FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Sun, BF Kobayashi, H Le, N Yoo, TM Drumm, D Paik, CH McAfee, JG Carrasquillo, JA AF Sun, BF Kobayashi, H Le, N Yoo, TM Drumm, D Paik, CH McAfee, JG Carrasquillo, JA TI Effects of insulinlike growth factor binding proteins on insulinlike growth factor-I biodistribution in tumor-bearing nude mice SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE insulinlike growth factor-I; insulinlike growth factor receptor; insulinlike growth factor binding proteins; endocytosis ID HUMAN BREAST-CARCINOMA; CELL LUNG-CANCER; IGF-I; ESTROGEN-RECEPTOR; GENE-EXPRESSION; FACTOR (IGF)-I; DIFFERENTIATION; RAT; HEPARIN; LINE AB This study evaluated the biodistribution and tumor targeting ability of radiolabeled insulinlike growth factor (IGF)-1. Because IGF binding proteins (IGFBPs) play a critical role in modulating IGF activity, the binding properties of I-125-labeled IGF-1 to IGFBPs were investigated in vitro and in vivo. Because a large amount of the IGF-1 was catabolized in vivo, we also studied the catabolism of IGF-1 by tumor cells in vitro. Methods: I-125-labeled-IGF-1 was prepared using the chloramine T method. The biodistribution of I-125-labeled-IGF-1 in tumor-bearing nude mice was compared between groups injected with I-125-labeled IGF-1 alone or coinjected with unlabeled peptide. in vitro and in vivo chromatography studies were performed to evaluate the binding profile to IGFBPs and the degree of catabolites in serum as well as urine. Results: Data indicated that the binding of radiolabeled IGF-1 to IGFBPs in vitro was dose dependent. However, there was a difference in complex formation between the serum and the heparinized plasma. In heparinized plasma, the radioactivity shifted from a 30- to 50-kDa complex to a 150-kDa complex and to a free ligand, because the binding of heparin with IGFBPs decreased its affinity for IGF-1. In plasma prepared with acid citrate dextrose a binding pattern identical to that of serum was observed. Moreover, there was a binding difference between mouse and rat. The I-125-labeled IGF-1 catabolized very quickly when incubated at 37 degrees C but not at all at 4 degrees C. In tumor-bearing nude mice, the uptake of radioactivity in normal tissues decreased quickly, particularly in the kidneys, in mice coinjected with unlabeled carrier, the radioactivity in most normal tissues was lower and the tumor uptake higher than in the mice without carrier. Conclusion: These data confirm that I-125-labeled IGF-1 is avidly bound to IGFBPs, both in vitro and in vivo. By partially saturating this binding with unlabeled peptides, a favorable biodistribution was achieved, including faster clearance from normal tissue and higher tumor uptake, which resulted in better tumor-to-nontumor ratios. Nevertheless, the rapid catabolism and release of the radiolabel from tumor tissue result in a suboptimal targeting agent. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Carrasquillo, JA (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 1C496,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 40 TC 13 Z9 13 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2000 VL 41 IS 2 BP 318 EP 326 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 283CX UT WOS:000085259500023 PM 10688118 ER PT J AU Merrill, AH Bowman, BB Preusch, PC AF Merrill, AH Bowman, BB Preusch, PC TI Mechanistic aspects of vitamin and coenzyme utilization and function: A symposium in recognition of the distinguished career of Donald B. McCoumick SO JOURNAL OF NUTRITION LA English DT Editorial Material C1 Emory Univ, Dept Biochem, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. Natl Inst Gen Med Sci, Bethesda, MD 20892 USA. RP Merrill, AH (reprint author), Emory Univ, Dept Biochem, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2000 VL 130 IS 2 SU S BP 321S EP 322S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 282MF UT WOS:000085221300014 PM 10721896 ER PT J AU Kelloff, GJ Crowell, JA Steele, VE Lubet, RA Malone, WA Boone, CW Kopelovich, L Hawk, ET Lieberman, R Lawrence, JA Ali, I Viner, JL Sigman, CC AF Kelloff, GJ Crowell, JA Steele, VE Lubet, RA Malone, WA Boone, CW Kopelovich, L Hawk, ET Lieberman, R Lawrence, JA Ali, I Viner, JL Sigman, CC TI Progress in cancer chemoprevention: Development of diet-derived chemopreventive agents SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Nutritional-Sciences CY APR 17-21, 1999 CL WASHINGTON, D.C. SP Amer Soc Nutr Sci DE cancer chemoprevention; drug development; food-derived agents; breast; prostate; colon; lung ID PROSTATE-CANCER; RISK; ASPIRIN; TRIAL; SUPPLEMENTATION; CARCINOGENS; PREVENTION AB Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g,, growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. CCS Associates, Mt View, CA 94043 USA. RP Kelloff, GJ (reprint author), NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 33 TC 115 Z9 123 U1 0 U2 9 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2000 VL 130 IS 2 SU S BP 467S EP 471S PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 282MF UT WOS:000085221300051 PM 10721931 ER PT J AU Belshe, RB Gruber, WC Mendelman, PM Cho, I Reisinger, K Block, SL Wittes, J Iacuzio, D Piedra, P Treanor, J King, J Kotloff, K Bernstein, DI Hayden, FG Zangwill, K Yan, LH Wolff, M AF Belshe, RB Gruber, WC Mendelman, PM Cho, I Reisinger, K Block, SL Wittes, J Iacuzio, D Piedra, P Treanor, J King, J Kotloff, K Bernstein, DI Hayden, FG Zangwill, K Yan, LH Wolff, M TI Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine SO JOURNAL OF PEDIATRICS LA English DT Article ID CHILDREN; PREVENTION; VIRULENCE; STRAINS; MUTANT; H3N2; H1N1 AB Objective: To determine the safety, immunogenicity, and efficacy of revaccination of children with live attenuated influenza vaccine. Study design: A 2-year multicenter, double-blind, placebo-controlled, efficacy field trial of live attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray to children. This report summarizes year 2 results, a year in which the epidemic strain of influenza A/Sydney was not well matched to the vaccine strains, Each year, vaccine strains were antigenically equivalent to the contemporary inactivated influenza vaccine. In year 2, a single intranasal revaccination was administered. Active surveillance for influenza was conducted during the influenza season by means of viral cultures. Influenza cases were defined as illnesses with wild-type influenza virus isolated from respiratory secretions. Results: In year 2, 1358 (85%) children, 26 to 85 months of age, returned for revaccination. The intranasal vaccine was easily accepted, well tolerated, and immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in a subset studied for immunogenicity being seropositive as compared with 26% to 65% of placebo recipients, depending on the influenza strain tested. No serious adverse events were associated with the vaccine. In addition to the strains in the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2, influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70 cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in preventing A/Sydney influenza. Eight cases of lower respiratory tract disease were associated with A/Sydney influenza; all cases were in the placebo group. Conclusions: This live attenuated, cold-adapted influenza vaccine was safe, immunogenic, and efficacious against influenza A/H3N2 (including a variant, A/Sydney, not contained in the vaccine) and influenza B. The characteristics of this vaccine make it suitable for routine use in children to prevent influenza. C1 St Louis Univ, Hlth Sci Ctr, Div Infect Dis, Dept Med, St Louis, MO 63110 USA. Vanderbilt Univ, Dept Pediat, Nashville, TN USA. Aviron, Mt View, CA USA. Pittsburgh Pediat Res, Pittsburgh, PA USA. Kentucky Pediat Res Inc, Bardstown, KY USA. Stat Collaborat, Washington, DC USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. Univ Rochester, Dept Med, Rochester, NY USA. Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH USA. Univ Virginia, Dept Internal Med, Charlottesville, VA USA. Univ Virginia, Dept Pathol, Charlottesville, VA USA. Univ Calif Los Angeles, Harbor Med Ctr, Kaiser UCLA Vaccine Program, Dept Pediat, Los Angeles, CA 90024 USA. EMMES Corp, Potomac, MD USA. RP Belshe, RB (reprint author), St Louis Univ, Hlth Sci Ctr, Div Infect Dis, Dept Med, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 NR 26 TC 304 Z9 320 U1 0 U2 13 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 FEB PY 2000 VL 136 IS 2 BP 168 EP 175 DI 10.1016/S0022-3476(00)70097-7 PG 8 WC Pediatrics SC Pediatrics GA 283RP UT WOS:000085289400010 PM 10657821 ER PT J AU Zimliki, CL Mears, D Atwater, I Bertram, R Sherman, A AF Zimliki, CL Mears, D Atwater, I Bertram, R Sherman, A TI Mechanism underlying frequency modulation of glucose-induced bursts of electrical activity in the pancreatic beta-cell: the phantom burst model SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. Univ Chile, Fac Med, ICBM, Santiago, Chile. NIDDK, LCBB, NIH, Bethesda, MD USA. NIDDK, MRB, NIH, Bethesda, MD USA. Penn State Univ, Sch Sci, Erie, PA 16563 USA. Penn State Univ, Ctr Math Biol, Erie, PA 16563 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2000 VL 523 SU S BP 10P EP 10P PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 294XZ UT WOS:000085937100014 ER PT J AU Arriagada, C Olivares, A Alvarez, RM Rapoport, SI Caviedes, R Cardenas, AM Caviedes, P AF Arriagada, C Olivares, A Alvarez, RM Rapoport, SI Caviedes, R Cardenas, AM Caviedes, P TI Morphological characterization and intracellular calcium signals in cell lines derived from the spinal cord of normal and trisomy 16 fetal mice, an animal model of human Down's syndrome SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Univ Chile, Fac Med, ICBM, Morphol Program, Santiago 7, Chile. Ctr Estudios Cient, Valdivia, Chile. Univ Valparaiso, Sch Med, Valparaiso, Chile. NIA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2000 VL 523 SU S BP 29P EP 30P PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 294XZ UT WOS:000085937100047 ER PT J AU Martin, J Cardenas, AM Shimahara, T Rapoport, SI Caviedes, R Allen, DD Caviedes, P AF Martin, J Cardenas, AM Shimahara, T Rapoport, SI Caviedes, R Allen, DD Caviedes, P TI Impaired cholinergic function in cell lines derived from the cerebral cortex of normal and trisomy 18 mice. An animal model of human Down's syndrome SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Univ Chile, Fac Med, ICBM, Morphol Program, Santiago, Chile. Ctr Estudios Cient, Valdivia, Chile. Univ Valparaiso, Sch Med, Valparaiso, Chile. Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Amarillo, TX USA. NIA, LNS, NIH, Bethesda, MD USA. NBCM, CNRS, Gif Sur Yvette, France. NR 2 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2000 VL 523 SU S BP 63P EP 63P PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 294XZ UT WOS:000085937100096 ER PT J AU Kawahara, M Kuroda, Y Arispe, N Rojas, E AF Kawahara, M Kuroda, Y Arispe, N Rojas, E TI Alzheimer's beta-amyloid, human islet amylin and prion protein fragment evoke intracellular free-calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Tokyo Metropolitan Inst Neurosci, Dept Mol & Cellular Neurobiol, Tokyo, Japan. USUHS, Dept Anat & Cell Biol, Bethesda, MD USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD USA. Univ Chile, Fac Med, ICBM, Santiago 7, Chile. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2000 VL 523 SU S BP 67S EP 67S PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 294XZ UT WOS:000085937100486 ER PT J AU Ebert, AD Wechselberger, C Martinez-Lacaci, I Bianco, C Weitzel, HK Salomon, DS AF Ebert, AD Wechselberger, C Martinez-Lacaci, I Bianco, C Weitzel, HK Salomon, DS TI Expression and function of EGF-related peptides and their receptors in gynecological cancer - From basic science to therapy? SO JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; EPITHELIAL OVARIAN-CANCER; HUMAN PAPILLOMAVIRUS TYPE-16; TYROSINE KINASE INHIBITOR; SQUAMOUS-CELL CARCINOMA; HUMAN BREAST-CANCER; ENDOMETRIAL ADENOCARCINOMA CELLS; UTERINE CERVICAL-CARCINOMA; POLYMERASE CHAIN-REACTION; MESSENGER-RNA EXPRESSION AB EGF-related peptides and their receptors play an important, but not fully understood role, both, in epithelial physiology and pathophysiology but also in human tumor carcinogenesis and tumor behavior, respectively. Overexpression of EGF-related growth factors from normal epithelium to carcinomas has been demonstrated for several human tissues such as breast, endometrium, cervix and ovary. Additionally, the differential overexpression of EGFR or erb B-2 in various malignancies has already proven to be efficacious in stratifying patients with respect to a poor prognosis. These data suggest that EGF-related growth factors, erb B receptors or signaling proteins that function either upstream or downstream from these receptors may represent novel targets for selective tumor therapy. In the future, conventional chemotherapy regimes will ultimately be wedded to more biologically-oriented therapies. One important target for these novel therapeutic approaches in solid tumors will be the EGF-related growth factors and their receptors. C1 NCI, Tumor Growth Factor Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Free Univ Berlin, Med Ctr Benjamin Franklin, Lab Tumor Biol & Microcirculat, Dept Obstet & Gynecol, D-12200 Berlin, Germany. RP Ebert, AD (reprint author), NCI, Tumor Growth Factor Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NR 203 TC 16 Z9 16 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1079-9893 J9 J RECEPT SIGNAL TR R JI J. Recept. Signal Transduct. Res. PD FEB PY 2000 VL 20 IS 1 BP 1 EP 46 DI 10.3109/10799890009150035 PG 46 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 288WY UT WOS:000085588500001 PM 10711495 ER PT J AU Farrell, M Gibson, S McMeeken, J Helme, R AF Farrell, M Gibson, S McMeeken, J Helme, R TI Pain and hyperalgesia in osteoarthritis of the hands SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE pain; osteoarthritis; psychophysics; hyperalgesia ID DORSAL-ROOT REFLEXES; TOPICAL CAPSAICIN; MECHANICAL HYPERALGESIA; RHEUMATOID-ARTHRITIS; OSTEO-ARTHRITIS; SKIN; KNEE; INFLAMMATION; STIMULATION; THRESHOLDS AB Objective. Tissue damage and pain can lead to a change in the stimulus/response characteristics of the nociceptive system. Hyperalgesia has been described in experimental pain slates and some clinical conditions, but has not been investigated in osteoarthritis (OA). We sought to establish the presence of hyperalgesia at the thumb in subjects with OA of the hand and to explore any relationship between sensitivity to extrinsic stimuli and the experience of clinical pain. Methods. Subjects with OA of the hand were divided into groups according to their pain profile. The sample also included pain-free OA cases and pain-free controls. Intensity ratings were obtained for each of 3 types of pain: continuous pain, incident pain. and movement pain, Thermal and mechanical detection and pain thresholds were measured over the forearm and the carpometacarpal joint of the thumb. Results. Lower thermal and mechanical pain thresholds were evident over the thumb relative to forearm in the groups with persistent pain. Subjects complaining only of incident pain, pain-free OA cases, and pain-free controls did not exhibit regional differences in sensitivity to thermal and mechanical stimuli. Increased ratings of continuous pain were associated with lower thermal and mechanical pain thresholds. Variance in movement pain ratings was predicted by mechanical forearm pain thresholds. Conclusion. OA in the hands is associated with cutaneous and deep hyperalgesia to thermal and mechanical stimuli. Increased levels of continuous pain are associated with more pronounced hyperalgesia, The associations of movement pain suggest the contribution of central mechanisms in the stimulus/response changes accompanying movement pain. C1 Univ Melbourne, Sch Physiotherapy, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia. Natl Ageing Res Inst, Parkville, Vic, Australia. RP Farrell, M (reprint author), NIH, Bldg 10,Room 1N 103, Bethesda, MD 20892 USA. OI Farrell, Michael/0000-0003-4126-8911 NR 40 TC 55 Z9 56 U1 0 U2 4 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD FEB PY 2000 VL 27 IS 2 BP 441 EP 447 PG 7 WC Rheumatology SC Rheumatology GA 281QQ UT WOS:000085172600028 PM 10685812 ER PT J AU Park, SS Shahabuddin, M AF Park, SS Shahabuddin, M TI Structural organization of posterior midgut muscles in mosquitoes, Aedes aegypti and Anopheles gambiae SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Aedes aegypti; Anopheles gambiae; insect; intestine; malaria vector mosquito; muscle; sarcomere; striation ID EARLY TRYPSIN; PLASMODIUM; ULTRASTRUCTURE; TRANSMISSION; VECTOR AB In order to adapt to diverse feeding behavior, animal intestines have evolved with distinct differences, Such adaptation may include the structure of the longitudinal and circular muscles that maintain the integrity and the tensile strength of the gut tissue in higher metazoans. Here we examined the structural organization of the posterior midgut muscles of two insects, Aedes aegypti and Anopheles gambiae. We found the estimated number of longitudinal muscles in a cross-section to be 168 in Ae. aegypti and 37 in An. gambiae. Within the region, the estimated number of circular muscles is 77 in Ae. aegypti and 57 in An. gambiae. In An. gambiae, longitudinal muscles appear as sets of parallel bundles. Each set overlaps its neighbor to form a continuous tube. We found that this novel mode of muscle fiber sharing makes all circular muscles interconnected. Both types of muscle lie orthogonally to form a grid that holds the epithelium of the posterior midgut. In Ae. aegypti, the muscle fibers between the bundles are shared extensively, making the organization more intricate. This study implies that, because of its simple structure, the insect midgut may provide a powerful tool with which to study the structural evolution and function of animal intestines. C1 NIAID, Parasit Dis Lab, Med Entomol Sect, NIH, Bethesda, MD 20892 USA. RP Shahabuddin, M (reprint author), NIAID, Parasit Dis Lab, Med Entomol Sect, NIH, 4 Ctr Dr,Room 4-126,MSC 0425, Bethesda, MD 20892 USA. NR 33 TC 16 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2000 VL 129 IS 1 BP 30 EP 37 DI 10.1006/jsbi.1999.4208 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 289PE UT WOS:000085630500003 PM 10675294 ER PT J AU Klimes-Dougan, B Radke-Yarrow, M AF Klimes-Dougan, B Radke-Yarrow, M TI Children of depressed mothers - Reply SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Klimes-Dougan, B (reprint author), NIMH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 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 FEB PY 2000 VL 39 IS 2 BP 137 EP 137 DI 10.1097/00004583-200002000-00005 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 279ER UT WOS:000085031900005 ER PT J AU Hoagwood, K AF Hoagwood, K TI Commentary: The dose effect in children's mental health services SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID GREAT SMOKY MOUNTAINS; YOUTH; CARE C1 NIMH, Bethesda, MD 20892 USA. RP Hoagwood, K (reprint author), NIMH, 6001 Execut Blvd, Bethesda, MD 20892 USA. NR 19 TC 8 Z9 8 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 FEB PY 2000 VL 39 IS 2 BP 172 EP 175 DI 10.1097/00004583-200002000-00016 PG 4 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 279ER UT WOS:000085031900016 PM 10673827 ER PT J AU Kupfer, DJ Baltimore, RS Berry, DA Breslau, N Ellinwood, EH Ferre, J Ferriero, DM Fuchs, LS Guze, SB Hamburg, BA