert its triglyceride- and HDL-lowering action. Furthermore, PPAR alpha mediates, at least partly, the decrease of apoA-I after fish oil treatment, whereas apoC-III and apoA-II levels are affected in a PPAR alpha -independent manner. Altogether, these results show major molecular differences in action between fibrates and fish oil providing a molecular rationale for combination treatment with these compounds. C1 Inst Pasteur, Dept Atherosclerose, F-59019 Lille, France. Inst Pasteur, INSERM, U508, F-59019 Lille, France. Inst Pasteur, INSERM, U325, F-59019 Lille, France. Univ Lille 2, Fac Pharm, F-59000 Lille, France. Penn State Univ, Ctr Mol Toxicol, University Pk, PA 16802 USA. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Dallongeville, J (reprint author), Inst Pasteur, Dept Atherosclerose, 1 Rue Professeur Calmette, F-59019 Lille, France. RI Peters, Jeffrey/D-8847-2011; Staels, Bart/N-9497-2016 OI Staels, Bart/0000-0002-3784-1503 NR 57 TC 56 Z9 56 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2001 VL 276 IS 7 BP 4634 EP 4639 DI 10.1074/jbc.M008809200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 428WH UT WOS:000168484300016 PM 11050100 ER PT J AU Liu, XW Gong, LJ Guo, LY Katagiri, Y Jiang, H Wang, ZY Johnson, AC Guroff, G AF Liu, XW Gong, LJ Guo, LY Katagiri, Y Jiang, H Wang, ZY Johnson, AC Guroff, G TI The Wilms' tumor gene product WT1 mediates the down-regulation of the rat epidermal growth factor receptor by nerve growth factor in PC12 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHEOCHROMOCYTOMA CELLS; DIFFERENTIATION; MUTANTS; RESPOND AB Recently, we characterized the rat epidermal growth factor receptor (EGFR) promoter and demonstrated that TCC repeat sequences are required for the downregulation of EGFR by nerve growth factor (NGF) in PC12 cells. In this study, we report that the Wilms' tumor gene product WT1, a zinc finger transcription factor, is able to enhance the activity of the rat EGFR promoter in cotransfection assays. Gel mobility shift assays demonstrate that WT1 binds to the TCC repeat sequences of the rat EGFR promoter. Overexpression of WT1 resulted in up-regulation of the expression levels of endogenous EGFR in PC12 cells. Interestingly, NGF down-regulated the expression levels of WT1 and EGFR in PC12 cells, but not in the p140(trk)-deficient variant PC12nnr5 cells or in cells expressing either dominant-negative Ras or dominant-negative Src. Most importantly, we evaluated the inhibitory effect of antisense WT1 RNA on EGFR expression, and we found that antisense WT1 RNA could substantially reduce EGFR repression in either histochemical staining study or immunoblot analysis. These results indicate that NGF-induced down-regulation of the EGFR in PC12 cells is mediated through WT1 and that WT1 may play an important role in the differentiation of nerve cells. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NICHHD, Growth Factors Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Dev & Mol Immun Lab, Bethesda, MD 20892 USA. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Growth Regulat, Boston, MA 02215 USA. RP Johnson, AC (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Rm 2D18, Bethesda, MD 20892 USA. NR 25 TC 26 Z9 27 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2001 VL 276 IS 7 BP 5068 EP 5073 DI 10.1074/jbc.M008776200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 428WH UT WOS:000168484300073 PM 11071895 ER PT J AU Phillips, SA Barr, VA Haft, DH Taylor, SI Haft, CR AF Phillips, SA Barr, VA Haft, DH Taylor, SI Haft, CR TI Identification and characterization of SNX15, a novel sorting nexin involved in protein trafficking SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT ADIPOSE-CELLS; GROWTH-FACTOR; SACCHAROMYCES-CEREVISIAE; INSULIN-RECEPTOR; SEQUENCE ALIGNMENT; MEMBRANE-PROTEINS; PDGF RECEPTORS; LATE-GOLGI; YEAST; GENE AB Sorting nexins are a family of phox homology domain containing proteins that are homologous to yeast proteins involved in protein trafficking. We have identified a novel 342-amino acid residue sorting nexin, SNX15, and a 252-amino acid splice variant, SNX15A. Unlike many sorting nexins, a SNX15 ortholog has not been identified in yeast or Caenorhabditis elegans, By Northern blot analysis, SNX15 mRNA is widely expressed. Although predicted to be a soluble protein, both endogenous and overexpressed SNX15 are found on membranes and in the cytosol. The phox homology domain of SNX15 is required for its membrane association and for association with the platelet-derived growth factor receptor. We did not detect association of SNX15 with receptors for epidermal growth factor or insulin. However, overexpression of SNX15 led to a decrease in the processing of insulin and hepatocyte growth factor receptors to their mature subunits. Immunofluorescence studies showed that SNX15 overexpression resulted in mislocalization of furin, the endoprotease responsible for cleavage of insulin and hepatocyte growth factor receptors. Based on our data and the existing findings with yeast orthologs of other sorting nexins, we propose that overexpression of SNX15 disrupts the normal trafficking of proteins from the plasma membrane to recycling endosomes or the trans-Golgi network. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Inst Genome Res, Rockville, MD 20850 USA. RP Haft, CR (reprint author), NIDDK, Diabet Branch, NIH, Bldg 10,Rm 8N244, Bethesda, MD 20892 USA. NR 45 TC 60 Z9 62 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2001 VL 276 IS 7 BP 5074 EP 5084 DI 10.1074/jbc.M004671200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 428WH UT WOS:000168484300074 PM 11085978 ER PT J AU Aravind, L Dixit, VM Koonin, EV AF Aravind, L Dixit, VM Koonin, EV TI Apoptotic molecular machinery: Vastly increased complexity in vertebrates revealed by genome comparisons SO SCIENCE LA English DT Article ID EVOLUTIONARY INFORMATION; CELL-DEATH; PROTEINS; ACTIVATION; IDENTIFICATION; EUKARYOTES; DIVERGENCE; INHIBITOR; SEQUENCE; YEAST AB A comparison of the proteins encoded in the recently (nearly) completed human genome to those from the fly and nematode genomes reveals a major increase in the complexity of the apoptotic molecular machinery in vertebrates, in terms of both the number of proteins involved and their domain architecture. Several components of the apoptotic system are shared by humans and flies, to the exclusion of nematodes, which seems to support the existence of a coelomate clade in animal evolution. A considerable repertoire of apoptotic protein domains was detected in Actinomycetes and Cyanobacteria, which suggests a major contribution of horizontal gene transfer to the early evolution of apoptosis. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI dixit, vishva/A-4496-2012 OI dixit, vishva/0000-0001-6983-0326 NR 42 TC 248 Z9 265 U1 1 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD FEB 16 PY 2001 VL 291 IS 5507 BP 1279 EP + DI 10.1126/science.291.5507.1279 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 402MX UT WOS:000166993400036 PM 11181990 ER PT J AU Kitzman, DW Gardin, JM Gottdiener, JS Arnold, A Boineau, R Aurigemma, G Marino, EK Lyles, M Cushman, M Enright, PL AF Kitzman, DW Gardin, JM Gottdiener, JS Arnold, A Boineau, R Aurigemma, G Marino, EK Lyles, M Cushman, M Enright, PL CA CHS Res Grp TI Importance of heart failure with preserved systolic function in patients >= 65 years at age SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR FUNCTION; PREVALENCE; PROGNOSIS AB Although congestive heart failure (CHF) is a common syndrome among the elderly, there is a relative paucity of population-based data, particularly regarding CHF with normal systolic left ventricular function. A total of 4,842 independent living, community-dwelling subjects aged 66 to 103 years received questionnaires on medical history, family history, personal habits, physical activity, and socioeconomic status, confirmation of preexisting cardiovascular and cerebrovascular disease, anthropometric measurements, casual seated random-zero blood pressure, forced vital capacity and expiratory volume in 1 second, 12-lead supine electrocardiogram, fasting glucose, creatinine, plasma lipids, carotid artery wall thickness by ultrasonagraphy, and echocardiography-Doppler examinations. participants with at least 1 confirmed episode of CHF by Cardiovascular Health Study criteria were considered prevalent for CHF. The prevalence of CHF was 8.8% and was associated with increased age, particularly for women, in whom it increased more than twofold from age 65 to 69 years (6.6%) to age greater than or equal to 85 years (14%). In multivariate analysis, subjects with CHF were more likely to be older (odds ratio [OR] 1.2 for 5-year difference, men OR 1.1), and more often had a history of myocardial infarction (OR 7.3), atrial fibrillation (OR 3.0), diabetes mellitus (OR 2.1), renal dysfunction (OR 2.0 for creatinine greater than or equal to1.5 mg/dl), and chronic pulmonary disease (OR 1.8; women only). The echocardiographic correlates of CHF were increased left atrial and ventricular dimensions. Importantly, 55% of subjects with CHF had normal left ventricular systolic function and 80% had either normal or only mildly reduced systolic function. Among subjects with CHF, women held normal systolic function more frequently than men (67% vs 42%; p < 0.001). Thus, CHF is common among community-dwelling elderly. It increases with age and is usually associated with normal systolic LV function, particularly among women. The finding that a large proportion of elderly with CHF have preserved LV systolic function is important because there is a paucity of data to guide management in this dominant subset. (C) 2001 by Excerpta Medica, Inc. C1 Wake Forest Univ, Sch Med, Cardiol Sect, Dept Med, Winston Salem, NC 27157 USA. Univ Calif Irvine, Dept Med, Div Cardiol, Irvine, CA 92717 USA. St Francis Hosp, Roslyn, NY USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Dept Med, Boston, MA 02125 USA. Univ Vermont, Burlington, VT USA. Univ Arizona, Tucson, AZ USA. RP Kitzman, DW (reprint author), Wake Forest Univ, Sch Med, Cardiol Sect, Dept Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85080, N01-HC-85081]; NIA NIH HHS [R01 AG012257] NR 24 TC 332 Z9 341 U1 0 U2 7 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2001 VL 87 IS 4 BP 413 EP 419 DI 10.1016/S0002-9149(00)01393-X PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401TV UT WOS:000166945100008 PM 11179524 ER PT J AU Gilbert, ES AF Gilbert, ES TI Invited commentary: Studies of workers exposed to low doses of radiation SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID EXTERNAL IONIZING-RADIATION; ATOMIC-BOMB SURVIVORS; CANCER MORTALITY C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Gilbert, ES (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MS 7238, Rockville, MD 20852 USA. NR 17 TC 32 Z9 35 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2001 VL 153 IS 4 BP 319 EP 322 DI 10.1093/aje/153.4.319 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 400RX UT WOS:000166886400002 PM 11207147 ER PT J AU Ananth, CV Wilcox, AJ AF Ananth, CV Wilcox, AJ TI Placental abruption and perinatal mortality in the United States SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research CY JUN, 1999 CL BALTIMORE, MARYLAND SP Soc Pediat Perinat Epidemiol DE abruptio placentae; birth weight; fetal growth retardation; infant mortality ID BIRTH; CERTIFICATE AB Placental abruption is an uncommon obstetric complication associated with high perinatal mortality rates. The authors explored the associations of abruption with fetal growth restriction, preterm delivery, and perinatal survival. The study was based on 7,508,655 singleton births delivered in 1995 and 1996 in the United States. Abruption was recorded in 6.5 per 1,000 births. Perinatal mortality was 119 per 1,000 births with abruption compared with 8.2 per 1,000 among all other births. The high mortality with abruption was due, in part, to its strong association with preterm delivery; 55% of the excess perinatal deaths with abruption were due to early delivery. Furthermore, babies in the lowest centile of weight (<1% adjusted for gestational age) were almost nine times as likely to be born with abruption than those in the heaviest (90%) birth weight centiles. This relative risk progressively declined with higher birth weight centiles. After controlling for fetal growth restriction and early delivery, the high risk of perinatal death associated with abruption persisted. Even babies born at 40 weeks of gestation and birth weight of 3,500-3,999 g (where mortality was lowest) had a 25-fold higher mortality with abruption. The link between fetal growth restriction and abruption suggests that the origins of abruption lie at least in midpregnancy and perhaps even earlier. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Obstet Gynecol & Reprod Sci, Div Epidemiol & Biostat, New Brunswick, NJ 08901 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Ananth, CV (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Obstet Gynecol & Reprod Sci, Div Epidemiol & Biostat, 125 Paterson St, New Brunswick, NJ 08901 USA. OI Wilcox, Allen/0000-0002-3376-1311 NR 18 TC 118 Z9 123 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2001 VL 153 IS 4 BP 332 EP 337 DI 10.1093/aje/153.4.332 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 400RX UT WOS:000166886400005 PM 11207150 ER PT J AU Kipnis, V Midthune, D Freedman, LS Bingham, S Schatzkin, A Subar, A Carroll, RJ AF Kipnis, V Midthune, D Freedman, LS Bingham, S Schatzkin, A Subar, A Carroll, RJ TI Empirical evidence of correlated biases in dietary assessment instruments and its implications SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE biological markers; dietary assessment methods; epidemiologic methods; measurement error; models, statistical; model selection; regression analysis; research design ID INDEPENDENT VALIDATORY MEASURE; FOOD FREQUENCY QUESTIONNAIRE; DOUBLY LABELED WATER; ISOLATED SOY PROTEIN; TRUE AVERAGE INTAKE; MEASUREMENT ERROR; NITROGEN-BALANCE; URINE NITROGEN; LONG-TERM; NUTRITIONAL EPIDEMIOLOGY AB Multiple-day food records or 24-hour recalls are currently used as "reference" instruments to calibrate food frequency questionnaires (FFQs) and to adjust findings from nutritional epidemiologic studies for measurement error. The common adjustment is based on the critical requirements that errors in the reference instrument be independent of those in the FFQ and of true intake. When data on urinary nitrogen level, a valid reference biomarker for nitrogen intake, are used, evidence suggests that a dietary report reference instrument does not meet these requirements. In this paper, the authors introduce a new model that includes, for both the FFQ and the dietary report reference instrument, group-specific biases related to true intake and correlated person-specific biases. Data were obtained from a dietary assessment validation study carried out among 160 women at the Dunn Clinical Nutrition Center, Cambridge, United Kingdom, in 1988-1990. Using the biomarker measurements and dietary report measurements from this study, the authors compare the new model with alternative measurement error models proposed in the literature and demonstrate that it provides the best fit to the data. The new model suggests that, for these data, measurement error in the FFQ could lead to a 51% greater attenuation of true nutrient effect and the need for a 2.3 times larger study than would be estimated by the standard approach. The implications of the results for the ability of FFQ-based epidemiologic studies to detect important diet-disease associations are discussed. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. MRC, Dunn Human Nutr Ctr, Cambridge, England. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Execut Plaza N,Room 344,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA-57030]; PHS HHS [P30-E509106] NR 49 TC 180 Z9 183 U1 0 U2 13 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 FEB 15 PY 2001 VL 153 IS 4 BP 394 EP 403 DI 10.1093/aje/153.4.394 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 400RX UT WOS:000166886400013 PM 11207158 ER PT J AU Subar, AF Ziegler, RG Thompson, FE Johnson, CC Weissfeld, JL Reding, D Kavounis, KH Hayes, RB AF Subar, AF Ziegler, RG Thompson, FE Johnson, CC Weissfeld, JL Reding, D Kavounis, KH Hayes, RB CA Prostate Lung Colorectal Ovarian C TI Is shorter always better? Relative importance of questionnaire length and cognitive ease on response rates and data quality for two dietary questionnaires SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; diet surveys; epidemiologic methods; food habits; nutrition assessment; nutrition surveys; questionnaires ID FOOD FREQUENCY QUESTIONNAIRE; POPULATION; DESIGN AB In this study, the authors sought to determine the effects of length and clarity on response rates and data quality for two food frequency questionnaires (FFQs): the newly developed 36-page Diet History Questionnaire (DHQ), designed to be cognitively easier for respondents, and a 16-page FFQ developed earlier for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The PLCO Trial is a 23-year randomized controlled clinical trial begun in 1992. The sample for this substudy, which was conducted from January to April of 1998, consisted of 900 control and 450 screened PLCO participants aged 55-74 years. Controls received either the DHQ or the PLCO FFQ by mail. Screenees, who had previously completed the PLCO FFQ at baseline, were administered the DHQ. Among controls, the response rate for both FFQs was 82%. Average amounts of time needed by controls to complete the DHQ and the PLCO FFQ were 68 minutes and 39 minutes, respectively. Percentages of missing or uninterpretable responses were similar between instruments for questions on frequency of intake but were approximately 3 and 9 percentage points lower (p less than or equal to 0.001) in the DHQ for questions on portion size and use of vitamin/mineral supplements, respectively. Among screenees, response rates for the DHQ and the PLCO FFQ were 84% and 89%, respectively, and analyses of questions on portion size and supplement use showed few differences. These data indicated that the shorter FFQ was not better from the perspective of response rate and data quality, and that clarity and ease of administration may compensate for questionnaire length. C1 NCI, Risk Factor Monitoring & Methods Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Epidemiol & Biostat Program, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. NCI, Environm Epidemiol Branch, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. Josephine Ford Canc Ctr, Detroit, MI USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Marshfield Med Res & Educ Fdn, Marshfield, WI USA. Westat Inc, Rockville, MD USA. RP Subar, AF (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. OI Johnson, Christine Cole/0000-0002-6864-6604 NR 13 TC 87 Z9 88 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2001 VL 153 IS 4 BP 404 EP 409 DI 10.1093/aje/153.4.404 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 400RX UT WOS:000166886400014 PM 11207159 ER PT J AU Li, RL Folsom, AR Sharrett, AR Couper, D Bray, M Tyroler, HA AF Li, RL Folsom, AR Sharrett, AR Couper, D Bray, M Tyroler, HA TI Interaction of the glutathione S-transferase genes and cigarette smoking on risk of lower extremity arterial disease: the Atherosclerosis Risk in Communities (ARIC) study SO ATHEROSCLEROSIS LA English DT Article DE GSTM1; GSTT1; gene-smoking interaction; lower extremity arterial disease ID CORONARY HEART-DISEASE; INTERMITTENT CLAUDICATION; MONOCLONAL ORIGIN; LUNG-CANCER; M1 GSTM1; SUSCEPTIBILITY; GSTT1; THETA; EXPOSURE; POLYMORPHISMS AB Glutathione S-transferases Ml or T1 (GSTM1/GSTT1) affect the body's ability either to detoxify or to activate chemicals in cigarette smoke. Cigarette smoking increases the risk of lower extremity arterial disease (LEAD). We conducted a cross-sectional study to evaluate a hypothesized interaction of the genetic polymorphisms of GSTM1 and T1 with cigarette smoking in the risk of LEAD in the ARIC study. A stratified-random sample, including 212 LEAD cases (ankle-brachial index < 0.9 in men or < 0.85 in women) and 1277 non-cases, was selected From the ARIC cohort of 12 041 middle-aged participants free of CHD, transient ischemic attack and stroke at baseline (1987-1989). Overall, the differences in the Frequencies of GSTM1-0 and GSTT1-0 (the homozygous deletion genotype) were not statistically significant between cases and non-cases (44 vs. 41% and 28 vs. 18%). However. smoking was more prevalent among LEAD cases than non-cases. The results suggest that the non-deletion genotype GSTM1-1 interacts with smoking to increase the risk of LEAD, but this interaction was not statistically significant. The functional genotype GSTT1-1 was significantly associated with increased risk of LEAD given smoking after adjustment for other risk factors. In individuals with GSTT1-1, the odds ratios (ORs) (95% confidence intervals) of LEAD were 3.6 (1.4, 9.0) for current smoking and 5.0 (1.9, 13.0) for 20 + pack-years. However, in those with GSTT1-0, the ORs were 0.8 (0.2, 2.8) for current smoking and 0.6 (0.1,2.1) for 20 + pack-years. The interaction was significant (P < 0.05) on the additive scale for current smoking and on both the additive and multiplicative scales for 20 + pack-years. Among non-smokers, GSTT1-1 was not associated with LEAD. The results suggest that the GSTT1-1 polymorphism may be a susceptibility factor modifying the risk of LEAD associated with cigarette smoking. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55454 USA. NHLBI, DECA, NIH, Bethesda, MD 20892 USA. Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX 77225 USA. RP Li, RL (reprint author), Univ N Carolina, Dept Epidemiol, Suite 306,Bank Amer Ctr,137 E Franklin St, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 55 TC 45 Z9 48 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD FEB 15 PY 2001 VL 154 IS 3 BP 729 EP 738 DI 10.1016/S0021-9150(00)00582-7 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 411CR UT WOS:000167481000026 PM 11257276 ER PT J AU Armstrong, JM Chen, JF Schwarzschild, MA Apasov, S Smith, PT Caldwell, C Chen, P Figler, H Sullivan, G Fink, S Linden, J Sitkovsky, M AF Armstrong, JM Chen, JF Schwarzschild, MA Apasov, S Smith, PT Caldwell, C Chen, P Figler, H Sullivan, G Fink, S Linden, J Sitkovsky, M TI Gene dose effect reveals no G(s)-coupled A(2A) adenosine receptor reserve in murine T-lymphocytes: studies of cells from A(2A)-receptor-gene-deficient mice SO BIOCHEMICAL JOURNAL LA English DT Article DE apoptosis; cAMP; gene targeting; purinergic receptors; thymocytes ID PURINERGIC RECEPTOR; EXTRACELLULAR ATP; EXPRESSION; SPARE; INHIBITION; RESPONSES; ACTIVATION; DEFICIENCY; AGONISTS; SUBSETS AB Agonist binding to extracellular A(2A) adenosine receptors (A(2A)Rs) inhibits the activation of virtually all tested functions of T-cells and can induce apoptosis in thymocytes. The evaluation of levels of expression of these immunosuppressive receptors is expected to clarify whether the absence of spare A(2A)Rs (no 'receptor reserve') might be one of the mechanisms of attenuation of the effects of extracellular adenosine on T-cells. A(2A) transcript is found in T-cells and functional receptors can be demonstrated, but the density of receptor on T-cells is too low to be detected by radioligand binding. Studies of direct radioligand binding to murine brain with the selective A(2A)R agonist [H-3]CGS21680 (2-{4-[(2-carboxyethyl)-phenyl]ethylamino}-5'-N-ethylcarbox-amidoadenosine) established that striata levels of A(2A)R are virtually absent from A(2A) knock-out mice. Mice that are heterozygous (A(2A)R(+/-)) for the A(2A)R express significantly decreased levels of A(2A)R. To test for the presence of spare receptors in T-cells we took advantage of this gene dose effect and examined whether the decrease in the number of receptors in thymocytes from A(2A)R(+/-) mice was proportionately reflected in a decrease in the functional cAMP response of T-cells to adenosine. cAMP accumulation and apoptosis induced by adenosine and by A(2A)R agonist are of a lower magnitude in T-cells from A(2A)R(+/-) heterozygous mice than in T-cells from A(2A)R(+/+) littermate control mice. These results indicate that there is no A(2A)R reserve in murine T-cells. Strongly decreased adenosine-triggered cAMP increases were detected in thymocytes from A(2A)R(-/-) mice, suggesting that A(2A) adenosine receptors cannot fully compensate for the loss of A(2A)Rs in murine T-cells. We conclude that the number of A(2A)Rs is the limiting factor in determining the maximal cAMP response of T-lymphocytes to extracellular adenosine, thereby minimizing the immunosuppressive effects of extracellular adenosine. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20982 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurobiol Lab, Boston, MA 02129 USA. Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. RP Sitkovsky, M (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20982 USA. FU NIDA NIH HHS [DA07496] NR 36 TC 53 Z9 55 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2001 VL 354 BP 123 EP 130 DI 10.1042/0264-6021:3540123 PN 1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 403ZR UT WOS:000167073400016 PM 11171087 ER PT J AU Barr, CL Xu, C Kroft, J Feng, Y Wigg, K Zai, G Tannock, R Schachar, R Malone, M Roberts, W Nothen, MM Grunhage, F Vandenbergh, DJ Uhl, G Sunohara, G King, N Kennedy, JL AF Barr, CL Xu, C Kroft, J Feng, Y Wigg, K Zai, G Tannock, R Schachar, R Malone, M Roberts, W Nothen, MM Grunhage, F Vandenbergh, DJ Uhl, G Sunohara, G King, N Kennedy, JL TI Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE genetics; dopamine transporter; attention-deficit/hyperactivity disorder; transmission disequilibrium test; haplotypes; polymorphism ID DEFICIT HYPERACTIVITY DISORDER; TRANSMISSION/DISEQUILIBRIUM TEST; RECEPTOR GENE; CODING REGION; TRANSMISSION; ASSOCIATION; CHILDREN; DAT1; DNA; RELATIVES AB Background: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. Methods: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. Results: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele, We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. Conclusions: Our results support previous findings of an association between the DAT1 gene and ADHD. Biol (C) 2001 Society of Biological Psychiatry. C1 Univ Toronto, Toronto Western Hosp, Dept Psychiat, Toronto, ON, Canada. Univ Toronto, Hosp Sick Children, Dept Psychiat, Toronto, ON, Canada. Univ Toronto, Hosp Sick Children, Div Neurol, Toronto, ON, Canada. Univ Toronto, Ctr Addict & Mental Hlth, Neurogenet Sect, Clarke Div, Toronto, ON, Canada. Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD USA. Penn State Univ, Dept Biobehav Hlth, State Coll, PA USA. RP Barr, CL (reprint author), Toronto Hosp, Western Div, 399 Bathurst St,MP14-302, Toronto, ON M5T 1S8, Canada. OI Schachar, Russell/0000-0002-2015-4395; Barr, Cathy/0000-0003-0361-0106 NR 28 TC 121 Z9 126 U1 8 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2001 VL 49 IS 4 BP 333 EP 339 DI 10.1016/S0006-3223(00)01053-2 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405WG UT WOS:000167183100004 PM 11239904 ER PT J AU Ruskin, DN Bergstrom, DA Shenker, A Freeman, LE Baek, D Walters, JR AF Ruskin, DN Bergstrom, DA Shenker, A Freeman, LE Baek, D Walters, JR TI Drugs used in the treatment of attention-deficit/hyperactivity disorder affect postsynaptic firing rate and oscillation without preferential dopamine autoreceptor action SO BIOLOGICAL PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder; amphetamine; methylphenidate; autoreceptor; globus pallidus; substantia nigra pars compacta ID DEFICIT HYPERACTIVITY DISORDER; FREELY MOVING RATS; HEART-RATE; EMISSION TOMOGRAPHY; MAGNETIC-RESONANCE; BRAIN DOPAMINE; AMPHETAMINE; AGONISTS; CHILDREN; METHYLPHENIDATE AB Background: Current theories propose that low doses of catecholaminergic stimulants reduce symptoms in patients with attention-deficient/hyperactivity disorder by acting on autoreceptors to reduce catecholaminergic transmission; few data are available that directly address this hypothesis. Methods: We investigated the autoreceptor and postsynaptic receptor actions of systematically administered stimulants on dopaminergic systems in rats with single-unit recording in the substantia nigra pars compacta and globus pallidus, respectively. Results: Dose-response curves for rate indicated that the potencies of the indirect-acting agonists methylphenidate and D-amphetamine at dopaminergic autoreceptors were not greater than at postsynaptic receptors; in fact, D-amphetamine was more potent postsynaptically. In addition to effects on firing rate, spectral/wavelet analyses indicated that these drugs had prominent effects on postsynaptic multisecond oscillations. These oscillations were shifted by stimulants from baseline periods of similar to 30 sec to periods of 5-10 sec. Effects on pattern were found at doses as low as 1.0 mg/kg (methylphanidate) and 0.2 mg/kg (D-amphetamine). At this latter dose, D-amphetamine had little effect presynaptically. Conclusions: These are prior results demonstrate that there is no autoreceptor-preferring dose range of catecholaminergic stimulants; these drugs at low doses are unlikely to reduce motor activity by this mechanism. Nonetheless, they might affect attentive and cognitive processes by modulating multisecond temporal patterns of central activity. (C) 2001 Society of Biological Psychiatry. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ruskin, DN (reprint author), NINDS, Expt Therapeut Branch, NIH, 10 Ctr Dr,Room 5C103, Bethesda, MD 20892 USA. NR 61 TC 43 Z9 44 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2001 VL 49 IS 4 BP 340 EP 350 DI 10.1016/S0006-3223(00)00987-2 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405WG UT WOS:000167183100005 PM 11239905 ER PT J AU Enoch, MA Greenberg, BD Murphy, DL Goldman, D AF Enoch, MA Greenberg, BD Murphy, DL Goldman, D TI Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive-compulsive disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE obsessive-compulsive; gender; genes; serotonin; receptor ID FAMILY-BASED ASSOCIATION; ANOREXIA-NERVOSA; GENE PROMOTER; FENFLURAMINE; RESPONSES; SYMPTOMS AB Background: In an earlier analysis of 73 subjects from this study, the reduced activity catechol O-methyltransferase variant was shown to be associated with obsessive-compulsive disorder in men only. We hypothesized that the 5-HT2A promoter polymorphism, -1438G>A, previously associated with anorexia nervosa, would be more abundant in women with obsessive-compulsive disorder. Methods: One hundred and one Caucasian obsessive-compulsive disorder patients (48 women, 53 men) and 138 control subjects (77 women, 61 men), were genotyped. DSM-III-R psychiatric diagnoses were assigned based on the SCID-I. Results: As hypothesized, the -1438A allele frequency was higher in obsessive-compulsive disorder women (.57) than female control subjects (.42) (p = .015). The genotype frequencies were also significantly different (p = .020). Allele frequencies did not differ between male obsessive-compulsive disorder patients (.44) and male control subjects (.41). Conclusions: We have found that a 5-HT2A promoter polymorphism is associated with obsessive-compulsive disorder in women but not in men, strengthening the argument that there may be fundamental gender differences in the genetic susceptibility to obsessive-compulsive disorder. (C) 2001 Society of Biological Psychiatry. C1 NIAAA, Neurogenet Lab, M AE DG, DICBR,NIH, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, M AE DG, DICBR,NIH, 12420 Parklawn Dr,Pk 5 Bldg,Room 451,MSC 8110, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 27 TC 61 Z9 70 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2001 VL 49 IS 4 BP 385 EP 388 DI 10.1016/S0006-3223(00)01040-4 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 405WG UT WOS:000167183100010 PM 11239910 ER PT J AU Vishveshwara, S Madhusudhan, MS Maizel, JV AF Vishveshwara, S Madhusudhan, MS Maizel, JV TI Short-strong hydrogen bonds and a low barrier transition state for the proton transfer reaction in RNase A catalysis: a quantum chemical study SO BIOPHYSICAL CHEMISTRY LA English DT Article DE hydrogen bond; proton transfer; RNA hydrolysis; Rnase A ID MOLECULAR-DYNAMICS SIMULATIONS; SERINE PROTEASES; MECHANISM; COMPLEXES; EXCHANGE; TRIAD; ACIDS; GAS AB There is growing evidence that some enzymes catalyze reactions through the formation of short-strong hydrogen bonds as first suggested by Gerlt and Gassman. Support comes from several experimental and quantum chemical studies that include correlation energies on model systems. In the present study, the process of proton transfer between hydroxyl and imidazole groups. a model of the crucial step in the hydrolysis of RNA by the enzymes of the RNase A family. is investigated at the quantum mechanical level of density functional theory and perturbation theory at the MP2 level, The model focuses on the nature of the formation of a complex between the important residues of the protein and the hydroxyl group of the substrate. We have also investigated different configurations of the ground state that are important in the proton transfer reaction. The nature of bonding between the catalytic unit of the enzyme and the substrate in the model is investigated by Bader's atoms in molecule theory. The contributions of solvation and vibrational energies corresponding to the reactant. the transition state: and the product configurations are also evaluated. Furthermore. the effect of protein environment is investigated by considering the catalytic unit surrounded by complete proteins-RNase A and Angiogenin. The results, in general, indicate the formation of a short-strong hydrogen bond and the formation of a low barrier transition state fur the proton transfer model of the enzyme. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Vishveshwara, S (reprint author), Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. EM sv@mbu.iisc.ernet.in NR 39 TC 24 Z9 24 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 EI 1873-4200 J9 BIOPHYS CHEM JI Biophys. Chem. PD FEB 15 PY 2001 VL 89 IS 2-3 BP 105 EP 117 DI 10.1016/S0301-4622(00)00221-0 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 404GR UT WOS:000167089500001 PM 11254205 ER PT J AU Brummendorf, TH Maciejewski, JP Mak, J Young, NS Lansdorp, PM AF Brummendorf, TH Maciejewski, JP Mak, J Young, NS Lansdorp, PM TI Telomere length in leukocyte subpopulations of patients with aplastic anemia SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; BONE-MARROW TRANSPLANTATION; CULTURE-INITIATING CELLS; LIFE-SPAN; DYNAMICS; CANCER; AGE; RECONSTITUTION; RECIPIENTS AB In most human cells, the average length of telomere repeats at the ends of chromosomes provides indirect information about their mitotic history. To study the turnover of stem cells in patients with bone marrow failure syndromes, the telomere length in peripheral blood granulocytes and lymphocytes from patients with aplastic anemia (AA, n = 56) and hemolytic paroxysmal nocturnal hemoglobinuria (n = 6) was analyzed relative to age-matched controls by means of fluorescence in situ hybridization and flow cytometry. The telomere lengths in granulocytes from patients with AA were found to be significantly shorter than those in age-adjusted controls (P=.001). However, surprisingly, telomere length in granulocytes from AA patients who had recovered after immunosuppressive therapy did not differ significantly from controls, whereas untreated patients and nonresponders with persistent severe pancytopenia showed marked and significant telomere shortening. These results support extensive proliferation of hematopoietic stem cells in subgroups of AA patients. Because normal individuals show significant variation in telomere length, individual measurements in blood cells from AA patients may be of limited value. Whether sequential telomere length measurements can be used as a prognostic tool in this group of disorders remains to be clarified.(C) 2001 by The American Society of Hematology. C1 British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada. Univ Tubingen, Med Klin, Abt Hamatol Onkol & Immunol, Tubingen, Germany. NHLBI, Hamatol Branch, NIH, Bethesda, MD 20892 USA. RP Lansdorp, PM (reprint author), British Columbia Canc Agcy, Terry Fox Lab, 601 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. FU NIAID NIH HHS [AI29524] NR 42 TC 125 Z9 141 U1 0 U2 5 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 FEB 15 PY 2001 VL 97 IS 4 BP 895 EP 900 DI 10.1182/blood.V97.4.895 PG 6 WC Hematology SC Hematology GA 400HY UT WOS:000166867200014 PM 11159514 ER PT J AU Dunn, SE Torres, JV Oh, JS Cykert, DM Barrett, JC AF Dunn, SE Torres, JV Oh, JS Cykert, DM Barrett, JC TI Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase SO CANCER RESEARCH LA English DT Article ID HUMAN BREAST-CANCER; CELL-LINES; COLLAGENASE GENE; AP-1 COMPLEX; METASTASIS; EXPRESSION; INVASION; GELDANAMYCIN; SYSTEM; PROLIFERATION AB Elevated levels of urokinase plasminogen activator-1 (uPA) and the insulin-like growth factor-1 receptor (IGF-IR) are associated with breast cancer recurrence and decreased survival. It is possible that activation of IGF-IR and elevations in uPA are mechanistically linked, Our laboratory recently showed that insulin-like growth factor-I (IGF-I) induces uPA protein and mRNA in the breast cancer cell line MDA-MB-231. We also found that IGF-IR and uPA were commonly overexpressed in primary breast cancers. In this study, we investigated the signal transduction pathway through which IGF-I regulates uPA, Phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p70 kinase were inhibited with LY294002, PD98059, and rapamycin, respectively. Induction of uPA protein by IGF-I was partially inhibited by LY294002 (60% inhibition) or PD98059 (30% inhibition) but not by rapamycin, The production of uPA protein induced by IGF-I was blocked up to 90% by the tyrosine kinase inhibitor herbimycin A, Furthermore, herbimycin A suppressed the phosphorylation of AKT and Erk1/2. Next, we tested the impact of the signal transduction inhibitors on uPA gene expression, Both LY294002 and PD98059 were required to completely inhibit uPA mRNA expression, whereas each drug alone resulted in approximately 50% reduction in uPA expression. Next, using a minimal uPb-luciferase promoter construct containing the binding sites for the AP-I and Ets transcription factors, we observed that IGF-I stimulated the uPA promoter via these sites. Furthermore, both Ly294002 and PD98059 were necessary to block IGF-I-stimulated uPA-Luc activity. In summary, we conclude that IGF-I requires both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase-dependent pathways to optimally induce uPA expression. These findings suggest that the development of drugs targeting these pathways may benefit breast cancer patients at a high risk of recurrence, such as those who have primary tumors overexpressing IGF-IR and uPA. C1 NCI, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. RP Dunn, SE (reprint author), N Carolina State Univ, Dept Anat Physiol & Radiol, Funct Genom Program, 4700 Hillsborough St,Room C-296, Raleigh, NC 27606 USA. NR 53 TC 74 Z9 82 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2001 VL 61 IS 4 BP 1367 EP 1374 PG 8 WC Oncology SC Oncology GA 407DD UT WOS:000167255400026 PM 11245436 ER PT J AU Hardman, RA Afshari, CA Barrett, JC AF Hardman, RA Afshari, CA Barrett, JC TI Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress SO CANCER RESEARCH LA English DT Article ID DNA MISMATCH REPAIR; CELL-CYCLE CHECKPOINT; CYTOCHROME-C; MICROSATELLITE INSTABILITY; TUMOR-CELLS; DAMAGE; CANCER; INDUCTION; CISPLATIN; MUTATION AB MLH1 is an integral part of the mismatch repair complex, and the loss of this protein is associated with the acquisition of a mutator phenotype, microsatellite instability, and a predisposition to cancer. Deficiencies in the mismatch repair complex, including the loss of MLH1, result in elevated resistance to specific inducers of DNA damage, get the mechanisms involved in this DNA-damage resistance are largely unknown, Abnormal cellular responses to DNA damage can lead to the selection of cells with a greater propensity for neoplastic transformation and might also reduce the effectiveness of certain chemotherapeutic drugs. It is therefore important to identify agents that provide selective pressure for growth of MLH1-deficient cells and to characterize further the pathways involved. In this study, we show that both human epithelial and mouse embryo fibroblast cell lines lacking the MLH1 protein are more resistant to two inducers of oxidative stress, hydrogen peroxide and tert-butyl hydroperoxide. Our analyses suggest that the observed differences in cellular viability are mediated primarily through apoptotic pathways and not through deficiencies in cell cycle checkpoint controls. Additional characterization of the signaling pathways for hydrogen peroxide-induced apoptosis in MLH1-proficient cells demonstrates the involvement of increased mitochondrial permeability, the release of cytochrome c, and caspase 3 activation. Together, our data indicate that cells lacking MLH1 may possess a selective growth advantage under oxidatively stressed conditions via the disregulation of apoptosis, possibly involving the mitochondria. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27514 USA. RP Barrett, JC (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 39 TC 53 Z9 55 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 FEB 15 PY 2001 VL 61 IS 4 BP 1392 EP 1397 PG 6 WC Oncology SC Oncology GA 407DD UT WOS:000167255400030 PM 11245440 ER PT J AU Li, JN Gorospe, M Chrest, FJ Kumaravel, TS Evans, MK Han, WF Pizer, ES AF Li, JN Gorospe, M Chrest, FJ Kumaravel, TS Evans, MK Han, WF Pizer, ES TI Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53 SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; WILD-TYPE P53; ANTIBIOTIC CERULENIN; DNA-DAMAGE; APOPTOSIS; CYCLE; EXPRESSION; HYPOXIA; MUTANTS; TUMOR AB Patty acid synthetic metabolism is abnormally elevated in tumor cells, and pharmacological inhibitors of the anabolic enzyme fatty acid synthase (FAS), including the natural product cerulenin and the novel synthetic compound c75, are selective inhibitors of tumor cell growth. We have recently reported that these two FAS inhibitors both produce rapid, potent inhibition of DNA replication and S-phase progression in human cancer cells, as well as apoptotic death, Here we report an additional characterization of the cellular response to FAS inhibition. RKO colon carcinoma cells were selected for study because they undergo little apoptosis within the first 24 h after FAS inhibition. Instead, RKO cells exhibited a biphasic stress response with a transient accumulation in S and G(2) at 4 and 8 h that corresponds to a marked reduction in cyclin A- and B1-associated kinase activities, and then by accumulation of p53 and p21 proteins at 16 and 24 h and growth arrest in G(1) and G(2). The response of RKO cells to FAS inhibition resembled a genotoxic stress response, but DNA damage did not appear to be an important downstream effect of FAS inhibition, because none was detected using the single cell gel electrophoresis assay (comet assay) to assess DNA damage. p53 function is probably important in protecting RKO cells from FAS inhibition because, similar to many other tumor lines, RKO cells expressing a dominant negative mutant p53 gene underwent extensive apoptosis within 24 h after FAS inhibition. Sensitization of cells to FAS inhibitors by the loss of p53 raises the possibility that these agents may be clinically useful against malignancies carrying p53 mutations, Whereas induction of apoptosis appeared related to accumulation of the substrate, malonyl-CoA, after FAS inhibition, the cytostatic effects mere independent of malonyl-CoA accumulation and may have resulted from product depletion. C1 Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21224 USA. NIA, Biol Chem Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Gerontol Res Ctr, Flow Cytometry Unit, Baltimore, MD 21224 USA. NIA, Genet Mol Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Pizer, ES (reprint author), Johns Hopkins Bayview Med Ctr, Dept Pathol, AA154C,4940 Eastern Ave, Baltimore, MD 21224 USA. FU NCI NIH HHS [R29CA75219] NR 44 TC 125 Z9 131 U1 2 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2001 VL 61 IS 4 BP 1493 EP 1499 PG 7 WC Oncology SC Oncology GA 407DD UT WOS:000167255400046 PM 11245456 ER PT J AU Bonvini, P An, WG Rosolen, A Nguyen, P Trepel, J de Herreros, AG Dunach, M Neckers, LM AF Bonvini, P An, WG Rosolen, A Nguyen, P Trepel, J de Herreros, AG Dunach, M Neckers, LM TI Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription SO CANCER RESEARCH LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; ADHESION MOLECULE UVOMORULIN; EPIDERMAL-GROWTH-FACTOR; ALPHA-CATENIN; CYCLIN D1; COLON-CARCINOMA; FACTOR RECEPTOR; BREAST-CANCER; FACTOR LEF-1; IN-VIVO AB beta -catenin undergoes both serine and tyrosine phosphorylation. Serine phosphorylation in the amino terminus targets beta -catenin for proteasome degradation, whereas tyrosine phosphorylation in the COOH terminus influences interaction with E-cadherin. We examined the tyrosine phosphorylation status of beta -catenin in melanoma cells expressing proteasome-resistant beta -catenin, as well as the effects that perturbation of beta -catenin tyrosine phosphorylation had on its association with E-cadherin and on its transcriptional activity. beta -catenin is tyrosine phosphorylated in three melanoma cell lines and associates with both the ErbB2 receptor tyrosine kinase and the LAR receptor tyrosine phosphatase. Geldanamycin, a drug which destabilizes ErbB2, caused rapid cellular depletion of the kinase and loss of its association with beta -catenin without perturbing either LAR or beta -catenin levels or LAR/beta -catenin association. Geldanamycin also stimulated tyrosine dephosphorylation of beta -catenin and increased beta -catenin/E-cadherin association, resulting in substantially decreased cell motility. Geldanamycin also decreased the nuclear beta -catenin level and inhibited beta -catenin-driven transcription, as assessed using two different beta -catenin-sensitive reporters and the endogenous cyclin D1 gene. These findings were confirmed by transient transfection of two beta -catenin point mutants, Tyr-654Phe and Tyr-654Glu, which, respectively, mimic the dephosphorylated and phosphorylated states of Tyr-654, a tyrosine residue contained within the beta -catenin-ErbB2-binding domain. These data demonstrate that the functional activity of proteasome-resistant beta -catenin is regulated further by geldanamycin-sensitive tyrosine phosphorylation in melanoma cells. C1 NCI, Med Branch, Dept Cell & Canc Biol, Rockville, MD 20850 USA. Univ Padua, Pediat Clin, Oncol & Hematol Branch, I-35128 Padua, Italy. Univ Pompeu Fabra, Inst Municipal Invest Med, E-08003 Barcelona, Spain. Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, E-08193 Bellaterra, Spain. RP Neckers, LM (reprint author), 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. EM len@helix.nih.gov RI Garcia de Herreros, A/H-3104-2014; Dunach, Mireia/E-3604-2015 OI Garcia de Herreros, A/0000-0001-5270-0808; Dunach, Mireia/0000-0001-9844-5603 NR 48 TC 70 Z9 73 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2001 VL 61 IS 4 BP 1671 EP 1677 PG 7 WC Oncology SC Oncology GA 407DD UT WOS:000167255400072 PM 11245482 ER PT J AU Zhu, ZY Sanchez-Sweatman, O Huang, XJ Wiltrout, R Khokha, R Zhao, Q Gorelik, E AF Zhu, ZY Sanchez-Sweatman, O Huang, XJ Wiltrout, R Khokha, R Zhao, Q Gorelik, E TI Anoikis and metastatic potential of Cloudman S91 melanoma cells SO CANCER RESEARCH LA English DT Article ID CYCLE PROGRESSION; INDUCED APOPTOSIS; EPITHELIAL-CELLS; TUMOR-CELLS; EXPRESSION; ADHESION; ACTIVATION; INTEGRIN; KINASE; INVOLVEMENT AB Anoikis is a form of apoptosis induced in normal cells as a result of loss of their adhesion to substrate. In the present study, we have tested whether tumor cells are also sensitive to anoikis and whether selection of tumor cells for resistance to anoikis could increase their metastatic ability, In vitro cultured Cloudman S91 melanoma cells are strongly adherent to the plastic, Prevention of their adherence by rocking or by covering culture plates with polyhydroxyethylmethacrylate resulted in induction of anoikis and death of almost all cells. Their death was prevented in the presence of caspase inhibitor Z-Val-Ala-Asp-fluoromethyl ketone. To select anoikis-resistant cells, S91 cells floating in the culture medium were sequentially isolated and transferred for seven generations. As a result, a new subline of S91 cells capable of growing in free cell suspension was selected, These S91 nonadherent (S91Nadh) cells were completely resistant to anoikis and manifested higher metastatic ability than S91Adh cells, Anoikis resistance of S91Nadh cells was not attributable to their resistance to other apoptotic signals in vitro, and they showed no increase in their survival in vivo in the lungs after i.v. inoculation. Increased metastatic potential of the anoikis-resistant S91Nadh cells was associated with various phenotypic changes, including increased proliferation and loss of VLA-4 integrin expression because of down-regulation of the VLA-49 alpha (CD49d) gene. In parallel, they showed a reduction in homotypic aggregation and binding to endothelial cells, increased Matrigel invasiveness, and decreased matrix metalloproteinase-2 and matrix metalloproteinase-9 activity that paralleled up-regulation of the TIMP-1 gene. S91Nadh cells also manifested changes in cell surface carbohydrates, such as appearance of alpha -galactosyl epitopes as a result of up-regulation of the alpha1,3-galactosyltransferase gene and concomitant reduction in cell membrane sialylation, Thus, selection of S91 melanoma cells for anoikis resistance resulted in an increase in their metastatic potential in parallel with multiple alterations in their phenotypic properties. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Expt Therapeut Sect,NIH, Frederick, MD 21702 USA. RP Gorelik, E (reprint author), Univ Pittsburgh, Inst Canc, BST,W954, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [CA59903] NR 42 TC 90 Z9 105 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2001 VL 61 IS 4 BP 1707 EP 1716 PG 10 WC Oncology SC Oncology GA 407DD UT WOS:000167255400077 PM 11245487 ER PT J AU Mehta, SD Rothman, RE Kelen, GD Quinn, TC Zenilman, JM AF Mehta, SD Rothman, RE Kelen, GD Quinn, TC Zenilman, JM TI Clinical aspects of diagnosis of gonorrhea and Chlamydia infection in an acute care setting SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED DISEASES; TRACHOMATIS INFECTIONS; EMERGENCY; PREVENTION AB We found a 10.4% prevalence of unrecognized genital gonorrhea and Chlamydia infection among young adults of an urban emergency department. Intensified detection and treatment policies are needed to prevent continued transmission and complications of sexually transmitted infections. C1 Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Emergency Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Zenilman, JM (reprint author), 720 Rutland Ave,Ross 1159, Baltimore, MD 21205 USA. OI Rothman, Richard/0000-0002-1017-9505; Kelen, Gabor/0000-0002-3236-8286; Mehta, Supriya/0000-0002-7926-2489 FU NIAID NIH HHS [K24AI01633, U19AI38533] NR 16 TC 22 Z9 22 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 FEB 15 PY 2001 VL 32 IS 4 BP 655 EP 659 DI 10.1086/318711 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 400DX UT WOS:000166857900023 PM 11181134 ER PT J AU Taga, K AF Taga, K TI Changes in light scatter properties are a general feature of cell death but are not characteristic of apoptotically dying cells - Reply SO CYTOMETRY LA English DT Letter ID INFECTIOUS-MONONUCLEOSIS; LYMPHOCYTES-T; APOPTOSIS; PHOSPHATIDYLSERINE; EXPRESSION; NECROSIS C1 NCI, DCS, NIH, Bethesda, MD 20892 USA. RP Taga, K (reprint author), NCI, DCS, NIH, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOMETRY JI Cytometry PD FEB 15 PY 2001 VL 46 IS 1 BP 65 EP 66 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403CZ UT WOS:000167026100009 ER PT J AU Isogai, S Horiguchi, M Weinstein, BM AF Isogai, S Horiguchi, M Weinstein, BM TI The vascular anatomy of the developing zebrafish: An atlas of embryonic and early larval development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE zebrafish; vascular anatomy; blood vessels; fluorescent dye confocal microangiography; confocal microscopy ID CARDIOVASCULAR-SYSTEM; RAINBOW-TROUT; ORGANS; GENE AB We have used confocal microangiography to examine and describe the vascular anatomy of the developing zebrafish, Danio rerio. This method and the profound optical clarity of zebrafish embryos make it possible to view the entire developing vasculature with unprecedented resolution. A staged series of three-dimensional images of the vascular system were collected beginning shortly after the onset of circulation at 1 day postfertilization through early- to midlarval stages at approximately 7 days postfertilization. Blood vessels in every region of the animal were imaged at each stage, and detailed "wiring patterns" were derived describing the interconnections between every major vessel. We present an overview of these data here in this paper and in an accompanying Web site "The interactive atlas of zebrafish vascular anatomy" online at (http://eclipse.nichd.nih.gov/nichd/lmg/redirect.html). We find a highly dynamic but also highly stereotypic pattern of vascular: connections, with different sets of primitive embryonic vessels severing connections and rewiring in new configurations according to a reproducible plan. We also find that despite variation in the details of the vascular anatomy, the basic vascular plan of the developing zebrafish shows strong similarity to that of other vertebrates. This atlas will provide an invaluable foundation for future genetic and experimental studies of vascular development in the zebrafish. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Iwate Med Univ, Sch Med, Dept Anat, Morioka, Iwate 0208505, Japan. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. NR 31 TC 425 Z9 438 U1 10 U2 57 PU ACADEMIC PRESS INC 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 FEB 15 PY 2001 VL 230 IS 2 BP 278 EP 301 DI 10.1006/dbio.2000.9995 PG 24 WC Developmental Biology SC Developmental Biology GA 404ZN UT WOS:000167132900014 PM 11161578 ER PT J AU Valasek, L Phan, L Schoenfeld, LW Valaskova, V Hinnebusch, AG AF Valasek, L Phan, L Schoenfeld, LW Valaskova, V Hinnebusch, AG TI Related elF3 subunits TIF32 and HCR1 interact with an RNA recognition motif in PRT1 required for elF3 integrity and ribosome binding SO EMBO JOURNAL LA English DT Article DE eIF3; HCR1; PRT1 RRM; 40S ribosome; translation initiation ID TRANSLATION INITIATION-FACTOR; SACCHAROMYCES-CEREVISIAE HOMOLOG; COMPLEX-FORMATION; ESCHERICHIA-COLI; PROTEIN COMPLEX; FACTOR EIF3; YEAST; GENES; GCN4 AB eIF3 binds to 40S ribosomal subunits and stimulates recruitment of Met-tRNA(i)(Met) and mRNA to the preinitiation complex. Saccharomyces cerevisiae contains an ortholog of human eIF3 subunit p35, HCR1, whose interactions with yeast eIF3 are not well defined, We found that HCR1 has a dual function in translation initiation: it binds to, and stabilizes, the eIF3-eIF5-eIF1-eIF2 multifactor complex and is required for the normal level of 40S ribosomes, The RNA recognition motif (RRM) of eIF3 subunit PRT1 interacted simultaneously with HCR1 and with an internal domain of eIF3 subunit TIF32 that has sequence and functional similarity to HCR1, PRT1, HCR1 and TIF32 were also functionally linked by genetic suppressor analysis. We propose that HCR1, stabilizes or modulates interaction between TIF32 and the PRT1 RRM, Removal of the PRT1 RRM resulted in dissociation of TIF32, NIP1, HCR1 and eIF5 from eIF3 in vivo, and destroyed 40S ribosome binding by the residual PRT1-TIF34-TLF35 subcomplex, Hence, the PRT1 RRM is crucial for the integrity and ribosome-binding activity of eIF3. C1 NICHHD, Eukaryot Mol Genet Lab, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Eukaryot Mol Genet Lab, Bethesda, MD 20892 USA. RI Valasek, Leos/I-5743-2014 NR 34 TC 68 Z9 70 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 2001 VL 20 IS 4 BP 891 EP 904 DI 10.1093/emboj/20.4.891 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 404FR UT WOS:000167087200026 PM 11179233 ER PT J AU Zhou, JM Ahn, J Wilson, SH Prives, C AF Zhou, JM Ahn, J Wilson, SH Prives, C TI A role for p53 in base excision repair SO EMBO JOURNAL LA English DT Article DE AP endonuclease; base excision repair; DNA polymerase beta; p53 ID DNA-POLYMERASE-BETA; HUMAN APURINIC ENDONUCLEASE; GLOBAL GENOMIC REPAIR; C-TERMINAL DOMAIN; HYDROPHOBIC AMINO-ACIDS; ABASIC SITE; IONIZING-RADIATION; PURIFIED PROTEINS; LIGASE-III; IN-VITRO AB Wild-type p53 protein can markedly stimulate base excision repair (BER) in vitro, either reconstituted with purified components or in extracts of cells. In contrast, p53 with missense mutations either at hotspots in the core domain or within the N-terminal transactivation domain is defective in this function. Stimulation of BER by p53 is correlated with its ability to interact directly both with the AP endonuclease (APE) and with DNA polymerase beta (pol beta), Furthermore, p53 stabilizes the interaction between DNA pol beta and abasic DNA. Evidence that this function of p53 is physiologically relevant is supported by the facts that BER activity in human and murine cell extracts closely parallels their levels of endogenous p53, and that BER activity is much reduced in cell extracts immunodepleted of p53. These data suggest a novel role for p53 in DNA repair, which could contribute to its function as a key tumor suppressor. C1 Columbia Univ, Dept Biol Sci, New York, NY 10025 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Prives, C (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10025 USA. FU NCI NIH HHS [CA58316, R01 CA058316, R37 CA058316] NR 78 TC 217 Z9 227 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 2001 VL 20 IS 4 BP 914 EP 923 DI 10.1093/emboj/20.4.914 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 404FR UT WOS:000167087200028 PM 11179235 ER PT J AU Oberley, TD Verwiebe, E Zhong, WX Kang, SW Rhee, SG AF Oberley, TD Verwiebe, E Zhong, WX Kang, SW Rhee, SG TI Localization of the thioredoxin system in normal rat kidney SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE thioredoxin; thioredoxin reductase; peroxiredoxin; reactive oxygen species; kidney; free radicals ID LEUKEMIA-DERIVED FACTOR; DNA-BINDING ACTIVITY; MAMMALIAN PEROXIREDOXIN; REDOX REGULATION; GROWTH-FACTOR; ANTIOXIDANT ENZYMES; HYDROGEN-PEROXIDE; REDUCTASE; CELLS; SELENOCYSTEINE AB Components of the thioredoxin system were localized in normal rat kidney using immunoperoxidase techniques at the light microscopic level and immunogold techniques at the ultrastructural level. Results from both methods were similar. Thioredoxin, thioredoxin reductases, and peroxiredoxins showed cell-type-specific localization, with the same cell types (proximal and distal tubular epithelial, papillary collecting duct, and transitional epithelial cells) previously identified as having high amounts of antioxidant enzyme immunoreactive proteins and oxidative damage products also having high levels of proteins of the thioredoxin system. In addition, peroxiredoxins II and IV were found in high levels in the cytoplasm of red blood cells, identified in kidney blood vessels. While thioredoxin and thioredoxin reductase 1 were found in all subcellular locations in kidney cells, thioredoxin reductase 2 was found predominantly in mitochondria. Thioredoxin reductase 1 was identified in rat plasma, suggesting it is a secreted protein. Peroxiredoxins often had specific subcellular locations, with peroxiredoxins III and V found in mitochondria and peroxiredoxin IV found in lysosomes. Our results emphasize the complex nature of the thioredoxin system, demonstrating unique cell-type and organelle specificity. (C) 2001 Elsevier Science Inc. C1 William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, Madison, WI 53705 USA. Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, 2500 Overlook Terrace,Room A35, Madison, WI 53705 USA. NR 56 TC 89 Z9 89 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2001 VL 30 IS 4 BP 412 EP 424 DI 10.1016/S0891-5849(00)00486-X PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 401YD UT WOS:000166955900009 PM 11182297 ER PT J AU Voloshin, ON Ramirez, BE Bax, A Camerini-Otero, RD AF Voloshin, ON Ramirez, BE Bax, A Camerini-Otero, RD TI A model for the abrogation of the SOS response by an SOS protein: a negatively charged helix in DinI mimics DNA in its interaction with RecA SO GENES & DEVELOPMENT LA English DT Article DE DinI; RecA; SOS response; molecular mimicry ID SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; PAIRING DOMAIN; MUTATION; BINDING; ISFA; RECOMBINATION; INHIBITION; COPROTEASE; RESIDUES AB DinI is a recently described negative regulator of the SOS response in Escherichia coli. Here we show that it physically interacts with RecA and prevents the binding of single-stranded DNA to RecA, which is required for the activation of the latter. DinI also displaces ssDNA from a stable RecA-DNA cofilament, thus eliminating the SOS signal. In addition, DinI inhibits RecA-mediated homologous DNA pairing, but has no effect on actively proceeding strand exchange. Biochemical data, together with the molecular structure, define the C-terminal cy-helix in DinI as the active site of the protein. In an unusual example of molecular mimicry, a negatively charged surface on this a-helix, by imitating single-stranded DNA, interacts with the loop L2 homologous pairing region of RecA and interferes with the activation of RecA. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 37 TC 54 Z9 56 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2001 VL 15 IS 4 BP 415 EP 427 DI 10.1101/gad.862901 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 406GT UT WOS:000167207100007 PM 11230150 ER PT J AU Lee, DK Park, SH Yi, Y Choi, SG Lee, C Parks, WT Cho, H de Caestecker, MP Shaul, Y Roberts, AB Kim, SJ AF Lee, DK Park, SH Yi, Y Choi, SG Lee, C Parks, WT Cho, H de Caestecker, MP Shaul, Y Roberts, AB Kim, SJ TI The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis SO GENES & DEVELOPMENT LA English DT Article DE hepatitis B virus pX; Smad; TGF-beta; fibrosis; signaling ID GROWTH-FACTOR-BETA; X-PROTEIN; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSGENIC MICE; TRANSCRIPTION FACTORS; BINDING-PROTEIN; EXPRESSION; TRANSACTIVATOR; GENE; COACTIVATOR AB Hepatitis B, one of the most common infectious diseases in the world, is closely associated with acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Many clinical investigations have revealed that hepatic fibrosis is an important component of these liver diseases caused by chronic hepatitis B. TGF-beta signaling plays an important role in the pathogenesis of fibrosis in chronic hepatitis and cirrhosis. As these diseases are associated with hepatitis B virus (HBV) infection, we examined the possibility that the HBV-encoded pX oncoprotein regulates TGF-beta signaling. We show that pX enhances transcriptional activity in response to TGF-beta, BMP-2, and activin by stabilizing the complex of Smad4 with components of the basic transcriptional machinery. Additionally, confocal microscopic studies suggest that pX facilitates and potentiates the nuclear translocation of Smads, further enhancing TGF-beta signaling. Our studies suggest a new paradigm for amplification of Smad-mediated signaling by an oncoprotein and suggest that enhanced Smad-mediated signaling may contribute to HBV-associated liver fibrosis. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Ajou Univ, Sch Med, Dept Biochem & Mol Biol, Suwon 442721, South Korea. Weizmann Inst Sci, IL-76100 Rehovot, Israel. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NR 52 TC 91 Z9 99 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2001 VL 15 IS 4 BP 455 EP 466 DI 10.1101/gad.856201 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 406GT UT WOS:000167207100010 PM 11230153 ER PT J AU Sanders, AR Cao, QH Taylor, J Levin, TE Badner, JA Cravchik, A Comeron, JM Naruya, S Del Rosario, A Salvi, DA Walczyk, KA Mowry, BJ Levinson, DF Crowe, RR Silverman, JM Gejman, PV AF Sanders, AR Cao, QH Taylor, J Levin, TE Badner, JA Cravchik, A Comeron, JM Naruya, S Del Rosario, A Salvi, DA Walczyk, KA Mowry, BJ Levinson, DF Crowe, RR Silverman, JM Gejman, PV TI Genetic diversity of the human serotonin receptor 1B (HTR1B) gene SO GENOMICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; HUMAN 5-HT1B RECEPTOR; GRADIENT GEL-ELECTROPHORESIS; KNOCKOUT MICE LACKING; 5-HYDROXYTRYPTAMINE(1B) RECEPTOR; LINKAGE DISEQUILIBRIUM; DIAGNOSTIC INTERVIEW; SUSCEPTIBILITY LOCUS; FUNCTIONAL-ANALYSIS; BINDING AFFINITIES AB We systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, -182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P = 0.04 via AS-PEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene, (C) 2001 Academic Press. C1 Univ Chicago, Dept Psychiat, Jules F Knapp Res Ctr, Schizophrenia Genet Res Program, Chicago, IL 60637 USA. NIMH, Unit Mol Clin Invest, Clin Neurogenet Branch, Bethesda, MD 20892 USA. Univ Queensland, Dept Psychiat, Brisbane, Qld, Australia. Wolston Pk Hosp, Queensland Ctr Schizophrenia Res, Brisbane, Qld, Australia. Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. Natl Inst Genet, Lab Evolut Genet, Mishima, Shizuoka 411, Japan. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Iowa, Coll Med, Mental Hlth Clin Res Ctr, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Gejman, PV (reprint author), Univ Chicago, Dept Psychiat, Jules F Knapp Res Ctr, Schizophrenia Genet Res Program, 924 E 57th St,Room R-010, Chicago, IL 60637 USA. EM pgejman@uchicago.edu RI Taylor, Jennifer/A-1686-2010; Comeron, Josep/G-6630-2012 OI Taylor, Jennifer/0000-0003-4231-0181; NR 63 TC 29 Z9 29 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB 15 PY 2001 VL 72 IS 1 BP 1 EP 14 DI 10.1006/geno.2000.6411 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 412KN UT WOS:000167553700001 PM 11247661 ER PT J AU Hisada, M Okayama, A Spiegelman, D Mueller, NE Stuver, SO AF Hisada, M Okayama, A Spiegelman, D Mueller, NE Stuver, SO TI Sex-specific mortality from adult T-cell leukemia among carriers of human T-lymphotropic virus type I SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ATL; mortality rate; sex-specific; perinatal infection; HTLV-I ID ABNORMAL LYMPHOCYTES; MIYAZAKI COHORT; JAPAN; LYMPHOMA; RISK; TRANSMISSION; INFECTION; BLOOD; LEVEL AB Perinatal infection with human T-lymphotropic virus type I (HTLV-I) is considered a risk factor far adult T-cell leukemia (ATL). Incidence of ATL in japan is generally higher in males compared with females, perhaps partly due to an earlier average age of infection among males. We estimated sex-specific ATL mortality among perinatally-infected HTLV-I carriers in the prospective Miyazaki Cohort Study in japan. Based on the approximated proportion of perinatally-infected carriers, the relative risk (RR) of ATL for males compared with females was calculated. Six ATL deaths (4 males, 2 females) occurred among the 550 HTLV-I carriers in the cohort during 13 years of follow-up. The overall ATL mortality was 190.5 (95% CI 51.9-487.7) per 10(5) person-years for males and 51.7(6.3-186.8) per 105 person-years for females (age-standardized RR = 3.9, p = 0.02). By approximating the number of persons who acquired infection perinatally, the estimated mortality among those perinatally-infected HTLV-I carriers was 209.1 (57.0-535.2) per 105 person-years for males and 60.9 (7.4-2 19.9) per 10(5) person-years for females (age-standardized RR 3.7, p = 0.02). The adjusted RR changed minimally from the unadjusted RR, suggesting that earlier age of infection alone is unlikely the explanation for the male predominance in ATL. Based on the small number of cases available for analysis, aspects of gender itself appear to play a role in the development of this malignancy. (C) 2001 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Rockville, MD 20852 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Miyazaki Med Coll, Dept Internal Med 2, Miyazaki 88916, Japan. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Hisada, M (reprint author), NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, 6120 Execut Blvd,EPS-8008, Rockville, MD 20852 USA. FU NCI NIH HHS [5RO1-CA38450] NR 22 TC 19 Z9 19 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2001 VL 91 IS 4 BP 497 EP 499 DI 10.1002/1097-0215(20010215)91:4<497::AID-IJC1044>3.0.CO;2-A PG 3 WC Oncology SC Oncology GA 398AZ UT WOS:000166732700010 PM 11251972 ER PT J AU Vitale, F Briffa, DV Whitby, D Maida, I Grochowska, A Levin, A Romano, N Goedert, JJ AF Vitale, F Briffa, DV Whitby, D Maida, I Grochowska, A Levin, A Romano, N Goedert, JJ TI Kaposi's sarcoma herpes virus and Kaposi's sarcoma in the elderly populations of 3 Mediterranean islands SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter ID HUMAN-HERPESVIRUS-8 SEROPREVALENCE; NORTHEAST SARDINIA; VARIABILITY C1 Univ Palermo, Dept Hyg & Microbiol Giuseppe DAlessandro, I-90133 Sicily, Italy. Natl Canc Inst, Viral Epidemiol Lab, SAIC, Frederick, MD USA. Univ Sassari, Ist Igiene, I-07100 Sassari, Sardinia, Italy. St Lukes Hosp, Dept Hematol, Guardamangia, Malta. St Bartholomews Hosp, Sch Med, Dept Virol, London, England. RP Goedert, JJ (reprint author), 6120 Execut Blvd,Room 8012, Rockville, MD 20852 USA. FU NCI NIH HHS [N02-CP-40521, N01-CO-56000, N02-CP-91027] NR 21 TC 47 Z9 49 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 FEB 15 PY 2001 VL 91 IS 4 BP 588 EP 591 DI 10.1002/1097-0215(200002)9999:9999<::AID-IJC1089>3.0.CO;2-8 PG 4 WC Oncology SC Oncology GA 398AZ UT WOS:000166732700025 PM 11251987 ER PT J AU Fisher, B Anderson, S Tan-Chiu, E Wolmark, N Wickerham, DL Fisher, ER Dimitrov, NV Atkins, JN Abramson, N Merajver, S Romond, EH Kardinal, CG Shibata, HR Margolese, RG Farrar, WB AF Fisher, B Anderson, S Tan-Chiu, E Wolmark, N Wickerham, DL Fisher, ER Dimitrov, NV Atkins, JN Abramson, N Merajver, S Romond, EH Kardinal, CG Shibata, HR Margolese, RG Farrar, WB TI Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TUMORS; TRIAL; ANTIESTROGENS; CELLS; METHOTREXATE; FLUOROURACIL; PHARMACOLOGY; ANGIOGENESIS; INHIBITION; CARCINOMA AB Purpose: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. Patients and Methods: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAMI AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. Results: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and .8, respectively), for those aged less than or equal to 49 years (P = .97, .5, and .9, respectively), or for those aged greater than or equal to 50 years (P = .7, .6, and .6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P = .6), or S (89% and 90%, P = .4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged less than or equal to 49 or greater than or equal to 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P = .6), 87% in patients aged 49 (P =.9), land 88% and 87%, respectively (P = .4), in those aged greater than or equal to 50 years. Conclusion: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone. C1 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. RP Fisher, B (reprint author), 4 Allegheny Ctr, Natl Surg Adjuvant Breast & Bowel Project, Suite 602, Pittsburgh, PA 15212 USA. OI Anderson, Stewart/0000-0001-8948-0650 FU NCI NIH HHS [U10-CA-69974, U10-CA-12027, U10-CA-37377, U10-CA-69651] NR 41 TC 149 Z9 154 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 FEB 15 PY 2001 VL 19 IS 4 BP 931 EP 942 PG 12 WC Oncology SC Oncology GA 406MH UT WOS:000167219400004 PM 11181655 ER PT J AU Yancik, R Ganz, PA Varicchio, CG Conley, B AF Yancik, R Ganz, PA Varicchio, CG Conley, B TI Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; WOMEN; SURVIVAL; AGE AB Not only do persons 65 years and older bear a dispropartionate burden of cancer, advancing age is associated with increased vulnerability to other age-related health problems. Newly diagnosed older cancer patients who have lived into later years of life may have concurrent ailments (eg, diabetes, chronic obstructive pulmonary disease, heart disease, arthritis, and/or hypertension) that could affect treatment choice, prognosis, and survival. The clinician must often make cancer treatment decisions in the context of an older individual's pre-existing health problems tie, comorbidity). Ways to produce reliable information on comorbidity that can be effectively used in evaluation of older cancer patients are urgently needed. What is the nature and severity of the older patient's comorbid health problems? How do other age-related conditions influence treatment decisions and the cancer courser How do already compromised older patients tolerate the stress of cancer and its treatment? How are concomitant comorbid conditions managed? At present, no established, valid way to assess comorbidity in older cancer patients exists. Such technology, with a solid conceptual and scientific base, promises a high positive clinical yield to assure quality cancer care for older patients if reliable and valid instruments can be integrated into oncology practice. Much preliminary scientific work must be performed. A synthesis of viewpoints on what to include in comorbidity assessment of alder cancer patients and development approaches were expressed in a multidisciplinary working group convened by the National Institute on Aging and the National Cancer Institute. We share the key issues raised regarding complexities of comorbidity assessment and suggestions for scientific inquiry. C1 NIA, Geriatr Program, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD USA. NCI, Div Canc Treatment & Diag, Bethesda, MD USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90024 USA. RP Yancik, R (reprint author), NIA, Geriatr Program, Suite 3E327,7201 Wisconsin Ave, Bethesda, MD 20892 USA. NR 13 TC 180 Z9 182 U1 1 U2 13 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 FEB 15 PY 2001 VL 19 IS 4 BP 1147 EP 1151 PG 5 WC Oncology SC Oncology GA 406MH UT WOS:000167219400029 PM 11181680 ER PT J AU Rutschman, R Lang, R Hesse, M Ihle, JN Wynn, TA Murray, PJ AF Rutschman, R Lang, R Hesse, M Ihle, JN Wynn, TA Murray, PJ TI Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MURINE PERITONEAL-MACROPHAGES; SYNTHASE; CELLS; IL-4; TRANSCRIPTION; SUPPRESSION; EXPRESSION; INDUCTION; STAT6; INTERLEUKIN-4 AB The cytokines IL-4 and IL-13 inhibit the production of NO from activated macrophages through an unresolved molecular mechanism. We show here that IL-4 and IL-13 regulate NO production through depletion of arginine, the substrate of inducible NO synthase (iNOS). Inhibition of NO production from murine macrophages stimulated with LPS and IFN-gamma by IL-4 or IL-13 was dependent on Stat6, cell density in the cultures, and pretreatment for at least 6 h. IL-4/IL-13 did not interfere with the expression or activity of iNOS but up-regulated arginase I (the liver isoform of arginase) in a Stat6-dependent manner. Addition of exogenous arginine completely restored NO production in IL-4-treated macrophages, Furthermore, impaired killing of the intracellular pathogen Toxoplasma gondii in IL-4-treated macrophages was overcome by supplementing L-arginine. The simple system of regulated substrate competition between arginase and iNOS has implications for understanding the physiological regulation of NO production. C1 St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Murray, PJ (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. RI Wynn, Thomas/C-2797-2011; Lang, Roland/C-3287-2011; OI Lang, Roland/0000-0003-0502-3677 FU NCI NIH HHS [P30 CA 21765] NR 35 TC 193 Z9 201 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2173 EP 2177 PG 5 WC Immunology SC Immunology GA 400QA UT WOS:000166882000003 PM 11160269 ER PT J AU Kobrin, CB Bendandi, M Kwak, LW AF Kobrin, CB Bendandi, M Kwak, LW TI Novel secondary Ig V-H gene rearrangement and in-frame Ig heavy chain complementarity-determining region III insertion/deletion variants in de novo follicular lymphoma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REED-STERNBERG CELLS; MATURE B-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; V(D)J RECOMBINATION; LYMPHOPROLIFERATIVE DISORDERS; CHROMOSOMAL TRANSLOCATION; JUNCTIONAL DIVERSITY; CLONAL EVOLUTION AB Human germinal center B cell tumors retain the ability of their nontransformed counterparts to somatically hypermutate Ig V genes by nucleotide substitution, Among a survey of 60 primary previously untreated, clonal, follicular lymphomas we have identified a rare V-H rearrangement variant and two other in-frame nucleotide insertion/deletion variants within complementarity-determining region III of the Ig heavy chain, The neoplastic origin of the V-H rearrangement variant was directly demonstrated in cells isolated by microdissection from malignant follicles. In all three cases a common clonal origin for the variants was demonstrated by complementarity-determining region III nucleotide sequence homology and shared somatic mutations in germline encoded positions in framework region IV. The monoclonal nature of the tumors was independently confirmed by demonstrating a single t(14;18) translocation breakpoint in the two cases with a detectable translocation. All the variants occurred in functional V-H rearrangements, which in two cases were directly shown to encode functional Ab molecules, Both recombination-activating genes 1 and 2 were expressed in lymph node tumor cells containing the V-H rearrangement variant, although recombination-activating gene expression among a panel of lymphomas was not limited to this variant. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Div Clin Sci, Med Branch, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. RP Kobrin, CB (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Bldg 567,Room 221, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 59 TC 18 Z9 18 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 FEB 15 PY 2001 VL 166 IS 4 BP 2235 EP 2243 PG 9 WC Immunology SC Immunology GA 400QA UT WOS:000166882000011 PM 11160277 ER PT J AU Li, ZQ He, LS Wilson, KE Roberts, DD AF Li, ZQ He, LS Wilson, KE Roberts, DD TI Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTEGRIN-ASSOCIATED PROTEIN; SMOOTH-MUSCLE CELLS; ENDOTHELIAL-CELLS; KINASE-C; RECEPTOR; ADHESION; CD47; STIMULATION; ANTIGEN; PROLIFERATION AB Biological activities of the matrix glycoprotein thrombospondin-1 (TSP1) are cell type specific and depend on the relative expression or activation of several TSP1 receptors, Although engaging individual TSP1 receptors in T lymphocytes can elicit costimulating signals, in this study we show that intact TSP1 inhibits TCR-mediated T cell activation, assessed globally using cDNA microarrays. TSP1 signaling suppressed expression of several genes induced in Jurkat T cells, including the T cell activation markers CD69, early growth response gene-1 (Egr-1), and phosphatase of activated cells (PAC-1), TCR-stimulated and CD47-costimulated IL-2 secretion and cell surface CD69 expression were also inhibited by TSP1. The specific inhibitory effect of TSP1 was verified in freshly isolated human PBMCs. TSP1 inhibited TCR-mediated but not protein kinase C-mediated T cell activation. Using CD69 expression as a marker, we demonstrated that the inhibitory activity of TSP1 depended on two TSP1 receptors, CD47 and integrin-associated protein heparan sulfate proteoglycans, Signals from these receptors inhibited TCR signaling downstream of ZAP70, but upstream of NF-AT, Therefore, the expression of TSP1 induced during wound repair and in tumor stroma may limit T cell activation at these sites. The Journal of Immunology, 2001, 166: 2427-2436. C1 NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Div Clin Sci, 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 53 TC 57 Z9 58 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 FEB 15 PY 2001 VL 166 IS 4 BP 2427 EP 2436 PG 10 WC Immunology SC Immunology GA 400QA UT WOS:000166882000036 PM 11160302 ER PT J AU Sabzevari, H Kantor, J Jaigirdar, A Tagaya, Y Naramura, M Hodge, JW Bernon, J Schlom, J AF Sabzevari, H Kantor, J Jaigirdar, A Tagaya, Y Naramura, M Hodge, JW Bernon, J Schlom, J TI Acquisition of CD80 (B7-1) by T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HIV-INFECTED INDIVIDUALS; COSTIMULATORY MOLECULES; ANTIGEN PRESENTATION; ACTIVATION; EXPRESSION; LYMPHOCYTES; CD28; SYNERGIZE; INDUCTION; RECEPTOR AB Activation of T cells usually requires two signals. Signal 1 is mediated via a peptide-MHC on the APC; signal 2 is mediated via a costimulatory molecule on the APC surface. We demonstrate here that naive CD4(+) T cells actually acquire the costimulatory molecule CD80 (B7-1) from syngeneic APCs after activation. This phenomenon was demonstrated showing acquisition of CD80 by T cells from CD80/CD86 (B7-2) knockout mice, and by treating T cells with cyclohexamide to further rule out endogenous expression of CD80 by T cells. Moreover, no CD80 mRNA could be detected in T cells that had acquired CD80, The amount of acquisition of CD80 by T cells was shown to be directly related to both the strength of signal 1 and the amount of CD80 on the APC, Specificity of this acquisition was also shown by the lack of acquisition by T cells from CD28 knockout mice (implicating CD28 in this process), the lack of acquisition of CD40 (another molecule on the APC surface) by T cells, and confocal microscopy studies. We demonstrate for the first time that 1) naive T cells, following acquisition of CD80 from APCs, were themselves shown to be capable of acting as APCs; and 2) memory T cells that have acquired CD80 from APCs undergo apoptosis in the presence of increased levels of signal 1. Thus we demonstrate both immunostimulatory and immunoregulatory functions as a result of CD80 acquisition by different T cell populations. The Journal of Immunology, 2001, 166: 2505-2513. C1 NCI, Tumor Immunol & Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Div Basic Sci, NIH, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 38 TC 66 Z9 68 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2001 VL 166 IS 4 BP 2505 EP 2513 PG 9 WC Immunology SC Immunology GA 400QA UT WOS:000166882000045 PM 11160311 ER PT J AU Pechhold, K Patterson, NB Blum, C Fleischacker, CL Boehm, BO Harlan, DM AF Pechhold, K Patterson, NB Blum, C Fleischacker, CL Boehm, BO Harlan, DM TI Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PANCREATIC BETA-CELLS; CD28-DEFICIENT MICE; TRANSGENIC MICE; COSTIMULATOR B7-1; NOD MICE; EXPRESSION; ANTIGEN; TOLERANCE; RESPONSES; INDUCTION AB Although transgenic mice expressing murine B7-1 (mCD80) on their pancreatic beta cells under the rat insulin-1 promoter (RIPmCD80(+) mice) rarely develop spontaneous beta cell destruction and diabetes, we have previously reported the transgene-dependent induction of profound insulitis and lethal diabetes following multiple low dose injections of the beta cell toxin streptozotocin (MLDS) in RIP-mCD80(+) mice. Here, we have further characterized this MLDS-induced diabetes model using the RIP-mCD80(+) mice and now demonstrate that disease is critically dependent on T cell signaling via CD28. Thus, although naive RTP-mCD80(+) and nontransgenic littermates have comparable gross beta cell mass, and immediately following MLDS induction the mice display similar degrees of insulitis and decrements in the beta cell mass, only transgenic mice continued to destroy their P cells and develop insulin-dependent diabetes mellitus. Strikingly, MLDS-induced diabetes was completely prevented in CD28-deficient mice (RIP-mCD80(+)CD28(-/-)) due to abrogation of leukocytes infiltrating their pancreatic islets. We further characterized MLDS-induced diabetes in the RIP-mCD80(+) mice by demonstrating that the MLDS-induced lymphocytic islet infiltrate contained a substantial frequency of autoantigen-specific, IPN-gamma -secreting, CD8(+) T cells. We conclude that MLDS-induced P cell, destruction and subsequent insulin-dependent diabetes mellitus in RIP-mCD80(+) mice is T cell-mediated as it involves both Ag-specific recognition of self-target molecules in the inflamed pancreatic islet (signal 1) and is CD28 costimulation dependent (signal 2). The Journal of Immunology, 2001, 166: 2531-2539. C1 NIDDKD, Navy Transplantat & Autoimmun Branch, Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA. Univ Ulm, Dept Internal Med 1, Ulm, Germany. RP Pechhold, K (reprint author), NIDDKD, Navy Transplantat & Autoimmun Branch, Armed Forces Radiobiol Res Inst, Bldg 46,Room 2417,8901 Wisconsin Ave, Bethesda, MD 20889 USA. RI Boehm, Bernhard/F-8750-2015 NR 57 TC 25 Z9 25 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 FEB 15 PY 2001 VL 166 IS 4 BP 2531 EP 2539 PG 9 WC Immunology SC Immunology GA 400QA UT WOS:000166882000048 PM 11160314 ER PT J AU Mariner, JM Lantz, V Waldmann, TA Azimi, N AF Mariner, JM Lantz, V Waldmann, TA Azimi, N TI Human T cell lymphotropic virus type I tax activates IL-15R alpha gene expression through an NF-kappa B site SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HTLV-I; INTERLEUKIN-2 RECEPTOR; BETA-CHAIN; SPASTIC PARAPARESIS; IL-2 RECEPTOR; LYMPHOCYTES-T; KILLER-CELLS; ALPHA-CHAIN; LEUKEMIA; INDUCTION AB IL-15 mRNA levels are increased in diseases caused by human T cell lymphotropic virus type I(HTLV-I), In this study, we demonstrated that IL-15R alpha, the IL-15-specific binding receptor, mRNA and protein levels were also elevated in HTLV-I-infected cells, We showed that transient HTLV-I Tax expression lead to increased IL-15R alpha mRNA levers. In addition, by using a reporter construct that bears the human IL-15R alpha promoter, we demonstrated that Tax expression increased promoter activity by at least 4-fold. Furthermore, using promoter deletion constructs and gel shift analysis, we defined a functional NF-kappaB-binding motif in the human IL-15R alpha promoter, suggesting that Tax activation of IL-15R alpha is due, in part, to the induction of NF-kappaB. These data indicate that IL-15R alpha is transcriptionally regulated by the HTLV-I Tax protein through the action of NF-kappaB. These findings suggest a role far IL-15R alpha in aberrant T cell proliferation observed in HTLV-I-associated diseases. The Journal of Immunology, 2001, 166: 2602-2609. C1 NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. George Washington Univ, Inst Biomed Sci, Grad Genet Program, Washington, DC 20052 USA. RP Mariner, JM (reprint author), NCI, Metab Branch, Div Clin Sci, NIH, Bldg 10,Room 4N-102,10 Ctr Dr MSC 1374, Bethesda, MD 20892 USA. NR 55 TC 67 Z9 68 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 FEB 15 PY 2001 VL 166 IS 4 BP 2602 EP 2609 PG 8 WC Immunology SC Immunology GA 400QA UT WOS:000166882000056 PM 11160322 ER PT J AU McCartney-Francis, NL Song, XY Mizel, DE Wahl, SM AF McCartney-Francis, NL Song, XY Mizel, DE Wahl, SM TI Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ADJUVANT-INDUCED ARTHRITIS; WALL-INDUCED ARTHRITIS; AUTOIMMUNE-DISEASE; MESSENGER-RNA; INFLAMMATION; EXPRESSION; ARGININE; RATS; PCR AB NO is an essential cytotoxic agent in host defense, yet can be autotoxic if overproduced, as evidenced in inflammatory lesions and tissue destruction in experimental arthritis models. Treatment of streptococcal cell wall-induced arthritis in rats with NG-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO synthase (NOS), prevents intraarticular accumulation of leukocytes, joint swelling, and bone erosion. Because increased inducible NOS (iNOS) expression and NO generation are associated with pathogenesis of chronic inflammation, we investigated whether a selective inhibitor of iNOS, N-iminoethyl-L-lysine (L-NIL), would have more directed anti-arthritic properties. Whereas both L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall-stimulated rat mononuclear cells;in vitro and systemic treatment of arthritic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate resolution of inflammatory joint lesions. On the contrary; daily administration of L-NIL failed to reduce the acute response and exacerbated the chronic inflammatory response, as reflected by profound tissue destruction and loss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NB, immunohistochemical analyses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NIL treatment. These studies uncover a contribution of the constitutive isoforms of NOS to the evolution of acute and chronic inflammation pathology which may be important in the design of therapeutic agents. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP McCartney-Francis, NL (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, 30 Convent Dr,Bldg 30,Room 326, Bethesda, MD 20892 USA. NR 30 TC 92 Z9 97 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 FEB 15 PY 2001 VL 166 IS 4 BP 2734 EP 2740 PG 7 WC Immunology SC Immunology GA 400QA UT WOS:000166882000073 PM 11160339 ER PT J AU Kawakami, Y Wang, X Shofuda, T Sumimoto, H Tupesis, JP Fitzgerald, E Rosenberg, SA AF Kawakami, Y Wang, X Shofuda, T Sumimoto, H Tupesis, JP Fitzgerald, E Rosenberg, SA TI Isolation of a new melanoma antigen, MART-2, containing a mutated epitope recognized by autologous tumor-infiltrating T lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BETA-CATENIN; GENE; IDENTIFICATION; IMMUNOTHERAPY; PROTEINS; BINDING; CLONING; ENCODES; CELLS; GP100 AB Using cDNA expression cloning, a cDNA encoding a novel human melanoma Ag, MART-2 (melanoma Ag recognized by T cells-2), recognized by HLA-A1-restricted CD8(+) T cells from tumor-infiltrating lymphocytes (TIL1362) was isolated from an autologous melanoma cell line, 1362 mel. Homologous sequences to the cDNA had been registered in the EST database. This gene encoded an uncharacterized protein expressed ubiquitously in most normal and cancer cells, A mutation (A to G transition),was found in the cDNA obtained from the 1362 mel melanoma cell line in the sequences encoding the phosphate binding loop (P-loop) that resulted in loss of the ability to bind GTP, Transfection of NM-3T3 with the mutated MART-2 did not result in the development of significant foci, By screening 36 various cancer cell lines using single-strand conformation polymorphism, a possible mutation in the P-loop of MART-2 was found in one squamous cell lung cancer cell line, EBC1, The T cell epitope for TIL1362, FLEGNEVGKTY, was identified to be encoded by the mutated sequence of the MART-2 Ag, The mutation substituted glycine in the normal peptide with glutamic acid at the third amino acid of the epitope, which is an important primary anchor amino acid for HLA-A1 peptide binding. The normal peptide, FLGGNEVGKTY, was not recognized by TIL1362, suggesting that this T cell response was specific for the autologous tumor. Although transforming activity was not detected in the NM-3T3 assay, MART-2 with the mutation in the P-loop may be involved in the generation of melanoma through a loss of GTP binding activity. C1 Keio Univ, Sch Med, Inst Adv Med Res, Div Cellular Signaling,Shijuku Ku, Tokyo 1608582, Japan. NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Kawakami, Y (reprint author), Keio Univ, Sch Med, Inst Adv Med Res, Div Cellular Signaling,Shijuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan. RI Kawakami, Yutaka /E-7429-2013 OI Kawakami, Yutaka /0000-0003-4836-2855 NR 26 TC 46 Z9 47 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 FEB 15 PY 2001 VL 166 IS 4 BP 2871 EP 2877 PG 7 WC Immunology SC Immunology GA 400QA UT WOS:000166882000090 PM 11160356 ER PT J AU Ioannidis, JPA Abrams, EJ Ammann, A Bulterys, M Goedert, JJ Gray, L Korber, BT Mayaux, MJ Mofenson, LM Newell, ML Shapiro, DE Teglas, JP Wilfert, CM AF Ioannidis, JPA Abrams, EJ Ammann, A Bulterys, M Goedert, JJ Gray, L Korber, BT Mayaux, MJ Mofenson, LM Newell, ML Shapiro, DE Teglas, JP Wilfert, CM TI Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads < 1000 copies/mL SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID TO-CHILD TRANSMISSION; MATERNAL VIRAL LOAD; HIV-1 RNA; ZIDOVUDINE TREATMENT; INFANT TRANSMISSION; PLASMA; RISK; QUANTIFICATION; EXPOSURE; THAILAND AB In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P < .001), cesarean section (OR, 0.30; P = .022), greater birth weight (P = .003), and higher CD4 cell count (P = .039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia. C1 Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Columbia Univ, Harlem Hosp Ctr, Dept Pediat, New York, NY USA. Global Strategies HIV Prevent, San Rafael, CA USA. Ctr Dis Control & Prevent, Mother Child Transmiss & Pediat & Adolescent Stud, Epidemiol Branch, Div HIV AIDS Prevent, Atlanta, GA USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. Inst Child Hlth, Dept Paediat Epidemiol & Biostat, European Collaborat Study Coordinating Ctr, London, England. Santa Fe Inst, Santa Fe, NM 87501 USA. Univ Calif Los Alamos Natl Lab, Los Alamos, NM USA. Hop Kremlin Bicetre, INSERM, U292, Le Kremlin Bicetre, France. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. RP Ioannidis, JPA (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. RI Gray, Linsay/A-6741-2010; Ioannidis, John/G-9836-2011; OI Mofenson, Lynne/0000-0002-2818-9808; Newell, Marie-Louise/0000-0002-1074-7699; Korber, Bette/0000-0002-2026-5757 NR 41 TC 201 Z9 212 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2001 VL 183 IS 4 BP 539 EP 545 DI 10.1086/318530 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 395NG UT WOS:000166586000003 PM 11170978 ER PT J AU Daar, ES Lynn, H Donfield, S Gomperts, E O'Brien, SJ Hilgartner, MW Hoots, WK Chernoff, D Arkin, S Wong, WY Winkler, CA AF Daar, ES Lynn, H Donfield, S Gomperts, E O'Brien, SJ Hilgartner, MW Hoots, WK Chernoff, D Arkin, S Wong, WY Winkler, CA CA Hemophila Growth Dev Study TI Hepatitis c virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 7th Conference on Retroviruses and Opportunistic Infections CY JAN 29-FEB 03, 2000 CL SAN FRANCISCO, CALIFORNIA ID HIV-INFECTED PATIENTS; LIVER-DISEASE; HCV GENOTYPE; DRUG-USERS; PLASMA; COINFECTION; RNA; SURVIVAL; REPLICATION; BURDEN AB Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for similar to7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4+ cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P = .016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P = .036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals. C1 Cedars Sinai Burns & Allen Res Inst, Dept Med, Div Infect Dis, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Chiron Corp, Emeryville, CA 94608 USA. Rho, Chapel Hill, NC USA. Cornell Univ, Med Ctr, New York Hosp, Div Pediat Hematol & Oncol, New York, NY 10021 USA. Mt Sinai Sch Med, Div Pediat Hematol Oncol, New York, NY USA. Univ Texas, Sch Med, Dept Pediat, Houston, TX USA. Univ Texas, Sch Med, Dept Internal Med, Houston, TX USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. NCI, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Daar, ES (reprint author), Cedars Sinai Med Ctr, Div Infect Dis, B217,8700 Beverly Blvd, Los Angeles, CA 90048 USA. FU NCRR NIH HHS [MO1-RR02558, MO1-RR00059, MO1-RR00071, MO1-RR06020] NR 34 TC 96 Z9 112 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2001 VL 183 IS 4 BP 589 EP 595 DI 10.1086/318539 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 395NG UT WOS:000166586000009 PM 11170984 ER PT J AU Hoe, NP Vuopio-Varkila, J Vaara, M Grigsby, D De Lorenzo, D Fu, YX Dou, SJ Pan, X Nakashima, K Musser, JM AF Hoe, NP Vuopio-Varkila, J Vaara, M Grigsby, D De Lorenzo, D Fu, YX Dou, SJ Pan, X Nakashima, K Musser, JM TI Distribution of streptococcal inhibitor of complement variants in pharyngitis and invasive isolates in an epidemic of serotype M1 group a Streptococcus infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 100th Annual Meeting of the American-Society-for-Microbiology CY MAY 21-25, 2000 CL LOS ANGELS, CALIFORNIA SP Amer Soc Microbiol ID GROUP-A STREPTOCOCCUS; HYALURONIC-ACID CAPSULE; NEISSERIA-MENINGITIDIS; PYOGENES; PROTEIN; STRAINS; DISEASE; CARRIAGE; OUTBREAK; POPULATION AB Streptococcal inhibitor of complement (Sic) is a highly polymorphic extracellular protein made predominantly by serotype M1 group A Streptococcus (GAS). New variants of the Sic protein frequently appear in M1 epidemics as a result of positive natural selection. To gain further understanding of the molecular basis of M1 epidemics, the sic gene was sequenced from 471 pharyngitis and 127 pyogenic and blood isolates recovered from 598 patients living in metropolitan Helsinki, Finland, during a 37-month population-based surveillance study. Most M1 GAS subclones recovered from pyogenic infections and blood were abundantly represented in the pool of subclones causing pharyngitis. Alleles shared among the pharyngitis, pyogenic, and blood samples were identified in throat isolates a mean of 9.8 months before their recovery from pyogenic infections and blood, which indicates that selection of most sic variants occurs on mucosal surfaces. In contrast, no variation was identified in the emm and covR/covS genes. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Helsinki, Cent Hosp, Diagnost Lab, Clin Microbiol Sect, Helsinki, Finland. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. RP Musser, JM (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Vaara, Martti/D-1698-2013 FU NIGMS NIH HHS [GM-50428] NR 30 TC 38 Z9 38 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2001 VL 183 IS 4 BP 633 EP 639 DI 10.1086/318543 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 395NG UT WOS:000166586000015 PM 11170990 ER PT J AU Emery, S Lane, HC Neaton, JD AF Emery, S Lane, HC Neaton, JD TI Interleukin-2 in clinical trials: Other factors to be considered - Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2010, Australia. NIAID, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. RP Emery, S (reprint author), Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, 376 Victoria St, Sydney, NSW 2010, Australia. RI Emery, Sean/H-4920-2013 OI Emery, Sean/0000-0001-6072-8309 NR 3 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2001 VL 183 IS 4 BP 680 EP 680 DI 10.1086/318546 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 395NG UT WOS:000166586000025 ER PT J AU Newman, AH Robarge, MJ Howard, IM Wittkopp, SL George, C Kopajtic, T Izenwasser, S Katz, JL AF Newman, AH Robarge, MJ Howard, IM Wittkopp, SL George, C Kopajtic, T Izenwasser, S Katz, JL TI Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3 alpha-(3 '-chloro-, 4 '-chloro-, and 4 ', 4 ''-dichloro-substituted-diphenyl)methoxytropanes SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DOPAMINE UPTAKE INHIBITORS; 3-ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS; ADDICTIVE DRUGS; COCAINE ABUSE; BINDING; LIGANDS; REWARD; POTENT AB The design, synthesis, and evaluation of 3 alpha-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues in animal models of cocaine abuse has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the benztropine analogues do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus, and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporters as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl, and butylphenyl) analogues of 3'-chloro-, 4'-chloro-, and 4,4"-dichloro-3 alpha-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [H-3]WIN 35,428 from the dopamine transporter, [H-3]citalopram from the serotonin transporter, [H-3]nisoxetine from the norepinephrine transporter, and [H-3]-pirenzepine from muscarinic mi receptors. SARs were developed and compared to a series of N-substituted-3 alpha-(bis-4'-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4',4 " -difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3 alpha-(bis-4'-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of binding profile that might be targeted as a potential treatment for cocaine abuse. C1 NIDA, IRP, Med Chem Sect, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Psychobiol Sect, Baltimore, MD 21224 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Newman, AH (reprint author), NIDA, IRP, Med Chem Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Izenwasser, Sari/G-9193-2012 FU NIDA NIH HHS [DA09045] NR 24 TC 22 Z9 22 U1 1 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 FEB 15 PY 2001 VL 44 IS 4 BP 633 EP 640 DI 10.1021/jm000417f PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 400GP UT WOS:000166864100016 PM 11170654 ER PT J AU Teubner, B Odermatt, B Guldenagel, M Sohl, G Degen, J Bukauskas, FF Kronengold, J Verselis, VK Jung, YT Kozak, CA Schilling, K Willecke, K AF Teubner, B Odermatt, B Guldenagel, M Sohl, G Degen, J Bukauskas, FF Kronengold, J Verselis, VK Jung, YT Kozak, CA Schilling, K Willecke, K TI Functional expression of the new gap junction gene connexin47 transcribed in mouse brain and spinal cord neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Cx47; gap junctions; neuronal connexin; electrical synapses; voltage gating; permeability ID DIFFERENTIAL EXPRESSION; VOLTAGE-DEPENDENCE; MOLECULAR-CLONING; CHANNELS; PROTEINS; CELLS; OSCILLATIONS; CONDUCTANCE; NEOCORTEX; SYNAPSES AB A new mouse gap junction gene that codes for a protein of 46,551 Da has been identified and designated connexin47 (Cx47). It mapped as a single-copy gene to mouse chromosome 11. In human HeLa cells and Xenopus oocytes, expression of mouse Cx47 or a fusion protein of Cx47 and enhanced green fluorescent protein induced intercellular channels that displayed strong sensitivity to transjunctional voltage. Tracer injections in Cx47-transfected HeLa cells revealed intercellular diffusion of neurobiotin, Lucifer yellow, and 4',6-diamidino-2-phenylindole. Recordings of single channels yielded a unitary conductance of 55 pS main state and 8 pS substate. Cx47 mRNA expression was high in spinal cord and brain but was not found in retina, liver, heart, and lung. A low level of Cx47 expression was detected in ovaries. In situ hybridizations demonstrated high expression in a motor neurons of the spinal cord, pyramidal cells of the cortex and hippocampus, granular and molecular layers of the dentate gyrus, and Purkinje cells of the cerebellum as well as several nuclei of the brainstem. This expression pattern is distinct from, although partially overlapping with, that of the neuronally expressed connexin36 gene. Thus, electrical synapses in adult mammalian brain are likely to consist of different connexin proteins depending on the neuronal subtype. C1 Univ Bonn, Inst Genet, Abt Mol Genet, D-53117 Bonn, Germany. Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Bonn, Inst Anat, D-53115 Bonn, Germany. RP Willecke, K (reprint author), Univ Bonn, Inst Genet, Abt Mol Genet, Romerstr 164, D-53117 Bonn, Germany. FU NIGMS NIH HHS [R01 GM054179]; NINDS NIH HHS [R01 NS036706, NS07512, NS367060] NR 52 TC 91 Z9 97 U1 0 U2 0 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 FEB 15 PY 2001 VL 21 IS 4 BP 1117 EP 1126 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 399NR UT WOS:000166819700008 PM 11160382 ER PT J AU Ghiani, CA Gallo, V AF Ghiani, CA Gallo, V TI Inhibition of cyclin E-cyclin-dependent kinase 2 complex formation and activity is associated with cell cycle arrest and withdrawal in oligodendrocyte progenitor cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glia; development; cell proliferation; G(1) phase; cyclin D; cyclin-dependent kinase 4 ID POSTNATAL RAT FOREBRAIN; SUBVENTRICULAR ZONE; MAMMALIAN-CELLS; NERVOUS-SYSTEM; CDK INHIBITORS; DIFFERENTIATION; P27(KIP1); PROGRESSION; PHASE; ACCUMULATION AB Stimulatory and inhibitory signals regulate cell proliferation through the activity of specific enzymes that operate in distinct phases of the cell cycle. We have studied cell cycle progression, arrest, and withdrawal in the oligodendrocyte progenitor (OP) cell model system, focusing on the G(1) phase and G(1)-S transition. Not only were proliferating OPs found to display higher protein levels of cyclin E and D and cyclin-dependent kinases (cdk) 2, 4, and 6 than cells that had permanently withdrawn from the cycle, but the kinase activities of both cyclin D-cdk4/6 and cyclin E-cdk2 were also higher in dividing OPs. This was associated with a decrease in the formation of the cyclin E-cdk2 and cyclin D-cdk4/cyclin D-cdk6 complexes in differentiated oligodendrocytes that had permanently withdrawn from the cell cycle. Reversible cell cycle arrest in G1 induced by glutamatergic and beta -adrenergic receptor activation or cell depolarization, however, did not modify cyclin E and cdk2 protein expression compared with proliferating OPs. Instead, these agents caused a selective decrease in cdk2 activity and an impairment of cyclin E-cdk2 complex formation. Although cyclin D protein levels were higher than in proliferating cells, cyclin D-associated kinase activity was not modified in G(1)-arrested OPs. Analysis in corpus callosum in vivo showed that cyclin E-cdk2 activity increased between postnatal days 3 and 15 and decreased between postnatal days 15 and 30. Our results indicate that the cyclin E-cdk2 complex is a major regulator of OP cell cycle progression and that the cdks involved in reversible cell cycle arrest are distinct from those implicated in permanent cell cycle withdrawal. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bldg 49,Room 5A-78, Bethesda, MD 20892 USA. OI Ghiani, Cristina/0000-0002-9867-6185 NR 53 TC 49 Z9 51 U1 1 U2 1 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 FEB 15 PY 2001 VL 21 IS 4 BP 1274 EP 1282 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 399NR UT WOS:000166819700024 PM 11160398 ER PT J AU Shalev, U Yap, J Shaham, Y AF Shalev, U Yap, J Shaham, Y TI Leptin attenuates acute food deprivation-induced relapse to heroin seeking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE extinction; food deprivation; heroin self-administration; leptin; reinstatement; relapse; stress ID SELF-ADMINISTRATION BEHAVIOR; DRUG-ABUSE; STRESS; RATS; REINSTATEMENT; MORPHINE; WEIGHT; NOREPINEPHRINE; INJECTIONS; DISORDERS AB Studies in rats have shown that intermittent footshock stress reinstates drug seeking after prolonged drug-free periods. Recently, we found that another environmental stressor, acute 1 d food deprivation, potently reinstates heroin seeking in rats. Here we report that this effect of food deprivation can be blocked by leptin, a hormone involved in the regulation of energy balance and food intake. Rats were trained to self-administer heroin (0.05-0.1 mg/kg, i.v., per infusion, three 3 hr sessions per day) for 8-10 d. The heroin-reinforced behavior was then extinguished for 10-13 d, during which lever presses had no reinforced consequences. Subsequently, rats were tested for reinstatement after 1 d of food deprivation (experiment 1) or exposure to intermittent footshock (15 min, 0.6 mA) and heroin priming injections (0.25 mg/kg, s.c.) (experiment 2). Acute food deprivation reinstated heroin seeking, an effect that was attenuated by leptin (2 or 4 mug/rat, i.c.v.; two infusions, given 21 hr and 20-30 min before the start of the test sessions). In contrast, leptin had no effect on reinstatement of heroin seeking induced by intermittent footshock or priming injections of heroin. These data indicate that food deprivation can provoke relapse to heroin seeking via a leptin-dependent mechanism, which is not involved in relapse induced by footshock stress or reexposure to heroin. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI shaham, yavin/G-1306-2014 NR 45 TC 104 Z9 105 U1 1 U2 1 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 FEB 15 PY 2001 VL 21 IS 4 AR RC129 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 399NR UT WOS:000166819700001 PM 11160414 ER PT J AU Li, YM Qu, Y Vandenbussche, E Arckens, L Vandesande, F AF Li, YM Qu, Y Vandenbussche, E Arckens, L Vandesande, F TI Analysis of extracellular gamma-aminobutyric acid, glutamate and aspartate in cat visual cortex by in vivo microdialysis and capillary electrophoresis-laser induced fluorescence detection SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE capillary electrophoresis; microdialysis; gamma-aminobutyric acid; glutamate; aspartate ID MICROBORE LIQUID-CHROMATOGRAPHY; AMINO-ACIDS; ELECTROCHEMICAL DETECTION; NEUROTRANSMITTERS; BRAIN; SEPARATION; RECEPTORS; PATHWAYS; RAT AB To investigate the influence of a partial sensory deprivation on the extracellular concentration of amino acid neurotransmitters in cat visual cortex, a capillary electrophoresis method was developed for the quantification of gamma -aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) in in vivo microdialysis samples of cat brain. Microdialysis samples from different regions of area 17 were obtained every 15-min using CMA 12 2-mm probes perfused with synthetic cerebrospinal fluid and derivatized using fluorescein isothiocyanate (FITC). Laser-induced fluorescence (LIF) detection was employed. Good selectivity was obtained with a berate buffer (20 mM, pH 10.25). The whole procedure, including the washing step takes only 15 min. The conditions fur derivatization and separation were optimized. The parameters for validation such as linearity, precision and detection limit are also reported. The results are consistent with those of HPLC but, as the sample volumes needed are only 1-5 nl, a much better time resolution can be obtained. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Katholieke Univ Leuven, Inst Zool, Lab Neuroendocrinol & Immunol Biotechnol, Louvain, Belgium. Katholieke Univ Leuven, Sch Med, Neuropsychol Lab, Louvain, Belgium. RP Qu, Y (reprint author), NIA, Sect Brain Physiol & Metab, NIH, Bldg 10,Rm 6N202, Bethesda, MD 20892 USA. RI Arckens, Lutgarde/C-3822-2016 NR 19 TC 29 Z9 29 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD FEB 15 PY 2001 VL 105 IS 2 BP 211 EP 215 DI 10.1016/S0165-0270(00)00371-X PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 413WB UT WOS:000167633600011 PM 11275278 ER PT J AU Lanuza, MA Garcia, N Santafe, M Nelson, PG Fenoll-Brunet, MR Tomas, J AF Lanuza, MA Garcia, N Santafe, M Nelson, PG Fenoll-Brunet, MR Tomas, J TI Pertussis toxin-sensitive G-protein and protein kinase C activity are involved in normal synapse elimination in the neonatal rat muscle SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE neuromuscular junction; postnatal development; synaptogenesis; polyneuronal innervation; thrombin; confocal microscope ID GENE-RELATED PEPTIDE; SKELETAL-MUSCLE; POLYNEURONAL INNERVATION; THROMBIN-RECEPTOR; NEUROMUSCULAR-JUNCTION; CALCITONIN-GENE; ACETYLCHOLINE-RECEPTORS; PHORBOL ESTER; POSTNATAL-DEVELOPMENT; AXON WITHDRAWAL AB Individual skeletal muscle fibers in most new-born rodents are innervated at a single endplate by several motor axons. During the first postnatal weeks, the poly neuronal innervation decreases in a process of synaptic elimination. Previous studies showed that the naturally occurring serine-protease thrombin mediates the activity-dependent synapse reduction at the neuromuscular junction (NMJ) in vitro and that thrombin-receptor activation may modulate nerve terminal consolidation through a protein kinase mechanism. To test whether these mechanisms may be operating in vivo, we applied external thrombin and its inhibitor hirudin, and several substances affecting the G protein-protein kinase C system (GP-PKC) directly over the external surface of the neonatal rat Levator auris longus muscle. Muscles were processed for immunocytochemistry to simultaneously detect acetylcholine receptors (AChRs) and axons for counting the percentage of polyinnervated NMJ, We found that exogenous thrombin accelerated synapse loss and hirudin blocked axonal removal. Phorbol-12-myristate-13-acetate, a potent PKC activator, had a similar effect as thrombin, whereas the PKC inhibitors, calphostin C and staurosporine, prevented axonal removal. Pertussis toxin, an effective blocker of GP function, blocked synapse elimination. These findings suggest that the normal synapse elimination in the neonatal rat muscle may be modulated, at least in part, by the pertussis-sensitive G-protein and PKC activity and that thrombin could play a role in the postnatal synaptic maturation in vivo. (C) 2001 Wiley-Liss, Inc. C1 Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, Tarragona 43201, Spain. NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD USA. RP Lanuza, MA (reprint author), Univ Rovira & Virgili, Fac Med & Ciencies Salut, Unitat Histol & Neurobiol, Sant Llorenc 21, Tarragona 43201, Spain. OI Santafe, Manel/0000-0002-5462-5108 NR 67 TC 37 Z9 38 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 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 15 PY 2001 VL 63 IS 4 BP 330 EP 340 DI 10.1002/1097-4547(20010215)63:4<330::AID-JNR1027>3.0.CO;2-W PG 11 WC Neurosciences SC Neurosciences & Neurology GA 398EQ UT WOS:000166744300004 PM 11170183 ER PT J AU Wolfsberg, TG McEntyre, J Schuler, GD AF Wolfsberg, TG McEntyre, J Schuler, GD TI Guide to the draft human genome SO NATURE LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISMS; SEQUENCE; GENE; DATABASE; LOCUSLINK; PROTEINS; REFSEQ; MAP AB There are a number of ways to investigate the structure, function and evolution of the human genome. These include examining the morphology of normal and abnormal chromosomes, constructing maps of genomic landmarks, following the genetic transmission of phenotypes and DNA sequence variations, and characterizing thousands of individual genes. To this list we can now add the elucidation of the genomic DNA sequence, albeit at 'working draft' accuracy. The current challenge is to weave together these disparate types of data to produce the information infrastructure needed to support the next generation of biomedical research. Here we provide an overview of the different sources of information about the human genome and how modern information technology, in particular the internet, allows us to link them together. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Schuler, GD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM schuler@ncbi.nim.nih.gov NR 25 TC 31 Z9 37 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 824 EP 826 DI 10.1038/35057000 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800045 PM 11236998 ER PT J AU Nestler, EJ Landsman, D AF Nestler, EJ Landsman, D TI Learning about addiction from the genome SO NATURE LA English DT Article ID MU-OPIOID RECEPTOR; PROTEINS; NEUROSCIENCE; SENSITIVITY; PROGRESS; GENES AB Drug addiction can be defined as the compulsive seeking and taking of a drug despite adverse consequences. Although addiction involves many psychological and social factors, it also represents a biological process: the effects of repeated drug exposure on a vulnerable brain. The sequencing of the human and other mammalian genomes will help us to understand the biology of addiction by enabling us to identify both genes that contribute to individual risk for addiction and those through which drugs cause addiction. We illustrate this potential impact by searching a draft sequence of the human genome for genes related to desensitization of receptors that mediate the actions of drugs of abuse on the nervous system. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20892 USA. RP Nestler, EJ (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. RI Landsman, David/C-5923-2009; OI Landsman, David/0000-0002-9819-6675 NR 15 TC 52 Z9 55 U1 1 U2 5 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 834 EP 835 DI 10.1038/35057015 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800049 PM 11237002 ER PT J AU Lander, ES Int Human Genome Sequencing Consortium Linton, LM Birren, B Nusbaum, C Zody, MC Baldwin, J Devon, K Dewar, K Doyle, M FitzHugh, W Funke, R Gage, D Harris, K Heaford, A Howland, J Kann, L Lehoczky, J LeVine, R McEwan, P McKernan, K Meldrim, J Mesirov, JP Miranda, C Morris, W Naylor, J Raymond, C Rosetti, M Santos, R Sheridan, A Sougnez, C Stange-Thomann, N Stojanovic, N Subramanian, A Wyman, D Rogers, J Sulston, J Ainscough, R Beck, S Bentley, D Burton, J Clee, C Carter, N Coulson, A Deadman, R Deloukas, P Dunham, A Dunham, I Durbin, R French, L Grafham, D Gregory, S Hubbard, T Humphray, S Hunt, A Jones, M Lloyd, C McMurray, A Matthews, L Mercer, S Milne, S Mullikin, JC Mungall, A Plumb, R Ross, M Shownkeen, R Sims, S Waterston, RH Wilson, RK Hillier, LW McPherson, JD Marra, MA Mardis, ER Fulton, LA Chinwalla, AT Pepin, KH Gish, WR Chissoe, SL Wendl, MC Delehaunty, KD Miner, TL Delehaunty, A Kramer, JB Cook, LL Fulton, RS Johnson, DL Minx, PJ Clifton, SW Hawkins, T Branscomb, E Predki, P Richardson, P Wenning, S Slezak, T Doggett, N Cheng, JF Olsen, A Lucas, S Elkin, C Uberbacher, E Frazier, M Gibbs, RA Muzny, DM Scherer, SE Bouck, JB Sodergren, EJ Worley, KC Rives, CM Gorrell, JH Metzker, ML Naylor, SL Kucherlapati, RS Nelson, DL Weinstock, GM Sakaki, Y Fujiyama, A Hattori, M Yada, T Toyoda, A Itoh, T Kawagoe, C Watanabe, H Totoki, Y Taylor, T Weissenbach, J Heilig, R Saurin, W Artiguenave, F Brottier, P Bruls, T Pelletier, E Robert, C Wincker, P Rosenthal, A Platzer, M Nyakatura, G Taudien, S Rump, A Yang, HM Yu, J Wang, J Huang, GY Gu, J Hood, L Rowen, L Madan, A Qin, SZ Davis, RW Federspiel, NA Abola, AP Proctor, MJ Myers, RM Schmutz, J Dickson, M Grimwood, J Cox, DR Olson, MV Kaul, R Raymond, C Shimizu, N Kawasaki, K Minoshima, S Evans, GA Athanasiou, M Schultz, R Roe, BA Chen, F Pan, HQ Ramser, J Lehrach, H Reinhardt, R McCombie, WR de la Bastide, M Dedhia, N Blocker, H Hornischer, K Nordsiek, G Agarwala, R Aravind, L Bailey, JA Bateman, A Batzoglou, S Birney, E Bork, P Brown, DG Burge, CB Cerutti, L Chen, HC Church, D Clamp, M Copley, RR Doerks, T Eddy, SR Eichler, EE Furey, TS Galagan, J Gilbert, JGR Harmon, C Hayashizaki, Y Haussler, D Hermjakob, H Hokamp, K Jang, WH Johnson, LS Jones, TA Kasif, S Kaspryzk, A Kennedy, S Kent, WJ Kitts, P Koonin, EV Korf, I Kulp, D Lancet, D Lowe, TM McLysaght, A Mikkelsen, T Moran, JV Mulder, N Pollara, VJ Ponting, CP Schuler, G Schultz, JR Slater, G Smit, AFA Stupka, E Szustakowki, J Thierry-Mieg, D Thierry-Mieg, J Wagner, L Wallis, J Wheeler, R Williams, A Wolf, YI Wolfe, KH Yang, SP Yeh, RF Collins, F Guyer, MS Peterson, J Felsenfeld, A Wetterstrand, KA Patrinos, A Morgan, MJ AF Lander, ES Int Human Genome Sequencing Consortium Linton, LM Birren, B Nusbaum, C Zody, MC Baldwin, J Devon, K Dewar, K Doyle, M FitzHugh, W Funke, R Gage, D Harris, K Heaford, A Howland, J Kann, L Lehoczky, J LeVine, R McEwan, P McKernan, K Meldrim, J Mesirov, JP Miranda, C Morris, W Naylor, J Raymond, C Rosetti, M Santos, R Sheridan, A Sougnez, C Stange-Thomann, N Stojanovic, N Subramanian, A Wyman, D Rogers, J Sulston, J Ainscough, R Beck, S Bentley, D Burton, J Clee, C Carter, N Coulson, A Deadman, R Deloukas, P Dunham, A Dunham, I Durbin, R French, L Grafham, D Gregory, S Hubbard, T Humphray, S Hunt, A Jones, M Lloyd, C McMurray, A Matthews, L Mercer, S Milne, S Mullikin, JC Mungall, A Plumb, R Ross, M Shownkeen, R Sims, S Waterston, RH Wilson, RK Hillier, LW McPherson, JD Marra, MA Mardis, ER Fulton, LA Chinwalla, AT Pepin, KH Gish, WR Chissoe, SL Wendl, MC Delehaunty, KD Miner, TL Delehaunty, A Kramer, JB Cook, LL Fulton, RS Johnson, DL Minx, PJ Clifton, SW Hawkins, T Branscomb, E Predki, P Richardson, P Wenning, S Slezak, T Doggett, N Cheng, JF Olsen, A Lucas, S Elkin, C Uberbacher, E Frazier, M Gibbs, RA Muzny, DM Scherer, SE Bouck, JB Sodergren, EJ Worley, KC Rives, CM Gorrell, JH Metzker, ML Naylor, SL Kucherlapati, RS Nelson, DL Weinstock, GM Sakaki, Y Fujiyama, A Hattori, M Yada, T Toyoda, A Itoh, T Kawagoe, C Watanabe, H Totoki, Y Taylor, T Weissenbach, J Heilig, R Saurin, W Artiguenave, F Brottier, P Bruls, T Pelletier, E Robert, C Wincker, P Rosenthal, A Platzer, M Nyakatura, G Taudien, S Rump, A Yang, HM Yu, J Wang, J Huang, GY Gu, J Hood, L Rowen, L Madan, A Qin, SZ Davis, RW Federspiel, NA Abola, AP Proctor, MJ Myers, RM Schmutz, J Dickson, M Grimwood, J Cox, DR Olson, MV Kaul, R Raymond, C Shimizu, N Kawasaki, K Minoshima, S Evans, GA Athanasiou, M Schultz, R Roe, BA Chen, F Pan, HQ Ramser, J Lehrach, H Reinhardt, R McCombie, WR de la Bastide, M Dedhia, N Blocker, H Hornischer, K Nordsiek, G Agarwala, R Aravind, L Bailey, JA Bateman, A Batzoglou, S Birney, E Bork, P Brown, DG Burge, CB Cerutti, L Chen, HC Church, D Clamp, M Copley, RR Doerks, T Eddy, SR Eichler, EE Furey, TS Galagan, J Gilbert, JGR Harmon, C Hayashizaki, Y Haussler, D Hermjakob, H Hokamp, K Jang, WH Johnson, LS Jones, TA Kasif, S Kaspryzk, A Kennedy, S Kent, WJ Kitts, P Koonin, EV Korf, I Kulp, D Lancet, D Lowe, TM McLysaght, A Mikkelsen, T Moran, JV Mulder, N Pollara, VJ Ponting, CP Schuler, G Schultz, JR Slater, G Smit, AFA Stupka, E Szustakowki, J Thierry-Mieg, D Thierry-Mieg, J Wagner, L Wallis, J Wheeler, R Williams, A Wolf, YI Wolfe, KH Yang, SP Yeh, RF Collins, F Guyer, MS Peterson, J Felsenfeld, A Wetterstrand, KA Patrinos, A Morgan, MJ CA Int Human Genome Sequencing Conso TI Initial sequencing and analysis of the human genome SO NATURE LA English DT Review ID GENETIC-LINKAGE MAP; SINGLE-NUCLEOTIDE POLYMORPHISMS; OLFACTORY RECEPTOR GENES; HIGH-FREQUENCY RETROTRANSPOSITION; ARTIFICIAL CHROMOSOME LIBRARIES; FAMILIAL ALZHEIMERS-DISEASE; WILLIAMS-BEUREN-SYNDROME; IN-SITU HYBRIDIZATION; DNA REGULATORY MOTIFS; RIBOSOMAL-RNA GENES AB The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence. C1 Whitehead Inst Biomed Res, Ctr Genome Res, Cambridge, MA 02142 USA. Sanger Ctr, Hinxton CB10 1RQ, Cambs, England. Washington Univ, Genome Sequencing Ctr, St Louis, MO 63108 USA. US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA. Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Univ Texas, Sch Med, Dept Microbiol & Mol Genet, Houston, TX 77225 USA. RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. Genoscope, F-91057 Evry, France. CNRS, UMR 8030, F-91057 Evry, France. Genome Therapeut Corp, GTC Sequencing Ctr, Waltham, MA 02453 USA. Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany. Chinese Acad Sci, Inst Genet, Ctr Human Genome, Beijing Genom Inst, Beijing 100101, Peoples R China. So China Natl Human Genome Res Ctr, Shanghai 201203, Peoples R China. No China Natl Human Genome Res Ctr, Beijing 100176, Peoples R China. Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA. Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Stanford Human Genome Ctrr, Sch Med, Stanford, CA 94305 USA. Univ Washington, Genome Ctr, Seattle, WA 98195 USA. Keio Univ, Sch Med, Dept Biol Mol, Shinjuku Ku, Tokyo 1608582, Japan. Univ Texas, SW Med Ctr, Dallas, TX 75235 USA. Univ Oklahoma, Adv Ctr Genome Technol, Dept Chem & Biochem, Norman, OK 73019 USA. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. Cold Spring Harbor Lab, Lita Annenberg Hazen Genome Ctr, Cold Spring Harbor, NY 11724 USA. GBF, German Res Ctr Biotechnol, D-38124 Braunschweig, Germany. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. EMBL, European Bioinformat Inst, Cambridge CB10 1SD, England. Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. MIT, Dept Biol, Cambridge, MA 02139 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA. Affymetrix Inc, Berkeley, CA 94710 USA. RIKEN, Yokoham Inst, Genom Sci Ctr, Genom Explorat Res Grp,Tsurumi Ku, Kanagawa 2300045, Japan. Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. Univ Dublin Trinity Coll, Dept Genet, Smurfit Inst, Dublin 2, Ireland. Compaq Comp Corp, Cambridge Res Lab, Cambridge, MA 02142 USA. MIT, Genome Ctr, Cambridge, MA 02142 USA. Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. Weizmann Inst Sci, Crown Human Genet Ctr, IL-71600 Rehovot, Israel. Weizmann Inst Sci, Dept Mol Genet, IL-71600 Rehovot, Israel. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, Oxford OX1 3QX, England. Inst Syst Biol, Seattle, WA 98105 USA. NHGRI, NIH, Bethesda, MD 20892 USA. US DOE, Off Sci, Germantown, MD 20874 USA. Wellcome Trust Res Labs, London NW1 2BE, England. RP Whitehead Inst Biomed Res, Ctr Genome Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM lander@genome.wi.mit.edu; jes@sanger.ac.uk; bwaterst@watson.wustl.edu; fc23a@nih.gov RI Stupka, Elia/J-6279-2012; Deloukas, Panos/B-2922-2013; Bork, Peer/F-1813-2013; Tang, Macy/B-9798-2014; Itoh, Takehiko/E-8873-2014; Smith, Andy/A-7512-2011; Duan, Yanwu/A-5786-2015; Marra, Marco/B-5987-2008; Hattori, Masahira/C-6958-2016; Wang, Jun/C-8434-2016; THIERRY-MIEG, Jean/F-1975-2017; Wang, Jun/B-9503-2016; Santoyo-Lopez, Javier/C-9714-2012; Mikkelsen, Tarjei/A-1306-2007; Wendl, Michael/A-2741-2008; Schultz, Joerg/B-9346-2008; Hubbard, Tim/C-2567-2008; Taylor, Todd/A-7121-2009; Wolfe, Kenneth/B-4653-2009; Hokamp, Karsten/C-5534-2009; Li, Wei/A-8544-2009; Li, Shuangding/C-1455-2011; Bateman, Alex/E-6518-2011; Glockner, Gernot/A-7800-2010; Gish, Warren/C-8123-2012; 郑, 征/C-8514-2011 OI Qureshi, Matloob/0000-0003-2208-4236; Birney, Ewan/0000-0001-8314-8497; Martin, Sancha/0000-0001-6213-5259; Hermjakob, Henning/0000-0001-8479-0262; Ponting, Chris/0000-0003-0202-7816; Wolfe, Kenneth/0000-0003-4992-4979; Glusman, Gustavo/0000-0001-8060-5955; Eddy, Sean/0000-0001-6676-4706; McLysaght, Aoife/0000-0003-2552-6220; Schultz, Brian/0000-0003-4964-976X; Deloukas, Panos/0000-0001-9251-070X; Bork, Peer/0000-0002-2627-833X; Smith, Andy/0000-0001-8580-278X; Duan, Yanwu/0000-0002-6000-0534; Hattori, Masahira/0000-0001-9467-0344; Wang, Jun/0000-0002-8540-8931; THIERRY-MIEG, Jean/0000-0002-0396-6789; Gilbert, James/0000-0001-8079-3159; McKernan, Kevin/0000-0002-3908-1122; Baum, Dana/0000-0002-2777-1708; Galagan, James/0000-0003-0542-3291; Furey, Terry/0000-0001-5546-9672; Durbin, Richard/0000-0002-9130-1006; Stupka, Elia/0000-0003-3154-4011; Hunt, Adrienne/0000-0002-1227-0310; Dunham, Ian/0000-0003-2525-5598; Wang, Jun/0000-0002-2113-5874; Bateman, Alex/0000-0002-6982-4660; McCombie, W. Richard/0000-0003-1899-0682; Rump, Andreas/0000-0001-7116-6364; Santoyo-Lopez, Javier/0000-0003-1988-5059; Mikkelsen, Tarjei/0000-0002-8133-3135; Hubbard, Tim/0000-0002-1767-9318; Taylor, Todd/0000-0003-4247-6253; Glockner, Gernot/0000-0002-9061-1061; FU NHGRI NIH HHS [U54 HG003273] NR 449 TC 12305 Z9 12860 U1 253 U2 1977 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 860 EP 921 DI 10.1038/35057062 PG 62 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800058 PM 11237011 ER PT J AU McPherson, JD Marra, M Hillier, L Waterston, RH Chinwalla, A Wallis, J Sekhon, M Wylie, K Mardis, ER Wilson, RK Fulton, R Kucaba, TA Wagner-McPherson, C Barbazuk, WB Gregory, SG Humphray, SJ French, L Evans, RS Bethel, G Whittaker, A Holden, JL McCann, OT Dunham, A Soderlund, C Scott, CE Bentley, DR Schuler, G Chen, HC Jang, WH Green, ED Idol, JR Maduro, VVB Montgomery, KT Lee, E Miller, A Emerling, S Kucherlapati, R Gibbs, R Scherer, S Gorrell, JH Sodergren, E Clerc-Blankenburg, K Tabor, P Naylor, S Garcia, D de Jong, PJ Catanese, JJ Nowak, N Osoegawa, K Qin, SZ Rowen, L Madan, A Dors, M Hood, L Trask, B Friedman, C Massa, H Cheung, VG Kirsch, IR Reid, T Yonescu, R Weissenbach, J Bruls, T Heilig, R Branscomb, E Olsen, A Doggett, N Cheng, JF Hawkins, T Myers, RM Shang, J Ramirez, L Schmutz, J Velasquez, O Dixon, K Stone, NE Cox, DR Haussler, D Kent, WJ Furey, T Rogic, S Kennedy, S Jones, S Rosenthal, A Wen, GP Schilhabel, M Gloeckner, G Nyakatura, G Siebert, R Schlegelberger, B Korenburg, J Chen, XN Fujiyama, A Hattori, M Toyoda, A Yada, T Park, HS Sakaki, Y Shimizu, N Asakawa, S Kawasaki, K Sasaki, T Shintani, A Shimizu, A Shibuya, K Kudoh, J Minoshima, S Ramser, J Seranski, P Hoff, C Poustka, A Reinhardt, R Lehrach, H AF McPherson, JD Marra, M Hillier, L Waterston, RH Chinwalla, A Wallis, J Sekhon, M Wylie, K Mardis, ER Wilson, RK Fulton, R Kucaba, TA Wagner-McPherson, C Barbazuk, WB Gregory, SG Humphray, SJ French, L Evans, RS Bethel, G Whittaker, A Holden, JL McCann, OT Dunham, A Soderlund, C Scott, CE Bentley, DR Schuler, G Chen, HC Jang, WH Green, ED Idol, JR Maduro, VVB Montgomery, KT Lee, E Miller, A Emerling, S Kucherlapati, R Gibbs, R Scherer, S Gorrell, JH Sodergren, E Clerc-Blankenburg, K Tabor, P Naylor, S Garcia, D de Jong, PJ Catanese, JJ Nowak, N Osoegawa, K Qin, SZ Rowen, L Madan, A Dors, M Hood, L Trask, B Friedman, C Massa, H Cheung, VG Kirsch, IR Reid, T Yonescu, R Weissenbach, J Bruls, T Heilig, R Branscomb, E Olsen, A Doggett, N Cheng, JF Hawkins, T Myers, RM Shang, J Ramirez, L Schmutz, J Velasquez, O Dixon, K Stone, NE Cox, DR Haussler, D Kent, WJ Furey, T Rogic, S Kennedy, S Jones, S Rosenthal, A Wen, GP Schilhabel, M Gloeckner, G Nyakatura, G Siebert, R Schlegelberger, B Korenburg, J Chen, XN Fujiyama, A Hattori, M Toyoda, A Yada, T Park, HS Sakaki, Y Shimizu, N Asakawa, S Kawasaki, K Sasaki, T Shintani, A Shimizu, A Shibuya, K Kudoh, J Minoshima, S Ramser, J Seranski, P Hoff, C Poustka, A Reinhardt, R Lehrach, H CA Int Human Genome Mapping Consortiu TI A physical map of the human genome SO NATURE LA English DT Article ID DROSOPHILA-MELANOGASTER; DNA-SEQUENCE; CHROMOSOME; HYBRIDIZATION; FRAGMENTS; SHOTGUN; CONTIGS; VECTOR; CLONES; GENES AB The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map. C1 Washington Univ, Sch Med, Genome Sequencing Ctr, Dept Genet, St Louis, MO 63108 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Inst Syst Biol, Multimegabase Sequencing Ctr, Seattle, WA 98105 USA. Fred Hutchinson Canc Res Inst, Div Human Biol, Seattle, WA 98109 USA. Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. NCI, Dept Genet, Med Branch, Washington, DC USA. Genoscope, Ctr Natl Sequencage, F-91057 Evry, France. US DOE, Joint Genome Inst, Walnut Creek, CA USA. Stanford Univ, Stanford Human Genome Ctr, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Dept Math, Santa Cruz, CA 95064 USA. British Columbia Canc Res Ctr, Vancouver, BC V5Z 4E6, Canada. Inst Mol Biotechnol, Dept Genome Anal, D-07745 Jena, Germany. Univ Kiel, Inst Human Genet, D-24098 Kiel, Germany. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. Keio Univ, Sch Med, Dept Mol Biol, Shinjuku Ku, Tokyo 1608582, Japan. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. Deutsch Krebsforschungszentrum, Abt Mol Genomanal, D-69120 Heidelberg, Germany. RP McPherson, JD (reprint author), Washington Univ, Sch Med, Genome Sequencing Ctr, Dept Genet, 4444 Forest Pk Blvd, St Louis, MO 63108 USA. EM jmcphers@watson.wustl.edu RI Siebert, Reiner/A-8049-2010; Glockner, Gernot/A-7800-2010; Tang, Macy/B-9798-2014; Marra, Marco/B-5987-2008; Hattori, Masahira/C-6958-2016; Jones, Steven/C-3621-2009 OI Glockner, Gernot/0000-0002-9061-1061; Hattori, Masahira/0000-0001-9467-0344; NR 46 TC 541 Z9 565 U1 3 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 934 EP 941 DI 10.1038/35057157 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800061 PM 11237014 ER PT J AU Montgomery, KT Lee, E Miller, A Lau, S Shim, C Decker, J Chiu, D Emerling, S Sekhon, M Kim, R Lenz, J Han, JH Ioshikhes, I Renault, B Marondel, I Yoon, SJK Song, K Murty, VVVS Scherer, S Yonescu, R Kirsch, IR Ried, T McPherson, J Gibbs, R Kucherlapati, R AF Montgomery, KT Lee, E Miller, A Lau, S Shim, C Decker, J Chiu, D Emerling, S Sekhon, M Kim, R Lenz, J Han, JH Ioshikhes, I Renault, B Marondel, I Yoon, SJK Song, K Murty, VVVS Scherer, S Yonescu, R Kirsch, IR Ried, T McPherson, J Gibbs, R Kucherlapati, R TI A high-resolution map of human chromosome 12 SO NATURE LA English DT Article ID PHYSICAL MAP; HUMAN GENOME; SEQUENCE AB Our sequence-tagged site-content map of chromosome 12 is now integrated with the whole-genome fingerprinting effort(1,2). It provides accurate and nearly complete bacterial clone coverage of chromosome 12. We propose that this integrated mapping protocol serves as a model for constructing physical maps for entire genomes. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. Catholic Univ, Coll Med, Res Inst Med Sci, Seoul 137404, South Korea. Univ Ulsan, Coll Med, Seoul 138736, South Korea. Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. NCI, Dept Genet, Med Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA. RP Kucherlapati, R (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Mol Genet, 1300 Morris Pk Ave, Bronx, NY 10461 USA. NR 14 TC 18 Z9 18 U1 0 U2 3 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 945 EP 946 DI 10.1038/35057174 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800064 PM 11237017 ER PT J AU Yu, A Zhao, CF Fan, Y Jang, WH Mungall, AJ Deloukas, P Olsen, A Doggett, NA Ghebranious, N Broman, KW Weber, JL AF Yu, A Zhao, CF Fan, Y Jang, WH Mungall, AJ Deloukas, P Olsen, A Doggett, NA Ghebranious, N Broman, KW Weber, JL TI Comparison of human genetic and sequence-based physical maps SO NATURE LA English DT Article ID HIGH-RESOLUTION ANALYSIS; HUMAN-CHROMOSOME 22; HUMAN GENOME; MEIOTIC RECOMBINATION; DNA-SEQUENCE; INTEGRATION; CROSSOVER; REPEATS; REGION AB Recombination is the exchange of information between two homologous chromosomes during meiosis. The rate of recombination per nucleotide, which profoundly affects the evolution of chromosomal segments, is calculated by comparing genetic and physical maps. Human physical maps have been constructed using cytogenetics(1), overlapping DNA clones(2) and radiation hybrids(3); but the ultimate and by far the most accurate physical map is the actual nucleotide sequence. The completion of the draft human genomic sequence(4) provides us with the best opportunity yet to compare the genetic and physical maps. Here we describe our estimates of female, male and sex-average recombination rates for about 60% of the genome. Recombination rates varied greatly along each chromosome, from 0 to at least 9 centiMorgans per megabase (cM Mb(-1)). Among several sequence and marker parameters tested, only relative marker position along the metacentric chromosomes in males correlated strongly with recombination rate. We identified several chromosomal regions up to 6 Mb in length with particularly low (deserts) or high (jungles) recombination rates. Linkage disequilibrium was much more common and extended for greater distances in the deserts than in the jungles. C1 Marshfield Med Res Fdn, Ctr Med Genet, Marshfield, WI 54449 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Sanger Ctr, Cambridge CB10 1SA, England. Joint Genome Inst, Walnut Creek, CA 94598 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. RP Weber, JL (reprint author), Marshfield Med Res Fdn, Ctr Med Genet, Marshfield, WI 54449 USA. EM weberj@cmg.mfldclin.edu RI Deloukas, Panos/B-2922-2013 OI Deloukas, Panos/0000-0001-9251-070X NR 30 TC 201 Z9 207 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 951 EP 953 DI 10.1038/35057185 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800067 PM 11237020 ER PT J AU Cheung, VG Nowak, N Jang, W Kirsch, IR Zhao, S Chen, XN Furey, TS Kim, UJ Kuo, WL Olivier, M Conroy, J Kasprzyk, A Massa, H Yonescu, R Sait, S Thoreen, C Snijders, A Lemyre, E Bailey, JA Bruzel, A Burrill, WD Clegg, SM Collins, S Dhami, P Friedman, C Han, CS Herrick, S Lee, J Ligon, AH Lowry, S Morley, M Narasimhan, S Osoegawa, K Peng, Z Plajzer-Frick, I Quade, BJ Scott, D Sirotkin, K Thorpe, AA Gray, JW Hudson, J Pinkel, D Ried, T Rowen, L Shen-Ong, GL Strausberg, RL Birney, E Callen, DF Cheng, JF Cox, DR Doggett, NA Carter, NP Eichler, EE Haussler, D Korenberg, JR Morton, CC Albertson, D Schuler, G de Jong, PJ Trask, BJ AF Cheung, VG Nowak, N Jang, W Kirsch, IR Zhao, S Chen, XN Furey, TS Kim, UJ Kuo, WL Olivier, M Conroy, J Kasprzyk, A Massa, H Yonescu, R Sait, S Thoreen, C Snijders, A Lemyre, E Bailey, JA Bruzel, A Burrill, WD Clegg, SM Collins, S Dhami, P Friedman, C Han, CS Herrick, S Lee, J Ligon, AH Lowry, S Morley, M Narasimhan, S Osoegawa, K Peng, Z Plajzer-Frick, I Quade, BJ Scott, D Sirotkin, K Thorpe, AA Gray, JW Hudson, J Pinkel, D Ried, T Rowen, L Shen-Ong, GL Strausberg, RL Birney, E Callen, DF Cheng, JF Cox, DR Doggett, NA Carter, NP Eichler, EE Haussler, D Korenberg, JR Morton, CC Albertson, D Schuler, G de Jong, PJ Trask, BJ CA BAC Resource Consortium TI Integration of cytogenetic landmarks into the draft sequence of the human genome SO NATURE LA English DT Article ID IN-SITU HYBRIDIZATION; PHYSICAL MAPS; RESOURCE; CLONES AB We have placed 7,600 cytogenetically defined landmarks on the draft sequence of the human genome to help with the characterization of genes altered by gross chromosomal aberrations that cause human disease. The landmarks are large-insert clones mapped to chromosome bands by fluorescence in situ hybridization. Each clone contains a sequence tag that is positioned on the genomic sequence. This genome-wide set of sequence-anchored clones allows structural and functional analyses of the genome. This resource represents the first comprehensive integration of cytogenetic, radiation hybrid, linkage and sequence maps of the human genome; provides an independent validation of the sequence map(1,2) and framework for contig order and orientation; surveys the genome for large-scale duplications, which are likely to require special attention during sequence assembly; and allows a stringent assessment of sequence differences between the dark and light bands of chromosomes. It also provides insight into large-scale chromatin structure and the evolution of chromosomes and gene families and will accelerate our understanding of the molecular bases of human disease and cancer. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NCI, NIH, Bethesda, MD 20889 USA. Inst Genom Res, Rockville, MD 20850 USA. Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Dept Human Genet, Los Angeles, CA 90048 USA. Univ Calif Santa Cruz, Dept Comp Sci, Santa Cruz, CA 95064 USA. CALTECH, Dept Biol, Pasadena, CA 91125 USA. Univ Calif San Francisco, Ctr Canc, San Francisco, CA 94143 USA. Stanford Univ, Genome Lab, Stanford, CA 94305 USA. Sanger Ctr, Cambridge CB10 1SA, England. Univ Washington, Dept Mol Biotechnol, Seattle, WA 98195 USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Case Western Reserve Univ, Dept Human Genet, Cleveland, OH 44106 USA. Los Alamos Natl Lab, Joint Genome Inst, Los Alamos, NM 87545 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Joint Genome Inst, Berkeley, CA 94720 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. Res Genet Inc, Huntsville, AL 35801 USA. Inst Syst Biol, Seattle, WA 98105 USA. Womens & Childrens Hosp, Dept Cytogenet & Mol Genet, Adelaide, SA 5006, Australia. Univ Calif Santa Cruz, Dept Comp Sci, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. RP Trask, BJ (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N C3-168,POB 19024, Seattle, WA 98109 USA. EM btrask@fhcrc.org RI Callen, David/G-1975-2012; Shen-Ong, Grace/C-8327-2014; OI Callen, David/0000-0002-6189-9991 FU NIGMS NIH HHS [P01 GM061354] NR 30 TC 212 Z9 217 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 15 PY 2001 VL 409 IS 6822 BP 953 EP 958 DI 10.1038/35057192 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401QC UT WOS:000166938800068 PM 11237021 ER PT J AU Chow, WH Fraumeni, JF AF Chow, WH Fraumeni, JF TI Obesity, hypertension, and renal cancer. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Chow, WH (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 15 PY 2001 VL 344 IS 7 BP 532 EP 532 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 401HL UT WOS:000166922100023 ER PT J AU Nishimoto, A Miura, N Horikawa, I Kugoh, H Murakami, Y Hirohashi, S Kawasaki, H Gazdar, AF Shay, JW Barrett, JC Oshimura, M AF Nishimoto, A Miura, N Horikawa, I Kugoh, H Murakami, Y Hirohashi, S Kawasaki, H Gazdar, AF Shay, JW Barrett, JC Oshimura, M TI Functional evidence for a telomerase repressor gene on human chromosome 10p15.1 SO ONCOGENE LA English DT Article DE microcell-mediated chromosome transfer; telomerase; chromosome 10p; telomerase repressor gene; hTERT ID HUMAN PROSTATE-CANCER; CATALYTIC SUBUNIT HTERT; TUMOR-SUPPRESSOR GENES; CELLULAR SENESCENCE; EFFICIENT MODIFICATION; INSITU HYBRIDIZATION; MAMMALIAN TELOMERASE; IMMORTAL CELLS; HUMAN GLIOMAS; ALLELIC LOSS AB Based on the sites of frequent allelic loss in hepatocellular carcinoma, five normal human chromosomes (2, 4, 5, 10 and 16) were transferred individually into a telomerase-positive human hepatocellular carcinoma cell line, Li7HM, by microcell-mediated chromosome transfer (MMCT). Chromosome 10, but not the others, repressed telomerase activity immediately and stopped cell growth after 50 population doublings (PDs), Loss of the transferred 10p loci resulted in the emergence of revertant cells that continued to proliferate and expressed telomerase activity, suggesting the presence of a telomerase repressor gene on this chromosomal arm. Transfer of a series of defined fragments from chromosome 10p successfully narrowed down the responsible region: a 28.9-cM region on 10p15 (between WI-4752 and D10S249), but not a 26.2-cM region (between D10S1728 and D10S249), caused repression of telomerase activity and progressive telomere shortening. A strong correlation between the expression level of telomerase catalytic subunit gene (hTERT) and telomerase activity was observed. These findings suggest that a novel telomerase repressor gene which controls the expression of hTERT is located on the 2.7-cM region (between WI-4752 and D10S1728) on chromosome 10p15.1. C1 Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, Tottori 6838503, Japan. NCI, Lab Biosyst & Canc, Canc & Aging Sect, Bethesda, MD 20892 USA. Natl Canc Ctr, Res Inst, Tumor Suppress & Funct Genom Project, Chuo Ku, Tokyo 1040045, Japan. Natl Canc Ctr, Res Inst, Div Pathol, Chuo Ku, Tokyo 1040045, Japan. Tottori Univ, Dept Internal Med 2, Tottori 6838503, Japan. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Cell Biol, Dallas, TX 75390 USA. RP Oshimura, M (reprint author), Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, Tottori 6838503, Japan. RI Shay, Jerry/F-7878-2011 NR 41 TC 43 Z9 44 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 15 PY 2001 VL 20 IS 7 BP 828 EP 835 DI 10.1038/sj.onc.1204165 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 401JL UT WOS:000166924400006 PM 11314017 ER PT J AU Rokman, A Koivisto, PA Matikainen, MP Kuukasjarvi, T Poutiainen, M Helin, HJ Karhu, R Kallioniemi, OP Schleutker, J AF Rokman, A Koivisto, PA Matikainen, MP Kuukasjarvi, T Poutiainen, M Helin, HJ Karhu, R Kallioniemi, OP Schleutker, J TI Genetic changes in familial prostate cancer by comparative genomic hybridization SO PROSTATE LA English DT Article DE hereditary prostate cancer; cancer predisposition; molecular cytogenetics; deletion ID SEQUENCE COPY NUMBER; SUSCEPTIBILITY LOCUS; BREAST-CANCER; SOLID TUMORS; CHROMOSOME; EPIDEMIOLOGY; GAINS AB BACKGROUND. Germline mutations in recessive cancer predisposition genes are uncovered by somatic genetic deletions during tumor development. Analysis of genetic changes in tumor tissues from patients with an inherited predisposition may therefore highlight regions of the genome containing susceptibility or modifier genes. Our aim was to characterize genetic changes in familial prostate cancer. METHODS. Twenty-one primary prostate cancers from 19 Finnish prostate cancer families were analyzed for somatic genetic changes by comparative genomic hybridization (CGH). RESULTS. The average number of genetic alterations per tumor was 4.0 +/- 1.9, distributed equally among losses and gains. The most common losses were found at chromosomal regions 13q14-q22 (29%), 8p12-pter (24%), and 6q13-q16 (14%), and the most common gains at 19p (25%), 19q (14%) and 7q (14%). CONCLUSIONS. These results suggest that prostate cancers in genetically predisposed individuals arise for the most part through similar somatic genetic progression pathways as sporadic prostate cancers. This also implies that the biological properties of tumors from the two groups may not be different from one another. (C) 2001 Wiley-Liss, Inc. C1 Tampere Univ, Inst Med Technol, Lab Canc Genet, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Pathol, FIN-33101 Tampere, Finland. Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD USA. RP Rokman, A (reprint author), Tampere Univ, Inst Med Technol, Lab Canc Genet, Lenkkeilijankatu 8,POB 607, FIN-33101 Tampere, Finland. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 FU NHGRI NIH HHS [N01-HG-55389] NR 26 TC 22 Z9 22 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 15 PY 2001 VL 46 IS 3 BP 233 EP 239 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 399RF UT WOS:000166825600008 PM 11170152 ER PT J AU Rose, PS Ahn, NU Levy, HP Ahn, UM Davis, J Liberfarb, RM Nallamshetty, L Sponseller, PD Francomano, CA AF Rose, PS Ahn, NU Levy, HP Ahn, UM Davis, J Liberfarb, RM Nallamshetty, L Sponseller, PD Francomano, CA TI Thoracolumbar spinal abnormalities in Stickler syndrome SO SPINE LA English DT Article DE arthro-ophthalmopathy; back pain; connective tissue dysplasia; kyphosis; scoliosis ID HEREDITARY ARTHRO-OPHTHALMOPATHY; II PROCOLLAGEN GENE; ARTHROOPHTHALMOPATHY; MANIFESTATIONS; MUTATIONS; KYPHOSIS; COL11A2 AB Study Design: Retrospective review of clinical and radiographic records of patients with Stickler syndrome. Objectives: To describe thoracolumbar spinal abnormalities and their correlation with age and back pain among patients with Stickler syndrome. Summary of Background Data: Stickler syndrome (hereditary arthro-ophthalmopathy) is an autosomal dominant connective tissue disorder characterized by skeletal, ocular, oral-facial, cardiac, and auditory manifestations. Prevalence is approximately 1 in 10,000 (similar to that of Marfan syndrome). No one has investigated spinal abnormalities in a large series of patients. Methods: A single-center evaluation of 53 patients from 24 families with Stickler syndrome (age range, 1-70 years) in a multidisciplinary genetics clinic. Thoracolumbar radiographs were analyzed for spinal abnormalities and correlation with age and back pain. Results: Thirty-four percent of patients had scoliosis, 74% endplate abnormalities, 64% Schmorl's nodes, 43% platyspondylia, and 43% Scheuermann-like kyphosis. Sixty-seven percent of patients and 85% of adults reported chronic back pain. Endplate abnormalities and Schmorl's nodes were associated with adult age; endplate abnormalities, Schmorl's nodes, and adult age were associated with back pain. Only one adult patient was free of spinal abnormalities. Conclusions: Spinal abnormalities are nearly uniformly observed in Stickler syndrome, progress with age, and are associated with back pain. Although common, scoliosis is generally self-limited (only one patient needed surgical treatment). Correct diagnosis of this syndrome facilitates early identification and management of other potentially severe systemic manifestations and genetic counseling for affected families. Moreover, recognition of Stickler syndrome allows accurate prognosis for skeletal abnormalities and anticipation of potential surgical complications. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Dept Orthopaed Surg, Baltimore, MD 21287 USA. RP Rose, PS (reprint author), NHGRI, NIH, Bldg 10,Room 10C101,10 Ctr Dr,MSC 1852, Bethesda, MD 20892 USA. FU NHGRI NIH HHS [97-HG-0089] NR 35 TC 20 Z9 20 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD FEB 15 PY 2001 VL 26 IS 4 BP 403 EP 409 DI 10.1097/00007632-200102150-00017 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 406AP UT WOS:000167193000014 PM 11224888 ER PT J AU Piaggio, G Carroli, G Villar, J Pinol, A Bakketeig, L Lumbiganon, P Bergsjo, P Al-Mazrou, Y Ba'aqeel, H Belizan, JM Farnot, U Berendes, H AF Piaggio, G Carroli, G Villar, J Pinol, A Bakketeig, L Lumbiganon, P Bergsjo, P Al-Mazrou, Y Ba'aqeel, H Belizan, JM Farnot, U Berendes, H TI Methodological considerations on the design and analysis of an equivalence stratified cluster randomization trial SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Workshop on Design and Analysis of Cluster Randomized Trials CY JUL 05-07, 1999 CL UNIV SHEFFIELD, SHEFFIELD, ENGLAND SP Univ Sheffield HO UNIV SHEFFIELD ID SEXUALLY-TRANSMITTED DISEASES; COMMUNITY INTERVENTION TRIAL; SAMPLE-SIZE REQUIREMENTS; CLINICAL-TRIALS; STATISTICAL DESIGN; SMOKING CESSATION; COLORECTAL-CANCER; NULL HYPOTHESIS; MODELS; ISSUES AB The World Health Organization and collaborating institutions in four developing countries have conducted a multi-centre randomized controlled trial, in which clinics were allocated at random to two antenatal care (ANC) models. These were the standard "Western" ANC model and a "new" ANC model consisting of tests, clinical procedures and follow-up actions scientifically demonstrated to be effective in improving maternal and newborn outcomes. The two models were compared using the equivalence approach. This paper discusses the implications of the equivalence approach in the sample size calculation, analysis and interpretation of results of this cluster randomized trial. It reviews the ethical aspects regarding informed consent, concluding that the Zelen design has a place in cluster randomization trials. It describes the estimation of the intracluster correlation coefficient (ICC) in a stratified cluster randomized trial using two methods and reports estimates of the ICC obtained for many maternal, newborn and perinatal outcomes. Finally, it discusses analytical problems that arose: issues encountered using a composite index, heterogeneity of the intervention effect across sites, the choice of the method of analysis and the importance of efficacy analyses. The choice of the clustered Woolf estimator and the generalized estimating equations (GEE) as the methods of analysis applied is discussed. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 WHO, UNDP WHo World Bank Special Programme Res, CH-1211 Geneva 27, Switzerland. Natl Guard King Khalid Hosp, Jeddah, Saudi Arabia. Minist Hlth, Riyadh, Saudi Arabia. Khon Kaen Univ, Khon Kaen, Thailand. Latin Amer Ctr Perinatol & Human Dev, Montevideo, Uruguay. Ctr Rosario Estudios Perinatales, Rosario, Argentina. Hosp Ginecoobstet Amer Arias, Havana, Cuba. Univ Bergen, Dept Obstet & Gynaecol, Bergen, Norway. Natl Publ Hlth Inst, Oslo, Norway. NICHD, NIH, Bethesda, MD USA. RP Piaggio, G (reprint author), WHO, UNDP WHo World Bank Special Programme Res, CH-1211 Geneva 27, Switzerland. OI Baaqeel, Hassan/0000-0002-0774-2790 NR 53 TC 24 Z9 24 U1 1 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 15 PY 2001 VL 20 IS 3 BP 401 EP 416 DI 10.1002/1097-0258(20010215)20:3<401::AID-SIM801>3.0.CO;2-1 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 400CB UT WOS:000166850100008 PM 11180310 ER PT J AU O'Brien, ML Cunningham, ML Spear, BT Glauert, HP AF O'Brien, ML Cunningham, ML Spear, BT Glauert, HP TI Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Wy-14,643; dibutylphthalate; gemfibrozil; glutathione; glutathione S-transferase; glutathione peroxidase; glutathione reductase; peroxisome proliferators; Sprague-Dawley rats; Syrian hamsters ID ALTERED HEPATIC FOCI; PEROXIDASE-ACTIVITY; HYDROGEN-PEROXIDE; DIETARY SELENIUM; OXIDATIVE STRESS; PERFLUORODECANOIC ACID; CELL REPLICATION; SYRIAN-HAMSTER; VITAMIN-E; CIPROFIBRATE AB Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice. Conversely, hamsters are less responsive to these compounds. PPs increase peroxisomal beta -oxidation and P4504A subfamily activity, which has been hypothesized to result in oxidative stress. We hypothesized that differential modulation of glutathione-related defenses could account for the resulting difference in species susceptibility following PP administration. Accordingly, we measured glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) activities, and total glutathione (GSH) in male Sprague-Dawley rats and Syrian hamsters fed two doses of three known peroxisome proliferators [dibutylphthalate (DBP), gemfibrozil, and Wy-14,643] for 6, 34, or 90 days. In rats, decreases in GR, GST, and selenium-dependent GPx were observed following PP treatment at various time points. In hamsters, we observed higher basal levels of activities for GR, GST, and selenium-dependent GPx compared to rats. In addition, hamsters showed decreases in GR and GST activities following PP treatment. Interestingly, selenium-dependent GPx activity was increased in hamsters following treatment with Wy-14,643 and DBP. Treatment for 90 days with Wy-14,643 resulted in no change in GPx1 mRNA in rats and increased GPx1 mRNA in hamsters. Sporadic changes in total GSH and selenium-independent GPx were observed in both species. This divergence in the hydrogen peroxide detoxification ability between rats and hamsters could be a contributing factor in the proposed oxidative stress mechanism of PPs observed in responsive and nonresponsive species. (C) 2001 Academic Press. C1 Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40506 USA. Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40506 USA. Univ Kentucky, Dept Microbiol & Immunol, Lexington, KY 40506 USA. Univ Kentucky, Dept Pathol & Lab Med, Lexington, KY 40506 USA. NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Glauert, HP (reprint author), Univ Kentucky, Grad Ctr Nutr Sci, 204 Funkhouser Bldg, Lexington, KY 40506 USA. OI Spear, Brett/0000-0002-4343-9393 FU NIEHS NIH HHS [T32 ES07266, ES09771] NR 52 TC 29 Z9 30 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 15 PY 2001 VL 171 IS 1 BP 27 EP 37 DI 10.1006/taap.2000.9111 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 407JE UT WOS:000167267800004 PM 11181109 ER PT J AU Taraporewala, ZF Chen, DY Patton, JT AF Taraporewala, ZF Chen, DY Patton, JT TI Multimers of the bluetongue virus nonstructural protein, NS2, possess nucleotidyl phosphatase activity: Similarities between NS2 and rotavirus NSP2 SO VIROLOGY LA English DT Article ID SINGLE-STRANDED RNA; MESSENGER-RNA; INCLUSION-BODIES; SIGMA-NS; IN-VIVO; BINDING; PHOSPHORYLATION; PHOSPHOPROTEIN; PARTICLES; INVITRO AB The nonstructural protein, NS2, of bluetongue virus is a nonspecific single-stranded RNA-binding protein that forms large homomultimers and accumulates in Viral inclusion bodies of infected cells. NS2 shares these features with the nonstructural protein, NSP2, of rotavirus, which like BTV is a member of the family Reoviridae. Recently, NSP2 was shown to have an NTPase activity and an autokinase activity that catalyzed its phosphorylation in vitro. To examine NS2 for similar enzymatic activities, the protein was expressed in bacteria with a C-terminal His-tag and purified to homogeneity. Recombinant (r)NS2 possessed nonspecific RNA-binding activity and formed 8-10S homomultimers of the same approximate size as rNSP2 homomultimers. Notably. enzymatic assays performed with rNS2 showed that the protein hydrolyzed the alpha, beta, and gamma phosphodiester bonds of all four NTPs. Therefore, rNS2 possesses a nucleotidyl phosphatase activity instead of the NTPase activity of NSP2, which only hydrolyzes the gamma phosphodiester bonds of NTPs. NS2 did not exhibit any autokinase activity in vitro, unlike NSP2. However, both NS2 and NSP2 were phosphorylated in vitro by cellular kinases. Although the nature of the enzymatic activities differs significantly. the fact that both NS2 and NSP2 hydrolyze NTPs, undergo phosphorylation, bind RNA, and assemble into multimers consisting of 6 +/- 2 subunits suggests that they are functional homologs. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0720,Room 117, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 34 TC 34 Z9 35 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 15 PY 2001 VL 280 IS 2 BP 221 EP 231 DI 10.1006/viro.2000.0764 PG 11 WC Virology SC Virology GA 405BF UT WOS:000167136800008 PM 11162836 ER PT J AU Johnson, JG Cohen, P Klein, DF Kasen, S Pine, DS Brook, JS AF Johnson, JG Cohen, P Klein, DF Kasen, S Pine, DS Brook, JS TI Cigarette smoking and anxiety disorders - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Columbia Univ, Dept Psychiat, New York, NY 10027 USA. NIMH, Program Mood & Anxiety Disorders, Bethesda, MD 20892 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. RP Johnson, JG (reprint author), Columbia Univ, Dept Psychiat, New York, NY 10027 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 14 PY 2001 VL 285 IS 6 BP 732 EP 733 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 399MP UT WOS:000166817200018 ER PT J AU Emanuel, EJ Emanuel, LL AF Emanuel, EJ Emanuel, LL TI Assessing requests for euthanasia from terminally ill patients - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID PHYSICIAN-ASSISTED SUICIDE C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Program Professionalism & Human Rights, Chicago, IL USA. RP Emanuel, EJ (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 14 PY 2001 VL 285 IS 6 BP 734 EP 735 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 399MP UT WOS:000166817200023 ER PT J AU Lie, RT Wilcox, AJ Skjaerven, R AF Lie, RT Wilcox, AJ Skjaerven, R TI Survival and reproduction among males with birth defects and risk of recurrence in their children SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article AB Context Few systematic data exist on survival and reproduction among males with birth defects and their contribution to occurrence of birth defects in the next generation. Objective To estimate survival of males with registered birth defects, their subsequent reproduction rates, and their risk of transmitting birth defects to their offspring. Design and Setting Population-based cohort study of data from the Medical Birth Registry of Norway. Subjects A total of 486207 males born in Norway between 1967 and 1982, 12292 of whom had a recorded birth defect. Main Outcome Measures Survival rates through 1992, reproduction rates through 1998, and risk of birth defects among offspring of males with vs without birth defects. Results Survival through 1992 was lower among males with birth defects (84% vs 97%). Compared with males without birth defects, affected males were 28% less likely to have had a child. Among offspring of affected males, 5.1% had a registered birth defect compared with 2.1% of offspring of males without birth defects (relative risk [RR], 2.4; 95% confidence interval [CI], 1.9-3.0), Offspring of affected fathers had an increased risk of the same defect as their fathers (RR, 6.5; 95% CI, 4.0-10.4) and an increased risk of dissimilar defects (RR, 1.8; 95% CI, 1.3-2.5). Conclusions Compared with unaffected males, males with birth defects have higher mortality and survivors are less likely to have a child. Fathers with birth defects are significantly more likely than unaffected fathers to have an affected child. C1 Univ Bergen, Med Birth Registry Norway, N-5021 Bergen, Norway. Univ Bergen, Sect Med Stat, N-5021 Bergen, Norway. NIEHS, Res Triangle Pk, NC 27709 USA. RP Lie, RT (reprint author), Univ Bergen, Sect Med Stat, Amauer Hansens Bldg, N-5021 Bergen, Norway. OI Wilcox, Allen/0000-0002-3376-1311 NR 12 TC 33 Z9 33 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 14 PY 2001 VL 285 IS 6 BP 755 EP 760 DI 10.1001/jama.285.6.755 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 399MP UT WOS:000166817200032 PM 11176913 ER PT J AU Lindberg, DAB AF Lindberg, DAB TI The National Library of Medicine's web site for physicians and patients SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Lindberg, DAB (reprint author), Natl Lib Med, NIH, Bethesda, MD 20894 USA. NR 0 TC 8 Z9 8 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 14 PY 2001 VL 285 IS 6 BP 806 EP 806 DI 10.1001/jama.285.6.806 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 399MP UT WOS:000166817200041 PM 11176923 ER PT J AU Maynard, AT Covell, DG AF Maynard, AT Covell, DG TI Reactivity of zinc finger cores: Analysis of protein packing and electrostatic screening SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TYPE-1 NUCLEOCAPSID PROTEIN; DNA-BINDING DOMAIN; ESTROGEN-RECEPTOR; ESCHERICHIA-COLI; RECOGNITION CODE; METALLOTHIONEIN; COORDINATION; THIONEIN; SITE; METHYLATION AB The chemical stability of 207 zinc fingers, derived from 92 experimental protein structures, is evaluated according to the protein packing and electrostatic screening of their zinc cores. These properties are used as measures of the protein protection of zinc cores, to predictively rank relative zinc finger reactivities and assess differences in function. On average, there is a substantial and concomitant increase in the screening of increasingly anionic core motifs, suggesting zinc fingers have evolved in a manner that promotes shielding of their potentially reactive core thiolates. In contrast, enzymatic zinc cores are functionally differentiated by negative electrostatic screening. Zinc finger cores are predominantly screened by networks of backbone:core NW-S hydrogen bonds that electronically stabilize core thiolates and enhance backbone packing. Stabilizing protein:core interactions can be mapped to conserved residues, including [Arg,Lys]:core salt-bridges in some protein families. Labile zinc fingers are identified by poorly screened cores, possibly indicating redox or metallothionein (MT) regulated function. Consistent with experiment, the cores of the C-terminal finger of the human immunodeficiency virus type I (HIV-I) nucleocapsid protein p7 (NCp7) and Escherichia coli Ada protein (Ada) "finger" are identified as reactive. The C-terminal zinc fingers of nuclear receptors are predicted to be the most labile in this study, particularly the human estrogen receptor (hER), which contains a triad of reactive thiolates. We propose that hER DNA binding is redox and MT regulated through the C-terminal finger and that,weak electrophilic agents may inhibit hER-mediated transcription, implicated in breast cancer progression. C1 NCI, Frederick Canc Res & Dev Ctr, Comp Technol Lab, Screening Technol Branch,DCTD,SAIC,NIH, Frederick, MD 21702 USA. RP Maynard, AT (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comp Technol Lab, Screening Technol Branch,DCTD,SAIC,NIH, Bldg 430,Room 215, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 62 TC 121 Z9 122 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 14 PY 2001 VL 123 IS 6 BP 1047 EP 1058 DI 10.1021/ja0011616 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 400LL UT WOS:000166873000005 PM 11456658 ER PT J AU Menon, RK Shaufl, A Yu, JH Stephan, DA Friday, RP AF Menon, RK Shaufl, A Yu, JH Stephan, DA Friday, RP TI Identification and characterization of a novel transcript of the murine growth hormone receptor gene exhibiting development and tissue-specific expression SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE GH receptor; mouse liver; transcription ID MESSENGER-RIBONUCLEIC-ACID; GH-BINDING-PROTEIN; 5'-UNTRANSLATED REGIONS; LIVER; PROMOTER; RAT; ONTOGENY; CLONING; RNAS; PCR AB The growth hormone (GH) receptor gene is characterized by heterogeneity in the 5'-untranslated region (UTR). The technique of 5'-rapid amplification of cDNA ends (RACE) was employed to identify potentially novel 5'-UTRs for the GH receptor gene. One of the RACE clones displayed sequence homology to the human V5-UTR; hence this transcript was designated as L5. Sequence analysis of genomic DNA established that L5 was immediately upstream of exon 2. Northern blot analysis indicated that two bands of sizes congruent to 4.8 kb, corresponding to GH receptor mRNA, and congruent to 1.5 kb corresponding to GH binding protein mRNA, were detectable in liver, skeletal muscle, kidney and heart but not in brain, spleen, lung or testis. Fluorescent 5'-nuclease rear-time RT-PCR based analysis indicated that in the placenta and fetal liver, the L5 transcript represented 10-15% of the GH receptor transcripts. In the adult liver, heart and kidney, the L5 transcript is less abundant accounting for 1-5% of the total GH receptor transcripts. Primer extension and ribonuclease protection assays were performed to identify the major transcription start site at 778 bp from the ATG codon. Transient transfection experiments revealed that the 5'-flanking sequence had promoter activity in rat placental trophoblast (HRP.1), Chinese hamster ovary (CHO) and mouse liver (BNL CL.2) cells. Analysis of expression of the LS transcript in the non-obese diabetic (NOD) mouse, a model of spontaneous autoimmune diabetes, indicated that the expression of the L5 transcript was decreased in liver and kidney by 80-90 and 40-50%, respectively, but expression remained unchanged in the heart. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Pittsburgh, Sch Med, Childrens Hosp Pittsburgh, Dept Pediat,Div Endocrinol, Pittsburgh, PA 15213 USA. NHGRI, Can Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15213 USA. RP Menon, RK (reprint author), Univ Pittsburgh, Sch Med, Childrens Hosp Pittsburgh, Dept Pediat,Div Endocrinol, 3705 5th Ave, Pittsburgh, PA 15213 USA. FU NIDDK NIH HHS [R29-DK49845] NR 23 TC 40 Z9 40 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 14 PY 2001 VL 172 IS 1-2 BP 135 EP 146 DI 10.1016/S0303-7207(00)00375-0 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 397UF UT WOS:000166715200015 PM 11165047 ER PT J AU Zhang, ZP Teng, CT AF Zhang, ZP Teng, CT TI Estrogen receptor alpha and estrogen receptor-related receptor alpha 1 compete for binding and coactivator SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE coactivator transactivation; repressing; DNA-binding; AF2 domain ID ORPHAN NUCLEAR RECEPTOR; THYROID-HORMONE RECEPTOR; ACTIVATION FUNCTION-2; LACTOFERRIN GENE; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; CRYSTAL-STRUCTURE; RETINOIC ACID; ERR-ALPHA; PROMOTER AB The human estrogen receptor (ER alpha) and the human estrogen receptor-related receptor (ERR alpha1, NR3B1a) are members of the steroid/thyroid hormone receptor superfamily. We previously cloned an isoform of ERR alpha1 cDNA and demonstrated that ERR alpha1 binds to the human lactoferrin gene promoter and enhances estrogen responsiveness during transient transfection experiments. In this study, we show that ERR alpha1 and ERa may interfere in each other's transcriptional activity by competition for binding and coactivator. PI VP16-ERR alpha1 chimera was constructed and transiently transfected into human endometrial carcinoma HEC-1B cells. This chimera activated reporter constructs containing the human lactoferrin gene estrogen response element (ERE) and the synthetic palindromic 3X-ERE, suggesting that ERR alpha1 binds to these EREs. Therefore, ERR alpha1 can compete with ER alpha for binding to the same EREs. ERR alpha1 is organized into modules which include a N-terminal region that shows repression function, a Zn-finger region that binds DNA and an activation region at the C terminus. The activation function of ERR alpha1 was mapped to the conserved AF2 region in the C-terminus by deletion analysis. The transactivation activity of ERR alpha1 can be enhanced by coactivator (SRC-la) and suppressed by ER alpha in the presence of estrogen, suggesting that SRC-la is required by both receptors for their activity. The repression of ERR alpha1 activation function by estrogen bound ER alpha, however, could not be reversed by increasing concentration of SRC-1a in the cells. This finding is consistent with the squelching phenomenon that exists between ER alpha and other steroid receptor family members. The studies demonstrated that ERR alpha1 and ER alpha may potentially regulate the same target gene independently as well as interfere with each other's functional activity by competition for binding and coactivator. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Gene REgulat Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Gene REgulat Grp, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 49 TC 49 Z9 56 U1 0 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 14 PY 2001 VL 172 IS 1-2 BP 223 EP 233 DI 10.1016/S0303-7207(00)00372-5 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 397UF UT WOS:000166715200024 PM 11165056 ER PT J AU Hiser, C Mills, DA Schall, M Ferguson-Miller, S AF Hiser, C Mills, DA Schall, M Ferguson-Miller, S TI C-terminal truncation and histidine-tagging of cytochrome c oxidase subunit II reveals the native processing site, shows involvement of the C-terminus in cytochrome c binding, and improves the assay for proton pumping SO BIOCHEMISTRY LA English DT Article ID RHODOBACTER-SPHAEROIDES; PARACOCCUS-DENITRIFICANS; CHEMICAL MODIFICATION; ELECTRON-TRANSFER; DEFINITION; PURIFICATION; VESICLES; KINETICS; DOMAINS; PROTEOLIPOSOMES AB TO enable metal affinity purification of cytochrome c oxidase reconstituted into phospholipid vesicles, a histidine-tag was engineered onto the C-terminal end of the Rhodobacter sphaeroides cytochrome c oxidase subunit II. Characterization of the natively processed wildtype oxidase and artificially processed forms (truncated with and without a his-tag) reveals Km values for cytochrome c that are 6-14-fold higher for the truncated and his-tagged forms than for the wildtype. This lowered ability to bind cytochrome c indicates a previously undetected role for the C-terminus in cytochrome c binding and is mimicked by reduced affinity for an FPLC anion exchange column. The elution profiles and kinetics indicate that the removal of 16 amino acids from the C-terminus, predicted from the known processing site of the Paracoccus denitrificans oxidase, does not produce the same enzyme as the native processing reaction. MALDI-TOF MS data show the true C-terminus of subunit II is at serine 290, three amino acids longer than expected. When the his-tagged form is reconstituted into lipid vesicles and further purified by metal affinity chromatography, significant improvement is observed in proton pumping analysis by the stopped-flow method. The improved kinetic results are attributed to a homogeneous, correctly oriented vesicle population with higher activity and less buffering from extraneous lipids. C1 Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. Michigan State Univ, Mass Spectrometry Facil, NIH, MSU, E Lansing, MI 48824 USA. RP Ferguson-Miller, S (reprint author), Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. FU NIGMS NIH HHS [R01-GM26916] NR 38 TC 36 Z9 36 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 13 PY 2001 VL 40 IS 6 BP 1606 EP 1615 DI 10.1021/bi0018988 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401RM UT WOS:000166942100013 PM 11327819 ER PT J AU Shah, D Kelly, J Zhang, Y Dande, P Martinez, J Ortiz, G Fronza, G Tran, H Soto, AM Marky, L Gold, B AF Shah, D Kelly, J Zhang, Y Dande, P Martinez, J Ortiz, G Fronza, G Tran, H Soto, AM Marky, L Gold, B TI Evidence in Escherichia coli that N3-methyladenine lesions induced by a minor groove binding methyl sulfonate ester can be processed by both base and nucleotide excision repair SO BIOCHEMISTRY LA English DT Article ID 3-METHYLADENINE DNA GLYCOSYLASE; SEQUENCE-SELECTIVE ALKYLATION; HMG-DOMAIN PROTEIN; NITROGEN MUSTARDS; IN-VITRO; ADAPTIVE RESPONSE; N-NITROSOUREA; ADDUCTS; DAMAGE; AGENTS AB It has been previously reported that a neutral DNA equilibrium binding agent based on an N-methylpyrrolecarboxamide dipeptide (lex) and modified with an O-methyl sulfonate ester functionality (MeOSO2-lex) selectively affords N3-methyladenine lesions. To study the interaction of the neutral lex dipeptide with calf thymus DNA, we have prepared stable, nonmethylating sulfone analogues of MeOSO2-lex that are neutral and cationic. Thermodynamic studies show that both the neutral and monocationic sulfone compounds bind to DNA with K-b's Of 10(5) ill primarily entropy-driven reactions. To determine how the cytotoxic N3-methyladenine adduct generated from MeOSO2-lex is repaired in E. coli, MeOSO2-lex was tested for toxicity in wild-type E. coli and in mutant strains defective in base excision repair (tag and/or alkA glycosylases or npn endonuclease), nucleotide excision repair (uvrA), and both base and nucleotide excision repair (tag/alkA/uvrA). The results clearly demonstrate the cellular toxicity of the N3-methyladenine lesion, and the protective role of base excision glycosylase proteins. A novel finding is that in the absence of functional base excision glycosylases, nucleotide excision repair can also protect cells from this cytotoxic minor groove lesion. Interaction between base and nucleotide excision repair systems is also seen in the protection of cells treated with cis-diamminedichloroplatinum(II) but not with anti-(+/-)-r-7,t-8-dihydroxy-t-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE 68198 USA. Natl Canc Inst, Mutagenesis Lab, I-16132 Genoa, Italy. RP Gold, B (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 600 S 42nd St, Omaha, NE 68198 USA. FU NCI NIH HHS [P30 CA36727, R01 CA29088]; NIGMS NIH HHS [R01 GM42223] NR 62 TC 20 Z9 20 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 13 PY 2001 VL 40 IS 6 BP 1796 EP 1803 DI 10.1021/bi0024658 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401RM UT WOS:000166942100036 PM 11327842 ER PT J AU Collis, T Devereux, RB Roman, MJ de Simone, G Yeh, JL Howard, BV Fabsitz, RR Welty, TK AF Collis, T Devereux, RB Roman, MJ de Simone, G Yeh, JL Howard, BV Fabsitz, RR Welty, TK TI Relations of stroke volume and cardiac output to body composition - The strong heart study SO CIRCULATION LA English DT Article DE American Indians; diabetes mellitus; echocardiography; ventricles ID M-MODE ECHOCARDIOGRAPHY; LEFT-VENTRICULAR MASS; AMERICAN-INDIANS; CARDIOVASCULAR-DISEASE; RISK-FACTORS; OBESITY; REGURGITATION; HYPERTENSION; VALIDATION; CHILDREN AB Background-Although cardiac output (CO) plays the vital role of delivering nutrients to body tissues, few data are available concerning the relations of stroke volume (SV) and CO to body composition in large population samples. Methods and Results-Doppler and 2D echocardiography and bioelectric impedance in 2744 Strong Heart Study participants were used to calculate SV and CO and to relate them to fat-free body mass (FFM), adipose mass, and demographic variables. Both SV and CO were higher in men than women and in overweight than normal-weight individuals, but these differences were diminished or even reversed by normalization for FFM or body surface area. In both sexes, SV and CO were more strongly related to FFM than adipose mass, other body habitus measures, arterial pressure, diabetes, or age. In multivariate analyses using the average of Doppler and left ventricular SV to minimize measurement variability, FFM was the strongest correlate of SV and CO; other independent correlates were adipose mass, systolic pressure, diabetes, age, and use of digoxin and calcium channel and beta -blockers. Conclusions-In a population-based sample, SV and CO are more strongly related to FFM than other variables; increased FFM may be the primary determinant of increased SV and CO in obesity. C1 Cornell Univ, Med Ctr, Div Cardiol, New York, NY 10021 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. MedStar Res Inst, Washington, DC USA. NHLBI, Bethesda, MD 20892 USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. RP Devereux, RB (reprint author), Cornell Univ, Med Ctr, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. RI de Simone, Giovanni/D-1767-2011 OI de Simone, Giovanni/0000-0001-8567-9881 FU NCRR NIH HHS [M10-RR-0047-34]; NHLBI NIH HHS [U01-HL-41654, U01-HL-41642, U01-HL-41652] NR 26 TC 100 Z9 103 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 13 PY 2001 VL 103 IS 6 BP 820 EP 825 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NU UT WOS:000167561900019 PM 11171789 ER PT J AU Dalakas, MC Koffman, B Fujii, M Spector, S Sivakumar, K Cupler, E AF Dalakas, MC Koffman, B Fujii, M Spector, S Sivakumar, K Cupler, E TI A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM SO NEUROLOGY LA English DT Article ID INCLUSION-BODY MYOSITIS; INFLAMMATORY MYOPATHIES; DUCHENNE DYSTROPHY; DISEASES; DERMATOMYOSITIS; EXPRESSION; THERAPY AB Objective: To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (s-IBM). Background: In a previous controlled trial in s-IBM, Mg did not significantly improve strength in spite of modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with Mg prompted another controlled trial. Methods: Thirty-six patients with biopsy-proven IBM were randomized to receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing; and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers. Results: Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or 4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p < 0.0001), denoting a steroid effect. Conclusion: IVIg combined with prednisone for a 3-month period was not effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of clinical significance. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. NR 27 TC 139 Z9 140 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 13 PY 2001 VL 56 IS 3 BP 323 EP 327 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 401DK UT WOS:000166911700009 PM 11171896 ER PT J AU Garvey, MA Toro, C Goldstein, S Altarescu, G Wiggs, EA Hallett, M Schiffmann, R AF Garvey, MA Toro, C Goldstein, S Altarescu, G Wiggs, EA Hallett, M Schiffmann, R TI Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease SO NEUROLOGY LA English DT Article ID CORTICAL MYOCLONUS AB The authors compared stretch-evoked somatosensory evoked potentials (SEP) of 18 type 3 Gaucher disease (GD3) patients (two with progressive myoclonus epilepsy [PME]) with 22 age-matched normal controls and six patients with type 1 (nonneuronopathic) Gaucher disease (GD1). The mean P1-N2 SEP amplitude in GD3 patients was significantly larger than the SEP in controls and in GD1 patients, and there was a significant negative correlation between SEP amplitude and the IQ of GD3 patients. The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Garvey, MA (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, 10 Ctr Dr,4N208,MSC 1255, Bethesda, MD 20892 USA. NR 10 TC 11 Z9 11 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 FEB 13 PY 2001 VL 56 IS 3 BP 391 EP 394 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 401DK UT WOS:000166911700021 PM 11171908 ER PT J AU de Paulsen, N Brychzy, A Fournier, MC Klausner, RD Gnarra, JR Pause, A Lee, S AF de Paulsen, N Brychzy, A Fournier, MC Klausner, RD Gnarra, JR Pause, A Lee, S TI Role of transforming growth factor-alpha in von Hippel-Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FACTOR RECEPTOR ANTIBODY; UBIQUITIN LIGASE; MESSENGER-RNA; FACTOR-BETA; GENE; EXPRESSION; PROTEIN; CANCER; KINASE; IDENTIFICATION AB Mutations of the VHL tumor suppressor gene occur in patients with VHL disease and in the majority of sporadic clear cell renal carcinomas (VHL-/- RCC), Loss of VHL protein function is associated with constitutive expression of mRNAs encoding hypoxia-inducible proteins, such as Vascular endothelial growth factor. Overproduction of angiogenic factors might explain why VHL-/- RCC tumors are so highly vascularized, but whether this overproduction is sufficient for oncogenesis still remains unknown. In this report, we examined the activity of transforming growth factor-alpha (TGF-alpha), another VHL-regulated growth factor. We show that TGF-alpha mRNA and protein are hypoxia-inducible in VHL-/- RCC cells expressing reintroduced VHL, In addition to its overexpression by VHL-/- RCC cells, TGF-alpha can also act as a specific growth-stimulatory factor for VHL-/- RCC cells expressing reintroduced wild-type VHL, as well as primary renal proximal tubule epithelial cells, the likely site of origin of RCC, This role is in contrast to those of other growth factors overexpressed by VHL-/- RCC. cells, such as vascular endothelial growth factor and TGF-beta1, which do not stimulate RCC cell proliferation. A TGF-cr-specific antisense oligodeoxynucleotide blocked TGF-alpha production in VHL-/- RCC cells, which led to the dependence of those cells on exogenous growth factors to sustain growth in culture. Growth of VHL-/- RCC cells was also significantly reduced by a drug that specifically inhibits the epidermal growth factor receptor, the receptor through which TGF-alpha stimulates proliferation. These results suggest that the generation of a TGF-alpha autocrine loop as a consequence of VHL inactivation in renal proximal tubule epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis. C1 Max Planck Inst Biochem, D-82152 Martinsried, Germany. Univ Ottawa, Fac Med, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada. Univ Ottawa, Fac Med, Kidney Res Ctr, Ottawa, ON K1H 8M5, Canada. NCI, Off Director, NIH, Bethesda, MD 20814 USA. Louisiana State Univ, Hlth Sci Ctr, Stanely S Scott Canc Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. RP Lee, S (reprint author), Boehringer Ingelheim Canada, Res & Dev, 2100 Cunard St, Laval, PQ H7S 2G5, Canada. NR 35 TC 143 Z9 148 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2001 VL 98 IS 4 BP 1387 EP 1392 DI 10.1073/pnas.031587498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200017 PM 11171960 ER PT J AU Umland, TC Taylor, KL Rhee, S Wickner, RB Davies, DR AF Umland, TC Taylor, KL Rhee, S Wickner, RB Davies, DR TI The crystal structure of the nitrogen regulation fragment of the yeast prion protein Ure2p SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GLUTATHIONE S-TRANSFERASES; SACCHAROMYCES-CEREVISIAE; 3-DIMENSIONAL STRUCTURE; ACTIVE-SITE; ARABIDOPSIS-THALIANA; ESCHERICHIA-COLI; DIFFRACTION DATA; IN-VITRO; ARCHITECTURE; DOMAIN AB The yeast nonchromosomal gene [URE3] is due to a prion form of the nitrogen regulatory protein Ure2p. It is a negative regulator of nitrogen catabolism and acts by inhibiting the transcription factor Gln3p. Ure2p residues 1-80 are necessary for prion generation and propagation. The C-terminal fragment retains nitrogen regulatory activity, albeit somewhat less efficiently than the full-length protein, and it also lowers the frequency of prion generation. The crystal structure of this C-terminal fragment, Ure2p(97-354), at 2.3 A resolution is described here. It adopts the same fold as the glutathione S-transferase superfamily. consistent with their sequence similarity. However, Ure2p(97-354) lacks a properly positioned catalytic residue that is required for S-transferase activity. Residues within this regulatory fragment that have been indicated by mutational studies to influence prion generation have been mapped onto the three-dimensional structure, and possible implications for prion activity are discussed. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biochem & Genet Lab, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Umland, Timothy/0000-0002-0772-9510 NR 52 TC 89 Z9 90 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2001 VL 98 IS 4 BP 1459 EP 1464 DI 10.1073/pnas.041607898 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200030 PM 11171973 ER PT J AU Wang, GA Gu, PD Kaufman, S AF Wang, GA Gu, PD Kaufman, S TI Mutagenesis of the regulatory domain of phenylalanine hydroxylase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT-LIVER; STRUCTURAL BASIS; ESCHERICHIA-COLI; ACTIVATION; PHENYLKETONURIA; LYSOLECITHIN; STIMULATION; ENZYME AB The regulatory domain of phenylalanine hydroxylase (PAH. EC 1.14.16.1) consists of more than 100 amino acids at the N terminus, the removal of which significantly activates the enzyme. To study the regulatory properties controlled by the N terminus, a series of truncations and site-specific mutations were made in this region of rat PAH. These enzymes were expressed highly in Escherichia coli and purified through a pterin-conjugated Sepharose affinity column. The removal of the first 26 amino acids of the N terminus increased the activity by about 20-fold, but removal of the first 15 amino acids increased the activity by only 2-fold. Replacing serine-29 of rat PAH with cysteine from the same site of human PAH increased the activity by more than 4-fold. Mutation of serine to other amino acids with varying side chains: alanine, methionine, leucine, aspartic acid, asparagine, and arginine also resulted in significant activation. indicating a serine-specific inhibitory effect. But these site-specific mutants showed 30-40% lower activity when assayed with 6-methyl-5,6,7,8-tetrahydropterin, Stimulation of hydroxylase activity by preincubation of the enzyme with phenylalanine was inversely proportional to the activation state of all these mutants. Combined with recent crystal structures of PAH [Kobe, B. et al. (1999) Nat. Struct. Biol, 6, 442-448; and Erlandsen, H., Bjorgo, E., Flatmark, T. & Stevens, R. C, (2000) Biochemistry 39, 2208-2217], these data suggest that residues 16-26 have a controlling regulatory effect on the activity by interaction with the dihydroxypropyl side chain of (6R)-5,6,7,8-tetrahydrobiopterin. The serine/cysteine switch explains the difference in regulatory properties between human and rat PAH. The IU terminus as a whole is important for maintaining rat PAH in an optimum catalytic conformation. C1 NIMH, Neurochem Lab, Bethesda, MD 20892 USA. RP Wang, GA (reprint author), MIT, Dept Biol, 77 Massachusetts Ave,68-380, Cambridge, MA 02139 USA. NR 29 TC 15 Z9 15 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 FEB 13 PY 2001 VL 98 IS 4 BP 1537 EP 1542 DI 10.1073/pnas.031561698 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200043 PM 11171986 ER PT J AU Zhu, WZ Zheng, M Koch, WJ Lefkowitz, RJ Kobilka, BK Xiao, RP AF Zhu, WZ Zheng, M Koch, WJ Lefkowitz, RJ Kobilka, BK Xiao, RP TI Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta-adrenergic receptor subtypes; G proteins; apoptosis ID CONGESTIVE-HEART-FAILURE; ACTIVATED PROTEIN-KINASE; TRANSGENIC MICE; VENTRICULAR MYOCYTES; AKT PHOSPHORYLATION; GENE-TRANSFER; APOPTOSIS; RECEPTOR; PATHWAY; HYPERTROPHY AB The goal of this study was to determine whether beta (1)-adrenergic receptor (AR) and beta (2)-AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac beta (2)-AR can activate both G(s) and G(i) proteins, whereas cardiac beta (1)-AR couples only to G(s). To avoid complicated crosstalk between beta -AR subtypes, we expressed beta (1)-AR or beta (2)-AR individually in adult beta (1)/beta (2)-AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of beta (1)-AR, but not beta (2)-AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, beta (2)-AR (but not beta (1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), C-beta gamma, or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively. This indicates that beta (2)-AR activates Akt via a G(i)-G(beta gamma)-PI3K pathway. More importantly, inhibition of the G(i)-G beta gamma -PI3K-Akt pathway converts beta (2)-AR signaling from survival to apoptotic, Thus, stimulation of a single class of receptors, beta (2)-ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G(i)-G(beta gamma)-PI3K-Akt signaling pathway. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA. Stanford Univ, Med Ctr, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Xiao, RP (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NR 44 TC 269 Z9 288 U1 0 U2 8 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 FEB 13 PY 2001 VL 98 IS 4 BP 1607 EP 1612 DI 10.1073/pnas.98.4.1607 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200055 PM 11171998 ER PT J AU Fishman, D Irena, B Kellman-Pressman, S Karas, M Segal, S AF Fishman, D Irena, B Kellman-Pressman, S Karas, M Segal, S TI The role of MHC class I glycoproteins in the regulation of induction of cell death in immunocytes by malignant melanoma cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MARROW GRAFT-REJECTION; FAS-LIGAND; T-CELLS; DIFFERENTIAL EXPRESSION; METASTATIC PROPERTIES; TUMOR-CELLS; ANTIGEN; CANCER; COUNTERATTACK; INHIBITION AB A deranged expression of MHC class I glycoproteins, characteristic of a variety of malignancies, contributes to the ability of cancer to avoid destruction by T cell-mediated immunity. An abrogation of the metastatic capacity of B16 melanoma cells has been achieved by transfecting an MHC class I-encoding vector into class I-deficient B16 melanoma clones [Gorelik, E., Kim, M., Duty, L. & Calili, U. (1993) Clin. Exp. Metastasis 11, 439-452]. We report here that the deranged expression of class I molecules by B16 melanoma cells is more than a mere acquisition of the capacity to escape immune recognition. Namely, cells of the B16 melanoma prompted splenic lymphocytes to commit death after coculture, However, a class I-expressing and nonmetastatic CL8-2 clone was found to be less potent as an inducer of apoptosis than class I-deficient and metastatic BL9 and BL12 clones. Both Thy1.2(+) and Thy1,2(-) splenocytes underwent cell death when exposed to the class I-deficient BL9 clone. A proportion of CD4(+) and CD8(+) cells among splenocytes exposed to the BL9 clone was lower than that observed in a coculture with cells of the CL8-2 clone. Consistently, none of the melanoma clones studied produced a ligand to the FAS receptor (FAS-L). Thus, our results provide evidence that (i) the production of FAS-L may not be the sole mechanism by which malignant cells induce apoptosis in immunocytes, and (ii) absence of MHC class I glycoproteins plays an important role in preventing the elimination of potential effector immunocytes by tumor cells. C1 Ben Gurion Univ Negev, Fac Hlth Sci, Deans Off, Ctr Canc Res,Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel. NIH, Diabet Branch, Bethesda, MD 20892 USA. RP Segal, S (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Deans Off, Ctr Canc Res,Dept Microbiol & Immunol, POB 653, IL-84105 Beer Sheva, Israel. NR 29 TC 14 Z9 14 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 FEB 13 PY 2001 VL 98 IS 4 BP 1740 EP 1744 DI 10.1073/pnas.041591298 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200078 PM 11172021 ER PT J AU Tijms, MA van Dinten, LC Gorbalenya, AE Snijder, EJ AF Tijms, MA van Dinten, LC Gorbalenya, AE Snijder, EJ TI A zinc finger-containing papain-like protease couples subgenomic mRNA synthesis to genome translation in a positive-stranded RNA virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EQUINE ARTERITIS VIRUS; DEHYDROGENASE-ELEVATING VIRUS; REPLICASE ORF1A PROTEIN; SINDBIS VIRUS; STRUCTURAL PROTEINS; MINUS-STRAND; IDENTIFICATION; SEQUENCES; COMPLEX; RECOMBINATION AB The genome expression of positive-stranded RNA viruses starts with translation rather than transcription. For some viruses, the genome is the only viral mRNA and expression is regulated primarily at the translational level and by limited proteolysis of polyproteins. Other virus groups also generate subgenomic mRNAs later in the reproductive cycle. For nidoviruses, subgenomic mRNA synthesis (transcription) is discontinuous and yields a 5' and 3' coterminal nested set of mRNAs, Nidovirus transcription is not essential for genome replication, which relies on the autoprocessing products of two replicase polyproteins that are translated from the genome. We now show that the N-terminal replicase subunit, nonstructural protein 1 (nsp1), of the nidovirus equine arteritis virus is in fact dispensable for replication but crucial for transcription, thereby coupling replicase expression and subgenomic mRNA synthesis in an unprecedented manner. Nsp1 is composed of two papain-like protease domains and a predicted N-terminal zinc finger, which was implicated in transcription by site-directed mutagenesis, The structural integrity of nsp1 is essential, suggesting that the protease domains form a platform for the zinc finger to operate in transcription. C1 Leiden Univ, Med Ctr, Ctr Infect Dis, Dept Virol, NL-2300 RC Leiden, Netherlands. NCI, Sci Applicat Int Corp, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Gorbalenya, AE (reprint author), Leiden Univ, Med Ctr, Ctr Infect Dis, Dept Virol, POB 9600, NL-2300 RC Leiden, Netherlands. RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-56000] NR 47 TC 81 Z9 92 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 FEB 13 PY 2001 VL 98 IS 4 BP 1889 EP 1894 DI 10.1073/pnas.041390398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 401VL UT WOS:000166949200103 PM 11172046 ER PT J AU Tian, XR Hsin, LW Webster, EL Contoreggi, C Chrousos, GP Gold, PW Habib, K Ayala, A Eckelman, WC Jacobson, AE Rice, KC AF Tian, XR Hsin, LW Webster, EL Contoreggi, C Chrousos, GP Gold, PW Habib, K Ayala, A Eckelman, WC Jacobson, AE Rice, KC TI The development of a potential single photon emission computed tomography (SPECT) imaging agent for the corticotropin-releasing hormone receptor type 1 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID PITUITARY; BRAIN AB A high-affinity radioligand for CRHR1 has been prepared that can serve as a template For the development of SPECT imaging agents. The 5-chloro-N-cyclopropylmethyl-N-(2,6-dichloro-4-iodophenyl)-2-methyl-N-propylpyrimidine-4,6-diamine (6b, K-i= 14 nM). and the corresponding 4-bromophenyl analogue (6a, K-i = 21 nM), were synthesized in four steps from compound 3. Published by Elsevier Science Ltd. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDA, Brain Imaging Unit, Baltimore, MD 21224 USA. NICHD, Pediat Endocrinol Sect, PREB,Clin Ctr, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. OI HSIN, LING-WEI/0000-0001-5018-4491 NR 12 TC 18 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 12 PY 2001 VL 11 IS 3 BP 331 EP 333 DI 10.1016/S0960-894X(00)00661-2 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 399BE UT WOS:000166790300013 PM 11212103 ER PT J AU Sizemore, J Mitre, E AF Sizemore, J Mitre, E TI Leg pain in a patient with chronic hepatitis C SO LANCET LA English DT Editorial Material ID VIBRIO-VULNIFICUS C1 Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. NIAID, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), NIH, Bldg 4 Room B1-09, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 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 FEB 10 PY 2001 VL 357 IS 9254 BP 440 EP 440 DI 10.1016/S0140-6736(00)04009-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 400HF UT WOS:000166865600014 PM 11273065 ER PT J AU Dasso, M AF Dasso, M TI Running on ran: Nuclear transport and the mitotic spindle SO CELL LA English DT Review ID MICROTUBULE; DYNAMICS; CYCLE C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 18,Room 106,18 Lib Dr MSC-5431, Bethesda, MD 20892 USA. OI Dasso, Mary/0000-0002-5410-1371 NR 19 TC 130 Z9 132 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 9 PY 2001 VL 104 IS 3 BP 321 EP 324 DI 10.1016/S0092-8674(01)00218-5 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 402RZ UT WOS:000167003100001 PM 11239388 ER PT J AU Liu, JH Akoulitchev, S Weber, A Ge, H Chuikov, S Libutti, D Wang, XW Conaway, JW Harris, CC Conaway, RC Reinberg, D Levens, D AF Liu, JH Akoulitchev, S Weber, A Ge, H Chuikov, S Libutti, D Wang, XW Conaway, JW Harris, CC Conaway, RC Reinberg, D Levens, D TI Defective interplay of activators and repressors with TFIIH in xeroderma pigmentosum SO CELL LA English DT Article ID RNA-POLYMERASE-II; GENERAL TRANSCRIPTION FACTORS; FAR UPSTREAM ELEMENT; C-MYC; PROMOTER ESCAPE; TERMINAL DOMAIN; IN-VIVO; DNA; INITIATION; COMPLEX AB Inherited mutations of the TFIIH helicase subunits xeroderma pigmentosum (XP) B or XPD yield overlapping DNA repair and transcription syndromes. The high risk of cancer in these patients is not fully explained by the repair defect. The transcription defect is subtle and has proven more difficult to evaluate. Here, XPB and XPD mutations are shown to block transcription activation by the FUSE Binding Protein (FBP), a regulator of c-myc expression, and repression by the FBP Interacting Repressor (FIR). Through TFIIH, FBP facilitates transcription until promoter escape, whereas after initiation, FIR uses TFIIH to delay promoter escape. Mutations in TFIIH that impair regulation by FBP and FIR affect proper regulation of c-myc expression and have implications in the development of malignancy. C1 NCI, Gene Regulat Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem, Div Nucl Acids Enzymol,HHMI, Piscataway, NJ 08854 USA. Oklahoma Med Res Fdn, Program Mol & Cell Biol, Oklahoma City, OK 73104 USA. RP Levens, D (reprint author), NCI, Gene Regulat Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009; Levens, David/C-9216-2009; OI Levens, David/0000-0002-7616-922X; Conaway, Joan/0000-0002-2786-0663 FU NIGMS NIH HHS [R37 GM41628, GM48518, GM37120] NR 70 TC 93 Z9 98 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 9 PY 2001 VL 104 IS 3 BP 353 EP 363 DI 10.1016/S0092-8674(01)00223-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 402RZ UT WOS:000167003100006 PM 11239393 ER PT J AU Petrotchenko, EV Pedersen, LC Borchers, CH Tomer, KB Negishi, M AF Petrotchenko, EV Pedersen, LC Borchers, CH Tomer, KB Negishi, M TI The dimerization motif of cytosolic sulfotransferases SO FEBS LETTERS LA English DT Article DE sulfotransferase; protein-protein interaction; mass spectrometry; crystal structure; site-directed mutagenesis ID CRYSTAL-STRUCTURE; ESTROGEN SULFOTRANSFERASE; SULFATION AB Cytosolic sulfotransferases sulfate steroids such as estrogens and hydroxysteroids. The enzymes, including human estrogen sulfotransferase (hEST) and hydroxysteroid sulfotransferase (hHST), are generally homodimers in solution with mouse estrogen sulfotransferase (mEST) being one of few exceptions. To identify the amino acid residues responsible for the dimerization, eight residues on the surface of hEST mere mutated to their counterparts in mEST and mutated hESTs were then analyzed by gel filtration chromatography. A single mutation of Val(269) to Glu was sufficient to convert hEST to a monomer and the corresponding mutation of Val(260) also altered hHST to a monomer. The hHST crystal structure revealed a short stretch of peptide with the side-chains from two hHST monomers forming a hydrophobic zipper-like structure enforced by ion pairs at both ends. This peptide consisted of 10 residues near the C-terminus that, including the critical Val residue, is conserved as KXXXTVXXXE in nearly all cytosolic sulfotransferases, When mEST underwent the double mutations Pro269Thr/Glu270Val dimerization resulted. Thus, the KXXXTVXXXE sequence appears to be the common protein-protein interaction motif that mediates the homo- as well as heterodimerization of cytosolic sulfotransferases. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 NR 20 TC 55 Z9 56 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 9 PY 2001 VL 490 IS 1-2 BP 39 EP 43 DI 10.1016/S0014-5793(01)02129-9 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 402VB UT WOS:000167007900008 PM 11172807 ER PT J AU Ellis, CE Schwartzberg, PL Grider, TL Fink, DW Nussbaum, RL AF Ellis, CE Schwartzberg, PL Grider, TL Fink, DW Nussbaum, RL TI alpha-Synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG-TERM POTENTIATION; T-CELL ACTIVATION; A-BETA COMPONENT; ALZHEIMERS-DISEASE; C-SRC; PARKINSONS-DISEASE; SYNAPTIC VESICLES; MUTATION; IDENTIFICATION; ASSOCIATION AB alpha -Synuclein (alpha -Syn) is implicated in the pathogenesis of Parkinson's Disease, genetically through missense mutations linked to early onset disease and pathologically through its presence in Lewy bodies. alpha -Syn is phosphorylated on serine residues; however, tyrosine phosphorylation of alpha -Syn has not been established (1, 2). A comparison of the protein sequence between Synuclein family members revealed that all four tyrosine residues of alpha -Syn are conserved in all orthologs and beta -Syn paralogs described to date, suggesting that these residues may be of functional importance (3). For this reason, experiments were performed to determine whether alpha -Syn could be phosphorylated on tyrosine residue(s) in human cells. Indeed, alpha -Syn is phosphorylated within 2 min of pervanadate treatment in alpha -Syn-transfected cells. Tyrosine phosphorylation occurs primarily on tyrosine 125 and was inhibited by PP2, a selective inhibitor of Src protein-tyrosine kinase (PTK) family members at concentrations consistent with inhibition of Src function (4). Finally, we demonstrate that alpha -Syn can be phosphorylated directly both in cotransfection experiments using c-Src and Fyn expression vectors and in in vitro kinase assays with purified kinases. These data suggest that alpha -Syn can be a target for phosphorylation by the Src family of PTKs. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Lab Stem Cell Biol Neurotroph Factors, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. NR 42 TC 89 Z9 92 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 9 PY 2001 VL 276 IS 6 BP 3879 EP 3884 DI 10.1074/jbc.M010316200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401HB UT WOS:000166921200023 PM 11078745 ER PT J AU Bortner, CD Gomez-Angelats, M Cidlowski, JA AF Bortner, CD Gomez-Angelats, M Cidlowski, JA TI Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OUTWARD POTASSIUM CURRENT; PROGRAMMED CELL-DEATH; HUMAN LYMPHOCYTE-T; GATED K+ CHANNELS; PERMEABILITY TRANSITION; NEURONAL APOPTOSIS; FLOW-CYTOMETRY; AMINO-ACIDS; ION-CHANNEL; X-RAY AB The movement of intracellular monovalent cations has previously been shown to play a critical role in events leading to the characteristics associated with apoptosis. A loss of intracellular potassium and sodium occurs during apoptotic cell shrinkage establishing an intracellular environment favorable for nuclease activity and caspase activation. We have now investigated the potential movement of monovalent ions in Jurkat cells that occur prior to cell shrinkage following the induction of apoptosis. A rapid increase in intracellular sodium occurs early after apoptotic stimuli suggesting that the normal negative plasma membrane potential may change during cell death, We report here that diverse apoptotic stimuli caused a rapid cellular depolarization of Jurkat T-cells that occurs prior to and after cell shrinkage. In addition to the early increase in intracellular Na+, Rb-86(+) studies reveal a rapid inhibition of K+ uptake in response to anti-Fas. These effects on Na+ and K+ ions were accounted far by the inactivation of the Na+/K+-ATPase protein and its activity. Furthermore, ouabain, a cardiac glycoside inhibitor of the Na+/K+-ATPase, potentiated anti-Fas-induced apoptosis. Finally, activation of an anti-apoptotic signal, i.e. protein kinase C, prevented both cellular depolarization in response to anti-Pas and all downstream characteristics associated with apoptosis. Thus cellular depolarization is an important early event in anti-Pas-induced apoptosis, and the inability of cells to repolarize via inhibition of the Na+/K+-ATPase is a likely regulatory component of the death process. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 106 Z9 109 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 9 PY 2001 VL 276 IS 6 BP 4304 EP 4314 DI 10.1074/jbc.M005171200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401HB UT WOS:000166921200077 PM 11050080 ER PT J AU Kumari, D Usdin, K AF Kumari, D Usdin, K TI Interaction of the transcription factors USF1, USF2, and alpha-Pal/Nrf-1 with the FMR1 promoter - Implications for Fragile X mental retardation syndrome SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TISSUE-SPECIFIC EXPRESSION; TRANSGENIC MICE; BINDING-PROTEIN; GENE; CELLS; REACTIVATION; METHYLATION; INSTABILITY; INITIATION; REGION AB Hypermethylation of the FMR1 promoter reduces its transcriptional activity, resulting in the mental retardation and macroorchidism characteristic of Fragile X syndrome. How exactly methylation causes transcriptional silencing is not known but is relevant if current attempts to reactivate the gene are to be successful. Understanding the effect of methylation requires a better understanding of the factors responsible for FMR1 gene expression, To this end we have identified five evolutionarily conserved transcription factor binding sites in this promoter and shown that four of them are important for transcriptional activity in neuronally derived cells. We have also shown that USF1, USF2, and alpha -Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. We also show that methylation abolishes alpha -Pal/Nrf-1 binding to the promoter and affects binding of USF1 and USF2 to a lesser degree. Methylation may therefore inhibit FMR1 transcription not only by recruiting histone deacetylases but also by blocking transcription factor binding. This suggests that for efficient reactivation of the FMR1 promoter, significant demethylation must occur and that current approaches to gene reactivation using histone deacetylase inhibitors alone may therefore have limited effect. C1 NIDDK, Sect Genomic Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Genomic Struct & Funct, Mol & Cellular Biol Lab, NIH, Bldg 8,Rm 202,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. NR 28 TC 56 Z9 57 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 9 PY 2001 VL 276 IS 6 BP 4357 EP 4364 DI 10.1074/jbc.M009629200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401HB UT WOS:000166921200084 PM 11058604 ER PT J AU Kawai, J Shinagawa, A Shibata, K Yoshino, M Itoh, M Ishii, Y Arakawa, T Hara, A Fukunishi, Y Konno, H Adachi, J Fukuda, S Aizawa, K Izawa, M Nishi, K Kiyosawa, H Kondo, S Yamanaka, I Saito, T Okazaki, Y Gojobori, T Bono, H Kasukawa, T Saito, R Kadota, K Matsuda, H Ashburner, M Batalov, S Casavant, T Fleischmann, W Gaasterland, T Gissi, C King, B Kochiwa, H Kuehl, P Lewis, S Matsuo, Y Nikaido, I Pesole, G Quackenbush, J Schriml, LM Staubli, F Suzuki, R Tomita, M Wagner, L Washio, T Sakai, K Okido, T Furuno, M Aono, H Baldarelli, R Barsh, G Blake, J Boffelli, D Bojunga, N Carninci, P de Bonaldo, MF Brownstein, MJ Bult, C Fletcher, C Fujita, M Gariboldi, M Gustincich, S Hill, D Hofmann, M Hume, DA Kamiya, M Lee, NH Lyons, P Marchionni, L Mashima, J Mazzarelli, J Mombaerts, P Nordone, P Ring, B Ringwald, M Rodriguez, I Sakamoto, N Sasaki, H Sato, K Schonbach, C Seya, T Shibata, Y Storch, KF Suzuki, H Toyo-oka, K Wang, KH Weitz, C Whittaker, C Wilming, L Wynshaw-Boris, A Yoshida, K Hasegawa, Y Kawaji, H Kohtsuki, S Hayashizaki, Y AF Kawai, J Shinagawa, A Shibata, K Yoshino, M Itoh, M Ishii, Y Arakawa, T Hara, A Fukunishi, Y Konno, H Adachi, J Fukuda, S Aizawa, K Izawa, M Nishi, K Kiyosawa, H Kondo, S Yamanaka, I Saito, T Okazaki, Y Gojobori, T Bono, H Kasukawa, T Saito, R Kadota, K Matsuda, H Ashburner, M Batalov, S Casavant, T Fleischmann, W Gaasterland, T Gissi, C King, B Kochiwa, H Kuehl, P Lewis, S Matsuo, Y Nikaido, I Pesole, G Quackenbush, J Schriml, LM Staubli, F Suzuki, R Tomita, M Wagner, L Washio, T Sakai, K Okido, T Furuno, M Aono, H Baldarelli, R Barsh, G Blake, J Boffelli, D Bojunga, N Carninci, P de Bonaldo, MF Brownstein, MJ Bult, C Fletcher, C Fujita, M Gariboldi, M Gustincich, S Hill, D Hofmann, M Hume, DA Kamiya, M Lee, NH Lyons, P Marchionni, L Mashima, J Mazzarelli, J Mombaerts, P Nordone, P Ring, B Ringwald, M Rodriguez, I Sakamoto, N Sasaki, H Sato, K Schonbach, C Seya, T Shibata, Y Storch, KF Suzuki, H Toyo-oka, K Wang, KH Weitz, C Whittaker, C Wilming, L Wynshaw-Boris, A Yoshida, K Hasegawa, Y Kawaji, H Kohtsuki, S Hayashizaki, Y CA RIKEN Genome Exploration Res Grp TI Functional annotation of a full-length mouse cDNA collection SO NATURE LA English DT Article ID CLONING; TOOL AB The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones. C1 Yokohama Inst, RIKEN Genom Sci Ctr, Lab Genome Explorat, Res Grp,Tsurumi Ku, Kanagawa 2300045, Japan. JST, CREST, Tsukuba, Ibaraki 3050074, Japan. Natl Inst Genet, Ctr Informat Biol, Shizuoka 4118540, Japan. NTT Software Corp, Naka Ku, Kanagawa 2318554, Japan. Osaka Univ, Osaka 5608531, Japan. European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. Univ Iowa, Coordinated Lab Computat Genom, Iowa City, IA 52242 USA. Rockefeller Univ, New York, NY 10021 USA. Univ Milan, Dipartimento Fisiol & Biochim Gen, I-20133 Milan, Italy. Jackson Lab, Bar Harbor, ME 04609 USA. Keio Univ, Fac Environm Informat, Lab Bioinformat, Kanagawa 2520816, Japan. Univ Maryland, Dept Mol & Cell Biol, Baltimore, MD 20201 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Yokohama Inst, RIKEN Genom Sci Ctr, Bioinformat Grp, Computat Proteom Team,Tsurumi Ku, Kanagawa 2300045, Japan. Tokai Univ, Grad Sch Marine Sci & Technol, Shizuoka 4248610, Japan. Inst Genom Res, Rockville, MD 20850 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. LION Biosci AG, D-69120 Heidelberg, Germany. Stanford Univ, Sch Med, Beckman Ctr B271A, Stanford, CA 94305 USA. Lawrence Berkeley Lab, Berkeley, CA 94710 USA. Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. NIMH, Genet Lab, NHGRI, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1138655, Japan. Ist Tumori Milano, I-20133 Milan, Italy. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. Univ Cambridge, Addenbrookes Hosp, Wellcome Trust Ctr Mol Mechanisms Dis, Dept Med Genet, Cambridge CB2 2XY, England. LNCIB, I-34012 Trieste, Italy. Univ Penn, Ctr Bioinformat, Computat & Bioinformat Lab, Philadelphia, PA 19104 USA. Univ Buffalo, Roswell Pk Canc Inst, Amherst, NY 14226 USA. Stanford Univ, Dept Genet, Beckman Ctr B281, Stanford, CA 94305 USA. RIKEN, Brain Sci Inst, Wako, Saitama 3510198, Japan. Natl Canc Res Inst, Chuo Ku, Tokyo 1040045, Japan. Yokohama Inst, RIKEN Genom Sci Ctr, Bioinformat Grp, Computat Genom Team,Tsurumi Ku, Kanagawa 2300045, Japan. Osaka Med Ctr Canc, Higashinari Ku, Osaka 5378511, Japan. Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. MIT, Ctr Learning & Memory, Cambridge, MA 02139 USA. MIT, MIT CCR, Cambridge, MA 02139 USA. Sanger Ctr, Hinxton CB10 1SA, Cambs, England. Univ Tsukuba, Tsukuba, Ibaraki 3058577, Japan. RP Kawai, J (reprint author), Yokohama Inst, RIKEN Genom Sci Ctr, Lab Genome Explorat, Res Grp,Tsurumi Ku, 1-7-22 Suehiro Cho, Kanagawa 2300045, Japan. RI Seya, Tsukasa/A-4336-2012; Konno, Hideaki/A-9191-2012; shibata, kazuhiro/A-9527-2008; Brownstein, Michael/B-8609-2009; Saito, Takashi/C-9684-2009; Pesole, Graziano/C-1408-2009; Hume, David/C-7695-2013; Mashima, Jun/F-3706-2010; Pesole, Graziano/E-9051-2014; NIKAIDO, Itoshi/K-2058-2014; Carninci, Piero/K-1568-2014; Konno, Hideaki/N-4366-2014; Kasukawa, Takeya/N-5070-2015; Kadota, Koji/C-9168-2011; Itoh, Masayoshi/N-5363-2015; Suzuki, Harukazu/N-9553-2015; Wang, Kuan Hong/J-1150-2016; Kawai, Jun/A-6451-2016; Schonbach, Christian/B-1998-2009; Kawaji, Hideya/N-5116-2015; gariboldi, manuela/K-4744-2016; OI Saito, Takashi/0000-0001-9495-3547; Pesole, Graziano/0000-0003-3663-0859; Mashima, Jun/0000-0003-4138-1893; Pesole, Graziano/0000-0003-3663-0859; NIKAIDO, Itoshi/0000-0002-7261-2570; Carninci, Piero/0000-0001-7202-7243; Konno, Hideaki/0000-0002-8470-4835; Kasukawa, Takeya/0000-0001-5085-0802; Schriml, Lynn/0000-0001-8910-9851; Blake, Judith/0000-0001-8522-334X; Bono, Hidemasa/0000-0003-4413-0651; Itoh, Masayoshi/0000-0002-1772-318X; Suzuki, Harukazu/0000-0002-8087-0836; Wang, Kuan Hong/0000-0002-2249-5417; Schonbach, Christian/0000-0002-0693-7617; Kawaji, Hideya/0000-0002-0575-0308; gariboldi, manuela/0000-0001-8406-165X; Gissi, Carmela/0000-0002-2269-079X; Lewis, Suzanna/0000-0002-8343-612X NR 26 TC 475 Z9 504 U1 2 U2 22 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 8 PY 2001 VL 409 IS 6821 BP 685 EP 690 DI 10.1038/35055500 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MF UT WOS:000166816400034 PM 11217851 ER PT J AU Sukharev, S Betanzos, M Chiang, CS Guy, HR AF Sukharev, S Betanzos, M Chiang, CS Guy, HR TI The gating mechanism of the large mechanosensitive channel MscL SO NATURE LA English DT Article ID ESCHERICHIA-COLI; ION-CHANNEL; SINGLE RESIDUE; PROTEIN; PRESSURE; HELIX AB The mechanosensitive channel of large conductance, MscL, is a ubiquitous membrane-embedded valve involved in turgor regulation in bacteria(1-5). The crystal structure of MscL from Mycobacterium tuberculosis(6) provides a starting point for analysing molecular mechanisms of tension-dependent channel gating. Here we develop structural models in which a cytoplasmic gate is formed by a bundle of five amino-terminal helices (S1), previously unresolved in the crystal structure. When membrane tension is applied, the transmembrane barrel expands and pulls the gate apart through the S1-M1 linker. We tested these models by substituting cysteines for residues predicted to be near each other only in either the closed or open conformation. Our results demonstrate that S1 segments form the bundle when the channel is closed, and crosslinking between S1 segments prevents opening. S1 segments interact with M2 when the channel is open, and crosslinking of S1 to M2 impedes channel closing. Gating is affected by the length of the S1-M1 linker in a manner consistent with the model, revealing critical spatial relationships between the domains that transmit force from the lipid bilayer to the channel gate. C1 Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NCI, Lab Expt & Computat Biol, DBS, NIH, Bethesda, MD 20892 USA. RP Sukharev, S (reprint author), Univ Maryland, Dept Biol, Bldg 144, College Pk, MD 20742 USA. NR 21 TC 251 Z9 263 U1 1 U2 18 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 8 PY 2001 VL 409 IS 6821 BP 720 EP 724 DI 10.1038/35055559 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 399MF UT WOS:000166816400044 PM 11217861 ER PT J AU Yang, HS Jansen, AP Nair, R Shibahara, K Verma, AK Cmarik, JL Colburn, NH AF Yang, HS Jansen, AP Nair, R Shibahara, K Verma, AK Cmarik, JL Colburn, NH TI A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappa B or ODC transactivation SO ONCOGENE LA English DT Article DE pdcd4; AP-1; NF-kappa B; transformation ID MOUSE EPIDERMAL-CELLS; NEOPLASTIC TRANSFORMATION; TUMOR PROMOTION; JB6 CELLS; TRANSCRIPTIONAL REGULATION; ANCHORAGE INDEPENDENCE; HUMAN KERATINOCYTES; TRANSGENIC MICE; EXPRESSION; ACTIVATION AB Pdcd4 is a novel transformation suppressor that is highly expressed in promotion-resistant (P-) mouse epidermal JB6 cells but not in susceptible (P+) cells. Overexpression of pdcd4 cDNA in stably transfected P+ cells rendered cells resistant to tumor promoter-induced transformation, indicating that elevated expression of Pdcd4 protein is sufficient to suppress neoplastic transformation. To determine whether Pdcd4 suppresses neoplastic transformation through inhibiting known transformation required events, se examined the possibility that pdcd4 inhibited the activation of AP-1 or NF-kappaB dependent transcription or of ornithine decarboxylase (ODC) activity. Activation of AP-1-dependent transcriptional activity mas inhibited bai pdcd4 expression in a concentration dependent manner. In contrast, Pdcd4 slightly increased NF-kappaB-dependent transcription and did not alter ODC enzymatic activity. Previous studies suggested that activation of AP-1 was required for P+ cell transformation as well as for tumor promotion in vivo. These results indicate that Pdcd4 functions as a transformation suppressor, possibly through inhibiting AP-1 activation in combination with other factors such as enhancing NF-kappaB activation. Pdcd4 may thus constitute a useful molecular target for cancer prevention. C1 NCI, Basic Res Lab, Gene Regulat Sect, Frederick, MD 21702 USA. Univ Wisconsin, Sch Med, Dept Human Oncol, Madison, WI 53792 USA. Kyoto Univ, Sakyo Ku, Kyoto 606, Japan. RP Yang, HS (reprint author), NCI, Basic Res Lab, Gene Regulat Sect, Frederick, MD 21702 USA. RI Yang, Hsin-Sheng/A-6419-2008 NR 41 TC 134 Z9 139 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 8 PY 2001 VL 20 IS 6 BP 669 EP 676 DI 10.1038/sj.onc.1204137 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 399HR UT WOS:000166806000002 PM 11314000 ER PT J AU Johnson, CA Sofer, A AF Johnson, CA Sofer, A TI A primal-dual method for large-scale image reconstruction in emission tomography SO SIAM JOURNAL ON OPTIMIZATION LA English DT Article DE tomography; estimation; large-scale problems; parallel computation; applications of nonlinear programming; primal-dual methods ID PENALIZED LIKELIHOOD ESTIMATION; EXPECTATION MAXIMIZATION ALGORITHM; TRUNCATED-NEWTON METHODS; INTERIOR-POINT METHOD; EM ALGORITHM; MAXIMUM-LIKELIHOOD; BAYESIAN RECONSTRUCTION; ITERATIVE RECONSTRUCTION; TRANSMISSION TOMOGRAPHY; 3D RECONSTRUCTION AB In emission tomography, images can be reconstructed from a set of measured projections using a maximum likelihood( ML) criterion. In this paper, we present a primal-dual algorithm for large-scale three-dimensional image reconstruction. The primal-dual method is specialized to the ML reconstruction problem. The reconstruction problem is extremely large; in several of our data sets the Hessian of the objective function is the product of a 1.4 million by 63 million matrix and its scaled transpose. As such, we consider only approaches that are suitable for large-scale parallel computation. We apply a stabilization technique to the system of equations for computing the primal direction and demonstrate the need for stabilization when approximately solving the system using an early-terminated conjugate gradient iteration. We demonstrate that the primal-dual method for this problem converges faster than the logarithmic barrier method and considerably faster than the expectation maximization algorithm. The use of extrapolation in conjunction with the primal-dual method further reduces the overall computation required to achieve convergence. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. George Mason Univ, Dept Syst Engn & Operat Res, Fairfax, VA 22030 USA. RP Johnson, CA (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 2 Z9 2 U1 0 U2 0 PU SIAM PUBLICATIONS PI PHILADELPHIA PA 3600 UNIV CITY SCIENCE CENTER, PHILADELPHIA, PA 19104-2688 USA SN 1052-6234 J9 SIAM J OPTIMIZ JI SIAM J. Optim. PD FEB 8 PY 2001 VL 11 IS 3 BP 691 EP 715 DI 10.1137/S1052623497330148 PG 25 WC Mathematics, Applied SC Mathematics GA 414PK UT WOS:000167675100006 ER PT J AU Treanor, JJ Wilkinson, BE Masseoud, F Hu-Primmer, J Battaglia, R O'Brien, D Wolff, M Rabinovich, G Blackwelder, W Katz, JM AF Treanor, JJ Wilkinson, BE Masseoud, F Hu-Primmer, J Battaglia, R O'Brien, D Wolff, M Rabinovich, G Blackwelder, W Katz, JM TI Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans SO VACCINE LA English DT Article; Proceedings Paper CT ECPI World Vaccine Congress CY SEP 27-29, 1999 CL GENEVA, SWITZERLAND DE avian influenza; vaccines; clinical trials ID HEALTHY-ADULTS; A VIRUSES; HONG-KONG; ANTIBODY; RESPONSES; DISEASE AB Recent outbreaks of avian influenza in humans have demonstrated the need for vaccines for influenza viruses with pandemic potential. Recombinant hemagglutinins are an attractive option for such vaccines because they do not require handling potentially highly pathogenic influenza viruses for vaccine production. In order to evaluate the immunogenicity, optimum dosing and timing of administration of a recombinant baculovirus-expressed H5 HA (rH5) in humans, 147 healthy adults were assigned randomly to receive intramuscular rH5 as two doses of 25, 45 or 90 mug each, one dose of 90 mug followed by a dose of 10 mug, or two doses of placebo, at intervals between doses of 21, 18 or 42 days. All doses of rH5 were well tolerated. The rH5 vaccine was modestly immunogenic at high dose. Neutralizing antibody responses to a titer of 1:80 or greater were seen in 23% (14/60) of individuals after a single dose of 90 mug, and in 52% (15/29) after two doses of 90 mug. Varying intervals between doses from 21 to 42 days had no significant effect on antibody responses to vaccination. These results suggest that baculovirus-expressed H5 HA can induce functional antibody in individuals who have not had prior exposure to H5 viruses, but that further studies to improve the immunogenicity of the vaccine are needed. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Rochester, Infect Dis Unit, Rochester, NY 14642 USA. Prot Sci Inc, Meriden, CT USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Influenza Branch, Atlanta, GA USA. EMMES Corp, Rockville, MD USA. NIAID, Bethesda, MD 20892 USA. RP Treanor, JJ (reprint author), Univ Rochester, Infect Dis Unit, 601 Elmwood Ave, Rochester, NY 14642 USA. FU NCRR NIH HHS [M01 RR00044]; PHS HHS [A1 45248] NR 18 TC 255 Z9 271 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 FEB 8 PY 2001 VL 19 IS 13-14 BP 1732 EP 1737 DI 10.1016/S0264-410X(00)00395-9 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 402NN UT WOS:000166995200024 PM 11166898 ER PT J AU Xiao, DM Wang, JN Hampton, LL Weber, HC AF Xiao, DM Wang, JN Hampton, LL Weber, HC TI The human gastrin-releasing peptide receptor gene structure, its tissue expression and promoter SO GENE LA English DT Article DE bombesin; gene regulation; human cancer; polymorphisms ID CELL LUNG-CANCER; BOMBESIN-LIKE PEPTIDES; GRPR LOCUS; BREAST; HYBRIDIZATION; CARCINOMA; MOUSE; TUMOR AB The human gastrin-releasing peptide receptor (hGRP-R) is aberrantly expressed in cancers of the colon, lung and prostate and mediates signals of cellular proliferation. However, the underlying mechanisms of aberrant and/or activation of hCRP-R expression are unknown. Therefore, a genomic clone is identified, the hGRP-R gene is characterized, and the hCRP-R promoter is defined. The protein coding region is divided into three exons and exon/intron splice sites occur in the proximal 2nd and distal 3rd intracellular loops of the receptor molecule. The hGRP-R locus extends over more than 27 kb and is assigned to the chromosomal band Xp22 by fluorescence in situ hybridization. With primer extension experiments, we demonstrate two major transcription start sites in gastrointestinal and breast cancer cells, located 43 and 36 bp downstream of a TTTAAA motif which is identified 407 to 402 bp upstream of the ATG start codon. The hGRP-R is found most abundantly expressed in the normal human pancreas, where four gene-specific transcripts can be detected by Northern blot analysis, whereas only two transcripts are detected in the human stomach and, very weakly, in the adrenal cortex and the brain. In contrast, the human GRP-R is not expressed in the normal human colon, lung, and prostate. Steady state hGRP-R mRNA can also be detected in some cultured cells from breast, lung, and duodenal cancer. Robust hGRP-R promoter activity is demonstrated in a duodenal carcinoma cell line that natively expresses the functional hCRP-R. Truncation studies suggest a CRE motif, located 112 bp upstream of the major transcription start site, is required to confer basal hGRP-R promoter activity in duodenal cancer cells. These studies provide the necessary data to further elucidate molecular mechanisms of aberrant hGRP-R expression in human cancers. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Boston Univ, Sch Med, Gastroenterol Sect, Boston, MA 02118 USA. Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. RP Weber, HC (reprint author), Boston Univ, Sch Med, Gastroenterol Sect, 650 Albany St,EBRC,5th Floor, Boston, MA 02118 USA. NR 32 TC 57 Z9 59 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 FEB 7 PY 2001 VL 264 IS 1 BP 95 EP 103 DI 10.1016/S0378-1119(00)00596-5 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 412BQ UT WOS:000167534500012 PM 11245983 ER PT J AU Collins, FS McKusick, VA AF Collins, FS McKusick, VA TI Implications of the Human Genome Project for medical science SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DNA-SEQUENCE; GENE-EXPRESSION; THERAPY; DISEASE AB The year 2000 marked both the start of the new millennium and the announcement that the vast majority of the human genome had been sequenced. Much work remains to understand how this "instruction book for human biology" carries out its multitudes of functions. But the consequences for the practice of medicine are likely to be profound. Genetic prediction of individual risks of disease and responsiveness to drugs will reach the medical mainstream in the next decade or so. The development of designer drugs, based on a genomic approach to targeting molecular pathways that are disrupted in disease, will follow soon after. Potential misuses of genetic information, such as discrimination in obtaining health insurance and in the workplace, will need to be dealt with swiftly and effectively. Genomic medicine holds the ultimate promise of revolutionizing the diagnosis and treatment of many illnesses. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Collins, FS (reprint author), NHGRI, NIH, 31 Ctr Dr,MSC 2152,Bldg 31,Room 4B09, Bethesda, MD 20892 USA. EM fc23a@nih.gov NR 27 TC 366 Z9 382 U1 3 U2 32 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 7 PY 2001 VL 285 IS 5 BP 540 EP 544 DI 10.1001/jama.285.5.540 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 397TV UT WOS:000166714200008 PM 11176855 ER PT J AU Blumberg, RS Strober, W AF Blumberg, RS Strober, W TI Prospects for research in inflammatory bowel disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CROHNS-DISEASE; ULCERATIVE-COLITIS; MICE; INTERLEUKIN-12; ANTIBODIES; CELLS; ALPHA AB Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract that manifests as ulcerative colitis and Crohn disease. Both these clinical entities result from interrelated genetic and environmental factors that may be channeled through an abnormality in mucosal immune function, possibly due to dysregulated or excessive T helper cell (T-H)1 (Crohn disease) or T(H)2 (ulcerative colitis) responses. This article reviews current knowledge of the role of immune factors in inflammatory bowel disease and the potential therapeutic strategies that target the pathways of T(H)1- or T(H)2-induced inflammation. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. NIH, Mucosal Immun Sect, Bethesda, MD USA. RP Blumberg, RS (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. NR 25 TC 89 Z9 102 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 7 PY 2001 VL 285 IS 5 BP 643 EP 647 DI 10.1001/jama.285.5.643 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 397TV UT WOS:000166714200027 PM 11176874 ER PT J AU Bewley, CA AF Bewley, CA TI Rapid validation of the overall structure of an internal domain-swapped mutant of the anti-HIV protein cyanovirin-N using residual dipolar couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID INACTIVATING PROTEIN; NMR STRUCTURES RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 19 TC 24 Z9 24 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 7 PY 2001 VL 123 IS 5 BP 1014 EP 1015 DI 10.1021/ja005714o PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 399ZJ UT WOS:000166843900042 PM 11456652 ER PT J AU Limburg, PJ Qiao, YL Mark, SD Wang, GQ Perez-Perez, GI Blaser, MJ Wu, YP Zou, XN Dong, ZW Taylor, PR Dawsey, SM AF Limburg, PJ Qiao, YL Mark, SD Wang, GQ Perez-Perez, GI Blaser, MJ Wu, YP Zou, XN Dong, ZW Taylor, PR Dawsey, SM TI Helicobacter pylori seropositivity and subsite-specific gastric cancer risks in Linxian, China SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GASTROESOPHAGEAL REFLUX DISEASE; SQUAMOUS-CELL CARCINOMA; INTESTINAL METAPLASIA; SOCIOECONOMIC-STATUS; BARRETTS-ESOPHAGUS; MONGOLIAN GERBILS; CAGA(+) STRAINS; YOUNG-ADULTS; INFECTION; ADENOCARCINOMA AB Background: Helicobacter pylori carriage (i.e., persistent exposure to the organism without gastric epithelial cell invasion) is an established risk factor for noncardia gastric cancer, However, its association with the risk of cancer of the gastric cardia is controversial. Consequently, we designed this prospective, nested case-control study to further explore the subsite-specific gastric cancer risks associated with H. pylori seropositivity (a surrogate marker for persistent exposure), Methods: A total of 99 patients with gastric cardia cancer, 82 patients with noncardia gastric cancer, and 192 cancer-free subjects were selected from among the participants (n = 29 584) of a nutrition intervention trial previously conducted in Linxian, China. H, pylori seropositivity was determined by assaying for the presence of H. pylori whole cell and CagA antibodies in baseline serum samples from all subjects. Seropositivity was defined as one or both serum assays being positive. Odds ratios (ORs) for subsite-specific gastric cancer were estimated by multivariate logistic regression analyses. All statistical comparisons were two-sided (alpha =.05), Results: H, pylori seropositivity rates for subjects with gastric cardia cancer, noncardia gastric cancer, and gastric cardia and noncardia cancers combined were 70% (P = .02), 72% (P = .01), and 71% (P = .003) compared with 56% for cancer-free control subjects. OR estimates for H. pylori seropositivity were 1.87 (95% confidence interval [CI] = 1.10 to 3.17) for gastric cardia cancer, 2.29 (95% CI = 1.26 to 4.14) for noncardia gastric cancer, and 2.04 (95% CI = 1.31 to 3.18) for gastric cardia and noncardia cancers combined. Conclusions: H. pylori seropositivity was associated with increased risks for both gastric cardia cancer and noncardia gastric cancer in this well-characterized cohort. Thus, H. pylori carriage may increase the risk of cancer throughout the stomach. C1 Vet Affairs Med Ctr, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Div Infect Dis, Nashville, TN 37212 USA. Chinese Acad Med Sci, Inst Canc, Beijing 100037, Peoples R China. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Prevent Studies Branch, Biostat Branch, Bethesda, MD 20892 USA. RP Limburg, PJ (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, 200 1st St SW, Rochester, MN 55905 USA. RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 62 TC 75 Z9 78 U1 0 U2 4 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 7 PY 2001 VL 93 IS 3 BP 226 EP 233 DI 10.1093/jnci/93.3.226 PG 8 WC Oncology SC Oncology GA 399WJ UT WOS:000166837000013 PM 11158192 ER PT J AU Blagosklonny, MV AF Blagosklonny, MV TI Re: Role of the heat shock response and molecular chaperones in oncogenesis and cell death SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID P53; MDM2; DEGRADATION; STABILITY C1 NCI, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Blagosklonny, MV (reprint author), NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. NR 7 TC 13 Z9 16 U1 0 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 7 PY 2001 VL 93 IS 3 BP 239 EP 240 PG 2 WC Oncology SC Oncology GA 399WJ UT WOS:000166837000018 PM 11158196 ER PT J AU Huff, J AF Huff, J TI Re: Journal to encourage analysis by sex/ethnicity SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID CELL-PROLIFERATION; CARCINOGENESIS; CANCER C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 7 PY 2001 VL 93 IS 3 BP 239 EP 239 DI 10.1093/jnci/93.3.239 PG 1 WC Oncology SC Oncology GA 399WJ UT WOS:000166837000017 PM 11158197 ER PT J AU Dauter, Z Dauter, M AF Dauter, Z Dauter, M TI Entering a new phase: Using solvent halide ions in protein structure determination SO STRUCTURE LA English DT Article ID ANOMALOUS SCATTERING; SIGNAL; REFINEMENT; LYSOZYME; COMPLEX; SULFUR; ATOM C1 NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Upton, NY 11973 USA. NSLS, Upton, NY 11973 USA. SAIC Intramural Res Support Program, Upton, NY 11973 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Upton, NY 11973 USA. NR 21 TC 36 Z9 36 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD FEB 7 PY 2001 VL 9 IS 2 BP R21 EP R26 DI 10.1016/S0969-2126(01)00565-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 421FB UT WOS:000168050500001 PM 11250204 ER PT J AU Newman, AB Arnold, AM Burke, GL O'Leary, DH Manolio, TA AF Newman, AB Arnold, AM Burke, GL O'Leary, DH Manolio, TA TI Cardiovascular disease and mortality in older adults with small abdominal aortic aneurysms detected by ultrasonography: The cardiovascular health study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RISK-FACTORS; PREVALENCE; ATHEROSCLEROSIS; SURVEILLANCE; RUPTURE; FATE AB Background: Persons with abdominal aortic aneurysm are more likely to have a higher prevalence of risk factors for and clinical manifestations of cardiovascular disease. It is unknown whether these factors explain the high mortality rate associated with abdominal aortic aneurysm. Objective: To describe the risk for mortality, cardiovascular mortality, and cardiovascular morbidity in persons screened for abdominal aortic aneurysm. Design: Longitudinal cohort study. Setting: Four communities in the United States. Participants: 4734 men and women older than 65 years of age recruited from Medicare eligibility lists. Measurements: Abdominal ultrasonography was used to measure the aortic diameter and the ratio of infrarenal to suprarenal measurement of aortic diameter in 1992-1993. Abdominal aortic aneurysm was defined as aortic diameter of 3 cm or greater or infrarenal-to-suprarenal ratio of 1.2 or greater. Mortality, cardiovascular disease mortality, incident cardiovascular disease, and repair or rupture were assessed after 4.5 years. Results: The prevalence of aneurysm was 8.8%, and 87.7% of aneurysms were 3.5 cm or less in diameter, Rates of total mortality (65.1 vs. 32.8 per 1000 person-years), cardiovascular mortality (34.3 vs. 13.8 per 1000 person-years), and incident cardiovascular disease (47.3 vs. 31.0 per 1000 person-years) were higher in participants with aneurysm than in those without aneurysm; after adjustment for age, risk factors, and presence of other cardiovascular disease, the respective relative risks were 1.32, 1.36, and 1.57. Rates of repair and rupture were low. Conclusions: Rates of total mortality, cardiovascular disease mortality, and incident cardiovascular disease were higher in participants with abdominal aortic aneurysm than in those without aneurysm, independent of age, sex, other clinical cardiovascular disease, and extent of atherosclerosis detected by noninvasive testing. Persons with smaller aneurysms detected by ultrasonography should be advised to modify risk factors for cardiovascular disease while under surveillance for increase in the size of the aneurysm. C1 Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. Univ Washington, Seattle, WA 98195 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Tufts New England Med Ctr, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. RP Newman, AB (reprint author), Univ Pittsburgh, Sch Med, Div Geriatr Med, 3520 5th Ave,Suite 300, Pittsburgh, PA 15213 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 24 TC 89 Z9 94 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 FEB 6 PY 2001 VL 134 IS 3 BP 182 EP 190 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 397KR UT WOS:000166695300002 PM 11177330 ER PT J AU Lovett, BD Strumberg, D Blair, IA Pang, SK Burden, DA Megonigal, MD Rappaport, EF Rebbeck, TR Osheroff, N Pommier, YG Felix, CA AF Lovett, BD Strumberg, D Blair, IA Pang, SK Burden, DA Megonigal, MD Rappaport, EF Rebbeck, TR Osheroff, N Pommier, YG Felix, CA TI Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints SO BIOCHEMISTRY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ANTITUMOR DRUG ETOPOSIDE; EUKARYOTIC TOPOISOMERASE; CLUSTER REGION; CHROMOSOMAL BREAKPOINTS; RECIPROCAL EXCHANGE; CYTOCHROME-P450 3A4; RELIGATION REACTION; SEQUENCE-ANALYSIS; CHO CELLS AB Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis of leukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint cluster region in a DNA topoisomerase II-dependent manner Like the parent drug and the nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase Bo, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1) among the unique sites, which differs from the parent drug. Cleavage at most:sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained within the substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays using the same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may be relevant to translocations. C1 Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Canc Pharmacol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Canc, Philadelphia, PA 19104 USA. NCI, Div Canc Treatment, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. RP Felix, CA (reprint author), Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. RI Blair, Ian/B-3320-2010 FU NCI NIH HHS [CA66140, CA77683, CA80175 , +] NR 65 TC 63 Z9 64 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2001 VL 40 IS 5 BP 1159 EP 1170 DI 10.1021/bi002361x PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 399YQ UT WOS:000166842200004 PM 11170441 ER PT J AU Root, DD Wang, K AF Root, DD Wang, K TI High-affinity actin-binding nebulin fragments influence the ActoS1 complex SO BIOCHEMISTRY LA English DT Article ID FLUORESCENCE ENERGY-TRANSFER; SKELETAL-MUSCLE SARCOMERE; MYOSIN SUBFRAGMENT-1; THIN-FILAMENTS; F-ACTIN; MONOCLONAL-ANTIBODIES; PROTEIN; ASSOCIATION; SITE; POLYMERIZATION AB Human nebulin fragments, NA3 and NA4, corresponding to individual superrepeats display high-affinity interactions with individual actin protomers in cosedimentation and solid-phase binding assays. Stoichiometric analysis of nebulin fragment-induced actin polymerization and inhibition of actin-activated S1 ATPase indicate that one superrepeat influences multiple actin molecules along the F-actin filament, consistent with a combination of strong and weak interactions of nebulin over the length of the actin filament. The mechanisms by which human nebulin fragments affect the interaction between actin and myosin S1 are studied by fluorescence quenching, polarization, and resonance energy transfer. We show that, under strong binding conditions, premixing actin with the NA3 prior to adding myosin subfragment 1 (S1) inhibits the rate of actoS1 association. The nebulin fragments, NA3 and NA4, caused little effect on the extent of actoS1 binding at equilibrium but did alter the nature of the complex as evidenced by an increase in the resonance energy transfer efficiencies between S1 and actin in the absence of ATP. The addition of low concentrations of ATP rapidly dissociates the strong-binding actoS1 irrespective of the presence or absence of nebulin fragment. Interestingly, the strongly bound state reforms rapidly after S1 hydrolyzes all available ATP. These observations are consistent with the notion that nebulin might contribute to optimizing the alignment of actomyosin interactions and inhibit suboptimal actomyosin contacts. C1 Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. Univ N Texas, Dept Biol Sci, Denton, TX 76203 USA. NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, K (reprint author), Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. FU NIAMS NIH HHS [AR43512, AR44737] NR 65 TC 26 Z9 26 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2001 VL 40 IS 5 BP 1171 EP 1186 DI 10.1021/bi0015010 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 399YQ UT WOS:000166842200005 PM 11170442 ER PT J AU Maki, AH Ozarowski, A Misra, A Urbaneja, MA Casas-Finet, JR AF Maki, AH Ozarowski, A Misra, A Urbaneja, MA Casas-Finet, JR TI Phosphorescence and optically detected magnetic resonance of HIV-1 nucleocapsid protein complexes with stem-loop sequences of the genomic Psi-recognition element SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; DNA BINDING-PROTEIN; ZINC-FINGER; RNA RECOGNITION; NUCLEIC-ACIDS; IN-VIVO; TYPE-1; TRYPTOPHAN; MUTANTS AB The binding of NCp7, the nucleocapsid protein of human immunodeficiency virus type I, to oligonucleotide stem-loop (SL) sequences of the genomic Psi -recognition element has been studied using fluorescence, phosphorescence, and optically detected magnetic resonance (ODMR). RNA SL2, SL3, and SL4 constructs bind with higher affinity than the corresponding DNAs. G to I substitutions in the SL3 DNA loop sequence lead to reduced binding affinity and significant changes in the triplet state properties of Trp37 of NCp7, implicating these bases in contacts with aromatic amino acid residues of the zinc finger domains of NCp7, in agreement with the NMR structure of the 1:1 complex of NCp7 and SL3 RNA [DeGuzman, R. N., Wu, Z. R., Stalling, C. C., Pappaladro, L., Borer, P. N., and Summers, M. F. (1998) Science 279, 384-388]. The NCp7 to SL binding stoichiometry is 2:1 for intact SL sequences but is reduced to 1:I for SL variants with an abasic or hydrocarbon loop. It is proposed that DeltaD/DeltaE(0),(0) where DeltaD is the change in the zero-field splitting D parameter and DeltaE(0,0) is the shift of the tryptophan phosphorescence origin, provides a measure of aromatic stacking interactions with nucleic acid bases. Values on the order of 10(-5) indicate significant stacking interactions, while values closer to 10(-6) result from interactions not involving aromatic stacking. Binding of NCp7 to oligonucleotide substrates produces shortened Trp37 triplet state lifetimes by enhancement of k(x) and an increase of the relative value of P-x, the intersystem crossing rate to the T-x sublevel. These effects are attributed to a reduction in the degree of electronic symmetry of Trp37 in the complexes. Guanine and adenine triplet states produced by optical pumping of SL3 DNA are characterized. We find, as with tryptophan, that /D/ < 3/E/. C1 Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. EM maki@chem.ucdavis.edu FU NIEHS NIH HHS [ES-02662]; PHS HHS [N01-56000] NR 46 TC 27 Z9 28 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 FEB 6 PY 2001 VL 40 IS 5 BP 1403 EP 1412 DI 10.1021/bi002010i PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 399YQ UT WOS:000166842200031 PM 11170468 ER PT J AU Padayatty, SJ Levine, M AF Padayatty, SJ Levine, M TI New insights into the physiology and pharmacology of vitamin C SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID TERMINAL HUMAN CANCER; ASCORBIC-ACID; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT; SURVIVAL TIMES; PROLONGATION; VOLUNTEERS; TRANSPORT C1 NIDDKD, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDKD, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Rm 4D52-MSC 1372, Bethesda, MD 20892 USA. RI Padayatty, Sebastian/A-8581-2012 OI Padayatty, Sebastian/0000-0001-8758-3170 NR 16 TC 97 Z9 101 U1 2 U2 6 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD FEB 6 PY 2001 VL 164 IS 3 BP 353 EP 355 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 398QA UT WOS:000166766100016 PM 11232136 ER PT J AU Allessie, MA Boyden, PA Camm, AJ Kleber, AG Lab, MJ Legato, MJ Rosen, MR Schwartz, PJ Spooner, PM Van Wagoner, DR Waldo, AL AF Allessie, MA Boyden, PA Camm, AJ Kleber, AG Lab, MJ Legato, MJ Rosen, MR Schwartz, PJ Spooner, PM Van Wagoner, DR Waldo, AL TI Pathophysiology and prevention of atrial fibrillation SO CIRCULATION LA English DT Article DE risk factors; atrial fibrillation; prevention ID ACUTE MYOCARDIAL-INFARCTION; RECTIFYING K+-CHANNEL; CURRENT I-F; CARDIAC MYOCYTES; SLOW CONDUCTION; CATHETER ABLATION; IONIC MECHANISMS; CALCIUM CURRENTS; OUTWARD CURRENT; HEART-FAILURE C1 Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. Univ Limburg, NL-6200 MD Maastricht, Netherlands. Univ London St Georges Hosp, London SW17 0RE, England. Univ Bern, CH-3012 Bern, Switzerland. Univ London Imperial Coll Sci Technol & Med, London, England. Univ Pavia, I-27100 Pavia, Italy. NHLBI, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Rosen, MR (reprint author), Columbia Univ Coll Phys & Surg, Dept Pharmacol, 630 W 168th St,PH7W-321, New York, NY 10032 USA. RI Van Wagoner, David/C-6783-2008; Schwartz, Peter/J-4267-2016 OI Van Wagoner, David/0000-0001-8250-9828; Schwartz, Peter/0000-0003-0367-1048 NR 96 TC 417 Z9 446 U1 4 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 6 PY 2001 VL 103 IS 5 BP 769 EP 777 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 412NT UT WOS:000167561800026 PM 11156892 ER PT J AU Song, SG Lee, KS AF Song, SG Lee, KS TI A novel function of Saccharomyces cerevisiae Cdc5 in cytokinesis SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Cdc5; polo-box; mitosis; cytokinesis; septin ID ANAPHASE-PROMOTING COMPLEX; CELL-CYCLE PROGRESSION; MAMMALIAN POLO KINASE; BUD-SITE SELECTION; BUDDING YEAST; PROTEIN-KINASE; SCHIZOSACCHAROMYCES-POMBE; ACTIN CYTOSKELETON; CONTRACTILE RING; MITOTIC EXIT AB Coordination of mitotic exit with timely initiation of cytokinesis is critical to ensure completion of mitotic events before cell division. The Saccharomyces cerevisiae polo kinase Cdc5 functions in a pathway leading to the degradation of mitotic cyclin C1b2, thereby permitting mitotic exit. Here we provide evidence that Cdc5 also plays a role in regulating cytokinesis and that an intact polo-box, a conserved motif in the noncatalytic COOH-terminal domain of Cdc5, is required for this event. Depletion of Cdc5 function leads to an arrest in cytokinesis. Overexpression of the COOH-terminal domain of Cdc5 (cnc5 DeltaN), but not the corresponding polo-box mutant, resulted in connected cells. These cells shared cytoplasms with incomplete septa, and possessed aberrant septin ring structures. Provision of additional copies of endogenous CDCS remedied this phenotype, suggesting a dominant-negative inhibition of cytokinesis. The polo-box-dependent interactions between Cdc5 and septins (Cdc11 and Cdc12) and genetic interactions between the dominant-negative cdc5 DeltaN and Cyk2/Hof1 or Myo1 suggest that direct interactions between cdc5 DeltaN and septins resulted in inhibition of Cyk2/Hof1- and Myo1-mediated cytokinetic pathways. Thus, we propose that Cdc5 may coordinate mitotic exit with cytokinesis by participating in both anaphase promoting complex activation and a polo-box-dependent cytokinetic pathway. C1 NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP NCI, Lab Metab, Div Basic Sci, NIH, 9000 Rockville Pke,Bldg 37,Rm 3D25, Bethesda, MD 20892 USA. EM kyunglee@pop.nci.nih.gov NR 61 TC 86 Z9 86 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 5 PY 2001 VL 152 IS 3 BP 451 EP 469 DI 10.1083/jcb.152.3.451 PG 19 WC Cell Biology SC Cell Biology GA 400QK UT WOS:000166882900003 PM 11157974 ER PT J AU Ramesha, AR Kroth, H Jerina, DM AF Ramesha, AR Kroth, H Jerina, DM TI Novel trifluoroethanol mediated synthesis of benzo[a]pyrene 7,8-diol 9,10-epoxide adducts at the N-2-position of deoxyguanosine and the N-6-position of deoxyadenosine SO TETRAHEDRON LETTERS LA English DT Article DE benzo[a]pyrene; diol epoxides; dA acid dG adducts; trifluoroethanol ID POLYCYCLIC AROMATIC-HYDROCARBONS; SITE-SPECIFIC INCORPORATION; DNA OLIGOMER; DIHYDRODIOL; EPOXIDE AB The exocyclic amino groups of deoxyadenosine and deoxygnanosine readily add to C-10 of the benzo[il]pyrene 7,8-diol 9,10-epoxides at room temperature overnight in trifluorocthanol. Whereas the dG adducts are obtained as a mixture of cis- and trans-opened diastereomers, the dA adducts arise exclusively by cis-opening. Published by Elsevier Science Ltd. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 17 TC 9 Z9 9 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD FEB 5 PY 2001 VL 42 IS 6 BP 1003 EP 1005 DI 10.1016/S0040-4039(00)02220-6 PG 3 WC Chemistry, Organic SC Chemistry GA 400WJ UT WOS:000166894400010 ER PT J AU Koch, CA Sarlis, NJ AF Koch, CA Sarlis, NJ TI Multilocular thyroidectomy SO DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT LA German DT Letter C1 NIDDK, NICHD, NIH, Bethesda, MD 20892 USA. RP Koch, CA (reprint author), NIDDK, NICHD, NIH, Bldg 10,Rm 9D42, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008 OI Koch, Christian/0000-0003-3127-5739 NR 7 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0012-0472 J9 DEUT MED WOCHENSCHR JI Dtsch. Med. Wochenschr. PD FEB 2 PY 2001 VL 126 IS 5 BP 127 EP 127 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 398PC UT WOS:000166764000008 PM 11225390 ER PT J AU Brosh, RM Majumdar, A Desai, S Hickson, ID Bohr, VA Seidman, MM AF Brosh, RM Majumdar, A Desai, S Hickson, ID Bohr, VA Seidman, MM TI Unwinding of a DNA triple helix by the Werner and Bloom syndrome helicases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYNDROME GENE-PRODUCT; SINGLE-STRANDED-DNA; REPLICATION PROTEIN-A; BINDING-PROTEIN; HUMAN-CELLS; FORMING-OLIGONUCLEOTIDES; QUARTET STRUCTURES; MUTATOR PHENOTYPE; TELOMERIC DNA; 3RD STRAND AB Bloom syndrome and Werner syndrome are genome instability disorders, which result from mutations in two different genes encoding helicases, Both enzymes are members of the RecQ family of helicases, have a 3' --> 5' polarity, and require a 3' single strand tail. In addition to their activity in unwinding duplex substrates, recent studies show that the two enzymes are able to unwind G2 and G4 tetraplexes, prompting speculation that failure to resolve these structures in Bloom syndrome and Werner syndrome cells may contribute to genome instability. The triple helix is another alternate DNA structure that can be formed by sequences that are widely distributed throughout the human genome. Here we show that purified Bloom and Werner helicases can unwind a DNA triple helix. The reactions are dependent on nucleoside triphosphate hydrolysis and require a free 3' tail attached to the third strand. The two enzymes unwound triplexes without requirement for a duplex extension that would form a fork at the junction of the tail and the tripler. In contrast, a duplex formed by the third strand and a complement to the tripler region was a poor substrate for both enzymes. However, the same duplex was readily unwound when a noncomplementary 5' tail was added to form a forked structure. It seems likely that structural features of the tripler mimic those of a fork and thus support efficient unwinding by the two helicases. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Imperial Canc Res Fund Labs, Oxford OX3 9DS, England. RP Seidman, MM (reprint author), NIA, Mol Genet Lab, NIH, Box 1,GRC,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 95 TC 80 Z9 81 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3024 EP 3030 DI 10.1074/jbc.M006784200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900009 PM 11110789 ER PT J AU Li, JF Huang, FL Huang, KP AF Li, JF Huang, FL Huang, KP TI Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione - Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALMODULIN-BINDING-PROTEIN; CARBONIC-ANHYDRASE-III; KINASE-C SUBSTRATE; NITRIC-OXIDE; IN-VIVO; PHOSPHATASE-ACTIVITY; NITROSO-GLUTATHIONE; FATTY ACYLATION; CYSTEINE; THIOLS AB S-Nitrosoglutathione (GSNO) undergoes spontaneous degradation that generates several nitrogen-containing compounds and oxidized glutathione derivatives. We identified glutathione sulfonic acid, glutathione disulfide S-oxide (GS(O)SG), glutathione disulfide S-dioxide, and GSSG as the major decomposition products of GSNO. Each of these compounds and GSNO were tested for their efficacies to modify rat brain neurogranin/RC3 (Ng) and neuromodulin/GAP-43 (Nm), Among them, GS(O)SG was found to be the most potent in causing glutathiolation of both proteins; four glutathiones were incorporated into the four Cys residues of Ng, and two were incorporated into the two Cys residues of Nm. Ng and Nm are two in vivo substrates of protein kinase C; their phosphorylations by protein kinase C attenuate the binding affinities of both proteins for calmodulin. When compared with their respective unmodified forms, the glutathiolated Ng was a poorer substrate and glutathiolated Nm a better substrate for protein kinase C. Glutathiolation of these two proteins caused no change in their binding affinities for calmodulin. Treatment of [S-35]cysteine-labeled rat brain slices with xanthine/xanthine oxidase or a combination of xanthine/xanthine oxidase with sodium nitroprusside resulted in an increase in cellular level of GS(O)SG. These treatments, as well as those by other oxidants, all resulted in an increase in thiolation of proteins; among them, thiolation of Ng was positively identified by immunoprecipitation. These results show that GS(O)SG is one of the most potent glutathiolating agents generated upon oxidative stress. C1 NICHD, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Huang, KP (reprint author), NICHD, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. NR 40 TC 70 Z9 75 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3098 EP 3105 DI 10.1074/jbc.M008260200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900018 PM 11060308 ER PT J AU Sun, QA Zappacosta, F Factor, VM Wirth, PJ Hatfield, DL Gladyshev, VN AF Sun, QA Zappacosta, F Factor, VM Wirth, PJ Hatfield, DL Gladyshev, VN TI Heterogeneity within animal thioredoxin reductases - Evidence for alternative first exon splicing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SELENOCYSTEINE INSERTION-SEQUENCE; LUNG ADENOCARCINOMA CELLS; HELA-CELLS; FUNCTIONAL EXPRESSION; GENOMIC ORGANIZATION; CDNA CLONING; GENE; IDENTIFICATION; HEPARIN; PURIFICATION AB Animal thioredoxin reductases (TRs) are selenocysteine-containing flavoenzymes that utilize NADPH for reduction of thioredoxins and other protein and nonprotein substrates. Three types of mammalian TRs are known, with TR1 being a cytosolic enzyme, and TR3, a mitochondrial enzyme. Previously characterized TR1 and TR3 occurred as homodimers of 55-57-kDa subunits, We report here that TR1 isolated from mouse liver, mouse liver tumor, and a human T-cell line exhibited extensive heterogeneity as detected by electrophoretic, immunoblot, and mass spectrometry analyses. In particular, a 67-kDa band of TR1 was detected. Furthermore, a novel form of mouse TR1 cDNA encoding a 67-kDa selenoprotein subunit with an additional N-terminal sequence was identified. Subsequent homology analyses revealed three distinct isoforms of mouse and rat TR1 mRNA These forms differed in 5' sequences that resulted from the alternative use of the first three exons but had common downstream sequences. Similarly, expression of multiple mRNA forms was observed for human TR3 and Drosophila TR, In these genes, alternative first exon splicing resulted in the formation of predicted mitochondrial and cytosolic proteins. In addition, a human TR3 gene overlapped with the gene for catechol-O-methyltransferase (COMT) on a complementary DNA strand, such that mitochondrial TR3 and membrane-bound COMT mRNAs had common first exon sequences; however, transcription start sites for predicted cytosolic TR3 and soluble COMT forms were separated by similar to 30 kilobases, Thus, this study demonstrates a remarkable heterogeneity within TRs, which, at least in part, results from evolutionary conserved genetic mechanisms employing alternative first exon splicing. Multiple transcription start sites within TR genes may be relevant to complex regulation of expression and/or organelle- and cell type-specific location of animal thioredoxin reductases. C1 Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RI Gladyshev, Vadim/A-9894-2013 NR 36 TC 67 Z9 75 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3106 EP 3114 DI 10.1074/jbc.M004750200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900019 PM 11060283 ER PT J AU Hoegy, SE Oh, HR Corcoran, ML Stetler-Stevenson, WG AF Hoegy, SE Oh, HR Corcoran, ML Stetler-Stevenson, WG TI Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEPENDENT PROTEIN-KINASE; FACTOR RECEPTOR; CELL-SURFACE; IN-VITRO; PROMOTING ACTIVITY; GELATINASE-A; MATRIX; INVASION; BINDING; PROLIFERATION AB The tissue inhibitors of metalloproteinases (TIMPs) block matrix metalloproteinase (MMP)-mediated increases in cell proliferation, migration, and invasion that are associated with extracellular matrix (ECM) turnover. Here we demonstrate a direct role for TIMP-2 in regulating tyrosine kinase-type growth factor receptor activation. We show that TIMP-2 suppresses the mitogenic response to tyrosine kinase-type receptor growth factors in a fashion that is independent of MMP inhibition. The TIMP-2 suppression of mitogenesis is reversed by the adenylate cyclase inhibitor SQ22536, and implicates cAMP as the second messenger in these effects. TIMP-2 neither altered the release of transforming growth factor alpha from the cell surface, nor epidermal growth factor (EGF) binding to the cognate receptor, EGFR, TIMP-2 binds to the surface of AS49 cells in a specific and saturable fashion (K-d = 147 pM), that is not competed by the synthetic MMP inhibitor BB-94 and is independent of MT-1-MMP. TIMP-2 induces a decrease in phosphorylation of EGFR and a concomitant reduction in Grb-2 association. TIMP-2 prevents SH2-protein-tyrosine phosphatase-l (SHP-1) dissociation from immunoprecipitable EGFR complex and a selective increase in total SHP-1 activity. These studies represent a new functional paradigm for TIMP-2 in which TIMP suppresses EGF-mediated mitogenic signaling by short-circuiting EGFR activation. C1 NCI, Pathol Lab, Extracellular Matrix Pathol Sect, Div Clin Sci,NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Pathol Lab, Extracellular Matrix Pathol Sect, Div Clin Sci,NIH, Bldg 10,Room 2A33,MSC 1500, Bethesda, MD 20892 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 67 TC 79 Z9 85 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3203 EP 3214 DI 10.1074/jbc.M008157200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900031 PM 11042184 ER PT J AU Berg, BJV Beard, WA Wilson, SH AF Berg, BJV Beard, WA Wilson, SH TI DNA structure and aspartate 276 influence nucleotide binding to human DNA polymerase beta - Implication for the identity of the rate-limiting conformational change SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; BASE-EXCISION-REPAIR; DEPENDENT RNA-POLYMERASE; HEPATITIS-C VIRUS; CRYSTAL-STRUCTURE; KLENOW FRAGMENT; GAPPED DNA; REPLICATION FIDELITY; SECONDARY STRUCTURE; TERNARY COMPLEXES AB Structures of DNA polymerase (pol) beta bound to single-nucleotide gapped DNA had revealed that the lyase and pol domains form a "doughnut-shaped" structure altering the dNTP binding pocket in a fashion that is not observed when bound to non-gapped DNA, We have investigated dNTP binding to pol beta -DNA complexes employing steady-state and pre-steady-state kinetics. Although po beta has a kinetic scheme similar to other DNA polymerases, polymerization by pol beta is limited by at least two partially rate-limiting steps: a conformational change after dNTP ground-state binding and product release. The equilibrium binding constant, K-d(dNTP) decreased and the insertion efficiency increased with a one-nucleotide gapped DNA substrate, as compared with non-gapped DNA. Valine substitution for Asp(276), which interacts with the base of the incoming nucleotide, increased the binding affinity for the incoming nucleotide indicating that the negative charge contributed by Asp(276) weakens binding and that an interaction between residue 276 with the incoming nucleotide occurs during ground-state binding. Since the interaction between Asp276 and the nascent base pair is observed only in the "closed" conformation of pol beta, the increased free energy in ground-state binding for the mutant suggests that the subsequent rate-limiting conformational change is not the "open" to "closed" structural transition, but instead is triggered in the closed pol conformation. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 62 TC 12 Z9 12 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3408 EP 3416 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900056 ER PT J AU Zhang, M Dwyer, NK Neufeld, EB Love, DC Cooney, A Comly, M Patel, S Watari, H Strauss, JF Pentchev, PG Hanover, JA Blanchette-Mackie, EJ AF Zhang, M Dwyer, NK Neufeld, EB Love, DC Cooney, A Comly, M Patel, S Watari, H Strauss, JF Pentchev, PG Hanover, JA Blanchette-Mackie, EJ TI Sterol-modulated glycolipid sorting occurs in Niemann-Pick C1 late endosomes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; MANNOSE 6-PHOSPHATE RECEPTOR; CHOLESTEROL STORAGE; PRELYSOSOMAL COMPARTMENT; ENDOCYTIC PATHWAY; ONE SET; DISEASE; TRANSPORT; ACCUMULATION; FIBROBLASTS AB The Niemann-Pick C1 (NPC1) protein and endocytosed low density lipoprotein (LDL)-derived cholesterol were shown to enrich separate subsets of vesicles containing lysosomal associated membrane protein 2, Localization of Rab7 in the NPC1-containing vesicles and enrichment of lysosomal hydrolases in the cholesterol-containing vesicles confirmed that these organelles were late endosomes and lysosomes, respectively. Lyso-bisphosphatidic acid, a lipid marker of the late endosomal pathway, was found in the cholesterol-enriched lysosomes, Recruitment of NPC1 to Rab7 compartments was stimulated by cellular uptake of cholesterol, The NPC1 compartment was shown to be enriched ill glyco lipids, and internalization of GalNAc beta1-4[NeuAc alpha2-3]Gal beta1-4Glc beta1-1'-ceramide (G(M2)) into endocytic vesicles depends on the presence of NPC1 protein. The glycolipid profiles of the NPC1 compartment could be modulated by LDL uptake and accumulation of lysosomal cholesterol, Expression in cells of biologically active NPC1 protein fused to green fluorescent protein revealed rapidly moving and flexible tubular extensions emanating from the NPC1-containing vesicles. We conclude that the NPC1 compartment is a dynamic, sterol-modulated sorting organelle involved in the trafficking of plasma membrane-derived glycolipids as well as plasma membrane and endocytosed LDL cholesterol, C1 NINDK, Lipid Cell Biol Sect, NIH, Bethesda, MD 20892 USA. NINDK, Cell Biochem Sect, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Neurol Res Lab, Newington, CT 06111 USA. Univ Penn, Ctr Res & Reprod & Womens Hlth, Philadelphia, PA 19104 USA. RP Blanchette-Mackie, EJ (reprint author), NINDK, Lipid Cell Biol Sect, NIH, Bldg 8,Rm 427,MSC 0850, Bethesda, MD 20892 USA. NR 34 TC 90 Z9 92 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3417 EP 3425 DI 10.1074/jbc.M005393200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900057 PM 11032830 ER PT J AU Ichida, M Finkel, T AF Ichida, M Finkel, T TI Ras regulates NFAT3 activity in cardiac myocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; COUPLED RECEPTOR AGONISTS; MUSCLE CELL HYPERTROPHY; NUCLEAR FACTOR; T-CELLS; VENTRICULAR MYOCYTES; GENE-EXPRESSION; ALPHA(1)-ADRENERGIC RECEPTOR; SIGNAL-TRANSDUCTION; EFFECTOR PATHWAYS AB Multiple distinct signal transduction pathways have been implicated in the development of cardiac myocyte hypertrophy. These hypertrophic pathways include those regulated by the Ras superfamily of small GTPases and a separate calcineurin-regulated pathway that culminates in the activation of the transcription factor NFAT3, In this report, we demonstrate a functional interaction between Ras-regulated and calcineurin-regulated pathways. In particular, expression in neonatal myocytes of a constitutively active form of Res (V12ras), but not activating mutants of Rad, RhoA, or Cdc42, results in an increase in NFAT activity. Similarly, expression of an activated Ras, but not other small GTPases, results in the nuclear translocation of an NFAT3 fusion protein. Expression of a dominant negative ras gene product blocks phenylephrine-stimulated NEAT transcriptional activity and the ligand-stimulated NFAT3 nuclear localization. Res proteins appear to function upstream of calcineurin, because cyclosporin A blocks the ability of V12ras to stimulate NFAT-dependent transcription and nuclear localization. Similarly, expression of a dominant negative ras gene inhibits phenylephrine-stimulated calcineurin activity. Pharmacological inhibition of MEK1 or expression of a dominant negative form of c-Raf or ERK2 inhibits phenylephrine-stimulated NFAT3 activation Conversely, NEAT activity was stimulated by expression of constitutively active forms of c-Raf or MEK1, Taken together, these results imply that, in cardiac myocytes, a Res-regulated pathway involving stimulation of mitogen-activated protein kinase regulates NFAT3 activity. C1 NHLBI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Mol Biol Lab, NIH, Bldg 10,10-6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 46 TC 62 Z9 65 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3524 EP 3530 DI 10.1074/jbc.M004275200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900070 PM 11044444 ER PT J AU Ravichandran, LV Esposito, DL Chen, J Quon, MJ AF Ravichandran, LV Esposito, DL Chen, J Quon, MJ TI Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT ADIPOSE-CELLS; TYROSINE PHOSPHORYLATION; GLUCOSE-TRANSPORT; SH2 DOMAINS; STIMULATED TRANSLOCATION; SERINE PHOSPHORYLATION; POTENTIAL ROLE; TNF-ALPHA; IN-VIVO; IRS-1 AB Protein kinase C-zeta (PKC-zeta is a serine/threonine kinase downstream from phosphatidylinositol 3-kinase in insulin signaling pathways. However, specific substrates for PKC-zeta that participate in the biological actions of insulin have not been reported. In the present study, we identified insulin receptor substrate-1 (IRS-1) as a novel substrate for PKC-zeta Under in vitro conditions, wild-type PKC-C (but not kinase-deficient mutant :PKC-zeta significantly phosphorylated IRS-1, This phosphorylation was reversed by treatment with the serine-specific phosphatase, protein phosphatase 2A, In addition, the overexpression of PKC-zeta in NIH-3T3(IR) cells caused significant phosphorylation of cotransfected IRS-1 as demonstrated by [P-32]orthophosphate labeling experiments. In rat adipose cells, endogenous IRS-1 coimmunoprecipitated with endogenous PKC-5, and this association was increased S-fold upon insulin stimulation. Furthermore, the overexpression of PKC-zeta in NIH-3T3(IR) cells significantly impaired insulin-stimulated tyrosine phosphorylation of cotransfected IRS-1. Importantly, this was accompanied by impaired IRS-l-associated phosphatidylinositol 3-kinase activity. Taken together, our results raise the possibility that IRS-1 is a novel physiological substrate for PKC-5. Because PKC-5 is located downstream from IRS-1 and phosphatidylinositol 3-kinase in established insulin signaling pathways, PKC-C may participate in negative feedback pathways to IRS-1 similar to those described previously for Akt and GSK-3. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Univ G DAnnunzio, Dept Oncol & Neurosci, I-66013 Chieti, Italy. RP NHLBI, Cardiol Branch, NIH, Bldg 10,Rm 8C-218,10 Ctr Dr,MSC 1755, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008 FU Telethon [E.0606] NR 47 TC 164 Z9 170 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3543 EP 3549 DI 10.1074/jbc.M007231200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900073 PM 11063744 ER PT J AU Xu, WP Mimnaugh, E Rosser, MFN Nicchitta, C Marcu, M Yarden, Y Neckers, L AF Xu, WP Mimnaugh, E Rosser, MFN Nicchitta, C Marcu, M Yarden, Y Neckers, L TI Sensitivity of mature ErbB2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE; HETEROPROTEIN COMPLEX; STRESS PROTEINS; NEU ONCOGENE; ANSAMYCINS; FAMILY; TRANSFORMATION; IDENTIFICATION; EXPRESSION AB ErbB receptors are a family of ligand-activated tyrosine kinases that play a central role in proliferation, differentiation, and oncogenesis, ErbB2 is overexpressed in >25% of breast and ovarian cancers and is correlated with poor prognosis. Although ErbB2 and ErbB1 are highly homologous, they respond quite differently to geldanamycin (GA), an antibiotic that is a specific inhibitor of the chaperone protein Hsp90. Thus, although both mature and nascent ErbB2 proteins are down-regulated by GA, only nascent ErbB1 is sensitive to the drug. To reveal the underlying mechanism behind these divergent responses, we made a chimeric receptor (ErbB1/2) composed of the extracellular and transmembrane domains of ErbB1 and the intracellular domain of ErbB2. The ErbB1/2 protein is functional since its kinase activity was stimulated by epidermal growth factor. The sensitivity of ErbB1/2 to GA was similar to that of ErbB2 and unlike that of ErbB1, indicating that the intracellular domain of the chimera confers GA sensitivity. This finding also suggests that the GA sensitivity of mature ErbB2 depends on cytosolic Hsp90, rather than Grp94,a homolog of Hsp90 that is restricted to the lumen of the endoplasmic reticulum, although both chaperones bind to and are inhibited by GA Lack of Grp94 involvement in mediating ErbB2 sensitivity to GA is further suggested by the fact that a GA derivative with low affinity for Grp94 efficiently depleted ErbB2 protein in treated cells. To localize the specific region of ErbB2 that confers GA sensitivity, we made truncated receptors with progressive deletions of the cytoplasmic domain and tested the GA sensitivity of these molecules. We found that ErbB2 constructs containing an intact kinase domain retained GA sensitivity, whereas those lacking the kinase domain (ErbB2/DK) lost responsiveness to GA completely. Hsp90 co-immunoprecipitated with all ErbB2 constructs that were sensitive to GA, but not with ErbB2/DK or ErbB1, Both tyrosine-phosphorylated and non-phosphorylated ErbB2 proteins were similarly sensitive to GA, as was a kinase-dead ErbB2 mutant. These data suggest that Hsp90 uniquely stabilizes ErbB2 via interaction with its kinase domain and that GA stimulates ErbB2 degradation secondary to disruption of ErbB2/Hsp90 association. C1 NCI, Dept Cell & Canc Biol, Med Branch, NIH, Rockville, MD 20850 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. RP Neckers, L (reprint author), NCI, Dept Cell & Canc Biol, Med Branch, NIH, 9610 Med Ctr Dr,Suite 300, Rockville, MD 20850 USA. RI YARDEN, YOSEF/K-1467-2012 NR 32 TC 270 Z9 277 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 2 PY 2001 VL 276 IS 5 BP 3702 EP 3708 DI 10.1074/jbc.M006864200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 398YW UT WOS:000166784900094 PM 11071886 ER PT J AU Fagioli, I Barbato, G Wehr, TA AF Fagioli, I Barbato, G Wehr, TA TI Dynamics of electroencephalographic slow wave activity and body temperature during monophasic and biphasic human sleep SO NEUROSCIENCE LETTERS LA English DT Article DE extended night; sleep; electroencephalogram time course; body temperature; night awakening; light ID BACKGROUND ACTIVITY LEVEL; QUIET SLEEP; EEG; INFANTS AB Dynamics of electroencephalographic (EEG) slow wave activity (0.5-4.5 Hz) and body temperature, as estimates, respectively, of the process S and process C, regulating sleep and waking alternate occurrence, were measured during monophasic and biphasic sleep patterns that occurred spontaneously in a 35-year-old woman who lived for 105 days in a winter-type photoperiod (10-14 h light-dark). In monophasic nights, rate of EEG synchronization showed a decreasing trend across the first three non-rapid eye movement (NREM) periods. In biphasic nights, rate of EEG synchronization increased during the third NREM period which precedes the nocturnal awakening. Temperature cycle was not different between biphasic and monophasic nights. Those results confirm that EEG dynamics reflects homeostatic sleep regulatory mechanism, and suggest that the period of prolonged wakefulness in the middle of biphasic night is preprogrammed. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Florence, Dept Psychol, I-50125 Florence, Italy. Univ Naples 2, Dept Psychol, Naples, Italy. NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. RP Fagioli, I (reprint author), Univ Florence, Dept Psychol, Via S Niccolo 93, I-50125 Florence, Italy. RI Barbato, Giuseppe/Q-9774-2016 OI Barbato, Giuseppe/0000-0001-6523-5327 NR 14 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 2 PY 2001 VL 298 IS 2 BP 83 EP 86 DI 10.1016/S0304-3940(00)01686-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 425YF UT WOS:000168318700001 PM 11163283 ER PT J AU Misteli, T AF Misteli, T TI Nuclear structure - Protein dynamics: Implications for nuclear architecture and gene expression SO SCIENCE LA English DT Review ID POLYMERASE-II TRANSCRIPTION; GREEN FLUORESCENT PROTEIN; LIVING CELLS; RNA; ORGANIZATION; CHROMATIN; CYTOPLASM; MOVEMENT; COMPLEX; BIOLOGY C1 NCI, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, Bethesda, MD 20892 USA. NR 59 TC 441 Z9 459 U1 2 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 2 PY 2001 VL 291 IS 5505 BP 843 EP 847 DI 10.1126/science.291.5505.843 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 398TD UT WOS:000166771700035 PM 11225636 ER PT J AU Dauter, Z Li, M Wlodawer, A AF Dauter, Z Li, M Wlodawer, A TI Practical experience with the use of halides for phasing macromolecular structures: a powerful tool for structural genomics SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID INSENSITIVE CARBOXYL PROTEINASE; CRYSTAL-STRUCTURE; ANOMALOUS SIGNAL; REFINEMENT; CRYSTALLOGRAPHY; MAD; IDENTIFICATION; RESIDUES; SULFUR; GENE AB The crystal structure of pepstatin-insensitive carboxyl proteinase (PCP) from Pseudomonas sp. 101, an enzyme with no overall sequence similarity to any other proteinases of known structure, was solved using crystals soaked in sodium bromide solution and then cryocooled. A data set collected at the bromine peak absorption wavelength was sufficient for calculation of an excellent map and the entire process of phasing and tracing the maps required almost no direct human intervention. The process of structure solution using single-wavelength data was compared with three-wavelength multi-wavelength anomalous diffraction (MAD); although the latter resulted in slightly better maps, the use of this much more labor-intensive approach did not significantly improve the ability to solve the structure. The successful phasing approaches are compared with several less successful attempts utilizing other crystal forms of the enzyme and the practical aspects of the use of bromine as a heavy-atom derivative are discussed. In conclusion, the use of halides with single-wavelength diffraction data fulfills the requirements of being a first-choice method of high-throughput structure solution for the emerging field of structural genomics. C1 NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Program Struct Biol, Upton, NY 11973 USA. Brookhaven Natl Lab, NSLS, Upton, NY 11973 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. NCI, Prot Struct Sect, Macromol Crystallog Lab, Program Struct Biol,FCRDC, Frederick, MD 21702 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Program Struct Biol, Bldg 725A-X9, Upton, NY 11973 USA. EM dauter@bnl.gov NR 42 TC 55 Z9 59 U1 0 U2 0 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 FEB PY 2001 VL 57 BP 239 EP 249 DI 10.1107/S0907444900015249 PN 2 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 395TX UT WOS:000166598300009 PM 11173470 ER PT J AU Nathanson, N AF Nathanson, N TI Microbicides 2000 - March 13-16, Hilton Alexandria Mark Center Washington, DC - Conference Proceedings - Foreword SO AIDS LA English DT Editorial Material C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Nathanson, N (reprint author), NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP VII EP VII DI 10.1097/00002030-200102001-00001 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100002 ER PT J AU Blauvelt, A Cohen, S Kawamura, T Neurath, A Orenstein, J AF Blauvelt, A Cohen, S Kawamura, T Neurath, A Orenstein, J TI Ex vivo HIV-1 infection of human immature Langerhans cells within epithelial tissue explants: a novel model for sexual transmission of HIV-1 SO AIDS LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. New York Blood Ctr, New York, NY 10021 USA. George Washington Univ, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S40 EP S40 DI 10.1097/00002030-200102001-00058 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100054 ER PT J AU Coombs, RW Reichelderfer, PS Wright, DJ Burns, DN Cohn, J Cu-Uvin, S Baron, PA Cohen, MH Landay, AL Lewis, S Kovacs, A AF Coombs, RW Reichelderfer, PS Wright, DJ Burns, DN Cohn, J Cu-Uvin, S Baron, PA Cohen, MH Landay, AL Lewis, S Kovacs, A TI Compartmentalization of HIV-1 within the female genital tract: implications for assessing antiretroviral interventions. SO AIDS LA English DT Meeting Abstract ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNA LEVELS; BLOOD C1 Univ Washington, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. WESTAT Inc, Rockville, MD USA. Wayne State Univ, Detroit, MI USA. Miriam Hosp, Providence, RI 02906 USA. St Lukes Roosevelt Hosp Ctr, New York, NY USA. Cook Cty Hosp, Chicago, IL 60612 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ So Calif, Los Angeles, CA USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S26 EP S27 DI 10.1097/00002030-200102001-00038 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100034 ER PT J AU Lederman, M Mosier, D Arts, E Letvin, N Flexner, C Blauvelt, A Cairns, S Bridges, S Sarver, N Offord, R AF Lederman, M Mosier, D Arts, E Letvin, N Flexner, C Blauvelt, A Cairns, S Bridges, S Sarver, N Offord, R CA IP CP chemokine receptor inhibitor TI Rationale for testing chemokine inhibitors (Virustats) for prevention of HIV-1 transmission. SO AIDS LA English DT Meeting Abstract C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Scripps Res Inst, La Jolla, CA USA. Johns Hopkins Univ, Baltimore, MD USA. NCI, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Geneva, Geneva, Switzerland. Harvard Univ, Sch Med, Boston, MA 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 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S57 EP S58 DI 10.1097/00002030-200102001-00081 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100076 ER PT J AU Nathanson, N Cargill, V Auerbach, J Eisinger, R AF Nathanson, N Cargill, V Auerbach, J Eisinger, R TI The role of the Office of AIDS Research, NIH, USA SO AIDS LA English DT Editorial Material C1 NIH, Off AIDS Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Nathanson, N (reprint author), NIH, Off AIDS Res, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S3 EP S3 DI 10.1097/00002030-200102001-00009 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100005 PM 11228107 ER PT J AU Pozzi, G Giomarelli, B Maggi, T Medaglini, D Mori, T Boyd, M AF Pozzi, G Giomarelli, B Maggi, T Medaglini, D Mori, T Boyd, M TI Mucosal delivery of microbicides by recombinant commensal bacteria: expression of the HIV-inactivating protein cyanovirin-N in gram-positive bacteria SO AIDS LA English DT Meeting Abstract C1 Univ Siena, Sch Med, I-53100 Siena, Italy. NCI, NIH, Frederick, MD 21701 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S58 EP S58 DI 10.1097/00002030-200102001-00083 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100078 ER PT J AU Quinn, T AF Quinn, T TI Viral load and transmission in Uganda SO AIDS LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NIAID, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S70 EP S71 DI 10.1097/00002030-200102001-00099 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100094 ER PT J AU Reichelderfer, PS AF Reichelderfer, PS TI Track A: Basic science SO AIDS LA English DT Editorial Material C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Reichelderfer, PS (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S72 EP S74 DI 10.1097/00002030-200102001-00102 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100097 ER PT J AU Wahl, SM AF Wahl, SM TI Secretory leukocyte protease inhibitor - an endogenous antimicrobial agent SO AIDS LA English DT Meeting Abstract C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB PY 2001 VL 15 SU 1 BP S54 EP S54 DI 10.1097/00002030-200102001-00076 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 404JW UT WOS:000167095100071 ER PT J AU Flexner, CW Cargill, VA Sinclair, J Kresina, TF Cheever, L AF Flexner, CW Cargill, VA Sinclair, J Kresina, TF Cheever, L TI Alcohol use can result in enhanced drug metabolism in HIV pharmacotherapy SO AIDS PATIENT CARE AND STDS LA English DT Letter ID HUMAN-IMMUNODEFICIENCY-VIRUS C1 NIAAA, Inst AIDS Coordinator, NIH, Bethesda, MD 20892 USA. NIH, Off AIDS Res, Bethesda, MD 20892 USA. Dartmouth Med Sch, VA Med Ctr, White River Junction, VT USA. Hlth Resources & Serv Adm, Rockville, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Kresina, TF (reprint author), NIAAA, Inst AIDS Coordinator, NIH, 6000 Execut Blvd,Room 402, Bethesda, MD 20892 USA. NR 6 TC 18 Z9 19 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD FEB PY 2001 VL 15 IS 2 BP 57 EP 58 DI 10.1089/108729101300003636 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 405LF UT WOS:000167160300001 PM 11224929 ER PT J AU Tulenko, TN Sumner, AE Chen, M Huang, Y Laury-Kleintop, L Ferdinand, FD AF Tulenko, TN Sumner, AE Chen, M Huang, Y Laury-Kleintop, L Ferdinand, FD TI The smooth muscle cell membrane during atherogenesis: A potential target for amlodipine in atheroprotection SO AMERICAN HEART JOURNAL LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; FACTOR-KAPPA-B; CHOLESTEROL-FED RABBITS; MAJOR RISK-FACTORS; ATHEROSCLEROTIC LESIONS; CARDIOVASCULAR-DISEASE; HYPERLIPIDEMIC RABBIT; HEART-DISEASE; BETA-CAROTENE; MYOCARDIAL-INFARCTION AB Background Atherosclerotic disease has been present in the human population apparently from the beginning of time. However, it has only been in the 20th century that improvements in the control of infectious diseases have allowed the average life span to increase to the point where atherosclerosis has been able to affect the general population. By the middle of the 20th century, atherosclerosis had reached epidemic levels, and it is currently pandemic and increasing worldwide. Despite its growing significance to health care, we still know relatively little about the cellular basis for plaque genesis in the vessel wall. Current thinking holds that atherosclerosis is caused by an unchecked chronic inflammatory process involving the cells of the arterial wall and their interaction with LDL and various inflammatory cells. Considerable evidence suggests that the principal insults underlying atherogenesis are serum dyslipidemias and oxidative stress mediated primarily by oxidized LDI. However, just how these insults alter the cell biology of vascular cells and lead to the atherosclerotic phenotype is still under intense investigation. Moreover, recent clinical trials have provided evidence that certain classes of drugs, including newer calcium channel blockers (CCBs), can remodel the arterial smooth muscle cell (SMC) membrane and inhibit the progression of atherosclerotic disease. Methods This review summarizes our current thinking on atherogenesis in the arterial SMC and considers recent developments regarding alterations in the SMC membrane during the very early period of atherogenesis. We also discuss how certain CCBs might operate to produce atheroprotection. Results The SMC membrane becomes enriched in unesterified cholesterol soon after the development of serum hypercholesterolemia. With excess membrane cholesterol, the membrane becomes thicker and develops distinct cholesterol domains. These alterations in the membrane increase the permeability of SMC to calcium and induce a variety of alterations in SMC function that contribute to cellular atherogenic processes during plaque genesis. Amlodipine, a third-generation CCB, markedly inhibits the progression of lesions. The explanation of this novel action may lie in the effects of this drug on various potential cellular targets. Conclusions Evidence is accumulating that excess membrane cholesterol may contribute to the cellular defects responsible for the transformation of the SMC to the atherosclerotic phenotype. Amlodipine, which has membrane-remodeling properties, is emerging as an important atheroprotective drug. C1 Lankenau Med Res Ctr, Div Vasc Biol, Wynnewood, PA 19095 USA. Thomas Jefferson Univ, Sch Med, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. NIH, Bethesda, MD 20892 USA. Univ Virginia, Sch Med, Div Med, Charlottesville, VA 22908 USA. RP Tulenko, TN (reprint author), Lankenau Med Res Ctr, Div Vasc Biol, 100 Lancaster Ave, Wynnewood, PA 19095 USA. FU NHLBI NIH HHS [HL-51538, HL-66273] NR 89 TC 25 Z9 27 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2001 VL 141 IS 2 SU S BP S1 EP S11 DI 10.1067/mhj.2001.109947 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 401PP UT WOS:000166936700001 PM 11174352 ER PT J AU Jones, EC Devereux, RB Roman, MJ Liu, JE Fishman, D Lee, ET Welty, TK Fabsitz, RR Howard, BV AF Jones, EC Devereux, RB Roman, MJ Liu, JE Fishman, D Lee, ET Welty, TK Fabsitz, RR Howard, BV TI Prevalence and correlates of mitral regurgitation in a population-based sample (The Strong Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; VALVULAR REGURGITATION; AMERICAN-INDIANS; ECHOCARDIOGRAPHIC ASSESSMENT; DOPPLER ECHOCARDIOGRAPHY; CARDIOVASCULAR-DISEASE; OBESE PATIENTS; SEVERITY; FLOW; VOLUME AB Evidence suggesting that mitral regurgitatian (MR) may be induced by appetite suppressant medications height ens the importance of understanding the prevalence and correlates of MR, especially its relation to obesity, in papulation-based samples. MR was assessed by color Doppler echocardiography in 3,486 American Indian participants in the Strong Heart Study. Mild (1+) MR was present in 19.2%, moderate (2+) MR in 1.6%, moderately severe (3+) in 0.3%, and severe (4+) in 0.2% of participants. In univariate analyses, MR was unrelated to gender, diabetes, or lipid levels, but was more frequent in North/South Dakota (28.3%) than in Oklahoma (21.6%) or Arizona (14.3%) (p <0.001). MR was related to lower body mass index (BMI) (p <0.001), older age (p <0.001), higher systolic blood pressure (p = 0.003), higher serum creatinine (9 <0.001), and higher urine albumin/creatinine ratio (p <0.001). In multivariate analyses, the presence and severity of MR were independently associated with higher serum creatinine, lower BMI, mitral stenosis, prior myocardial infarction, female gender, mitral valve prolapse and, variably, older age. In conclusion, MR, mostly mild, is detected by color Doppler echocardiography in > 20% of middle-aged and older adults. MR is independently associated with female gender, lower BMI, older age, and renal dysfunction, as well as with prior myocardial infarction, mitral stenosis, and mitral valve prolapse. It is not related to dyslipidemia or diabetes. (C) 2001 by Excerpta Medica, Inc. C1 New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Med, New York, NY 10021 USA. Univ Oklahoma, Hlth Sci Ctr, Sch Publ Hlth, Oklahoma City, OK USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. NHLBI, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Weill Cornell Med Ctr, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. FU NHLBI NIH HHS [U01-HL41654, U01-HL41642, U01-HL41652] NR 30 TC 84 Z9 85 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 1 PY 2001 VL 87 IS 3 BP 298 EP 304 DI 10.1016/S0002-9149(00)01362-X PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 396GZ UT WOS:000166629100009 PM 11165964 ER PT J AU Yanovski, JA AF Yanovski, JA TI Resting energy expenditure in African American and white children SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID CAUCASIAN GIRLS; BLACK C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, 10 Ctr Dr,MSC 1862,Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 19 TC 8 Z9 8 U1 0 U2 0 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 FEB PY 2001 VL 73 IS 2 BP 149 EP 150 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 395HU UT WOS:000166575600002 PM 11157307 ER PT J AU Andrieu, N Goldstein, AM Thomas, DC Langholz, B AF Andrieu, N Goldstein, AM Thomas, DC Langholz, B TI Counter-matching in studies of gene-environment interaction: Efficiency and feasibility SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; cohort studies; epidemiologic methods; interaction; matched-pair analysis; research design; statistics ID NESTED CASE-CONTROL; LOGISTIC-REGRESSION; 2-STAGE; DESIGN AB The interest in studying gene-environment interaction is increasing for complex diseases. However, most methods of detecting gene-environment interactions may not be appropriate for the study of interactions involving rare genes (G) or uncommon environmental exposures (E), because of poor statistical power. To increase this power, the authors propose the counter-matching design. This design increases the number of subjects with the rare factor without increasing the number of measurements that must be performed. In this paper, the efficiency and feasibility (required sample sizes) of counter-matching designs are evaluated and discussed. Counter-matching on both G and E appears to be the most efficient design for detecting gene-environment interaction. The sensitivity and specificity of the surrogate measures, the frequencies of G and E, and, to a lesser extent, the value of the interaction effect are the most important parameters for determining efficiency. Feasibility is also more dependent on the exposure frequencies and the interaction effect than on the main effects of G and E. Although the efficiency of counter-matching is greatest when the risk factors are very rare, the study of such rare factors is not realistic unless one is interested in very strong interaction effects. Nevertheless, counter-matching appears to be more appropriate than most traditional epidemiologic methods for the study of interactions involving rare factors. C1 Inst Gustave Roussy, INSERM U521, Unite Rech Epidemiol Canc, F-94805 Villejuif, France. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Dept Prevent Med, Los Angeles, CA USA. RP Andrieu, N (reprint author), Inst Gustave Roussy, INSERM U521, Unite Rech Epidemiol Canc, F-94805 Villejuif, France. RI ANDRIEU, Nadine/H-4255-2014 NR 18 TC 24 Z9 26 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2001 VL 153 IS 3 BP 265 EP 274 DI 10.1093/aje/153.3.265 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 397VK UT WOS:000166718300010 PM 11157414 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, CE Everhart, JE TI Relationship of iron-deficiency anemia with esophagitis and hiatal hernia: Hospital findings from a prospective, population-based study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID LINEAR GASTRIC-EROSION; GASTROESOPHAGEAL REFLUX AB OBJECTIVE: Iron-deficiency anemia is sometimes attributed to esophagitis and hiatal hernia; however, because these GI conditions are so common, such an association could be coincidental. We examined prospectively whether esophagitis and hiatal hernia increased the risk of iron-deficiency anemia in a national, population-based study. METHODS: The study population comprised 5069 adult participants in the first National Health and Nutrition Examination Survey, who were free of GI hemorrhage and anemia at baseline examination in 1971-1975 and who were hospitalized at some point during nearly 20 yr of follow-up. Rates of hospitalization with iron-deficiency or unspecified anemia were compared between patients with a hospital diagnosis of esophagitis or hiatal hernia and those who had not yet had a diagnosis of these disorders. Adjusted rate ratios were calculated using time-dependent, multivariable, proportional hazards analysis. RESULTS: During follow-up, 59 patients were hospitalized with esophagitis alone, 140 with hiatal hernia alone, and 70 with both diagnoses. A total of 102 participants were hospitalized with iron-deficiency anemia and 256 with unspecified anemia. Compared to those without a diagnosis of esophagitis or hiatal hernia, patients with a diagnosis of hiatal hernia had higher rates of subsequent hospitalization with iron-deficiency anemia. The hazard rate ratio (HRR) for hiatal hernia was 2.9 (95% confidence interval, 1.5-5.5). A trend was found for esophagitis with a HRR of 2.2 (95% confidence interval, 0.79-6.0). Results were similar with unspecified anemia as the outcome. CONCLUSIONS: Hiatal hernia should be considered as a possible cause of iron-deficiency anemia. The relationship of esophagitis with iron-deficiency anemia requires further study. (C) 2001 by Am. Coll. of Gastroenterology. C1 Social & Sci Syst Inc, Bethesda, MD 20814 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 7101 Wisconsin Ave,Suite 1300, Bethesda, MD 20814 USA. FU NIDDK NIH HHS [N01-DK-6-2220] NR 20 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2001 VL 96 IS 2 BP 322 EP 326 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 404EH UT WOS:000167084100009 PM 11232670 ER PT J AU Gaspar, C Lopes-Cendes, I Hayes, S Goto, J Arvidsson, K Dias, A Silveira, I Maciel, P Coutinho, P Lima, M Zhou, YX Soong, BW Watanabe, M Giunti, P Stevanin, G Riess, O Sasaki, H Hsieh, M Nicholson, GA Brunt, E Higgins, JJ Lauritzen, M Tranebjaerg, L Volpini, V Wood, N Ranum, L Tsuji, S Brice, A Sequeiros, J Rouleau, GA AF Gaspar, C Lopes-Cendes, I Hayes, S Goto, J Arvidsson, K Dias, A Silveira, I Maciel, P Coutinho, P Lima, M Zhou, YX Soong, BW Watanabe, M Giunti, P Stevanin, G Riess, O Sasaki, H Hsieh, M Nicholson, GA Brunt, E Higgins, JJ Lauritzen, M Tranebjaerg, L Volpini, V Wood, N Ranum, L Tsuji, S Brice, A Sequeiros, J Rouleau, GA TI Ancestral origins of the Machado-Joseph disease mutation: A worldwide haplotype study SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LINKAGE DISEQUILIBRIUM; INTRAGENIC POLYMORPHISMS; GENETIC DISORDER; CAG EXPANSIONS; FAMILIES; DEGENERATION; DOMINANT; ATAXIA; INSTABILITY; MJD1 AB Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms ((A) under bar (669)TG/(G) under bar (669)TG, (C) under bar (987)GG/(G) under bar (987)GG, and TA (A) under bar (1118) /TA (C) under bar (1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD. C1 Montreal Gen Hosp, Res Inst, Montreal, PQ H3G 1A4, Canada. McGill Univ, Ctr Res Neurosci, Montreal, PQ H3A 2T5, Canada. Univ Porto, Inst Mol Biol & Celular, UnIGENe, Porto, Portugal. Hosp Santo Antonio, Porto, Portugal. Niigata Univ, Brain Res Inst, Dept Neurol, Niigata 951, Japan. Unic Acores, Dept Biol, Ponta Delgada, Acores, Portugal. China Japan Friendship Hosp, Dept Neurol, Neurogenet Unit, Beijing, Peoples R China. Vet Gen Hosp, Neurol Inst, Taipei, Taiwan. Gunma Univ, Sch Med, Dept Neurol, Gunma, Japan. Univ London, Inst Neurobiol, London WC1E 7HU, England. Hop La Pitie Salpetriere, INSERM, U289, Expt Med Lab, Paris, France. Ruhr Univ Bochum, Dept Human Mol Genet, D-4630 Bochum, Germany. Hokkaido Univ, Sch Med, Dept Neurol, Sapporo, Hokkaido 060, Japan. Chung Shan Med & Dent Coll, Taichung, Taiwan. Univ Sydney, Concord Hosp, Dept Med, Mol Med Lab, Sydney, NSW 2006, Australia. Acad Ziekenhuis Groningen, Groningen, Netherlands. NINDS, Clin Neurogenet Unit, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Glostrup Hosp, Dept Clin Neurophysiol, DK-2600 Glostrup, Denmark. Univ Tromso Hosp, Dept Med Genet, N-9012 Tromso, Norway. Hosp Duran & Reynals, Med & Mol Genet Ctr IRO, Barcelona, Spain. Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. RP Rouleau, GA (reprint author), Montreal Gen Hosp, Res Inst, L7-224,1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. RI Giunti, Paola /E-5526-2012; Silveira, Isabel/D-6881-2012; Lopes-Cendes, Iscia/B-9416-2013; Coutinho, Paula/K-6053-2013; Maciel, Patricia/B-5989-2009; Wood, Nicholas/C-2505-2009; Stevanin, Giovanni/E-5038-2016; OI Giunti, Paola /0000-0003-3508-4788; Silveira, Isabel/0000-0002-2610-5260; Lopes-Cendes, Iscia/0000-0002-6221-6822; Maciel, Patricia/0000-0002-0920-6350; Wood, Nicholas/0000-0002-9500-3348; Sequeiros, Jorge/0000-0002-9846-1037; Coutinho, Paula/0000-0002-3461-230X; Lima, Manuela/0000-0002-3357-3273 FU NINDS NIH HHS [NS31687] NR 21 TC 56 Z9 57 U1 0 U2 4 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 FEB PY 2001 VL 68 IS 2 BP 523 EP 528 DI 10.1086/318184 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 394LD UT WOS:000166524800024 PM 11133357 ER PT J AU Ruder, AM Ward, EM Brown, DP AF Ruder, AM Ward, EM Brown, DP TI Mortality in dry-cleaning workers: An update SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE solvents; occupational exposure; tetrachloroethylene; cohort studies; cancer mortality ID TABLE ANALYSIS SYSTEM; RENAL-CELL CANCER; SAFETY-AND-HEALTH; CERVICAL-CANCER; UNITED-STATES; EPIDEMIOLOGIC EVIDENCE; OCCUPATIONAL EXPOSURE; HUMAN PAPILLOMAVIRUS; ORGANIC-SOLVENTS; PERCHLOROETHYLENE AB Background A cohort of 1,708 dry-cleaning workers identified from union records was exposed to perchloroethylene (PCE), a known animal carcinogen and probable human carcinogen, for at least 1 year before 1960. Many workers also had exposure to Stoddard solvent, a petroleum-based dry-cleaning solvent. Methods Vital status was updated through 1996 and life table analyses conducted. Results The cohort had excess cancer mortality (271 deaths, standardized mortality ratio [SMR] 1.25, 95% confidence interval [CI] 1.11-1.41). Elevated SMRs for tongue, bladder; esophagus, intestine, lung and cervical cancer; pneumonia, and diseases of the stomach and duodenum were statistically significant. Conclusion The current study confirms findings of prior updates and other studies that dry-cleaning workers have excess cancer mortality at several sites. Although important lifestyle and socioeconomic risk factors exist for both cervical and esophageal cancer mortality excesses of these sites in the PCE only subcohort and among workers with longer duration of PCE exposure suggest an association with PCE exposure. Am. J. Ind. Med. 39:121-132, 2001. (C) 2001 Wiley-Liss, Inc. C1 NIOSH, Cincinnati, OH 45226 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Ruder, AM (reprint author), NIOSH, Mailstop R-16,4676 Columbia Pkwy, Cincinnati, OH 45226 USA. RI Ruder, Avima/I-4155-2012 OI Ruder, Avima/0000-0003-0419-6664 NR 54 TC 40 Z9 43 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2001 VL 39 IS 2 BP 121 EP 132 DI 10.1002/1097-0274(200102)39:2<121::AID-AJIM1000>3.0.CO;2-H PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 398KV UT WOS:000166756400001 PM 11170155 ER PT J AU Kaveh, K Kimmel, PL AF Kaveh, K Kimmel, PL TI Compliance in hemodialysis patients: Multidimensional measures in search of a gold standard SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Review DE compliance; medication; diet; fluid; behavioral; interdialytic weight gain (IDWG) ID STAGE RENAL-DISEASE; INTERDIALYTIC WEIGHT-GAIN; QUALITY-OF-LIFE; BEHAVIORAL COMPLIANCE; DIALYSIS PATIENTS; SOCIAL SUPPORT; INTERMITTENT HEMODIALYSIS; PERSONALITY-FACTORS; DIETARY COMPLIANCE; CALCIUM-CARBONATE AB The gold standard to assess the compliance of hemodialysis (HD) patients has not been established. Compliance parameters should be easily measured and verified, reproducible, clearly interpretable, and accurate. They should have meaning for the patient, clear pathophysiological significance unrelated to other factors, and be related to important outcomes. There is poor correlation of subjective and objective measures and poor correlation of laboratory compliance measures. Different factors have been associated with differential compliance in different patient populations, depending on the measures assessed. Recently, behavioral measures of compliance with dialysis prescription, such as shortening or skipping HD treatments, have been developed. New data confirm that many compliance measures, including both laboratory and behavioral compliance indices, are associated with patient outcomes. It is the duty of the nephrologist and staff to make the importance of compliance understandable to patients, It is important for the health care team to understand patients' expectations end attitudes about their illness and their beliefs about the efficacy and importance of the treatment, as well as patients' demographic, medical, psychological, familial, and socioeconomic status, before realistically evaluating compliance. Such knowledge and approaches may be critical in achieving mutually agreed on compliance goals. We suggest that although assessment of indirect indices is useful, behavioral compliance measures that quantity shortening and skipping behaviors generally should be used in HD patients. Hopefully, analyses of results that control for multiple potentially confounding factors and effective interventions to improve compliance will be developed in the near future. (C) 2001 by the National Kidney Foundation, Inc. C1 George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. NR 119 TC 98 Z9 102 U1 5 U2 9 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 FEB PY 2001 VL 37 IS 2 BP 244 EP 266 DI 10.1053/ajkd.2001.21286 PG 23 WC Urology & Nephrology SC Urology & Nephrology GA 396QE UT WOS:000166647400002 PM 11157365 ER PT J AU Port, FK Wolfe, RA Hulbert-Shearon, TE Daugirdas, JT Agodoa, LYC Jones, C Orzol, SM Held, PJ AF Port, FK Wolfe, RA Hulbert-Shearon, TE Daugirdas, JT Agodoa, LYC Jones, C Orzol, SM Held, PJ TI Mortality risk by hemodialyzer reuse practice and dialyzer membrane characteristics: Results from the USRDS dialysis morbidity and mortality study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE hemodialysis (HD) mortality; dialysis reuse; dialyzer reprocessing; dialysis membrane; bleach in reuse; high-flux dialysis ID POLYSULFONE DIALYZERS; SURVIVAL; SAFETY; BETA(2)-MICROGLOBULIN; ASSOCIATION; INFECTIONS; CATHETERS; CELLULOSE; OUTBREAK; REMOVAL AB Hemodialyzer reuse is commonly practiced in the United States. Recent studies have raised concerns about the mortality risk associated with certain reuse practices. We evaluated adjusted mortality risk during 1- to 2-year follow-up in a representative sample of 12,791 chronic hemodialysis patients treated in 1,394 dialysis facilities from 1994 through 1995. Medical record abstraction provided data on reuse practice, use of bleach, dialyzer membrane, dialysis dose, and patient characteristics and comorbidity. Mortality risk was analyzed by bootstrapped Cox models by (1) no reuse versus reuse, (2) reuse agent, and (3) dialyzer membrane with and without the use of bleach, while considering dialysis and patient factors. The relative risk (RR) for mortality did not differ for patients in reuse versus no-reuse units (RR = 0.96; 95% confidence interval [CI], 0.86 to 1.08; P > 0.50), and similar results were found with different levels of adjustment and subgroups (RR = 1.01 to 1.05; 95% CI, lower bound > 0.90, upper bound < 1.19 each; each P > 0.40). The RR for peracetic acid mixture versus formalin varied significantly by membrane type and use of bleach during reprocessing, achieving borderline significance for synthetic membranes. Among synthetic membranes, mortality was greater with low-flux than high-flux membranes (RR = 1.24; 95% CI, 1.02 to 1.52; P = 0.04) and without than with bleach during reprocessing (RR = 1.24; 95% CI, 1.01 to 1.48; P = 0.04), Among all membranes, mortality was lowest for patients treated with high-flux synthetic membranes (RR = 0.82; 95% CI, 0.72 to 0.93; P = 0.002). Although mortality was not greater in reuse than no-reuse units overall, differences may exist in mortality risk by reuse agent. Use of high-flux synthetic membrane dialyzers was associated with lower mortality risk, particularly when exposed to bleach. Clearance of larger molecules may have a role. (C) 2001 by the National Kidney Foundation, Inc. C1 Univ Michigan, KECC, Dept Internal Med, Ann Arbor, MI 48103 USA. US Renal Data Syst Coordinating Ctr, Ann Arbor, MI 48103 USA. Univ Michigan, KECC, Dept Epidemiol, Ann Arbor, MI 48103 USA. Univ Michigan, KECC, Dept Biostat, Ann Arbor, MI 48103 USA. Univ Renal Res & Educ Assoc, Ann Arbor, MI USA. Westside Vet Adm Hosp, Chicago, IL USA. NIDDKD, Bethesda, MD 20892 USA. RP Port, FK (reprint author), Univ Michigan, KECC, Dept Internal Med, 315 W Huron St,Ste 240, Ann Arbor, MI 48103 USA. FU NIDDK NIH HHS [N01-DK-3-2202] NR 43 TC 110 Z9 118 U1 0 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 FEB PY 2001 VL 37 IS 2 BP 276 EP 286 DI 10.1053/ajkd.2001.21290 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 396QE UT WOS:000166647400004 PM 11157367 ER PT J AU Abbott, KC Sawyers, ES Oliver, JD Ko, CW Kirk, AD Welch, PG Peters, TG Agodoa, LY AF Abbott, KC Sawyers, ES Oliver, JD Ko, CW Kirk, AD Welch, PG Peters, TG Agodoa, LY TI Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE focal segmental glomerulosclerosis (FSGS); recurrent disease; living donor renal transplantation; cadaveric renal transplantation; graft loss; graft survival; African-American; white; pediatric; donor/recipient race matching; complications; United States Renal Data System (USRDS) ID CHILDREN; PREVALENCE; CAUTION; DISEASE; PLASMA; RISK AB Rates of and risk factors for graft loss and graft loss resulting from recurrent focal segmental glomerulosclerosis (FSGS) have not been studied in a national population. A retrospective analysis was performed on a national registry (1999 United States Renal Data System) of 101,808 renal transplant recipients (October 1, 1987, to December 31, 1996). Of these, 3,861 recipients of solitary renal transplants who had end-stage renal disease resulting from FSGS met inclusion criteria. Outcomes were graft loss and graft loss resulting from recurrent FSGS. As a percentage of all graft loss, recurrent FSGS accounted for 18.7% in living donor recipients and 7.8% in cadaveric recipients. In white recipients, the corresponding figures were 27% and 13%. In multivariate analysis, factors associated with graft loss resulting from recurrent FSGS were white recipient, donor African-American kidney in white recipient, younger recipient age, and treatment for rejection. African-American recipients had higher rates of graft loss overall. A living donor was associated with superior overall graft survival. Among renal transplant recipients with FSGS, white recipients had a higher risk of graft loss resulting from recurrent FSGS, disproportionately seen in recipients of African-American kidneys. The role of donor/recipient race pairing on graft loss resulting from recurrent FSGS should be validated. Living donor had no association with graft loss from recurrent FSGS after correction for other factors. African-American recipients with FSGS may have the most to gain from a living donor, given their improved graft survival and decreased risk of graft loss resulting from recurrent FSGS. C1 Walter Reed Army Med Ctr, Nephrol & Organ Transplant Serv, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDCD, Epidemiol Stat & Data Syst Branch, Organ Transplantat Serv, NIH, Bethesda, MD USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. RI Kirk, Allan/B-6905-2012; OI Abbott, Kevin/0000-0003-2111-7112 NR 32 TC 60 Z9 61 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2001 VL 37 IS 2 BP 366 EP 373 DI 10.1053/ajkd.2001.21311 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 396QE UT WOS:000166647400016 PM 11157379 ER PT J AU Hearns-Stokes, RM Santoro, NF Simon, JA AF Hearns-Stokes, RM Santoro, NF Simon, JA TI Surgically induced endometriosis attenuates accrual of bone mineral density in growing rats SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE bone mineral density; endometriosis; rat ID LUMBAR SPINE; PATHOGENESIS; WOMEN; MASS; OSTEOPOROSIS AB OBJECTIVE: A possible association of endometriosis with decreased bone mineral density in women has been proposed. It has been reported that cortical and trabecular bone mass of the distal portion of the radius is decreased in patients with endometriosis. The objective of this study was to investigate the relationship between endometriosis and bone mineral density with the use of a rat model. STUDY DESIGN: Cycling female Sprague-Dawley rats (180 days old) were randomly assigned to 1 of 2 groups. The treatment group (n = 16) underwent surgical induction of endometriosis. Female rats (n = 17) with surgically transplanted abdominal muscle served as control animals. Dual-energy x-ray absorptiometry measurements were obtained before surgery and after 90 days with a Lunar DPX-MD+ (GE Lunar, GE Medical Systems, Milwaukee, Wis) bone densitometer, with software standardized for small animal research. RESULTS: Experimental animals had grossly visible endometriotic disease at necropsy (90 days). The mean net change in total bone mineral density from baseline to 90 days in the control group was +0.019 +/- 0.002 g/cm(2), whereas the mean net change in total bone mineral density for the experimental group was +0.013 +/- 0.002 g/cm(2). The experimental group gained less bone than the control group (P = 02). CONCLUSION: The age-appropriate increase in bone mineral density known to occur in this animal model is attenuated by surgically induced endometriosis. This finding supports the idea that endometriosis might be associated with decreased bone mineral density. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Obstet & Gynecol, Newark, NJ 07103 USA. Womens Hlth Res Ctr, Laurel, MD USA. RP Hearns-Stokes, RM (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 9D-42, Bethesda, MD 20892 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2001 VL 184 IS 3 BP 331 EP 335 DI 10.1067/mob.2001.110025 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 408BF UT WOS:000167306100013 PM 11228482 ER PT J AU Goepfert, AR Goldenberg, RL Andrews, WW Hauth, JC Mercer, B Iams, J Meis, P Moawad, A Thom, E VanDorsten, JP Caritis, SN Thurnau, G Miodovnik, M Dombrowski, M Roberts, J McNellis, D AF Goepfert, AR Goldenberg, RL Andrews, WW Hauth, JC Mercer, B Iams, J Meis, P Moawad, A Thom, E VanDorsten, JP Caritis, SN Thurnau, G Miodovnik, M Dombrowski, M Roberts, J McNellis, D CA Natl Inst Child Hlth Human Dev Mat TI The Preterm Prediction Study: Association between cervical interleukin 6 concentration and spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE fibronectin; interleukin 6; preterm birth ID AMNIOTIC-FLUID INTERLEUKIN-6; FETAL FIBRONECTIN; GENITAL-TRACT; BACTERIAL VAGINOSIS; INTACT MEMBRANES; DELIVERY; LABOR; SECRETIONS; PREGNANCY; AGE AB OBJECTIVE: The aim of this study was to determine the interrelationship between cervical concentration of interleukin 6 and detection of fetal fibronectin and other risk factors for spontaneous preterm birth. STUDY DESIGN: All patients with spontaneous preterm birth at <35 weeks' gestation (case patients; n = 125) and subjects matched for race, parity, and center delivered at 37 weeks' gestation (n = 125; control subjects) were selected from women enrolled in the National Institute of Child Health and Human Development's Preterm Prediction Study. Interleukin 6 concentrations were determined by enzyme-linked immunosorbent assay in cervical swabs obtained at 22 weeks' to 24 weeks 6 days' gestation. Cutoffs to define an elevated interleukin 6 concentration included the 90th and 95th percentiles for control subjects (>305 and >538 pg/mL, respectively). RESULTS: The mean (+/-SD) interleukin 6 concentration was significantly higher in case patients than in control subjects (212 +/- 339 vs 111 +/- 186 pg/mL; P=.008). With either cutoff value elevated interleukin 6 concentration was significantly associated with spontaneous preterm birth (90th percentile, 20% vs 9.6%; P=.02; 95th percentile, 12% vs 4.8%; P=.04). Cervical interleukin 6 levels were highest within 4 weeks of delivery, and the trend continued until term. Elevated interleukin 6 concentration was not significantly associated with bacterial vaginosis, maternal body mass index <19.8 kg/m(2), or a short cervix (25 mm), but it was significantly associated with a positive cervicovaginal fetal fibronectin test result (90th percentile, odds ratio, 5.5; 95% confidence interval, 2.6-11.9; 95th percentile, odds ratio, 5.3, 95% confidence interval, 2.1-12.9). The mean interleukin 6 concentration among women with a positive fibronectin test result was 373 +/- 406 pg/mL; that among women with a negative fetal fibronectin test result was 130 +/- 239 pg/mL (P=.001). In a regression analysis that adjusted for risk factors significantly associated with spontaneous preterm birth in this population (positive fetal fibronectin test result, body mass index <19.8 kg/m(2), vaginal bleeding in the first or second trimester, previous spontaneous preterm birth, and short cervix) elevated cervical interleukin 6 concentration was not independently associated with spontaneous preterm birth (odds ratio, 1.8; 95% confidence interval. 0.8-4.3). CONCLUSIONS: At 24 weeks' gestation cervical interleukin 6 concentration in women who subsequently had a spontaneous preterm birth at <35 weeks' gestation was significantly elevated relative to those who were delivered at term. The association was particularly strong within 4 weeks of testing. A positive fetal fibronectin test result was strongly associated with elevated cervical interleukin 6 concentration, but bacterial vaginosis was not. C1 NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. RP Goepfert, AR (reprint author), Dept Obstet & Gynecol, 619 19th St S,Old Hillman Rd,Room 450, Birmingham, AL 35249 USA. OI caritis, steve/0000-0002-2169-0712 NR 18 TC 74 Z9 76 U1 0 U2 3 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 FEB PY 2001 VL 184 IS 3 BP 483 EP 488 DI 10.1067/mob.2001.109653 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 408BF UT WOS:000167306100038 PM 11228507 ER PT J AU Kassoff, A Kassoff, J Mehu, M Buehler, J Eglow, M Kaufman, F Kieval, S Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Lewis, B Zajechowski, M Falk, R Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Klein, ML Robertson, JE Wilson, DJ Beardsley, C Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD Crider, H Parker, S Sherman, K Martin, D Aaberg, TM Aaberg, TM Sternberg, P Curtis, L Gilman, J Myles, B Armiger, D Capone, A Saperstein, D Stribling, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Rosenberg, NJ Patel, P Crouse, VD Snow, KK Chew, EY Ferris, FL Csaky, K Dabas, KH Goodman, L Kim, YJ Mercer, R Palmer, MC Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Nashwinter, R Haughey, M Babilonia-Ayukawa, G La-Reau, A McCarthy, SA Ayres, LM Lopez, P Randall, A Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Paine, MK Corbin, PS Curtin, DY Ostroska, PP Warnicki, J Fijewski, E Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schnenning, S Sackett, C Belt, J Cain, D Emmert, D Herring, M George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Mathews, T Sotirakos, P Cain, T Ringrose, C Chandra, SR Davis, MD Ip, M Klein, R Nork, TM Stevens, T Blodi, B Gottlieb, J Walker, W Soderling, B Schmitz, M Perkins, T Blatz, M Harrison, B Knutson, G Neider, M Peterson, J Krolnik, D Somers, G Myers, FL Davis, MD Klein, BEK Klein, R Hubbard, L Armstrong, J Neider, M Wabers, H Kastorff, L Lang, K Badal, D Geithman, PL Miner, KD Dohm, KL Onofrey, JA Esser, B Hurtenbach, C Fisher, MR Robinson, NL Baliker, J Gai, C Craanen, S Webster, M Elledge, J Reed, S Bent, W Glander, KE Osterby, KR Reimers, J Magli, YL Brickbauer, J Ansay, S King, WN Miller, D Sowell, A Gunter, E Bowman, B Lindblad, AS Ederer, F Milton, RC Clemons, T Gensler, G Keller, A Entler, G Stine, E Brunson, K Berlin, SH Pallas, S Mengers, SA Scholl, PR Anand, R Ferris, FL Chew, EY Sperduto, R Kurinij, N AF Kassoff, A Kassoff, J Mehu, M Buehler, J Eglow, M Kaufman, F Kieval, S Margherio, RR Cox, MS Garretson, B Hassan, T Ruby, A Trese, MT Werner, JC Williams, GA Regan, V Manatrey, P Cumming, K Lewis, B Zajechowski, M Falk, R Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Klein, ML Robertson, JE Wilson, DJ Beardsley, C Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD Crider, H Parker, S Sherman, K Martin, D Aaberg, TM Aaberg, TM Sternberg, P Curtis, L Gilman, J Myles, B Armiger, D Capone, A Saperstein, D Stribling, B Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT MacLeod, C Morrison, C Bryant, DA Doherty, D Sandoval, S Seddon, JM Pinnolis, MK Jones-Devonish, DA Evans, C Davis, N Callahan, C Walsh, D Dubois, J Burton, I Rosenberg, NJ Patel, P Crouse, VD Snow, KK Chew, EY Ferris, FL Csaky, K Dabas, KH Goodman, L Kim, YJ Mercer, R Palmer, MC Ciatto, PF Kuehl, E Kivitz, I Koutsandreas, D Nashwinter, R Haughey, M Babilonia-Ayukawa, G La-Reau, A McCarthy, SA Ayres, LM Lopez, P Randall, A Friberg, TR Eller, A Gorin, MB Alexander, J Mack, B Paine, MK Corbin, PS Curtin, DY Ostroska, PP Warnicki, J Fijewski, E Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schnenning, S Sackett, C Belt, J Cain, D Emmert, D Herring, M George, T Wheeler, S Elman, MJ Ballinger, R Betancourt, A Glasser, D Lammlein, J Seff, R Shuman, M Starr, J Carrigan, A Mathews, T Sotirakos, P Cain, T Ringrose, C Chandra, SR Davis, MD Ip, M Klein, R Nork, TM Stevens, T Blodi, B Gottlieb, J Walker, W Soderling, B Schmitz, M Perkins, T Blatz, M Harrison, B Knutson, G Neider, M Peterson, J Krolnik, D Somers, G Myers, FL Davis, MD Klein, BEK Klein, R Hubbard, L Armstrong, J Neider, M Wabers, H Kastorff, L Lang, K Badal, D Geithman, PL Miner, KD Dohm, KL Onofrey, JA Esser, B Hurtenbach, C Fisher, MR Robinson, NL Baliker, J Gai, C Craanen, S Webster, M Elledge, J Reed, S Bent, W Glander, KE Osterby, KR Reimers, J Magli, YL Brickbauer, J Ansay, S King, WN Miller, D Sowell, A Gunter, E Bowman, B Lindblad, AS Ederer, F Milton, RC Clemons, T Gensler, G Keller, A Entler, G Stine, E Brunson, K Berlin, SH Pallas, S Mengers, SA Scholl, PR Anand, R Ferris, FL Chew, EY Sperduto, R Kurinij, N CA Age-Related Eye Disease Study Res TI The age-related eye disease study (AREDS) system for classifying cataracts from photographs: AREDS report No. 4 SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: To describe the system for grading cataracts from photographs in the Age Related Eye Disease Study (AREDS). METHODS: The system for grading cataracts in AREDS uses photographs taken in a standardized fashion with specially modified cameras at 11 clinical centers, The photographs are evaluated by graders for quality and cataract severity at a central reading center, The area of lens involvement is used to assess the severity of cortical and posterior subcapsular opacities, Optical density of nuclear opacity is graded against a series of seven standard photographs. Contemporaneous variability in grading is evaluated periodically by having a second examiner regrade a subset of the photographs. Temporal variability is assessed by annually regrading a subset of photographs. RESULTS: Photographs of 925 eyes, most with no or early lens opacities, were regraded to assess intergrader reliability. For cortical opacities, there was an absolute difference of 10% or greater of area involved in 1.9% of the replicate gradings. For posterior subcapsular opacities an absolute difference of 5% of area involved was noted in 2.8% of the regraded photographs. For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes. There was little evidence of temporal drift in grading any of the three types of opacity during four annual regrades. CONCLUSIONS: We have demonstrated a high degree of reliability in grading the severity of lens opacities in a large study cohort with mostly early lens changes, the type of cohort most likely to be entered in clinical trials involving cataract prevention. The Age-Related Eye Disease Study System for Classifying Cataracts From Photographs could be useful in studies where there is a need to standardize data collection over time and across different data collection sites. Limitations of the system include the cost of implementation and, currently, the limited amount of data on grading reproducibility for more advanced lens opacities. (Am J Ophthalmol 2001;131:167-175. (C) 2001 by Elsevier Science Inc. All rights reserved). C1 Associated Retinal Consultants PC, Royal Oak, MI USA. Devers Eye Inst, Portland, OR USA. Emory Univ, Atlanta, GA 30322 USA. Ingalls Mem Hosp, Harvey, IL USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NEI, Ctr Clin, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Wisconsin, Reading Ctr, Madison, WI 53706 USA. Ctr Dis Control & Prevent, Cent Lab, Atlanta, GA USA. NEI, Project Off, Bethesda, MD USA. NIH, Div Contracts & Grants, Bethesda, MD USA. Bausch & Lomb Pharmaceut, Rochester, NY USA. EMMES Corp, AREDS Coordinating Ctr, Potomac, MD 20854 USA. RP Kassoff, A (reprint author), EMMES Corp, AREDS Coordinating Ctr, 11325 7 Locks Rd, Potomac, MD 20854 USA. NR 3 TC 149 Z9 150 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 2001 VL 131 IS 2 BP 167 EP 175 PG 9 WC Ophthalmology SC Ophthalmology GA 400KK UT WOS:000166870600002 ER PT J AU Schraml, P Struckmann, K Bednar, R Fu, WT Gasser, T Wilber, K Kononen, J Sauter, G Mihatsch, MJ Moch, H AF Schraml, P Struckmann, K Bednar, R Fu, WT Gasser, T Wilber, K Kononen, J Sauter, G Mihatsch, MJ Moch, H TI CDKN2A mutation analysis, protein expression, and deletion mapping of chromosome 9p in conventional clear-cell renal carcinomas - Evidence for a second tumor suppressor gene proximal to CDKN2A SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN PROSTATE-CANCER; HOMOZYGOUS DELETIONS; MICROSATELLITE ANALYSIS; FAMILIAL MELANOMA; FREQUENT LOSS; LUNG-CANCER; P16; HETEROZYGOSITY; P16(INK4A) AB Inactivation of tumor suppressor genes on chromosome 9p is considered a critical event in renal cell carcinoma pathogenesis. Alterations of CDKN2A on 9p21 have been reported in renal cancer cell lines, but their relevance for primary renal carcinomas is unclear. Loss of heterozygosity (LOH) was analyzed by using four polymorphic microsatellites at D9S970 (9p12-9p13), D9SI71 (9p13), D9S1748 (9p21), and D9S156 (9p21) in 113 primary conventional clear-cell renal cell carcinomas (CRCCs). Allelic deletion was detected in 21 of 88 informative CRCCs (24%) with the highest rate of LOH being observed at D9SI71 on 9p13 (20%). Chromosome 9p LOH was associated with short tumor-specific survival in stage pT3 RCC (P = 0.01). Fluorescence in situ hybridization analysis of 54 CRCCs revealed no homozygous CDKN2A deletions indicating that this mechanism of CDKN2A inactivation is rare in CRCC: Sequencing of 113 CRCCs showed that 13 tumors (12%) had a 24-bp deletion abrogating codons 4 through 11 of CDKN2A. Immunohistochemical CDKN2A expression was absent in normal renal tissue and was only detected in six of 382 CRCCs (1.5%) on a renal tumor microarray. These data suggest that CDKN2A alterations are present in a small subset of CRCCs and a second, yet unknown tumor suppressor gene proximal to the CDKN2A locus, may play a role in CRCC development. C1 Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Univ Basel, Urol Clin, CH-4003 Basel, Switzerland. NHGRI, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. VYSIS Inc, Downers Grove, IL USA. RP Moch, H (reprint author), Univ Basel, Inst Pathol, Schonbeinstr 40, CH-4003 Basel, Switzerland. NR 61 TC 35 Z9 37 U1 0 U2 0 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 FEB PY 2001 VL 158 IS 2 BP 593 EP 601 DI 10.1016/S0002-9440(10)64001-1 PG 9 WC Pathology SC Pathology GA 401KC UT WOS:000166925900028 PM 11159196 ER PT J AU Gotoh, J Kuang, TY Nakao, Y Cohen, DM Melzer, P Itoh, Y Pak, H Pettigrew, K Sokoloff, L AF Gotoh, J Kuang, TY Nakao, Y Cohen, DM Melzer, P Itoh, Y Pak, H Pettigrew, K Sokoloff, L TI Regional differences in mechanisms of cerebral circulatory response to neuronal activation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE adenosine; nitric oxide; caffeine; 7-nitroindazole; N-G-nitro-L-arginine ID NITRIC-OXIDE SYNTHASE; SOMATOSENSORY-EVOKED POTENTIALS; INSULIN-INDUCED HYPOGLYCEMIA; BLOOD-FLOW; GLUCOSE-UTILIZATION; RAT; INHIBITION; STIMULATION; DEOXYGLUCOSE; ADENOSINE AB Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N-G-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. NIMH, Div Serv Intervent & Res, Bethesda, MD 20892 USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36,1A-05,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. NR 37 TC 53 Z9 53 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2001 VL 280 IS 2 BP H821 EP H829 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 393WJ UT WOS:000166492400038 PM 11158982 ER PT J AU MacGowan, GA Du, CW Cowan, DB Stamm, C McGowan, FX Solaro, RJ Koretsky, AP Del Nido, PJ AF MacGowan, GA Du, CW Cowan, DB Stamm, C McGowan, FX Solaro, RJ Koretsky, AP Del Nido, PJ TI Ischemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE calcium; ischemia ID PERFUSED MOUSE HEART; CALCIUM-INDUCED INOTROPY; CARDIAC MYOCYTES; TRANSIENTS; MYOFILAMENTS; MYOCARDIUM; INHIBITION; MGATPASE; FAILURE; MUSCLE AB To determine the in vivo functional significance of troponin I (TnI) protein kinase C (PKC) phosphorylation sites, we created a transgenic mouse expressing mutant TnI, in which PKC phosphorylation sites at serines-43 and -45 were replaced by alanine. When we used high-perfusate calcium as a PKC activator, developed pressures in transgenic (TG) perfused hearts were similar to wild-type (WT) hearts (P = not significant, NS), though there was a 35% and 32% decrease in peak-systolic intracellular calcium (P< 0.01) and diastolic calcium (P< 0.005), respectively. The calcium transient duration was prolonged in the TG mice also (12-27%, ANOVA, P< 0.01). During global ischemia, TG hearts developed ischemic contracture to a greater extent than WT hearts (41 +/- 18 vs. 69 +/- 10 mmHg, perfusate calcium 3.5 mM, P< 0.01). In conclusion, expression of mutant TnI lacking PKC phosphorylation sites results in a marked alteration in the calcium-pressure relationship, and thus susceptibility to ischemic contracture. The reduced intracellular calcium and prolonged calcium transients suggests that a potent feedback mechanism exists between the myofilament and the processes controlling calcium homeostasis. C1 Carnegie Mellon Univ, Pittsburgh Nucl Magnet Resonance Ctr Biomed Res, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Ctr Light Microscope Imaging & Biotechnol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15261 USA. NINDS, Bethesda, MD 20814 USA. Univ Illinois, Coll Med, Dept Physiol & Biophys, Chicago, IL 60612 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP MacGowan, GA (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, S550 Scaife Hall,200 Lothrop St, Pittsburgh, PA 15213 USA. EM macgowanga@msx.upmc.edu RI Stamm, Christof/J-5719-2014; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NHLBI NIH HHS [HL-03826, HL-40354, HL-46207] NR 29 TC 44 Z9 44 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2001 VL 280 IS 2 BP H835 EP H843 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 393WJ UT WOS:000166492400040 PM 11158984 ER PT J AU Michea, L Irribarra, V Goecke, A Marusic, ET AF Michea, L Irribarra, V Goecke, A Marusic, ET TI Reduced Na-K pump but increased Na-K-2Cl cotransporter in aorta of streptozotocin-induced diabetic rat SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE vascular tone; endothelial modulation; hypertension ID VASCULAR SMOOTH-MUSCLE; ENDOTHELIUM-DEPENDENT RELAXATION; SKELETAL-MUSCLE; NA+/K+-ATPASE; GENE-EXPRESSION; CL COTRANSPORT; UREMIC RATS; INSULIN; NA,K-ATPASE; HEART AB The activities of Na-K-ATPase and NaK-2Cl cotransporter (NKCC1) were studied in the aorta, heart, and skeletal muscle of streptozotocin (STZ)-induced diabetic rats and control rats. In the aortic rings of STZ rats, the Na-K-ATPase-dependent Rb-86/K uptake was reduced to 60.0 +/- 5.5% of the control value (P< 0.01). However, Na-K-ATPase activity in soleus skeletal muscle fibers of STZ rats and paired control rats was similar, showing that the reduction of Na-K-ATPase activity in aortas of STZ rats is tissue specific. To functionally distinguish the contributions of ouabain-resistant ((1)) and ouabain-sensitive (alpha (2) and alpha (3)) isoforms to the Na-K-ATPase activity in aortic rings, we used either a high (10(-3) M) or a low (10(-5) M) ouabain concentration during Rb-86/K uptake. We found that the reduction in total Na-K-ATPase activity resulted from a dramatic decrement in ouabain-sensitive mediated Rb-86/K uptake (26.0 +/- 3.9% of control, P< 0.01). Western blot analysis of membrane fractions from aortas of STZ rats demonstrated a significant reduction in protein levels of (1)- and alpha (2)-catalytic isoforms (alpha (1) = 71.3 +/- 9.8% of control values, P< 0.05; (2) = 44.5 +/- 11.3% of control, P<0.01). In contrast, aortic rings from the STZ rats demonstrated an increase in NKCC1 activity (172.5 +/- 9.5%, P< 0.01); however, in heart tissue no difference in NKCC1 activity was seen between control and diabetic animals. Transport studies of endothelium-denuded or intact aortic rings demonstrated that the endothelium stimulates both Na- K-ATPase and Na- K-2Cl dependent Rb-86/K uptake. The endothelium-dependent stimulation of Na-K-ATPase and Na-K-2Cl was not hampered by diabetes. We conclude that abnormal vascular vessel tone and function, reported in STZ-induced diabetic rats, may be related to ion transport abnormalities caused by changes in Na- K-ATPase and Na- K-2Cl activities. C1 Univ Los Andes, Fac Med, Lab Cellular & Mol Physiol, Santiago 6782468, Chile. Univ Chile, Inst Biomed Sci, Las Condes 6782468, Chile. NIH, Bethesda, MD 20892 USA. RP Michea, L (reprint author), Univ Los Andes, Fac Med, Lab Cellular & Mol Physiol, San Carlos Apoquindo 2200, Santiago 6782468, Chile. NR 49 TC 17 Z9 17 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2001 VL 280 IS 2 BP H851 EP H858 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 393WJ UT WOS:000166492400042 PM 11158986 ER PT J AU Schneider, S Chen, WN Hou, J Steenbergen, C Murphy, E AF Schneider, S Chen, WN Hou, J Steenbergen, C Murphy, E TI Inhibition of p38 MAPK alpha/beta reduces ischemic injury and does not block protective effects of preconditioning SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE SB-202190; P-31 nuclear magnetic resonance; necrosis; intracellular pH; left ventricular developed pressure ID ACTIVATED PROTEIN-KINASES; PERFUSED RAT HEARTS; N-TERMINAL KINASES; CELL INJURY; STRESS; PHOSPHORYLATION; REPERFUSION; MYOCARDIUM; INTERLEUKIN-1; ACCUMULATION AB We examined the effect of inhibition of p38 mitogen-activated protein kinase (MAPK) alpha/beta during ischemia and preconditioning by using the inhibitor SB-202190. Isolated rat hearts were perfused with Krebs-Henseleit buffer, while left ventricular developed pressure (LVDP) and P-31 nuclear magnetic resonance spectra were acquired continuously. After 20 min of ischemia and 25 min of reperfusion, recovery of LVDP in untreated hearts was 32 +/- 4%, whereas hearts treated with SB-202190 5 min before ischemia recovered 59 +/- 7% of their pretreatment LVDP. Preconditioning improved functional recovery to 65 +/- 5%, which was unaffected by SB-202190 treatment, added either throughout the preconditioning protocol (56 +/- 5% recovery) or during the final reperfusion period of preconditioning (71 +/- 11% recovery). Necrosis was assessed after 40 min of ischemia and 2 h of reperfusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining and creatine kinase release. The untreated group had 54 +/- 8% necrotic myocardium, whereas the SB-202190-treated group had 32 +/- 7% and the preconditioned group had 21 +/- 4% necrotic tissue by TTC staining. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Chapel Hill, NC 27516 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, NIH, Mail Drop D2-03,POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01 HL039752, R01-HL-39752] NR 39 TC 62 Z9 62 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2001 VL 280 IS 2 BP H499 EP H508 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 393WJ UT WOS:000166492400001 PM 11158945 ER PT J AU Lindroos, PM Wang, YZ Rice, AB Bonner, JC AF Lindroos, PM Wang, YZ Rice, AB Bonner, JC TI Regulation of PDGFR-alpha in rat pulmonary myofibroblasts by staurosporine SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE pulmonary fibrosis; protein kinase C; p38 mitogen-activated protein kinase; interleukin-1 beta; platelet-derived growth factor ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; SMOOTH-MUSCLE CELLS; GROWTH-FACTOR; UP-REGULATION; ALVEOLAR MACROPHAGES; RECEPTOR EXPRESSION; HUMAN FIBROBLASTS; TYROSINE KINASE; INDUCTION AB Upregulation of the platelet-derived growth factor (PDGF) receptor-alpha (PDGFR-alpha) is a mechanism of myofibroblast hyperplasia during pulmonary fibrosis. We previously identified interleukin (IL)-1 beta as a major inducer of the PDGFR-alpha in rat pulmonary myofibroblasts in vitro. In this study, we report that staurosporine, a broad-spectrum kinase inhibitor, upregulates PDGFR-alpha gene expression and protein. A variety of other kinase inhibitors did not induce PDGFR-alpha expression. Staurosporine did not act via an IL-1 beta autocrine loop because the IL-1 receptor antagonist protein did not block staurosporine-induced PDGFR-alpha expression. Furthermore, staurosporine did not activate a variety of signaling molecules that were activated by IL-1 beta, including nuclear factor-kappaB, extracellular signal-regulated kinase, and c-Jun NH2-terminal kinase. However, both staurosporine- and IL-1 beta -induced phosphorylation of p38 mitogen-activated protein kinase and upregulation of PDGFR-alpha by these two agents was inhibited by the p38 inhibitor SB-203580. Finally, staurosporine inhibited basal and PDGF-stimulated mitogenesis over the same concentration range that induced PDGFR-alpha expression. Collectively, these data demonstrate that staurosporine is a useful tool for elucidating the signaling mechanisms that regulate PDGFR expression in lung connective tissue cells and possibly for evaluating the role of the PDGFR-alpha as a growth arrest-specific gene. C1 NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Bonner, JC (reprint author), NIEHS, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 41 TC 10 Z9 10 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD FEB PY 2001 VL 280 IS 2 BP L354 EP L362 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 393BU UT WOS:000166450000020 PM 11159015 ER PT J AU Terris, JM Knepper, MA Wade, JB AF Terris, JM Knepper, MA Wade, JB TI UT-A3: localization and characterization of an additional urea transporter isoform in the IMCD SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE urinary concentrating mechanism; inner medullary collecting duct ID MEDULLARY COLLECTING DUCT; RAT-KIDNEY; MOLECULAR-CLONING; EXPRESSION; MEMBRANE; CELLS AB UT-A3 has recently been identified as a splicing variant transcript of the UT-A gene present in the kidney. To study the cellular and subcellular localization of UT-A3, we raised a new polyclonal antibody to its COOH-terminal end. Immunoblots identified bands at 44 and 67 kDa predominately in the inner medulla and showed that the antibody does not recognize UT-A1. Deglycosylation with PNGase decreased the molecular mass of both forms to 40 kDa. UT-A3 is most abundant in the inner third of the inner medulla and is present in membrane fractions. Cell fractionation studies showed that UT-A3 is only detectable in inner medullary collecting duct (IMCD) cells. These observations were confirmed with immunolocalization studies demonstrating an exclusive labeling of IMCD cells. Double-labeling studies with anti-Na-K-ATPase demonstrated UT-A3 in intracellular membranes and in the apical region but were incompatible with a basolateral site for UT-A3. Although the function of this isoform in the inner medulla is unknown, the large abundance suggests that it may be important in the renal handling of urea. C1 Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. RP Wade, JB (reprint author), Univ Maryland, Sch Med, Dept Physiol, 655 W Baltimore St, Baltimore, MD 21201 USA. EM jwade@umaryland.edu FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282]; NIDDK NIH HHS [DK-32839] NR 29 TC 69 Z9 71 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 FEB PY 2001 VL 280 IS 2 BP F325 EP F332 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 393BP UT WOS:000166449600016 PM 11208608 ER PT J AU Gerald, MS Bernstein, J Hinkson, R Fosbury, RAE AF Gerald, MS Bernstein, J Hinkson, R Fosbury, RAE TI Formal method for objective assessment of primate color SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE color; primates; measurements; methods ID MONKEYS CERCOPITHECUS-AETHIOPS AB To investigate primate color objectively, it is critical to employ tools that yield reliable measures of color samples. Primatologists have traditionally depended on color assessment methods that lack accuracy, precision, and replicability. In this work, we introduce the "red, green, and blue" (RGB) method, a technique combining digital video cameras and Adobe PhotoShop(R), as a means to assess and graphically represent primate color objectively. Here, we demonstrate the reliability and validity of the RGB method, and to outline the steps for assessing color samples, we report color measures obtained from the scrota of adult vervet monkeys. (C) 2001 Wiley-Liss, Inc. C1 Univ Calif Los Angeles, Dept Anthropol, Los Angeles, CA 90024 USA. Univ W Indies, Dept Biol, Cave hill, Barbados. European So Observ, Space Telescope, European Coordinating Facil, Munich, Germany. RP Gerald, MS (reprint author), NIAAA, Clin Studies Lab, Anim Ctr, NIH, POB 529,Bldg 112,Room 205, Poolesville, MD 20837 USA. NR 19 TC 41 Z9 42 U1 1 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD FEB PY 2001 VL 53 IS 2 BP 79 EP 85 DI 10.1002/1098-2345(200102)53:2<79::AID-AJP3>3.0.CO;2-N PG 7 WC Zoology SC Zoology GA 399GE UT WOS:000166802600003 PM 11170169 ER PT J AU Hommer, DW Momenan, R Kaiser, E Rawlings, RR AF Hommer, DW Momenan, R Kaiser, E Rawlings, RR TI Evidence for a gender-related effect of alcoholism on brain volumes SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID FEMALE ALCOHOLICS; HIPPOCAMPAL VOLUME; GRAY-MATTER; WOMEN; DISEASE; MEN; MRI; PERFORMANCE; CONSUMPTION; METABOLISM AB Objective: The goal of this study was to compare brain volumes of alcoholic and nonalcoholic men and women and determine if the magnitudes of differences in brain volumes between alcoholic women and nonalcoholic women are greater than the magnitudes of the differences between alcoholic men and nonalcoholic men. Method: The study group included 118 subjects: 79 inpatients 30-60 years of age who were alcohol dependent but had no clinically apparent cognitive impairment or medical illness (43 men and 36 women) and 39 healthy comparison subjects of similar age who were not alcoholic (20 men and 19 women). The volume of intracranial contents was segmented into gray matter, white matter, sulcal CSF, and ventricular CSF from a T-1-weighted magnetic resonance image obtained after the alcoholic subjects had attained 3 weeks of sobriety. Results: Alcoholic women had significantly smaller volumes of gray and white matter as well as greater volumes of sulcal and ventricular CSF than nonalcoholic women. The differences in gray and white matter volumes between alcoholic and nonalcoholic men were significant, but the significance of these differences was of a smaller magnitude than the significance of the differences between alcoholic and nonalcoholic women. Direct comparisons of alcoholic men and women showed that the proportion of intracranial contents occupied by gray matter was smaller in alcoholic women than in alcoholic men. The magnitudes of differences in brain volumes adjusted for intracranial size between alcoholic women and nonalcoholic women were greater than the magnitudes of the adjusted differences between alcoholic men and nonalcoholic men. Conclusions: These results are consistent with greater sensitivity to alcohol neurotoxicity among women. C1 NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, Bethesda, MD 20892 USA. RP Hommer, DW (reprint author), NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, 10 Ctr Dr,MSC 1256, Bethesda, MD 20892 USA. NR 29 TC 183 Z9 185 U1 0 U2 7 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2001 VL 158 IS 2 BP 198 EP 204 DI 10.1176/appi.ajp.158.2.198 PG 7 WC Psychiatry SC Psychiatry GA 398MZ UT WOS:000166761400008 PM 11156801 ER PT J AU Maki, PM Zonderman, AB Resnick, SM AF Maki, PM Zonderman, AB Resnick, SM TI Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 3rd Annual Meeting of the Society-for-Behavioral-Neuroendocrinology CY JUN 26-30, 1999 CL CHARLOTTESVILLE, VIRGINIA SP Soc Behav Neuroendocrinol ID SURGICALLY MENOPAUSAL WOMEN; OLDER WOMEN; POSTMENOPAUSAL WOMEN; COGNITIVE FUNCTION; GONADAL-STEROIDS; ESTROGEN USE; PERFORMANCE; SCOPOLAMINE; MODULATION; RATS AB Objective: This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women. Method: This prospective observational study in nondemented postmenopausal women aged 50-89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy (44 of whom were receiving adjuvant progesterone) and 81 women who had never received such therapy. Groups were naturally matched on education, health status, depressive symptoms, annual income, and general verbal ability. To restrict the study group to cognitively healthy women, prospective clinical data were used to exclude women who developed dementia up to 5 years after assessment. Data were cross-sectional. Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory, figural memory mental relations, attention, and working memory. Results: The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones, but there were no significant differences in scores on other cognitive tests. Specific aspects of memory performance, including encoding and retrieval, were superior among the women receiving hormone therapy. Conclusions: These findings, based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status, suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women. C1 NIA, Lab Personal & Cognit, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Maki, PM (reprint author), NIA, Lab Personal & Cognit, Ctr Gerontol Res, Box 3,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Zonderman, Alan B/0000-0002-6523-4778 NR 36 TC 171 Z9 179 U1 0 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2001 VL 158 IS 2 BP 227 EP 233 DI 10.1176/appi.ajp.158.2.227 PG 7 WC Psychiatry SC Psychiatry GA 398MZ UT WOS:000166761400012 PM 11156805 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI The "truth" Tobacco Memorial SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Theerman, P (reprint author), Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 1 Z9 1 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 FEB PY 2001 VL 91 IS 2 BP 195 EP 195 DI 10.2105/AJPH.91.2.195 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BK UT WOS:000170344900003 PM 11211626 ER PT J AU Parascandola, M AF Parascandola, M TI Cigarettes and the US Public Health Service in the 1950s SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID WORLD-WAR-II; LUNG-CANCER; UNITED-STATES; SMOKING; EPIDEMIOLOGY; TOBACCO; HISTORY; DISEASE AB The conclusion of the United States Surgeon General's Advisory Committee on Smoking and Health in 1964 that excessive cigarette smoking causes lung cancer is cited as the major turning point for public health action against cigarettes. But the surgeon general and US Public Health Service (PHS) scientists had concluded as early as 1957 that smoking was a cause of lung cancer, indeed, "the principal etiologic factor in the increased incidence of lung cancer." Throughout the 1950s, however, the PHS rejected further tobacco-related public health actions, such as placing warning labels on cigarettes or creating educational programs for schools. Instead, the agency continued to gather information and provided occasional assessments of the evidence as it came available. It was not until pressure mounted from outside the PHS in the early 1960s that more substantive action was taken. Earlier action was not taken because of the way in which PHS scientists (particularly those within the National Institutes of Health) and administrators viewed their roles in relation to science and public health. C1 NIH, Museum Med Res, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, Canc Prevent Fellowship Program, 6120 Execut Blvd,Suite T-41, Bethesda, MD 20892 USA. EM mparas@erols.com NR 81 TC 23 Z9 23 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2001 VL 91 IS 2 BP 196 EP 205 DI 10.2105/AJPH.91.2.196 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BK UT WOS:000170344900004 PM 11211627 ER PT J AU Idell, S Mazar, AP Bitterman, P Mohla, S Harabin, AL AF Idell, S Mazar, AP Bitterman, P Mohla, S Harabin, AL TI Fibrin turnover in lung inflammation and neoplasia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; PLASMINOGEN-ACTIVATOR INHIBITOR-1; INDUCED PULMONARY FIBROSIS; RNA-BINDING-PROTEIN; CELLS IN-VITRO; UROKINASE RECEPTOR; POSTTRANSCRIPTIONAL REGULATION; TRANSLATIONAL CONTROL; LOCAL ABNORMALITIES; TRANSGENIC MICE C1 NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Univ Texas Hlth Ctr, Dept Med Specialties, Tyler, TX USA. Attenuon LLC, San Diego, CA USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NCI, Div Canc Biol, Bethesda, MD 20892 USA. RP Harabin, AL (reprint author), NHLBI, Div Lung Dis, 6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 76 TC 36 Z9 41 U1 0 U2 1 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 FEB PY 2001 VL 163 IS 2 BP 578 EP 584 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 403PD UT WOS:000167050900045 PM 11179137 ER PT J AU Zhang, LM Rice, AB Adler, K Sannes, P Martin, L Gladwell, W Koo, JS Gray, TE Bonner, JC AF Zhang, LM Rice, AB Adler, K Sannes, P Martin, L Gladwell, W Koo, JS Gray, TE Bonner, JC TI Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor - A mitogen for lung fibroblasts SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID SMOOTH-MUSCLE CELLS; PRIMARY CULTURES; FACTOR RECEPTOR; EGF; INJURY; RATS; MACROPHAGES; ACTIVATION; EXPRESSION; PENTOXIDE AB The bronchial epithelium is a potential source of growth factors that could mediate airway fibrosis during the progression of diseases such as asthma and chronic bronchitis. We report that conditioned medium (CM) from normal human bronchial epithelial cells (NHBECs) contains mitogenic activity for human lung fibroblasts that is blocked by the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitor AG1478 and by neutralizing antibodies raised against heparin-binding epidermal growth factor-like growth factor (HB-EGF). Neutralizing antibodies against other EGF-R ligands (EGF and transforming growth factor-alpha) or other antibodies against growth factors (platelet-derived growth factors, insulin-like growth factor-1) had no affect on the mitogenic activity of NHBEC-CM. HB-EGF messenger RNA (mRNA) expression in NHBEC was detected by reverse transcriptase/polymerase chain reaction and Northern blot analysis. HB-EGF protein was detected by enzyme-linked immunosorbent assay. Vanadium pentoxide (V2O5), a fibrogenic metal associated with occupational asthma, caused a several-fold increase in HB-EGF mRNA expression and protein, whereas the inert metal titanium dioxide had no effect on HB-EGF expression. V2O5-induced HB-EGF mRNA expression was inhibited by the EGF-R tyrosine kinase inhibitor AG1478, the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580, and the MAP kinase kinase inhibitor PD98059. Finally, HB-EGF induced the production of fibroblast growth factor (FGF)-2 by human lung fibroblasts and anti-FGF-2 antibody partially blocked the mitogenic activity of NHBEC-CM on fibroblasts. These data suggest that HB-EGF is a fibroblast mitogen produced by NHBECs and that induction of an FGF-2 autocrine loop in fibroblasts by HB-EGF accounts for part of this mitogenic activity. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Dept Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Coll Vet Med, Raleigh, NC 27695 USA. RP Bonner, JC (reprint author), NIEHS, Pulm Pathobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01-HL-36982, R01 HL044497] NR 35 TC 39 Z9 39 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 FEB PY 2001 VL 24 IS 2 BP 123 EP 131 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 405JV UT WOS:000167157000004 PM 11159045 ER PT J AU Dwyer, AJ Chow, CK AF Dwyer, AJ Chow, CK TI John L. Doppman, 1928-2000 - Memorial SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Biographical-Item C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Dwyer, AJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2001 VL 176 IS 2 BP 457 EP 458 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 395RB UT WOS:000166594100032 ER PT J AU Choyke, PL Yim, P Marcos, H Ho, VB Mullick, R Summers, RM AF Choyke, PL Yim, P Marcos, H Ho, VB Mullick, R Summers, RM TI Hepatic MR angiography: A multiobserver comparison of visualization methods SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID MAXIMUM-INTENSITY-PROJECTION AB OBJECTIVE. MR angiography (MRA) is an established diagnostic method; however. controversy remains over the best technique for display. In this study, we compared five methods of depicting hepatic MRA including a novel skeletonization approach, using receiver operator characteristic (ROC) curves, interobserver variability (kappa values), and speed of interpretation. SUBJECTS AND METHODS. Twenty-one patients scheduled for isolated liver perfusion therapy for metastatic disease underwent contrast-enhanced three-dimensional MRA to determine vascular anatomy. Vascular anatomy was validated at the time of surgery. We dis played the image data, using five techniques: maximum intensity projection, targeted maximum intensity projection, isointensity surface (isosurface), connected isointensity surface (connected isosurface), and ordered region growing skeleton (skeleton). Four observers, blinded to the surgical results, interpreted each technique in random order without patient identifiers. Areas under the ROC curves, kappa values of interobserver variability, and time to interpret each display were compared. RESULTS. Skeletonized MRA had the highest area under the ROC curve (A(z), 0.90 +/- 0.04) compared with the other techniques (p < 0.013), Kappa scores of agreement were also highest for skeletonized MRA (0.75 +/- 0.04) and had no overlap at the 95% confidence level compared with other techniques. Compared with source images, all visualization methods were faster to interpret, but the skeleton technique was more quickly (p = 0.04) interpreted than the other techniques. CONCLUSION. Skeletonized MRA with the skeleton connectivity algorithm is a semiautomated method of displaying complex arterial anatomy. Compared with other techniques, it is more accurate, more consistent among observers, and slightly faster to interpret. Skeletonization should be applicable to CT angiography and MRA. C1 NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. RP Choyke, PL (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10,Rm 1C660, Bethesda, MD 20892 USA. NR 17 TC 10 Z9 10 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2001 VL 176 IS 2 BP 465 EP 470 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 395RB UT WOS:000166594100035 PM 11159097 ER PT J AU Vogel, I Francksen, H Soeth, E Henne-Bruns, D Kremer, B Juhl, H AF Vogel, I Francksen, H Soeth, E Henne-Bruns, D Kremer, B Juhl, H TI The carcinoembryonic antigen and its prognostic impact on immunocytologically detected intraperitoneal colorectal cancer cells SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE colorectal cancer; disseminated cancer cells; immunocytology; carcinoembryonic antigen ID TUMOR-CELLS; MONOCLONAL-ANTIBODIES; PERITONEAL-CAVITY; ADJUVANT THERAPY; BONE-MARROW; CARCINOMA; MOLECULE; MARKER; CEA AB Background: Carcinoembryonic antigen (CEA) has been suggested to promote colon cancer progression. In this study we analyzed the prognostic impact of CEA expression on intraperitoneally detected single colon cancer cells. Methods: Peritoneal lavage samples of 135 colorectal cancer patients were imunocytologically analyzed, including a staining of cellular CEA; serum CEA levels were measured; and 5-year survival rates were calculated according to immunocytological findings and CEA expression. Results: The worst survival rate of 20% was found in patients suffering from CEA-expressing intraperitoneal tumor cells (P = 0.0006). The prognostic impact of an intraperitoneal tumor cell finding significantly increased when serum CEA levels were elevated: only 23% survived 5 years in contrast to a 85% 5-year survival rate of patients who neither had signs of dissemination nor showed elevated serum CEA values (P = 0.0010). Conclusions: This study shows that the determination of CEA expression improves the prognostic impact of an intraperitoneal tumor cell finding. (C) 2001 Excerpta Medica, Inc. All rights reserved. C1 Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Univ Kiel, Dept Surg, Kiel, Germany. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Juhl, H (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, NRB Room E316A,2970 Reservoir Rd NW, Washington, DC 20007 USA. RI Vogel, Ilka/E-7529-2010; Kremer, Bernd/E-9474-2010 NR 20 TC 32 Z9 32 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD FEB PY 2001 VL 181 IS 2 BP 188 EP 193 DI 10.1016/S0002-9610(00)00555-9 PG 6 WC Surgery SC Surgery GA 427QK UT WOS:000168416800020 PM 11425064 ER PT J AU Carney, JA Boccon-Gibod, L Jarka, DE Tanaka, Y Swee, RG Unni, KK Stratakis, CA AF Carney, JA Boccon-Gibod, L Jarka, DE Tanaka, Y Swee, RG Unni, KK Stratakis, CA TI Osteochondromyxoma of bone - A congenital tumor associated with lentigines and other unusual disorders SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE bone; neoplasm; congenital; benign; osteochondromyxoma; Carney complex ID ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; CHEST-WALL; MESENCHYMAL HAMARTOMA; CHONDROMYXOID FIBROMA; CUSHING SYNDROME; CARDIAC MYXOMA; COMPLEX; CHONDROSARCOMA; INFANCY AB This article describes the clinical and pathologic features of four unusual bone tumors. Three were congenital or most likely so: the fourth, detected at age 1 year, was probably of considerable duration. The patients. three boys and one girl, each presented with a painless mass. Two had the Carney complex, a familial lentiginous and multiorgan tumorous syndrome: another probably had this disorder: the fourth did not show it. but his mother did. The tumors occurred in the nasal region (n = 2) and the diaphysis of the tibia and radius (n = 1 each). Roentgenographically. three had benign characteristics; the fourth, malignant features. Grossly, the tumors were gelatinous, cartilaginous, and bony. Microscopically, they featured benign-appearing polymorphic cells with few division figures arranged in sheets and lobules set in a myxomatous. cartilaginous, osseous, and hyaline fibrous matrix. Cellularity was low to moderate. The tumors eroded bone, one infiltrated between bony trabeculae. and three had soft tissue extension. Complete resection of one tumor was curative: incomplete excision of two tumors resulted in local recurrence (intracranial and fatal) in one and persistence in the other: the fourth tumor remains under observation after biopsy. No tumor metastasized. C1 Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Diagnost Radiol, Rochester, MN 55905 USA. Hop Trousseau, Dept Pathol, F-75571 Paris, France. Childrens Mercy Hosp, Sect Orthopaed Surg, Kansas City, MO 64108 USA. Kanagawa Childrens Med Ctr, Dept Pathol, Yokohama, Kanagawa, Japan. NICHHD, 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 34 TC 37 Z9 39 U1 1 U2 2 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 FEB PY 2001 VL 25 IS 2 BP 164 EP 176 DI 10.1097/00000478-200102000-00004 PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 397LG UT WOS:000166696700004 PM 11176065 ER PT J AU Collins, WA Maccoby, EE Steinberg, L Hetherington, EM Bornstein, MH AF Collins, WA Maccoby, EE Steinberg, L Hetherington, EM Bornstein, MH TI Toward nature with nurture SO AMERICAN PSYCHOLOGIST LA English DT Editorial Material ID ASSOCIATIONS; ADOLESCENCE C1 Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. Stanford Univ, Stanford, CA 94305 USA. Temple Univ, Philadelphia, PA 19122 USA. Univ Virginia, Charlottesville, VA 22903 USA. NICHHD, Bethesda, MD 20892 USA. RP Collins, WA (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. NR 11 TC 8 Z9 8 U1 1 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0003-066X J9 AM PSYCHOL JI Am. Psychol. PD FEB PY 2001 VL 56 IS 2 BP 171 EP 173 DI 10.1037//0003-066X.56.2.171b PG 3 WC Psychology, Multidisciplinary SC Psychology GA 463CG UT WOS:000170458800010 PM 11279811 ER PT J AU Devaney, JM Pettit, EL Kaler, SG Vallone, PM Butler, JM Marino, MA AF Devaney, JM Pettit, EL Kaler, SG Vallone, PM Butler, JM Marino, MA TI Genotyping of two mutations in the HFE gene using single-base extension and high-performance liquid chromatography SO ANALYTICAL CHEMISTRY LA English DT Article ID CAPILLARY-ELECTROPHORESIS; NUCLEOTIDE POLYMORPHISMS; PRIMER EXTENSION; DNA OLIGOMERS; HEMOCHROMATOSIS; OLIGONUCLEOTIDES; STABILITY AB Currently, a major focus of human genetics is the utilization of single-nucleotide polymorphisms for clinical diagnostics, whole-genome linkage disequilibrium screens to identify common disease genes such as Alzheimer disease, determination of the recent evolutionary history of a species, and the process of speciation, We have examined single-nucleotide extension coupled with highperformance liquid chromatography as a method to simultaneously genotype two SNPs occurring in the coding region of the HFE gene that produce clinical effects. This assay allows concurrent genotyping of the C282Y and H63D mutations in 11 min and is 100% concordant with current testing methods for both of these mutations. C1 Transgenom Inc, Gaithersburg, MD 20878 USA. NIH, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Div Biotechnol, Gaithersburg, MD 20899 USA. RP Devaney, JM (reprint author), Transgenom Inc, 11 Firstfield Rd,Suite E, Gaithersburg, MD 20878 USA. RI Butler, John/C-7812-2011 NR 24 TC 31 Z9 31 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 1 PY 2001 VL 73 IS 3 BP 620 EP 624 DI 10.1021/ac000912j PG 5 WC Chemistry, Analytical SC Chemistry GA 398WV UT WOS:000166780200039 PM 11217771 ER PT J AU Walcourt, A Scott, RL Nash, HA AF Walcourt, A Scott, RL Nash, HA TI Blockage of one class of potassium channel alters the effectiveness of halothane in a brain circuit of Drosophila SO ANESTHESIA AND ANALGESIA LA English DT Article ID SYNAPTIC TRANSMISSION; GENERAL-ANESTHETICS; MELANOGASTER; MUTANTS; SYSTEM; EXCITABILITY; MUTATIONS AB At concentrations comparable to those used in the clinic, halothane has profound effects on a neuronal pathway devoted to the escape reflex of the fruit fly, Drosophila melanogaster. We studied the influence of the potassium channel that is encoded by the Shaker gene on the halothane sensitivity of this circuit. Shaker channels were specifically inactivated either by genetic means, using strains with two different severe Shaker mutations, or by pharmacologic means, using ingestion of millimolar concentrations of 4-aminopyridine. In all cases, halothane potency decreased substantially. To ensure that the genetic alteration was specific, both mutations were studied as stocks that had been repeatedly backcrossed to a control strain. The specificity of the pharmacologic inhibition was demonstrated by the fact that 4-aminopyridine had no effect on halothane potency in a Shaker mutant. Quantitative differences in the effects of channel inhibition between males and females suggested a sexual dimorphism in the functional brain anatomy of the reflex circuit. C1 NIMH, LMB, Bethesda, MD 20892 USA. RP Nash, HA (reprint author), NIMH, LMB, Bldg 36,Rm 1B08, Bethesda, MD 20892 USA. NR 26 TC 16 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD FEB PY 2001 VL 92 IS 2 BP 535 EP 541 PG 7 WC Anesthesiology SC Anesthesiology GA 396RF UT WOS:000166649800047 PM 11159264 ER PT J AU Ueyama, S Jin, SJ Rhim, JS Ueyama, T Lim, DJ AF Ueyama, S Jin, SJ Rhim, JS Ueyama, T Lim, DJ TI Immortalization of rat middle ear epithelial cells by adeno 12-SV40 hybrid virus SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE adeno 12-SV40 hybrid virus; cell culture; cell line; immortalization; rat middle ear epithelial cells ID MONOCLONAL-ANTIBODIES; PRIMARY CULTURES; EXPRESSION; STRATIFICATION; CHINCHILLAS; TRANSPORT; PATTERNS; TISSUES; SERIES AB Rat middle ear epithelial cells were infected with the adeno 12-SV40 hybrid virus. The cell line thus obtained displays features of primary cultured epithelial cells in both light microscopic and ultrastructural examinations. The immortalized cells have been in continuous proliferation for 40 passages and more than 17 months. Immunohistochemical analysis of the immortalized cells was positive for the SV40 T antigen and the tumor suppressor protein p53. The cells also stained positive for cytokeratin, an epithelial cell marker, and negative for vimentin. a fibroblast marker. These results, together with karyotype analysis, indicate that this cell line originated from rat middle ear epithelial cells and retains the characteristics of epithelial cells. This cell line will be useful for studying the normal cellular biology of middle ear epithelial cells, as well as the cellular and molecular mechanisms involved in the bacteria-middle ear epithelial cell interaction. C1 House Ear Inst, Gonda Dept Cell & Mol Biol, Los Angeles, CA 90057 USA. NIDCD, Lab Cellular Biol, NIH, Rockville, MD USA. NCI, Lab Biochem Physiol, NIH, Frederick, MD 21701 USA. RP Lim, DJ (reprint author), House Ear Inst, Gonda Dept Cell & Mol Biol, 2100 W 3rd St,5th Floor, Los Angeles, CA 90057 USA. NR 32 TC 11 Z9 11 U1 0 U2 4 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD FEB PY 2001 VL 110 IS 2 BP 132 EP 141 PG 10 WC Otorhinolaryngology SC Otorhinolaryngology GA 400YQ UT WOS:000166900600008 PM 11219520 ER PT J AU Pinn, VW AF Pinn, VW TI Women in Thoracic Surgery Symposium - Fort Lauderdale, Florida - January 31, 2000 - Preface SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 NIH, Off Res Womens Hlth, HIH, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, HIH, Bldg 1,Room 201, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD FEB PY 2001 VL 71 IS 2 SU S BP S1 EP S2 DI 10.1016/S0003-4975(00)02487-5 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 404JT UT WOS:000167094800001 ER PT J AU Petraitis, V Petraitiene, R Groll, AH Sein, T Schaufele, RL Lyman, CA Francesconi, A Bacher, J Piscitelli, SC Walsh, TJ AF Petraitis, V Petraitiene, R Groll, AH Sein, T Schaufele, RL Lyman, CA Francesconi, A Bacher, J Piscitelli, SC Walsh, TJ TI Dosage-dependent antifungal efficacy of V-echinocandin (LY303366) against experimental fluconazole-resistant oropharyngeal and esophageal candidiasis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FUNGAL CELL-WALL; AMPHOTERICIN-B; PHARMACOKINETICS; RABBITS; SAFETY; CILOFUNGIN AB V-echinocandin (VER-002; LY303366) is a semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1, 3)-beta -D-glucan synthase. We studied the antifungal efficacy, the concentrations in saliva and tissue, and the safety of VER-002 at escalating dosages against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant Candida albicans in immunocompromised rabbits. Study groups consisted of untreated controls, animals treated with VER-002 at 1, 2.5, and 5 mg/kg of body weight/day intravenously (i.v.), animals treated with fluconazole at 2 mg/kg/day i.v., or animals treated with amphotericin B at 0.3 mg/kg/day. VER-002-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, esophagus, stomach, and duodenum in comparison to that for untreated controls. VER-002 also was superior to amphotericin B and fluconazole in clearing the organism from all sites studied. These in vivo findings are consistent with the results of in vitro time-kill assays, which demonstrated that VER-002 has concentration-dependent fungicidal activity. Esophageal tissue VER-002 concentrations were dosage proportional and exceeded the MIC at all dosages. Echinocandin concentrations in saliva were greater than or equal to the MICs at all dosages. There was no elevation of serum hepatic transaminase, alkaline phosphatase, bilirubin, potassium, or creatinine levels in VER-002-treated rabbits. In summary, the echinocandin VER-002 was well tolerated, penetrated the esophagus and salivary glands, and demonstrated dosage-dependent antifungal activity against fluconazole-resistant esophageal candidiasis in immunocompromised rabbits. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIH, Pharmacokinet Res Lab, Dept Pharm, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,Ctr Dr, Bethesda, MD 20892 USA. NR 35 TC 42 Z9 43 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2001 VL 45 IS 2 BP 471 EP 479 DI 10.1128/AAC.45.2.471-479.2001 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 394TP UT WOS:000166539600015 PM 11158743 ER PT J AU Hachiya, A Aizawa-Matsuoka, S Tanaka, M Takahashi, Y Ida, S Gatanaga, H Hirabayashi, Y Kojima, A Tatsumi, M Oka, S AF Hachiya, A Aizawa-Matsuoka, S Tanaka, M Takahashi, Y Ida, S Gatanaga, H Hirabayashi, Y Kojima, A Tatsumi, M Oka, S TI Rapid and simple phenotypic assay for drug susceptibility of human immunodeficiency virus type 1 using CCR5-expressing HeLa/CD4(+) cell clone 1-10 (MAGIC-5) SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID REVERSE-TRANSCRIPTASE GENE; PROTEASE INHIBITORS; RESISTANCE MUTATIONS; COMBINATION THERAPY; CONFERS RESISTANCE; ZIDOVUDINE AZT; HIV-1 ENTRY; IN-VIVO; RITONAVIR; SENSITIVITY AB We describe a rapid and simple novel phenotypic assay for drug susceptibility of human immunodeficiency virus type-1 (HIV-1) using a CCR5-expressing HeLa/CD4(+) cell clone 1-10 (MAGIC-5). MAGIC-5 cells produced large amounts of HIV-1in culture supernatants, which enabled us to perform the phenotypic resistance assay. Determination of HIV-1 susceptibility to various protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors was completed within 15 days in T-cell-tropic (X4) and macrophage-tropic (R5) viruses using fresh plasma samples containing at least 10(4) copies/ml. The nucleotide sequence of the envelope V3 region of HIV-1 in plasma was almost identical to that of the virus isolated by MAGIC-5 cells, suggesting a lack of selection bias in our assay. The assay variability was confined to within five-fold in all drugs examined. Accordingly, we used a 10-fold increase in the 50% inhibitory concentration as the cutoff value for viral resistance in the present assay. HIV-1 resistant to lamivudine, which was not detected by conventional genotypic assays, was isolated. In HIV-1with PI-associated primary amino acid substitutions, our assay showed that drug resistance profiles correlated well with previously reported genotypic-assay data.Furthermore, our assay provided comprehensive results regarding PI resistance in the presence of multiple mutations. The novel assay successfully quantified the level of resistance of clinical HIV-1 isolates to a battery of anti-HIV drugs, indicating its clinical usefulness, particularly in patients who failed to respond to antiretroviral chemotherapy. C1 Int Med Ctr Japan, AIDS Clin Ctr, Shinjuku Ku, Tokyo 1628655, Japan. NCI, Expt Retroviral Sect, Dept Med Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Infect Dis, Dept Pathol, Tokyo, Japan. Natl Inst Infect Dis, Dept Vet Sci, Tokyo, Japan. RP Oka, S (reprint author), Int Med Ctr Japan, AIDS Clin Ctr, Shinjuku Ku, 1-21-1 Toyama, Tokyo 1628655, Japan. NR 33 TC 69 Z9 71 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2001 VL 45 IS 2 BP 495 EP 501 DI 10.1128/AAC.45.2.495-501.2001 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 394TP UT WOS:000166539600018 PM 11158746 ER PT J AU Groll, AH Gullick, BM Petraitiene, R Petraitis, V Candelario, M Piscitelli, SC Walsh, TJ AF Groll, AH Gullick, BM Petraitiene, R Petraitis, V Candelario, M Piscitelli, SC Walsh, TJ TI Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID EXPERIMENTAL DISSEMINATED CANDIDIASIS; IN-VITRO; PNEUMOCANDIN ANTIFUNGAL; AMPHOTERICIN-B; L-743,872; LY303366; ASPERGILLOSIS; FLUCONAZOLE; CILOFUNGIN; RESISTANT AB The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C-max) +/- standard error of the mean increased from 16.01 +/- 0.61 mug/ml at the 1-mg/kg dose to 105.52 +/- 8.92 mug/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 +/- 2.37 to 158.43 +/- 15.58 mug . h/ml, respectively, The mean apparent volume of distribution at steady state (Vd(ss)) was 0.299 +/- 0.011 liter/kg at the 1-mg/kg dose and 0.351 +/- 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 +/- 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 +/- 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS), Except for a trend towards an increased Vd(ss), there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration, Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Pharm, Pharmacokinet Res Lab, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2001 VL 45 IS 2 BP 596 EP 600 DI 10.1128/AAC.45.2.596-600.2001 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 394TP UT WOS:000166539600033 PM 11158761 ER PT J AU Mattson, MP Duan, W Pedersen, WA Culmsee, C AF Mattson, MP Duan, W Pedersen, WA Culmsee, C TI Neurodegenerative disorders and ischemic brain diseases SO APOPTOSIS LA English DT Review DE Alzheimer's disease; caspases; mitochondrial permeability transition; neurotrophic factors; oxidative stress; Parkinson's disease; telomerase ID AMYLOID BETA-PEPTIDE; FOCAL CEREBRAL-ISCHEMIA; NF-KAPPA-B; MANGANESE SUPEROXIDE-DISMUTASE; PROSTATE APOPTOSIS RESPONSE-4; METABOLIC EXCITOTOXIC INSULTS; PROTECTS HIPPOCAMPAL-NEURONS; TRANSIENT GLOBAL-ISCHEMIA; SUBSTANTIA-NIGRA COMPACTA; TROPHIC FACTOR WITHDRAWAL AB Degeneration and death of neurons is the fundamental process responsible for the clinical manifestations of many different neurological disorders of aging, incuding Alzheimer's disease, Parkinson's disease and stroke. The death of neurons in such disorders involves apoptotic biochemical cascades involving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family members), mitochondrial alterations and caspase activation. Both genetic and environmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor protein and presenilin genes can cause Alzheimer's disease, while head injury is a risk factor for both Alzheimer's and Parkinson's diseases. At the cellular level, neuronal apoptosis in neurodegenerative disorders may be triggered by oxidative stress, metabolic compromise and disruption of calcium homeostasis. Neuroprotective (anti-apoptotic) signaling pathways involving neurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of neurodegenerative disorders. A better understanding of the molecular underpinnings of neuronal death is leading directly to novel preventative and therapeutic approaches to neurodegenerative disorders. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), Lab Neurosci 4F01, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 145 TC 211 Z9 224 U1 0 U2 8 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 69 EP 81 DI 10.1023/A:1009676112184 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800007 PM 11321043 ER PT J AU Yang, Y Ashwell, JD AF Yang, Y Ashwell, JD TI Exploiting the apoptotic process for management of HIV: Are we there yet ? SO APOPTOSIS LA English DT Article DE apoptosis; HIV; T cell ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; CD4(+) T-CELLS; BLOOD MONONUCLEAR-CELLS; FAS LIGAND EXPRESSION; RETINOIC ACID INHIBITION; CROSS-LINKING; FACTOR-ALPHA; UP-REGULATION; INFECTED INDIVIDUALS AB CD4(+) T cells die in individuals infected with HIV, either as a result of direct HIV infection or as uninfected "innocent bystanders". Possible mechanisms for bystander killing include generation of viral products such as Tat or gp120 and expression of death receptor ligands, such as FasL, that engage functional death receptors on uninfected cells. This review covers the sometimes conflicting in vitro and ex vivo studies that address these possible mechanisms of HIV-associated cell death. It is an intriguing possibility that manipulation of cell death processes, to decrease bystander death or increase death of infected cells, in patients infected with HIV might provide a useful adjunct to antiretroviral therapy. C1 NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Room 1B-40,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 95 TC 10 Z9 10 U1 1 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD FEB PY 2001 VL 6 IS 1-2 BP 139 EP 146 DI 10.1023/A:1009600901706 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 403LZ UT WOS:000167045800013 PM 11321037 ER PT J AU Daly, RC Su, TP Schmidt, PJ Pickar, D Murphy, DL Rubinow, DR AF Daly, RC Su, TP Schmidt, PJ Pickar, D Murphy, DL Rubinow, DR TI Cerebrospinal fluid and behavioral changes after methyltestosterone administration - Preliminary findings SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Biological-Psychiatry CY MAY 13-16, 1999 CL WASHINGTON, D.C. SP Soc Biol Psychiat ID CORTICOTROPIN-RELEASING HORMONE; CSF MONOAMINE METABOLITES; ANABOLIC-STEROIDS; INDUCED DOMINANCE; MAJOR DEPRESSION; ADRENOCORTICOTROPIN; IMMUNOREACTIVITY; SOMATOSTATIN; PERSONALITY; AGGRESSION AB Background: Anabolic androgen steroid abuse is associated with multiple psychiatric symptoms and is a significant public health problem. The biological mechanisms underlying behavioral symptom development are poorly understood. Subjects and Methods: We examined levels of monoamine metabolites, neurohormones, and neuropeptides in the cerebrospinal fluid (CSF) of 17 healthy men, at baseline and following 6 days of methyltestosterone (MT) administration (3 days of 40 mg/d, then 3 days of 240 mg/d). Subjects received MT or placebo in a fixed sequence, with neither subjects nor raters aware of the order. Potential relationships were examined between CSF measures, CSF MT levels, and behavioral changes measured on a visual analog scale. Results: Following MT administration, lei els of 3-methoxy-4-hydroxyphenylglycol (MHPG) were significantly lower (mean+/-SD, 103.8+/-47 vs 122.0+/-50.7 pmol/mL; P<.01), and 5-hydroxyindoleacetic acid (5- HIAA) levels were significantly higher (mean+/-SD, 104.7+/-31.3 vs 86.9+/-23.6 pmol/mL: P<.01). No significant MT-related changes were observed in CSF levels of corticotropin, norepinephrine, cortisol, arginine vasopressin, prolactin, corticotropin-releasing hormone, P-endorphin, and somatotropin release-inhibiting factor. Changes in CSF 5-HIAA significantly correlated with increases in "activation" symptoms (energy, sexual arousal, and diminished sleep) (r=0.55; P=.02). No significant correlation was observed between changes in CSF and plasma MT, CSF MHPG, and behavioral symptoms. Conclusions: Short-term anabolic androgenic steroid use affects brain neurochemistry, increasing CSF 5-HIAA and decreasing MHPG. Changes in 5-HIAA levels caused by anabolic androgenic steroids are related to the behavioral changes we observed. In this small sample, we did not observe a significant relationship between behavioral measures and either dose of MT or CSF and plasma levels of MT. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Natl Yang Ming Univ, Div Psychiat, Taipei 112, Taiwan. Vet Gen Hosp, Dept Psychiat, Taipei, Taiwan. RP Daly, RC (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Room 3N242,10 Ctr Dr,MSC 1277, Bethesda, MD 20892 USA. NR 40 TC 56 Z9 57 U1 1 U2 1 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 FEB PY 2001 VL 58 IS 2 BP 172 EP 177 DI 10.1001/archpsyc.58.2.172 PG 6 WC Psychiatry SC Psychiatry GA 399YV UT WOS:000166842600008 PM 11177119 ER PT J AU Muller, J Wenning, GK Verny, M McKee, A Chaudhuri, KR Jellinger, K Poewe, W Litvan, I AF Muller, J Wenning, GK Verny, M McKee, A Chaudhuri, KR Jellinger, K Poewe, W Litvan, I TI Progression of dysarthria and dysphagia in postmortem-confirmed Parkinsonian disorders SO ARCHIVES OF NEUROLOGY LA English DT Article ID LEWY-BODY-DISEASE; MULTIPLE SYSTEM ATROPHY; CLINICAL-FEATURES; CORTICOBASAL DEGENERATION; SUPRANUCLEAR PALSY; SWALLOWING ABNORMALITIES; INTERNATIONAL WORKSHOP; NATURAL-HISTORY; DEMENTIA; DIAGNOSIS AB Background: Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases. Objective: To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. Patients and Methods: Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States). Results: Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P = .7) and latency to a complaint of dysphagia was highly correlated with total survival time (p = 0.88; P < .001) in all disorders. Conclusions: Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time. C1 NINDS, Cognit Neuropharmacol Unit, Def & Vet Head Injury Program, Henry M Jackson Fdn & Med Branch,NIH, Bethesda, MD 20817 USA. Univ Innsbruck Hosp, Dept Neurol, A-6020 Innsbruck, Austria. Hop La Pitie Salpetriere, Raymond Escourolle Neuropathol Lab, Paris, France. Vet Adm Med Ctr, Geriatr Res Educ Clin Ctr, Bedford, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Inst Psychiat, Dept Neurol, London SE5 8AF, England. Ludwig Boltzmann Inst Clin Neurol, Vienna, Austria. RP Litvan, I (reprint author), NINDS, Cognit Neuropharmacol Unit, Def & Vet Head Injury Program, Henry M Jackson Fdn & Med Branch,NIH, Champlain Bldg,6410 Rockledge Dr,Suite 600, Bethesda, MD 20817 USA. OI Litvan, Irene/0000-0002-3485-3445; Ray Chaudhuri, K/0000-0003-2815-0505 NR 35 TC 138 Z9 142 U1 0 U2 9 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 FEB PY 2001 VL 58 IS 2 BP 259 EP 264 DI 10.1001/archneur.58.2.259 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 400YG UT WOS:000166899800012 PM 11176964 ER PT J AU Nyska, A Lomnitski, L Maronpot, R Moomaw, C Brodsky, B Sintov, A Wormser, U AF Nyska, A Lomnitski, L Maronpot, R Moomaw, C Brodsky, B Sintov, A Wormser, U TI Effects of iodine on inducible nitric oxide synthase and cyclooxygenase-2 expression in sulfur mustard-induced shin injury in guinea pigs SO ARCHIVES OF TOXICOLOGY LA English DT Article DE sulfur mustard; skin; COX-2; iNOS ID COX-2 EXPRESSION; MESSENGER-RNA; SKIN-LESIONS; IN-VIVO; CELLS; KERATINOCYTES; LOCALIZATION; ISOFORMS; MICE AB In a previous study we demonstrated the protective effect of topical iodine as postexposure treatment for sulfur mustard (SM) application. The iodine treatment results in significantly reduced inflammation and necrosis and increased epidermal hyperplasia. The expression and localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in paraffin-embedded skin samples from that study were evaluated in the present investigation. We compared the immunoreactivity of iNOS and COX-2 using five samples from each of the following four test sites: untreated control sites, SM-exposed sites, sites treated with iodine mixture 15 min after SM exposure, and sites treated with iodine 30 min after SM exposure. All animals were killed 2 days after irritant exposure. iNOS immunoreactivity was present only in skin sites exposed to SM without iodine treatment. The ulcerated skin was covered with a relatively thick band of exudate composed of iNOS-immunostained polymorphonuclear cells and macrophages. In untreated skin, COX-2 immunostaining was limited to the thin suprabasal epidermal layer. In SM-exposed skin, induction of COX-2 was noted in inflammatory cells located close to the site of epidermal injury. In skin sites treated with iodine 15 or 30 min after SM exposure, the regenerating hyperplastic epithelium showed moderate cytoplasmic staining localized to the epithelium overlying the basal layer. This pattern of staining was also present in the nearby dermal fibroblasts. Thus, in contrast to the skin samples exposed to SM without iodine treatment, the epidermal layer expressing immunohistochemical positivity for COX-2 was thicker and corresponded to the epidermal hyperplasia noted in samples treated with iodine. It is well documented that prostaglandins (PGs) promote epidermal proliferation, thereby contributing to the repair of injured skin. That the induction of the COX-2 shown in our study may also play a role in the healing process is indicated by the present evidence. The results suggest that nitric oxide radicals (NO .) are involved in mediating the damage induced by the SM and that iodine-related reduction in acute epidermal inflammation is associated with reduced iNOS expression. C1 NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. Bar Ilan Univ, Inst Life Sci, IL-52900 Ramat Gan, Israel. Hebrew Univ Jerusalem, Inst Life Sci, IL-91904 Jerusalem, Israel. Ben Gurion Univ Negev, Inst Appl Res, Beer Sheva, Israel. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, NIH, POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. NR 33 TC 32 Z9 32 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD FEB PY 2001 VL 74 IS 12 BP 768 EP 774 DI 10.1007/s002040000199 PG 7 WC Toxicology SC Toxicology GA 411WT UT WOS:000167523000005 PM 11305779 ER PT J AU Cushman, M Costantino, JP Tracy, RP Song, K Buckley, L Roberts, JD Krag, DN AF Cushman, M Costantino, JP Tracy, RP Song, K Buckley, L Roberts, JD Krag, DN TI Tamoxifen and cardiac risk factors in healthy women - Suggestion of an anti-inflammatory effect SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE tamoxifen; blood coagulation; inflammation; risk factors; cardiovascular disease ID C-REACTIVE PROTEIN; HORMONE REPLACEMENT THERAPY; CORONARY-HEART-DISEASE; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; ADJUVANT TAMOXIFEN; BREAST-CANCER; RANDOMIZED TRIAL; COAGULATION-FACTORS; HEMOSTATIC FUNCTION AB Tamoxifen reduces the incidence of breast cancer in women at risk for that disease. Because heart disease is the leading cause of death in women and because tamoxifen is also associated with venous thrombosis, an improved understanding of the association of tamoxifen with cardiovascular disease risk factors is required. In III healthy women at a single center, who were participating in a randomized double-blind breast cancer prevention trial, the 6-month effects of oral tamoxifen (20 mg/d) compared with placebo on factors related to inflammation, hemostasis, and lipids were studied. Tamoxifen was associated with reductions of 26% in median C-reactive protein, 22% in median fibrinogen, and 9% in cholesterol (all P<0.01 compared with placebo). There were no differences in treatment effects on factor VII coagulant activity, fragment 1-2, and triglycerides. In secondary analyses, the effect of tamoxifen on C-reactive protein was larger in postmenopausal women and in women with higher waist-to-hip ratios. The effect on fibrinogen was larger in women with higher baseline cholesterol. Tamoxifen demonstrated effects on inflammatory markers that were consistent with reduced cardiovascular risk. These findings are in contrast to recent reports of increased C-reactive protein associated with postmenopausal estrogen. The potential for beneficial cardiovascular effects of tamoxifen in healthy women is suggested. C1 Univ Vermont, Dept Med, Burlington, VT USA. Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. Univ Vermont, Dept Surg, Burlington, VT 05405 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Pediat, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA. RP Cushman, M (reprint author), Univ Vermont, Dept Med, 208 S Pk Dr,Suite 2, Colchester, VT 05446 USA. FU NCI NIH HHS [U10-CA-699974, U10-CA-7377]; NHLBI NIH HHS [HL-03618] NR 40 TC 63 Z9 65 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 FEB PY 2001 VL 21 IS 2 BP 255 EP 261 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 412PH UT WOS:000167563200015 PM 11156862 ER PT J AU Sharrett, AR Heiss, G Chambless, LE Boerwinkle, E Coady, SA Folsom, AR Patsch, W AF Sharrett, AR Heiss, G Chambless, LE Boerwinkle, E Coady, SA Folsom, AR Patsch, W TI Metabolic and lifestyle determinants of postprandial lipemia differ from those of fasting triglycerides - The Atherosclerosis Risk in Communities (ARIC) study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE lipoproteins; postprandial; chylomicrons ID MIDDLE-AGED MEN; HIGH-DENSITY-LIPOPROTEIN; CORONARY-ARTERY DISEASE; RETINYL PALMITATE RESPONSES; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; ALCOHOL; WOMEN; ASSOCIATION; CLEARANCE AB Despite the reported association of lipoprotein responses to a fatty meal with atherosclerosis, little is known about the determinants of these responses. Plasma triglyceride, retinyl palmitate, and apolipoprotein B-48 responses to a standardized fatty meal containing a vitamin A marker were measured in 602 Atherosclerosis Risk in Communities (ARIC) study participants. To focus on postprandial responses specifically, which have been reported to be related to atherosclerosis independently of fasting triglycerides, analyses for determinants of postprandial responses were adjusted for fasting triglycerides. Major determinants of fasting triglycerides, namely, diabetes, obesity, other factors related to insulin resistance, and male sex, were not independently associated with postprandial responses. Fasting triglycerides were the strongest predictor of postprandial lipids, but independent of triglycerides, the predictors of postprandial responses were smoking, diet, creatinine, and alcohol, Smokers had substantially increased retinyl palmitate and apolipoprotein B-48 responses, indicators of chylomicrons and their remnants. Persons who consume more calories or omega3 fatty acids had reduced chylomicron responses, Triglyceride responses were associated positively with serum creatinine levels and negatively with moderate alcohol consumption. Thus, determinants of fasting and postprandial lipids differ. The independent atherogenic influence of postprandial lipids may relate more to smoking and diet than to obesity and insulin resistance. C1 NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Univ Texas, Hlth Sci Ctr, Genet Ctr, Houston, TX USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Landeskrankenanstalten, Dept Lab Med, Salzburg, Austria. RP Sharrett, AR (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, Room 8164,MSC 7934,6701 Rockledge Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-55022, U01 HL-45467, N01-HC-55019, N01-HC-55021, N01-HC-55018, N01-HC-55016, N01-HC-5-5015, N01-HC-55020] NR 35 TC 50 Z9 51 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2001 VL 21 IS 2 BP 275 EP 281 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 412PH UT WOS:000167563200018 PM 11156865 ER PT J AU Casciola-Rosen, LA Pluta, AF Plotz, PH Cox, AE Morris, S Wigley, FM Petri, M Gelber, AC Rosen, A AF Casciola-Rosen, LA Pluta, AF Plotz, PH Cox, AE Morris, S Wigley, FM Petri, M Gelber, AC Rosen, A TI The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen SO ARTHRITIS AND RHEUMATISM LA English DT Article ID DEPENDENT PROTEIN-KINASE; SYSTEMIC LUPUS-ERYTHEMATOSUS; NONPOLYPOSIS COLON-CANCER; CATALYTIC SUBUNIT; MI-2 AUTOANTIGEN; GRANZYME-B; AUTOANTIBODIES; APOPTOSIS; DERMATOMYOSITIS; CLASSIFICATION AB Objective. The specificity of the autoantibody response in different autoimmune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may select unique molecules for an autoimmune response in specific diseases. Defining additional phenotype-specific autoantibodies may identify such circumstances. This study was undertaken to investigate the disease specificity of PMS1, an autoantigen previously identified in some sera from patients with myositis. Methods. We used immunoprecipitation analysis to determine the frequency of autoantibodies to PMS1 in sera from patients with myositis, systemic lupus erythematosus, or scleroderma and from healthy controls. Additional antigens recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases. Results. PMS1, a DNA mismatch repair enzyme, was identified as a myositis-specific autoantigen. Autoantibodies to PMS1 were found in 4 of 53 patients with autoimmune myositis (7.5%), but in no sera from 94 patients with other systemic autoimmune diseases (P = 0.016). Additional mismatch repair enzymes (PMS2, MLH1) were targeted, apparently independently. Sera recognizing PMS1 also recognized several other proteins involved in DNA repair and remodeling, including poly (ADP-ribose) polymerase, DNA-dependent protein kinase, and Mi-2. All of these autoantigens were efficiently cleaved by granzyme B, generating unique fragments not observed during other forms of cell death. Conclusion. PMS1 autoantibodies are myositis specific. The striking correlation between an immune response to a group of granzyme B substrates (functioning in DNA repair and remodeling) and the myositis phenotype strongly implies that tissue- and event-specific biochemical events play a role in selecting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Univ Maryland, Baltimore, MD 21201 USA. NIH, Bethesda, MD 20892 USA. RP Casciola-Rosen, LA (reprint author), Johns Hopkins Univ, Sch Med, 720 Rutland Ave,Room 1059, Baltimore, MD 21205 USA. FU NIAMS NIH HHS [AR-43727, AR-44684]; NIDCR NIH HHS [DE-12354] NR 33 TC 38 Z9 39 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD FEB PY 2001 VL 44 IS 2 BP 389 EP 396 DI 10.1002/1529-0131(200102)44:2<389::AID-ANR58>3.0.CO;2-R PG 8 WC Rheumatology SC Rheumatology GA 485JE UT WOS:000171750600019 PM 11229471 ER PT J AU Gray, T Nettesheim, P Basbaum, C Koo, JS AF Gray, T Nettesheim, P Basbaum, C Koo, JS TI Regulation of mucin gene expression in human tracheobronchial epithelial cells by thyroid hormone SO BIOCHEMICAL JOURNAL LA English DT Article DE retinoic acid; retinoic acid receptor; retinoic acid response element; thyroid receptor; tri-iodothyronine ID GROWTH-FACTOR RECEPTOR; RETINOIC-ACID; NEGATIVE REGULATION; V-ERBA; MUC5B; IDENTIFICATION; TRANSCRIPTION; GLYCOFORMS; TRACT; RXR AB We reported previously that the expression of the gene encoding MUC5AC mucin in human airway epithelial cells is controlled by retinoic acid via the retinoic acid receptor (RAR)-alpha and that 3,3',5-tri-iodothyronine (T-3) inhibits the expression of MUC5AC. The purpose of the present study was to identify mechanisms mediating the effect of T-3. T-3 has been shown to inhibit gene expression via several mechanisms, either by enhancing or repressing the transcription of target genes or by the regulation of post-transcriptional events. Results showed that T-3 strongly inhibited MUC5AC-driven luciferase activity in normal human tracheobronchial epithelial cells that had been transiently transfected with a MUC5AC-luciferase reporter construct; however, it did not affect MUC5AC mRNA stability. These results indicate that T-3 suppresses MUC5AC expression at the transcriptional level. An analysis of deletion constructs showed that deletion of the region downstream of 3 kb resulted in markedly decreased levels of MUC5AC transcription in the absence of T-3 (i.e. under control conditions) as well as a loss of responsiveness to the inhibitory effects of T-3. This suggests that this region might contain elements important for the activation as well as the repression of MUC5AC transcription. To determine whether T-3 modulates retinoic-acid-dependent MUC5AC transcription via an alteration in the abundance of retinoid receptor proteins, we examined the type and abundance of these receptors in nuclear extracts of airway epithelial cells grown in the presence or absence of T-3. Western blots showed that T-3 markedly decreased several types of retinoid receptor while not affecting T-3 receptor proteins. Consistent with this finding were gel-shift assays revealing a decrease in RAR-retinoic acid response element complexes obtained from T-3-treated cells. We propose that T-3 might inhibit retinoid-dependent NUC5AC expression by decreasing retinoid receptor levels and thereby decreasing the transcriptional activation of this gene for mucins. C1 NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, Sch Med, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Gray, T (reprint author), NIEHS, Pulm Pathobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 38 TC 14 Z9 14 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 1 PY 2001 VL 353 BP 727 EP 734 DI 10.1042/0264-6021:3530727 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 401RJ UT WOS:000166941800035 PM 11171071 ER PT J AU Hasan, CM Asha, KN Rashid, MA AF Hasan, CM Asha, KN Rashid, MA TI Aristolactams from the stem bark of Uvaria hamiltonii SO BIOCHEMICAL SYSTEMATICS AND ECOLOGY LA English DT Article DE Uvaria hamiltonii; annonaceae; aristolactams; chemotaxonomy ID ARISTOLOLACTAMS; ANNONACEAE; ALKALOIDS C1 Univ Dhaka, Fac Pharm, Phytochem Res Lab, Dhaka 1000, Bangladesh. RP Rashid, MA (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Bldg 560,Rm 32-63B,POB B, Frederick, MD 21702 USA. NR 11 TC 5 Z9 6 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-1978 J9 BIOCHEM SYST ECOL JI Biochem. Syst. Ecol. PD FEB PY 2001 VL 29 IS 2 BP 207 EP 208 DI 10.1016/S0305-1978(00)00035-1 PG 2 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 392XU UT WOS:000166438500012 ER PT J AU Shapiro, BA Wu, JC Bengali, D Potts, MJ AF Shapiro, BA Wu, JC Bengali, D Potts, MJ TI The massively parallel genetic algorithm for RNA folding: MIMD implementation and population variation SO BIOINFORMATICS LA English DT Article ID SECONDARY STRUCTURE; COMPUTER-SIMULATION; PREDICTION; POLIOVIRUS; PATHWAYS; IMPROVES AB A massively parallel Genetic Algorithm (GA) has been applied to RNA sequence folding on three different computer architectures. The GA, an evolution-like algorithm that is applied to a large population of RNA structures based on a pool of helical stems derived from an RNA sequence, evolves this population in parallel. The algorithm was originally designed and developed for a 16 384 processor SIMD (Single Instruction Multiple Data) MasPar MP-2. More recently it has been adapted to a 64 processor MIMD (Multiple Instruction Multiple Data) SGI ORIGIN 2000, and a 512 processor MIMD GRAY T3E. The MIMD version of the algorithm raises issues concerning RNA structure data-layout and processor communication. In addition, the effects of population variation on the predicted results are discussed. Also presented are the scaling properties of the algorithm from the perspective of the number of physical processors utilized and the number of virtual processors (RNA structures) operated upon. C1 NCI, Image Proc Sect, Lab Expt & Computat Biol, Div Basic Sci,Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, LECB, FCRDC, Frederick, MD 21702 USA. SGI Inc, Silver Spring, MD 20904 USA. RP Shapiro, BA (reprint author), NCI, Image Proc Sect, Lab Expt & Computat Biol, Div Basic Sci,Frederick Canc Res & Dev Ctr,NIH, Bldg 469,Rm 150, Frederick, MD 21702 USA. NR 25 TC 55 Z9 60 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB PY 2001 VL 17 IS 2 BP 137 EP 148 DI 10.1093/bioinformatics/17.2.137 PG 12 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 409RA UT WOS:000167396800004 PM 11238069 ER PT J AU Ramesh, R Kuenzel, WJ Proudman, JA AF Ramesh, R Kuenzel, WJ Proudman, JA TI Increased proliferative activity and programmed cellular death in the turkey hen pituitary gland following interruption of incubation behavior SO BIOLOGY OF REPRODUCTION LA English DT Article DE apoptosis; behavior; growth hormone; pituitary; prolactin ID VASOACTIVE-INTESTINAL-PEPTIDE; FOLLICLE-STIMULATING-HORMONE; ANTERIOR-PITUITARY; GROWTH-HORMONE; ESTROUS-CYCLE; APOPTOSIS; RAT; LACTOTROPHS; PROLACTIN; CELLS AB Incubation behavior or broodiness in turkey hens is characterized by ovarian regression, hyperprolactinemia, and persistent nesting. Nest-deprivation of incubating turkey hens results in disruption of broodiness accompanied by a precipitous decline in plasma prolactin (PRL) concentrations. The objective of the present study is to examine cellular changes in the pituitary gland associated with nest-deprivation for 0, 1,2, 3, 4, or 7 days. Bromodeoxyuridine (BrdU) was administered prior to kill to study proliferative activity. Pituitary tissue sections were immunostained using turkey growth hormone (CH) antibody, and/or chicken PRL peptide antibody, and BrdU antibody. Plasma PRL concentrations declined significantly following nest-deprivation for 1 or more days. The midsagittal pituitary area immunoreactive (ir) to GH was significantly increased while that of PRL was significantly decreased following nest-deprivation for 2 or more days. Terminal deoxy-UTP nick end labeling and PRL-immunostaining revealed an abundance of apoptotic nuclei in both cephalic and caudal lobes of the anterior pituitary gland, suggestive of programmed cellular death of lactotrophs in the pituitary gland of hens nest-deprived for 2 or more days. Mammosomatotrophs were abundant in hens nest-deprived on Day 0 but were absent in hens nest-deprived for 1 or more days. Proliferating (BrdU-ir) cells were significantly abundant in the pituitary cephalic and caudal lobes following nest-deprivation for 1 or more days but were absent on Day 0 or in laying hens. Dual-labeling studies indicated that most of the BrdU-ir nuclei in the caudal lobe were not colocalized in somatotrophs in hens nest-deprived for 1-4 days but did colocalize with GH following 7 days of nest-deprivation, In conclusion, nest-deprivation of incubating turkey hens results in 1) a precipitous decline in plasma PRL concentration, 2) programmed cell death of lactotrophs, 3) disappearance of mammosomatotrophs, 4) increased proliferative activity of pituitary cells, and 5) recruitment of somatotrophs arising primarily from mitosis of nonsomatotrophic cells. C1 USDA ARS, Germplasm & Gamete Physiol Lab, Beltsville, MD 20705 USA. Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. RP Ramesh, R (reprint author), NIMH, Sect Neural Gene Express, 36 Convent Dr,MSC 4068,Bldg 36,Rm 2A11, Bethesda, MD 20892 USA. NR 47 TC 9 Z9 9 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD FEB PY 2001 VL 64 IS 2 BP 611 EP 618 DI 10.1095/biolreprod64.2.611 PG 8 WC Reproductive Biology SC Reproductive Biology GA 396RM UT WOS:000166650400025 PM 11159364 ER EF