McGlothlin, J Turner, SM Vonnegut, M Abikoff, H Anderson, S Arnold, LE Barkley, RA Biederman, J Bird, HR Breggin, PR Carey, WB Chemers, B Conners, CK Cooper, JR Danielson, L Feussner, G Forness, SR Greenhill, LL Hinshaw, SP Hoagwood, K Jensen, PS Johnston, C Kalivas, PW Kelleher, KJ Klein, RG Lahey, BB Lambert, NM Loney, J Pelham, WE Rowland, AS Swanson, J Tannock, R Wilens, TE Wolraich, ML AF Kupfer, DJ Baltimore, RS Berry, DA Breslau, N Ellinwood, EH Ferre, J Ferriero, DM Fuchs, LS Guze, SB Hamburg, BA McGlothlin, J Turner, SM Vonnegut, M Abikoff, H Anderson, S Arnold, LE Barkley, RA Biederman, J Bird, HR Breggin, PR Carey, WB Chemers, B Conners, CK Cooper, JR Danielson, L Feussner, G Forness, SR Greenhill, LL Hinshaw, SP Hoagwood, K Jensen, PS Johnston, C Kalivas, PW Kelleher, KJ Klein, RG Lahey, BB Lambert, NM Loney, J Pelham, WE Rowland, AS Swanson, J Tannock, R Wilens, TE Wolraich, ML CA Consensus Dev Panel TI National Institutes of Health Consensus Development Conference Statement: Diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE attention-deficit/hyperactivity disorder; diagnosis; treatment; psychostimulants; risks; barriers ID DEFICIT-HYPERACTIVITY DISORDER; SUBSTANCE USE DISORDERS; IV FIELD TRIALS; AGE-OF-ONSET; BEHAVIORAL SENSITIZATION; PSYCHIATRIC COMORBIDITY; STIMULANT MEDICATION; MULTIMODAL TREATMENT; CONDUCT DISORDER; DRUG-USE AB Attention-deficit/hyperactivity disorder(ADHD) is a commonly diagnosed behavioral disorder of childhood that represents a costly major public health problem. Despite progress, ADHD and its treatment have remained controversial, especially the use of psychostimulants for both short- and long-term treatment. Although an independent diagnostic fast for ADHD does not exist, there is evidence supporting the validity of the disorder. Studies (primarily short-term, approximately 3 months), including randomized clinical trials, have established the efficacy of stimulants and psychosocial treatments for alleviating the symptoms of ADHD and associated aggressiveness and have indicated that stimulants are more effective than psychosocial therapies in treating these symptoms. Because of the lack of consistent improvement beyond the core symptoms and the paucity of long-term studies (beyond 14 months), there is a need for longer-term studies with drugs and behavioral modalities and their combination. Although trials are under way, conclusive recommendations concerning treatment for the long term cannot be made at present. There are wide variations in the use of psychostimulants across communities and physicians, suggesting no consensus regarding which ADHD patients should be treated with psychostimulants, and thus the need for improved assessment, treatment, and follow-up. Furthermore, the lack of insurance coverage, preventing the appropriate diagnosis and treatment of ADHD, and the lack of integration with educational services are substantial barriers and represent considerable long-term costs for society. Finally, after years of clinical research and experience with ADHD, knowledge about the cause or causes of ADHD remain largely speculative. Consequently, there are no documented strategies for the prevention of ADHD. C1 NIH, Bethesda, MD 20892 USA. RP Kupfer, DJ (reprint author), Care of Ferguson JH, NIH, 31 Ctr Dr,MSC-2082, Bethesda, MD 20892 USA. RI Breslau , Naomi/I-3196-2012 NR 104 TC 13 Z9 15 U1 5 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2000 VL 39 IS 2 BP 182 EP 193 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 279ER UT WOS:000085031900018 ER PT J AU Jensen, PS AF Jensen, PS TI Commentary: The NIM ADHD consensus statement: Win, lose, or draw? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID DEFICIT HYPERACTIVITY DISORDER C1 NIMH, Bethesda, MD 20892 USA. RP Jensen, PS (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Child Psychiat, 1051 Riverside Dr,Unit 78, New York, NY 10032 USA. OI Jensen, Peter/0000-0003-2387-0650 NR 7 TC 20 Z9 20 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 FEB PY 2000 VL 39 IS 2 BP 194 EP 197 DI 10.1097/00004583-200002000-00019 PG 4 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 279ER UT WOS:000085031900019 PM 10673830 ER PT J AU Hoagwood, K Kelleher, KJ Feil, M Comer, DM AF Hoagwood, K Kelleher, KJ Feil, M Comer, DM TI Treatment services for children with ADHD: A national perspective SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE services; treatments; attention-deficit hyperactivity disorder ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; GREAT SMOKY MOUNTAINS; COUNTY-WIDE SAMPLE; INATTENTIVE STUDENTS; PEDIATRIC RESEARCH; OFFICE SETTINGS; HEALTH; PREVALENCE; PATTERNS AB Objective: To summarize knowledge on treatment services for children and adolescents with attention-deficit hyperactivity disorder (ADHD), trends in services from 1989 to 1996, types of services provided, service mix, and barriers to care. Method: A review of the literature and analyses from 2 national surveys of physician practices are presented. Results: Major shifts have occurred in stimulant prescriptions since 1989, with prescriptions now comprising three fourths of all visits to physicians by children with ADHD. Between 1989 and 1996, related services, such as health counseling, for children with ADHD increased 10-fold, and diagnostic services increased 3-fold. Provision of psychotherapy, however, decreased from 40% of pediatric visits to only 25% in the same time frame. Follow-up care also decreased from more than 90% of visits to only 75%. Family practitioners were more likely than either pediatricians or psychiatrists to prescribe stimulants and less likely to use diagnostic services, provide mental health counseling, or recommend follow-up care. About 50% of children with identified ADHD seen in real-world practice settings receive care that corresponds to guidelines of the American Academy of Child and Adolescent Psychiatry. Physicians reported significant barriers to service provision for these children, including lack of pediatric specialists, insurance obstacles, and lengthy waiting lists. Conclusions: The trends in treatment services and physician variations in service delivery point to major gaps between the research base and clinical practice. Clinical variations may reflect training differences,unevenness in the availability of specialists and location of services, and changes in health care incentives. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. RP Hoagwood, K (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. RI Kelleher, Kelly/E-3361-2011 NR 45 TC 115 Z9 116 U1 4 U2 10 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 FEB PY 2000 VL 39 IS 2 BP 198 EP 206 DI 10.1097/00004583-200002000-00020 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 279ER UT WOS:000085031900020 PM 10673831 ER PT J AU Egan, CA O'Reilly, MA Meadows, KP Zone, JJ AF Egan, CA O'Reilly, MA Meadows, KP Zone, JJ TI Relapsing Henoch-Schonlein purpura associated with Pseudomonas aeruginosa pyelonephritis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID NEPHROPATHY; DEPOSITION; INFECTION; IGA AB Henoch-Schonlein purpura is a systemic vasculitis of unknown cause. It is frequently triggered by a streptococcal upper respiratory tract infection. Other bacteria have been implicated as triggering agents. We report a recurring case of Henoch-Schonlein purpura in a patient with Pseudomonas pyelonephritis. The Henoch-Schonlein purpura remitted only when the infection was eradicated. Pseudomonas infection should be added to the list of bacteria that can trigger Henoch-Schonlein purpura. C1 Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. Salt Lake City Vet Affairs Med Ctr, Dermatol Sect, Med Serv, Salt Lake City, UT USA. RP Egan, CA (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [R01 DK50678-01A1] NR 16 TC 7 Z9 8 U1 0 U2 0 PU MOSBY-YEAR BOOK 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 FEB PY 2000 VL 42 IS 2 SU S BP 381 EP 383 DI 10.1016/S0190-9622(00)90118-X PN 2 PG 3 WC Dermatology SC Dermatology GA 282LY UT WOS:000085220600018 PM 10640939 ER PT J AU Laham, RJ Chronos, NA Leimbach, M Pearlman, JD Pettigrew, R Dilsizian, V Udelson, J Whitehouse, MJ Pike, M Yoshizawa, C Simons, M AF Laham, RJ Chronos, NA Leimbach, M Pearlman, JD Pettigrew, R Dilsizian, V Udelson, J Whitehouse, MJ Pike, M Yoshizawa, C Simons, M TI Results of a phase I open label dose escalation study of intracoronary and intravenous basic fibroblast growth factor (rFGF-2) in patients (Pts) with severe ischemic heart disease: 6 months follow-up SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA USA. Atlanta Cardiovasc Res Inst, Atlanta, GA USA. Emory Univ, Atlanta, GA 30322 USA. NIH, Bethesda, MD 20892 USA. New England Med Ctr, Boston, MA 02111 USA. Chiron Corp, Emeryville, CA 94608 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 73A EP 73A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700282 ER PT J AU Udelson, JE Dilsizian, V Laham, RJ Chronos, NA Vansant, J Whitehouse, MJ Pike, M Yoshizawa, C Simons, M AF Udelson, JE Dilsizian, V Laham, RJ Chronos, NA Vansant, J Whitehouse, MJ Pike, M Yoshizawa, C Simons, M TI Reduction in stress myocardial ischemia by basic fibroblast growth factor (rFGF-2) in severe ischemic heart disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA USA. Atlanta Cardiol Res Inst, Atlanta, GA USA. Emory Univ, Atlanta, GA 30322 USA. Chiron Corp, Emeryville, CA 94608 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 74A EP 74A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700285 ER PT J AU Rowe, PC Calkins, H DeBusk, K Snader, S Lucas, KE Anand, R McKenzie, R Sharma, G Cuccherini, BA Soto, N Hohman, P Wolff, M Straus, SE AF Rowe, PC Calkins, H DeBusk, K Snader, S Lucas, KE Anand, R McKenzie, R Sharma, G Cuccherini, BA Soto, N Hohman, P Wolff, M Straus, SE TI Randomized, placebo-controlled trial of fludrocortisone to treat neurally mediated hypotension in chronic fatigue syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIAID, Lab Clin Invest, NIH, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 129A EP 129A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700495 ER PT J AU Benjamin, EJ Larson, MG Wolf, PA Evans, JC Kannel, WB D'Agostino, RB Levy, D AF Benjamin, EJ Larson, MG Wolf, PA Evans, JC Kannel, WB D'Agostino, RB Levy, D TI Is atrial fibrillation a heritable disorder? Insights from the Framingham Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Study, Framingham, MA USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 131A EP 132A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700505 ER PT J AU Exner, DV Schron, EB Yao, Q Vloka, ME Page, RL Powell, J Steinberg, JS AF Exner, DV Schron, EB Yao, Q Vloka, ME Page, RL Powell, J Steinberg, JS CA AVID Investigators TI Defibrillator shocks and self-perceived quality of life in the antiarrhythmics versus implantable defibrillators (AVID) trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. RI Page, Richard/L-5501-2014 OI Page, Richard/0000-0001-5603-1330 NR 0 TC 4 Z9 4 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 153A EP 153A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700590 ER PT J AU Begley, D Plexico, G Arai, A Mohiddin, S Fananapazir, L AF Begley, D Plexico, G Arai, A Mohiddin, S Fananapazir, L TI Gender-specific cardiac phenotypic differences detected by magnetic resonance imaging in hypertrophic cardiomyopathy caused by sarcomeric gene mutations SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 190A EP 190A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700728 ER PT J AU Begley, D Winkler, J Plexico, G Tripodi, D Arai, A Mohiddin, S Fananapazir, C AF Begley, D Winkler, J Plexico, G Tripodi, D Arai, A Mohiddin, S Fananapazir, C TI Brain natriuretic peptide in hypertrophic cardiomyopathy caused by sarcomeric gene mutations: A marker for poor outcome? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 191A EP 191A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700732 ER PT J AU Zieman, SJ Lakatta, EG Fleg, JL Gerstenblith, G O'Connor, FC Brant, LJ Bos, AJG AF Zieman, SJ Lakatta, EG Fleg, JL Gerstenblith, G O'Connor, FC Brant, LJ Bos, AJG TI Pulse pressure rises exponentially with age by longitudinal analysis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 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 FEB PY 2000 VL 35 IS 2 SU A BP 192A EP 192A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700737 ER PT J AU Walsh, CR Cuppies, LA Levy, D Wilson, PWF O'Donnell, CJ AF Walsh, CR Cuppies, LA Levy, D Wilson, PWF O'Donnell, CJ TI Subclinical atherosclerosis detected by lumbar aortic calcification is an important predictor of congestive heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 194A EP 194A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700744 ER PT J AU Lim, HW Begley, D Molkentin, JD Fananapazir, L AF Lim, HW Begley, D Molkentin, JD Fananapazir, L TI Possible role of calcineurin in etiology of maladaptive cardiac hypertrophy in familiar hypertrophic cardiomyopathy caused by missense sarcomeric mutations SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 7 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 FEB PY 2000 VL 35 IS 2 SU A BP 201A EP 201A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700773 ER PT J AU Domanski, MJ AF Domanski, MJ CA BEST Investigators TI Beta-blocker Evaluation of Survival Trial (BEST) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 15 Z9 15 U1 0 U2 1 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 FEB PY 2000 VL 35 IS 2 SU A BP 202A EP 203A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700778 ER PT J AU Qian, SJ Yu, ZX Yu, WH Takeda, K Chen, GG Zhong, XK Zeng, XH Ferrans, VJ AF Qian, SJ Yu, ZX Yu, WH Takeda, K Chen, GG Zhong, XK Zeng, XH Ferrans, VJ TI Remodeling of cardiac collagen and extracellular matrix in Keshan disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Harbin Med Univ, Harbin, Peoples R China. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 209A EP 209A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700804 ER PT J AU Escobar, JC Andrade, ZA Qian, SJ Andrade, SG Nelson, WK Sadigursky, M Yu, ZX Ferrans, V AF Escobar, JC Andrade, ZA Qian, SJ Andrade, SG Nelson, WK Sadigursky, M Yu, ZX Ferrans, V TI Apoptosis and inducible nitric oxide synthase in acute chagasic myocarditis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Fudacao Oswaldo Cruz, Bahia, Brazil. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 225A EP 225A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700867 ER PT J AU Prasad, A Mincemoyer, R Arevalo, J Quyyumi, AA AF Prasad, A Mincemoyer, R Arevalo, J Quyyumi, AA TI Angiotensin converting enzyme inhibition improves endothelial dysfunction and myocardial ischemia SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 246A EP 246A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700944 ER PT J AU Halcox, J Schenke, WH Mincemoyer, R Panza, JA Quyyumi, AA AF Halcox, J Schenke, WH Mincemoyer, R Panza, JA Quyyumi, AA TI Systemic and pulmonary hemodynamic effects of ETA receptor antagonism SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 249A EP 249A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700956 ER PT J AU Feng, D Lindpaintner, K Larson, MG O'Donnell, CJ Lipinska, I Sutherland, PA D'Agostino, RB Levy, D Tofler, GH AF Feng, D Lindpaintner, K Larson, MG O'Donnell, CJ Lipinska, I Sutherland, PA D'Agostino, RB Levy, D Tofler, GH TI The fibrinogen beta gene Hind III-148 polymorphism and prevalent cardiovascular disease: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 BI Deaconess Med Ctr, Div Cardiol, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Royal N Shore Hosp, Sydney, NSW, Australia. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 258A EP 259A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209700994 ER PT J AU Fan, L Friedman, DM Woods-Brown, A Fisher, M Krilov, L Quyyumi, A Ovadia, M AF Fan, L Friedman, DM Woods-Brown, A Fisher, M Krilov, L Quyyumi, A Ovadia, M TI Characteristic head-up tilt responses of pediatric chronic fatigue syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NYU, Sch Med, N Shore Univ Hosp, New York, NY USA. Cornell Univ, Clin Res Ctr, Coll Med, Long Island Jewish Med Ctr,Ped Rsch Ctr, New York, NY USA. NIH, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 260A EP 261A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701002 ER PT J AU Blum, A Hathaway, L Mincemoyer, R Schenke, WH Kirby, M Csako, G Waclawiw, MA Panza, JA Cannon, RO AF Blum, A Hathaway, L Mincemoyer, R Schenke, WH Kirby, M Csako, G Waclawiw, MA Panza, JA Cannon, RO TI Effects of oral L-arginine on endothelium-dependent vasodilation and markers of inflammation in healthy postmenopausal women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; NITRIC-OXIDE; L-SELECTIN; HYPERCHOLESTEROLEMIC RABBITS; ESTROGEN; CELLS; EXPRESSION; ATHEROSCLEROSIS; SUPERNATANTS; RELEASE AB OBJECTIVES We examined whether oral administration of L-arginine, the substrate for nitric oxide (NO) synthesis, increases NO bioactivity in healthy postmenopausal women. BACKGROUND Nitric oxide may protect arteries against atherosclerosis, as suggested by experimental studies in animals. Estrogen therapy, which has been shown to increase NO bioactivity in the vasculature of healthy postmenopausal women, is not acceptable for long-term use by many women. METHODS In a randomized, double-blind, crossover study, 10 postmenopausal women without additional risk factors for atherosclerosis received L-arginine 9 g or placebo daily for one month, with treatment periods separated by one month. Nitric oxide levels in serum (as an index of endothelial NO release), brachial artery endothelium-dependent dilator responses to hyperemia by ultrasonography (as an index of vascular NO bioactivity) and markers of inflammation in blood that are inhibited by NO in cell culture experiments were measured at the end of each treatment period. RESULTS L-arginine levels in plasma were increased in all women during L-arginine treatment compared with placebo (136.8 +/- 63.1 vs. 75.2 +/- 16.2 mu mol/liter, p = 0.009). However, there was no change in serum nitrogen oxide levels (42.1 +/- 24.5 vs. 39.1 +/- 16.6 mu mol/liter, p = 0.61), nor was there an effect of L-arginine on flow-mediated dilation during hyperemia (3.8 +/- 3.0% vs. 4.9 +/- 4.8%, p = 0.53) compared with placebo. Our study had sufficient power (beta = 0.80) to detect a true absolute treatment difference in flow-mediated brachial artery dilation of 1.7% or larger as statistically significant at alpha = 0.05. There was no effect of L-arginine on serum levels of soluble cell adhesion molecules compared with placebo: E-selectin (50.6 +/- 14.8 vs. 52.1 +/- 17.0 ng/ml, p = 0.45), intercellular adhesion molecule-1 (230 +/- 51 vs. 230 +/- 52 ng/ml, p = 0.97) and vascular cell adhesion molecule-1 (456 +/- 62 us. 469 +/- 91 ng/ml, p = 0.53). CONCLUSIONS Oral administration oil-arginine may not augment endothelial NO synthesis and release in postmenopausal women and is thus unlikely to be of general benefit to healthy postmenopausal women in protection from the development of atherosclerosis. (J Am Coll Cardiol 2000;35:271-6) (C) 2000 by the American College of Cardiology. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD USA. RP Cannon, RO (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr,MSC-1650, Bethesda, MD 20892 USA. NR 34 TC 36 Z9 38 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 BP 271 EP 276 DI 10.1016/S0735-1097(99)00553-7 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282FK UT WOS:000085207100002 PM 10676669 ER PT J AU Prasad, A Koh, KK Schenke, WH Mincemoyer, R Cannon, RO Quyyumi, AA AF Prasad, A Koh, KK Schenke, WH Mincemoyer, R Cannon, RO Quyyumi, AA TI Effect of angiotensin AT1 receptor inhibition on circulating markers of endothelial dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 288A EP 288A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701110 ER PT J AU Franklin, SS Khan, SA Wong, ND Larson, MG Levy, D AF Franklin, SS Khan, SA Wong, ND Larson, MG Levy, D TI The relation of blood pressure to coronary heart disease risk as a function of age: The framingham heart study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Univ Calif Irvine, Irvine, CA USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NR 0 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 291A EP 292A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701125 ER PT J AU Vasan, RS Larson, MG Kannel, WB Levy, D AF Vasan, RS Larson, MG Kannel, WB Levy, D TI Evolution of hypertension from non-hypertensive blood pressure levels: Rates of progression in the framingham heart study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 292A EP 292A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701126 ER PT J AU Weiss, CR Arai, AE Agyenan, KO Blum, A Csako, G Balaban, RS Cannon, RO AF Weiss, CR Arai, AE Agyenan, KO Blum, A Csako, G Balaban, RS Cannon, RO TI Evidence of arterial wall inflammation by MRI in patients with preclinical or established atherosclerosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 302A EP 302A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701167 ER PT J AU Cannon, RO Yang, BK Ardans, J Schenke, WH Zanger, D Blum, A Csako, G Wahl, LM AF Cannon, RO Yang, BK Ardans, J Schenke, WH Zanger, D Blum, A Csako, G Wahl, LM TI Increased serum matrix metalloproteinase-9 expression in postmenopausal women on estrogen therapy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 303A EP 303A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701169 ER PT J AU Fan, L Friedman, DM Woods-Brown, A Fisher, M Krilov, L Quyyumi, A Ovadia, M AF Fan, L Friedman, DM Woods-Brown, A Fisher, M Krilov, L Quyyumi, A Ovadia, M TI Esmolol causes paradoxical supine tachycardia response in a subgroup of pediatric chronic fatigue: Disturbance of adrenergic ligand-receptor pathway in blood pressure control? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Cornell Univ, Coll Med, Clin Rsch Ctr, Ped Rsch Ctr,Long Isl Jewish Med Ctr, Ithaca, NY USA. NYU, Sch Med, N Shore Univ Hosp, New York, NY 10003 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 331A EP 331A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701280 ER PT J AU Scuteri, A Bos, AJG Brant, LJ Fleg, JL Lakatta, EG AF Scuteri, A Bos, AJG Brant, LJ Fleg, JL Lakatta, EG TI Age-time-estrogen interactions in longitudinal changes in systolic blood pressure in postmenopausal women SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 FEB PY 2000 VL 35 IS 2 SU A BP 334A EP 335A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701292 ER PT J AU Paniagua, OA Bryant, MB Panza, JA AF Paniagua, OA Bryant, MB Panza, JA TI Transient hypertension directly impairs endothelium-dependent vasodilation in human resistance arteries SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 335A EP 335A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701293 ER PT J AU Dupuis, GH Kennedy, E Lindquist, R Barton, FB Terrin, ML Hoogwerf, BJ Czajkowski, SM Herd, A AF Dupuis, GH Kennedy, E Lindquist, R Barton, FB Terrin, ML Hoogwerf, BJ Czajkowski, SM Herd, A TI Determinants of cognitive functioning before and after coronary artery bypass graft SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Minneapolis Heart Inst, Minneapolis, MN USA. Maryland Med Res Inst, Baltimore, MD USA. Baylor Coll Med, Houston, TX 77030 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 342A EP 343A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701316 ER PT J AU Camarano, G Jones, M Freidlin, R Ernst, I Zetts, AD Panza, JA AF Camarano, G Jones, M Freidlin, R Ernst, I Zetts, AD Panza, JA TI Temporal evolution of the contractile state of neighboring myocardium in the early phase of acute myocardial infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 368A EP 369A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701416 ER PT J AU Domanski, MJ Sutton-Tyrrell, K Mitchell, GF Guo, P Faxon, DP Pitt, B Sopko, G AF Domanski, MJ Sutton-Tyrrell, K Mitchell, GF Guo, P Faxon, DP Pitt, B Sopko, G TI Prognostic importance of pulse pressure in coronary artery disease patients undergoing revascularization: Results from the bypass angioplasty revascularization investigation (BARI) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 382A EP 382A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701466 ER PT J AU Kitsiou, AN Bacharach, SL Miller-Davis, C Arai, AE Dilsizian, V AF Kitsiou, AN Bacharach, SL Miller-Davis, C Arai, AE Dilsizian, V TI N-13-ammonia myocardial uptake but not blood flow identifies regions with positive contractile reserve to low-dose dobutamine SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 429A EP 429A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701643 ER PT J AU Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Travaglini, A Greenberg, NL Panza, JA Thomas, JD AF Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Travaglini, A Greenberg, NL Panza, JA Thomas, JD TI Real-time 30 color Doppler echocardiography for analysis of the spatial velocity distribution in the left ventricular outflow tract SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 436A EP 437A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701671 ER PT J AU Rusk, RA Mori, Y Li, XN Jones, M Irvine, M Mehwald, PS Kenny, A Sahn, DJ AF Rusk, RA Mori, Y Li, XN Jones, M Irvine, M Mehwald, PS Kenny, A Sahn, DJ TI A validation study of aortic stroke volume using dynamic 4D color doppler: An in vivo study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, LAMS, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 440A EP 441A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701686 ER PT J AU Qin, JX Jones, M Shiota, T Tsujino, H Travaglini, A Zetts, AD Cardon, LA Morehead, AJ Bauer, F Thomas, JD AF Qin, JX Jones, M Shiota, T Tsujino, H Travaglini, A Zetts, AD Cardon, LA Morehead, AJ Bauer, F Thomas, JD TI Real-time 3D pulsed wave (PW) Doppler echocardiography for quantification of the left ventricular stroke volume SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, LAMS, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 442A EP 442A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701693 ER PT J AU Camarano, G Jones, M Shiota, T Ernst, I Zetts, AD Thomas, JD Panza, JA AF Camarano, G Jones, M Shiota, T Ernst, I Zetts, AD Thomas, JD Panza, JA TI Effect of remodeling following myocardial infarction on left ventricular size and function: A real-time 3-dimensional echocardiographic study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 443A EP 443A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701695 ER PT J AU Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Morehead, AJ Cardon, LA Travaglini, A Zetts, AD Panza, JA Thomas, JD AF Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Morehead, AJ Cardon, LA Travaglini, A Zetts, AD Panza, JA Thomas, JD TI Left atrial contractile function during left ventricular ischemia with and without left atrial ischemia SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 458A EP 459A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701754 ER PT J AU Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Travaglini, A Greenberg, NL Panza, JA Thomas, JD AF Tsujino, H Jones, M Shiota, T Qin, JX Cardon, LA Morehead, AJ Zetts, AD Bauer, F Travaglini, A Greenberg, NL Panza, JA Thomas, JD TI Quantification of the volumetric flow rate using real-time 3D (RT3D) color Doppler echocardiography: An animal study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 461A EP 462A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701763 ER PT J AU Travaglini, A Jones, M Shiota, T Qin, JX Bauer, F Tsujino, H Cardon, LA Morehead, AJ Greenberg, NL Panza, JA Zetts, AD Thomas, JD AF Travaglini, A Jones, M Shiota, T Qin, JX Bauer, F Tsujino, H Cardon, LA Morehead, AJ Greenberg, NL Panza, JA Zetts, AD Thomas, JD TI Measurement of left ventricular mass (LVM) using real-time 3D and 2D echocardiography in chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Cleveland, OH 44106 USA. NHLBI, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 468A EP 468A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701789 ER PT J AU Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Travaglini, A Zetts, AD Panza, JA Thomas, JD AF Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Travaglini, A Zetts, AD Panza, JA Thomas, JD TI Assessment of left atrial end-systolic pressure volume relationship in an animal model: A real-time 3D echocardiographic and hemodynamic study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 471A EP 471A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701802 ER PT J AU Bennett, SK Smith, MF Gottlieb, SG Fisher, ML Bacharach, SL Dilsizian, V AF Bennett, SK Smith, MF Gottlieb, SG Fisher, ML Bacharach, SL Dilsizian, V TI Changes in absolute myocardial blood flow with beta blocker therapy in heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 480A EP 480A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701834 ER PT J AU Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Travaglini, A Zetts, AD Panza, JA Thomas, JD AF Bauer, F Jones, M Shiota, T Qin, JX Tsujino, H Travaglini, A Zetts, AD Panza, JA Thomas, JD TI Left atrial volume and function: Relationship to left ventricular function SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 494A EP 495A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701888 ER PT J AU Mori, Y Jones, M Rusk, RA Irvine, T Sahn, DJ AF Mori, Y Jones, M Rusk, RA Irvine, T Sahn, DJ TI A two-dimensional digital color Doppler flow method (DCD) implemented using two orthogonal planes improves calculation of pulmonary regurgitant volumes and regurgitant fractions in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, LAMS, Bethesda, MD 20892 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 494A EP 494A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701887 ER PT J AU Mori, Y Li, XN Irvine, T Jones, M Sachdev, V Zetts, AD Detmer, PR Lennon, D Kenny, A Sahn, DJ AF Mori, Y Li, XN Irvine, T Jones, M Sachdev, V Zetts, AD Detmer, PR Lennon, D Kenny, A Sahn, DJ TI Quantification of pulmonary regurgitation from pulmonary and aortic stroke volumes determined using a 3 dimensional digital color Doppler method in a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 505A EP 506A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701925 ER PT J AU Mehwald, PS Irvine, T Rusk, RA Mori, Y Jones, M Zetts, AD Sachdev, V Panza, JA Sahn, DJ AF Mehwald, PS Irvine, T Rusk, RA Mori, Y Jones, M Zetts, AD Sachdev, V Panza, JA Sahn, DJ TI Multimodality real time so imaging color Doppler method for evaluation of RV function and pulmonary regurgitant flow: An in vivo study on a chronic animal model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Oregon Hlth Sci Univ, Portland, OR 97201 USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 507A EP 507A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701931 ER PT J AU Dagan, T Sable, C Taylor, P Zuckerman, J Zwerski, S Martin, G Wood, L AF Dagan, T Sable, C Taylor, P Zuckerman, J Zwerski, S Martin, G Wood, L TI Reversible cardiac dysfunction associated with zidovudine exposure in HIV-infected children SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NCI, NIH, Bethesda, MD 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB PY 2000 VL 35 IS 2 SU A BP 513A EP 513A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701953 ER PT J AU Rajanayagam, MAS Shou, M Thirumurti, V Lazarous, DF Quyyumi, AA Goncalves, L Stiber, J Epstein, SE Unger, EF AF Rajanayagam, MAS Shou, M Thirumurti, V Lazarous, DF Quyyumi, AA Goncalves, L Stiber, J Epstein, SE Unger, EF TI Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article; Proceedings Paper CT 46th Annual Scientific Session of the American-College-of-Cardiology CY MAR 15-19, 1997 CL ANAHEIM, CALIFORNIA SP Amer Coll Cardiol, Cardiol Branch, Natl Heart Lung & Blood Inst, Natl Inst Hlth ID ISCHEMIC MYOCARDIUM; ANGIOGENESIS; MODEL; HEART; FLOW AB OBJECTIVES In preparation for clinical trials of basic fibroblast growth factor (bFGF) to treat ischemic heart disease, we sought to identify a clinically feasible method of bFGF administration. BACKGROUND Basic FGF has been shown to promote collateral development after experimentally induced coronary occlusion; however, methods of bFGF delivery that have been shown to be effective in previous investigations would not be practical for clinical use. METHODS Four randomized, blinded, controlled investigations were conducted independently and sequentially in an established canine model. For:all studies, dogs underwent operative placement of proximal left circumflex: coronary artery ameroid constrictors. The four investigational regimens included: 1) bFGF by central venous bolus injection, 1,740 mu g/day for one, two or seven days; 2) bFGF by intravenous infusion, 100 mu g/kg body weight per day for seven days; 3) bFGF by pericardial instillation, 2,000 mu g/day for 7 days; and 4) bFGF by intracoronary injection (Judkin's technique); 100 mu g/kg per day for one or two days. Each substudy included a contemporaneous vehicle control group. Collateral perfusion (microspheres) was assessed during maximal coronary vasodilation during the first month after ameroid placement. RESULTS Maximal collateral perfusion in dogs that received intracoronary bFGF for two days exceeded that of concurrent control dogs by 31% (p < 0.01). Perfusion was not increased in dogs that received single-dose intracoronary bFGF. Basic FGF administration by central venous bolus injection, intravenous infusion and pericardial injection failed to enhance collateral perfusion. CONCLUSIONS Administration of bFGF by the intracoronary route, an intervention that is feasible in patients, augments collateral development:in dogs. These data provide a rationale for clinical testing of intracoronary bFGF in ischemic heart disease. (J Am Coll Cardiol 2000;35: 519-26) (C) 2000 by the American College of Cardiology. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Unger, EF (reprint author), NHLBI, Cardiol Branch, NIH, 10 Ctr Dr,MSC-1650,Bldg 10,Room 7B15, Bethesda, MD 20892 USA. OI Goncalves, Lino/0000-0001-9255-3064 NR 16 TC 60 Z9 66 U1 0 U2 1 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 FEB PY 2000 VL 35 IS 2 BP 519 EP 526 DI 10.1016/S0735-1097(99)00550-1 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282FK UT WOS:000085207100036 PM 10676703 ER PT J AU Tamura, K I-Ida, T Ishizaki, M Asano, G Tanaka, S Ferrans, VJ AF Tamura, K I-Ida, T Ishizaki, M Asano, G Tanaka, S Ferrans, VJ TI Increased activity of matrix metalloproteinases in floppy aortic valves SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Nippon Med Sch, Tokyo 113, Japan. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2000 VL 35 IS 2 SU A BP 525A EP 526A PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 282GL UT WOS:000085209701998 ER PT J AU Slavkin, HC AF Slavkin, HC TI Another approach to learning about health disparities: Working toward individualized therapy SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article C1 Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Slavkin, HC (reprint author), Natl Inst Dent & Craniofacial Res, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 2 U2 3 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD FEB PY 2000 VL 131 IS 2 BP 236 EP 240 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 281YM UT WOS:000085189100024 PM 10680393 ER PT J AU Newman, AB Spiekerman, CF Enright, P Lefkowitz, D Manolio, T Reynolds, CF Robbins, J AF Newman, AB Spiekerman, CF Enright, P Lefkowitz, D Manolio, T Reynolds, CF Robbins, J CA Cardiovascular Hlth Study Res Grp TI Daytime sleepiness predicts mortality and cardiovascular disease in older adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society/American-Federation-for-Aging-Research CY MAY 06-10, 1998 CL SEATTLE, WASHINGTON SP Amer Geriatr Soc, Amer Federat Aging Res DE sleep disorders; sleepiness ID ELDERLY PERSONS; HEALTH; PREVALENCE; DISORDERS; SCALE; RISK; ATHEROSCLEROSIS; COMPLAINTS; MORBIDITY; FAILURE AB INTRODUCTION: As part of the baseline examination in the Cardiovascular Health Study, sleep disturbance symptoms including snoring and daytime sleepiness, were assessed as potential risk factors or precipitants of cardiovascular disease (CVD). Because of the association of sleep disturbance with poorer health and the possible associations of sleep apnea with CVD, we hypothesized that those with poorer sleep or daytime sleepiness may be at increased risk of mortality or incident CVD. SETTING: Participants (n = 5888) were recruited in 1989, with an additional minority cohort recruited in 1993, in four US communities for a cohort study designed to evaluate risk factors for cardiovascular disease. METHODS: An interview-administered questionnaire regarding health and sleep habits with ongoing ascertainment of total mortality and cardiovascular disease morbidity and mortality, including total CVD morbidity and mortality, incident myocardial infarction, and congestive heart failure. RESULTS: Daytime sleepiness was the only sleep symptom that was significantly associated with mortality in both men and women. The unadjusted hazard ratio was 2.12 (1.66, 2.72) in women and 1.40 (1.12, 1.73) in men. Men who reported difficulty falling asleep also had an increased mor mortality rate (HR = 1.43 (1.14, 1.80)) which was not seen in women. The risks were attenuated with adjustment for age but remained significant for daytime sleepiness in women (HR = 1.82 (1.42, 2.34)) and for difficulty falling asleep in men. (HR = 1.29 (1.03, 1.63)). Frequent awakenings, early morning awakening, and snoring were not associated with a significantly increased risk of mortality in these older men and women. Crude event rates were evaluated for total incident cardiovascular morbidity and mortality, incident myo cardial infarction, and incident congestive heart failure (CHF). Incident CVD rates were higher in both men women with daytime sleepiness. The aged adjusted HR was 1.35 (95% CI = 1.03, 1.76) in men and was 1.66 (95% CI = 1.28, 2.16) in women. Incident CVD was not higher in those with any other sleep disturbance including snoring. The risk of CVD events associated with daytime sleepiness was attenuated but remained significant in women after adjustment for age. Incident myocardial infarction (MI) rates were also higher in women with daytime sleepiness but were not significantly higher in men. Incident CHF rates were increased in both men and women with daytime sleepiness. In men, the age adjusted HR was 1.49 (95% CI, 1.12- 1.98) and in women, was 2.21 (95% CI, 1.64-2.98). Women reporting both daytime sleepiness and frequent awakening had a hazard ratio of 2.34 (95% CI, 1.66-3.29) for incident CHF compared with those with daytime sleepiness but without frequent awakening. This interaction was not found in men. CONCLUSIONS: In this study, daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF. These findings were stronger in women than men, i.e., the associations persisted for mortality, CVD, and CHF in women after adjustment for age and other factors. Thus, a report of daytime sleepiness identifies older adults at increased risk for total and cardiovascular mortality, and is an independent risk factor in women. C1 Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. Univ Washington, Seattle, WA 98195 USA. Univ Arizona, Tucson, AZ USA. Wake Forest Univ, Winston Salem, NC 27109 USA. NHLBI, Bethesda, MD 20892 USA. Univ Calif Davis, Sacramento, CA 95817 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 FU NHLBI NIH HHS [N01-HC-87079, N01-HC-87080, N01-HC-87081] NR 43 TC 193 Z9 198 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2000 VL 48 IS 2 BP 115 EP 123 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 284BT UT WOS:000085311400001 PM 10682939 ER PT J AU Haydar, ZR Blackman, MR Tobin, JD Wright, JG Fleg, JL AF Haydar, ZR Blackman, MR Tobin, JD Wright, JG Fleg, JL TI The relationship between aerobic exercise capacity and circulating IGF-1 levels in healthy men and women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aerobic capacity; age, IGF-1 ID GROWTH-FACTOR-I; OLDER MEN; BODY-COMPOSITION; BONE-DENSITY; HORMONE REPLACEMENT; SOMATOMEDIN-C; AGE; DEFICIENCY; THERAPY; FITNESS AB OBJECTIVES: To determine whether aerobic capacity is associated independently with insulin-like growth factor-I (IGF-1) levels in healthy community-dwelling men and women. SETTING: The Baltimore Longitudinal Study on Aging (BLSA). DESIGN: A cross-sectional analysis of data from the population-based cohort of the Baltimore Longitudinal Study of Aging (BLSA). PARTICIPANTS: We studied 181 men and 92 women aged 20 to 93 years, volunteers in the Baltimore Longitudinal Study on Aging (BLSA). Subjects were free of endocrine, renal, hepatic, gastrointestinal, or cardiac diseases, and they were taking no medications known to interfere with the growth hormone-IGF-l axis. MEASUREMENTS: All subjects underwent a single measurement of serum IGF-1 in the fasting state, as well as peak Oo, determinations during maximal treadmill exercise testing performed within one visit of the IGF-1 determination. Dual energy X-ray absorptiometry (DEXA) scans were performed in a subset of 171 subjects (64 women and 107 men) for determination of fat free mass (FFM). RESULTS: In the pooled group of women and men, univariate regression analysis revealed that age was correlated strongly with decreasing IGF-1 levels (r = -0.53, P < .001) and with peak (V) over dot o(2) (r = -0.56, P < .001). IGF-1 levels were also significantly correlated with peak (V) over dot o(2), (r = 0.29, P < .001). There were no significant gender-related differences in these relationships. On multivariate analysis, age (P = -0.54, P < .001), but not peak (V) over dot o(2) (beta = -0.01, P = .840), remained strongly associated with IGF-1 levels. After adjustment of peak (V) over dot o(2) for FFM in subjects with DEXA scans, results were similar. CONCLUSIONS: These findings indicate that although both peak aerobic capacity and circulating IGF-1 levels decline with age, aerobic capacity is not independently related to circulating IGF-1 in healthy men and women across the adult life span. C1 Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD 21218 USA. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Fleg, JL (reprint author), Gerontol Res Ctr, Cardiovasc Sci Lab, Human Cardiovasc Studies Unit, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 19 TC 18 Z9 19 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2000 VL 48 IS 2 BP 139 EP 145 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 284BT UT WOS:000085311400004 PM 10682942 ER PT J AU Andrawis, N Jones, DS Abernethy, DR AF Andrawis, N Jones, DS Abernethy, DR TI Aging is associated with endothelial dysfunction in the human forearm vasculature SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE acetylcholine; angiotensin II; sodium nitroprusside; forearm vascular resistance; endothelial dysfunction; aging ID CONVERTING-ENZYME-INHIBITION; NITRIC-OXIDE; ESSENTIAL-HYPERTENSION; L-ARGININE; MEDIATED VASOCONSTRICTION; DEPENDENT VASODILATION; RESISTANCE VESSELS; SMOOTH-MUSCLE; BLOOD-FLOW; RELAXATION AB OBJECTIVE: Our objective was to examine the role of the endothelium in maintaining vascular tone in the basal as well as in the contracted state during aging. DESIGN/PARTICIPANTS : Responses to brachial artery infusion of acetylcholine in presence and absence of N-G-nitro-L-arginine methyl ester (L-NAME) and to angiotensin II were studied in 11 young and 12 old white subjects. MEASUREMENTS: Strain gauge plethysmography was used to measure forearm vascular resistance (FVR). The dose of acetylcholine at 50% maximal observed decrease in forearm vascular resistance (EC50) was significantly higher (11.0 +/- 1.59 vs 7.07 +/- .65 mu g/min, respectively; mean +/- SEM; P < .05) and the FVR at maximal acetylcholine effect (Emax) remained greater (12.6 +/- 1.75 vs 7.15 +/- 1.25 mm Hg/100 mt tissue volume/min; P < .02) in old compared with young subjects. Acetylcholine effect was significantly reversed by concomitant administration of L-NAME, as indicated by the increase in EC50 (old, 20.2 +/- 3.69; young, 11.9 +/- 1.68 mu g/min) RESULTS: There was no age-related difference in sodium nitroprusside-induced decrease in FVR. The EC50 and Emax for angiotensin II-mediated increase in FVR were 7.87 +/- 1.15 and 8.36 +/- 1.00 ng/min (EC50) and 5.30 +/- .67 vs 6.56 +/- 1.25 mm Hg/100 mt tissue volume/min (Emax), and these were not different in old and young subjects, respectively. CONCLUSIONS: These data indicate that aging is associated with impaired endothelial- dependent vascular relaxation and that this is selective, with no age-related change in endothelial-independent vascular relaxation or angiotensin II-mediated vascular contraction. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Georgetown Univ, Med Ctr, Dept Med, Div Clin Pharmacol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Div Clin Pharmacol, Washington, DC 20007 USA. RP Abernethy, DR (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 42 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2000 VL 48 IS 2 BP 193 EP 198 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 284BT UT WOS:000085311400011 PM 10682949 ER PT J AU Kachadorian, WA AF Kachadorian, WA TI Vasopressin: Induced structural change in toad bladder luminal membrane - Commentary SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID URINARY-BLADDER C1 NIA, Sci Review Off, Bethesda, MD 20892 USA. RP Kachadorian, WA (reprint author), NIA, Sci Review Off, Bethesda, MD 20892 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 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2000 VL 11 IS 2 BP 376 EP 379 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 280JK UT WOS:000085099500022 PM 10665946 ER PT J AU Talan, MI Roukoyatkina, NI AF Talan, MI Roukoyatkina, NI TI Sustained shivering is necessary for development of cold-induced hypertension in rats SO JOURNAL OF THERMAL BIOLOGY LA English DT Article; Proceedings Paper CT XIth International Symposium on the Pharmacology of Thermoregulation CY MAY 09-13, 1999 CL SEVILLE, SPAIN DE blood pressure; cold acclimation; shivering; thermogenesis; hypertension; body temperature; body weight; water consumptions; ageing; rats ID AGED C57BL/6J MICE; NONSHIVERING THERMOGENESIS; BLOOD-PRESSURE; CHRONIC EXPOSURE; ADULT; ELEVATION; THERMOREGULATION AB To test the hypothesis that sustained shivering is a determining factor in development of hypertension in rats subjected to prolonged exposure to cold, the effect of cold exposure to 6 degrees C was examined in two experimental models with reduced shivering response to cold: aged (18 months old) rats and adult rats (8 months old) preacclimated to a less severe cold. The slow increase of colonic temperature in response to 6 degrees C cold, characteristic for reduced shivering, was observed in both experimental groups, while systolic pressure failed to increase. Results support the hypothesis that sustained shivering is a determining factor in development of cold-induced hypertension. Published by Elsevier Science Ltd. C1 NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4565 J9 J THERM BIOL JI J. Therm. Biol. PD FEB-APR PY 2000 VL 25 IS 1-2 SI SI BP 111 EP 117 DI 10.1016/S0306-4565(99)00082-0 PN 2 PG 7 WC Biology; Zoology SC Life Sciences & Biomedicine - Other Topics; Zoology GA 277PD UT WOS:000084941200019 ER PT J AU Bulcao, CF Frank, SM Raja, SN Tran, KM Goldstein, DS AF Bulcao, CF Frank, SM Raja, SN Tran, KM Goldstein, DS TI Relative contribution of core and skin temperatures to thermal comfort in humans SO JOURNAL OF THERMAL BIOLOGY LA English DT Article; Proceedings Paper CT XIth International Symposium on the Pharmacology of Thermoregulation CY MAY 09-13, 1999 CL SEVILLE, SPAIN DE adrenergic; core temperature; hypothermia; metabolism; skin temperature; thermal comfort; thermoregulation; vasoconstriction AB 1. Although both skin-surface (Tsk) and core (Tc) temperatures are known afferent inputs to the thermoregulatory system, the relative contributions of Tsk and Tc to thermal comfort is unknown. 2. Tsk and Tc temperatures were independently altered in human subjects while measuring thermal comfort on a scale of 0-10. Multiple linear regression was used to determine the relative Tsk/Tc contribution ratio to thermal comfort using the ratio of regression coefficients for Tsk and Tc temperatures. 3. The proportional contribution ratio of Tsk/Tc to thermal comfort was approximate to 1:1. This represents a much greater Tsk/Tc contribution ratio for thermal comfort than previous studies have shown for swearing (1:20), or vasoconstriction and shivering (1:4). 4. Thermal comfort in humans is determined to a great extent by Tsk, while the physiological responses are determined primarily by changes in Tc. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. McGill Univ, Montreal, PQ, Canada. Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Bethesda, MD USA. RP Frank, SM (reprint author), Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. OI Yang, Shuman/0000-0002-9638-0890 NR 12 TC 32 Z9 34 U1 3 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4565 J9 J THERM BIOL JI J. Therm. Biol. PD FEB-APR PY 2000 VL 25 IS 1-2 SI SI BP 147 EP 150 DI 10.1016/S0306-4565(99)00039-X PN 2 PG 4 WC Biology; Zoology SC Life Sciences & Biomedicine - Other Topics; Zoology GA 277PD UT WOS:000084941200025 ER PT J AU Ornstein, DK Lubensky, IA Venzon, D Zbar, B Linehan, WM Walther, MM AF Ornstein, DK Lubensky, IA Venzon, D Zbar, B Linehan, WM Walther, MM TI Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer SO JOURNAL OF UROLOGY LA English DT Article DE kidney; neoplasms; neoplastic syndromes, hereditary; carcinoma, papillary ID CELL CARCINOMA; MET PROTOONCOGENE; MUTATIONS; FAMILIES; GENE AB Purpose: We describe the earliest renal lesions associated with hereditary papillary renal cancer and estimate the prevalence of microscopic papillary renal tumors. Materials and Methods. Grossly normal tissue was obtained from 12 kidneys during renal surgery in 9 patients with hereditary papillary renal cancer. Tissue was examined microscopically and findings were compared to those previously reported to be associated with von Hippel-Lindau disease and sporadic renal cell carcinoma. Results: A total of 92 microscopic papillary renal cell carcinoma lesions were identified on 46 of 88 slides (53%). No other lesions were identified. All tumors were solid and displayed the basophilic papillary histology characteristic of hereditary papillary renal cancer. Extrapolation of the data predicted the prevalence of 1,100 to 3,400 microscopic papillary tumors in a single kidney in a patient with hereditary papillary renal cancer. Conclusions: The basophilic papillary histology characteristic of clinically apparent renal tumors in patients with hereditary papillary renal cancer also characterizes the multiple microscopic lesions seen in the kidneys. These findings suggest that the earliest renal tumor in patients with an activating hereditary mutation of the met gene is papillary basophilic renal cancer. The large number of microscopic tumors in patients with hereditary papillary renal cancer was comparable to or greater than that seen in those with von Hippel-Lindau disease. C1 NCI, Urol Oncol Branch, Pathol Lab, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Ornstein, DK (reprint author), NCI, Urol Oncol Branch, Pathol Lab, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 14 TC 51 Z9 52 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2000 VL 163 IS 2 BP 431 EP 433 DI 10.1016/S0022-5347(05)67893-7 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 274KW UT WOS:000084765900007 PM 10647647 ER PT J AU Neill, JD Sosnovtsev, SV Green, KY AF Neill, JD Sosnovtsev, SV Green, KY TI Recovery and altered neutralization specificities of chimeric viruses containing capsid protein domain exchanges from antigenically distinct strains of feline calicivirus SO JOURNAL OF VIROLOGY LA English DT Article ID MIGUEL SEA-LION; MONOCLONAL-ANTIBODIES; NUCLEOTIDE-SEQUENCE; EXPRESSION; GENE; IDENTIFICATION; PRECURSOR; REGIONS; SITES AB Feline calicivirus (FCV) strains can show significant antigenic variation when tested for cross-reactivity,vith antisera produced against other FCV strains. Previous work has demonstrated the presence of hypervariable amino acid sequences in the capsid protein of FCV (designated regions C and E) that were postulated to constitute the major antigenic determinants of the virus. To examine the involvement of hypervariable sequences in determining the antigenic phenotype, the nucleotide sequences encoding the E regions from three antigenically distinct parental FCV strains (CFI, KCD, and NADC) were exchanged for the equivalent sequences in an FCV Urbana strain infectious cDNA clone. Two of the three constructs were recovered as viable, chimeric viruses. In six additional constructs, of which three were recovered as viable virus, the E region from the parental viruses was divided into left (N-terminal) and right (C-terminal) halves and engineered into the infectious clone. A final viable construct contained the C, D, and E regions of the NADC parental strain. Recovered chimeric viruses showed considerable antigenic variation from the parental viruses when tested against parental hyperimmune serum, No domain exchange was able to confer complete recognition by parental antiserum with the exception of the KCD E region exchange, which was neutralized at a near-homologous titer with KCD antiserum. These data demonstrate that it is possible to recover engineered chimeric FCV strains that possess altered antigenic characteristics. Furthermore, the E hypervariable region of the capsid protein appears to play a major role in the formation of the antigenic structure of the virion where conformational epitopes may be more important than linear in viral neutralization. C1 USDA ARS, Natl Anim Dis Ctr, Metab Dis & Immunol Res Unit, Ames, IA 50010 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Neill, JD (reprint author), USDA ARS, Natl Anim Dis Ctr, Metab Dis & Immunol Res Unit, 2300 Dayton Rd, Ames, IA 50010 USA. NR 31 TC 23 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 3 BP 1079 EP 1084 DI 10.1128/JVI.74.3.1079-1084.2000 PG 6 WC Virology SC Virology GA 273YZ UT WOS:000084738100003 PM 10627517 ER PT J AU Buchholz, UJ Granzow, H Schuldt, K Whitehead, SS Murphy, BR Collins, PL AF Buchholz, UJ Granzow, H Schuldt, K Whitehead, SS Murphy, BR Collins, PL TI Chimeric bovine respiratory syncytial virus with glycoprotein gene substitutions from human respiratory syncytial virus (HRSV): Effects on host range and evaluation as a live-attenuated HRSV vaccine SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSCRIPTION ELONGATION-FACTOR; ATTACHMENT PROTEIN; MESSENGER-RNA; SUBGROUP-B; MONOCLONAL-ANTIBODIES; NUCLEOTIDE-SEQUENCE; ANTIGENIC STRUCTURE; MEASLES VIRUSES; CELL-FUSION; N-PROTEIN AB We recently developed a system for the generation of infectious bovine respiratory syncytial virus (BRSV) from cDNA. Here, we report the recovery of fully viable chimeric recombinant BRSVs (rBRSVs) that carry human respiratory syncytial virus (HRSV) glycoproteins in place of their BRSV counterparts, thus combining the replication machinery of BRSV with the major antigenic determinants of HRSV. A cDNA encoding the BRSV antigenome was modified so that the complete G and F genes, including the gene start and gene end signals, were replaced by their HRSV A2 counterparts. Alternatively! the BRSV F gene alone was replaced by that of HRSV Long. Each antigenomic cDNA directed the successful recovery of recombinant virus, yielding rBRSV/A2 and rBRSV/LongF, respectively. The HRSV G and F proteins or the HRSV F in combination with BRSV G were expressed efficiently in cells infected,vith the appropriate chimeric virus and were efficiently incorporated into recombinant virions. Whereas BRSV and HRSV grew more efficiently in bovine and human cells, respectively, the chimeric rBRSV/A2 exhibited intermediate growth characteristics in a human cell line and grew better than either parent in a bovine line. The cytopathology induced by the chimera more closely resembled that of BRSV. BRSV was confirmed to be highly restricted for replication in the respiratory tract of chimpanzees, a host that is highly permissive for HRSV. Interestingly, the rBRSV/A2 chimeric virus was somewhat more competent than BRSV for replication in chimpanzees but remained highly restricted compared to HRSV. This showed that the substitution of the G and F glycoproteins alone was not sufficient to induce efficient replication in chimpanzees. Thug the F and G proteins contribute to the host range restriction of BRSV but are not the major determinants of this phenotype, Although rBRSV/A2 expresses the major neutralization and protective antigens of HRSV, chimpanzees infected with this chimeric virus were not significantly protected against subsequent challenge with wild-type HRSV. This suggests that the growth restriction of rBRSV/A2 was too great to provide adequate antigen expression and that the capacity of this chimeric vaccine candidate for replication in primates will need to be increased by the importation of additional HRSV genes. C1 Fed Res Ctr Virus Dis Anim, Inst Mol Biol, Friedrich Loeffler Inst, D-17498 Insel Riems, Germany. Fed Res Ctr Virus Dis Anim, Inst Infectol, Friedrich Loeffler Inst, D-17498 Insel Riems, Germany. NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), Fed Res Ctr Virus Dis Anim, Inst Mol Biol, Friedrich Loeffler Inst, Boddenblick 5A, D-17498 Insel Riems, Germany. NR 50 TC 63 Z9 66 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 3 BP 1187 EP 1199 DI 10.1128/JVI.74.3.1187-1199.2000 PG 13 WC Virology SC Virology GA 273YZ UT WOS:000084738100015 PM 10627529 ER PT J AU An, DS Wersto, RP Agricola, BA Metzger, ME Lu, S Amado, RG Chen, ISY Donahue, RE AF An, DS Wersto, RP Agricola, BA Metzger, ME Lu, S Amado, RG Chen, ISY Donahue, RE TI Marking and gene expression by a lentivirus vector in transplanted human and nonhuman primate CD34(+) cells SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; IN-VIVO EXPRESSION; BONE-MARROW CELLS; NUCLEAR-LOCALIZATION SIGNAL; HEMATOPOIETIC STEM-CELLS; SCID-HU MOUSE; RETROVIRAL VECTOR; NONDIVIDING CELLS; T-CELLS AB Recently, gene delivery vectors based on human immunodeficiency virus (HIV) have been developed as an alternative mode of gene delivery. These vectors have a number of advantages, particularly in regard to the ability to infect cells which are not actively dividing. However, the use of vectors based on human immunodeficiency virus raises a number of issues, not the least of which is safety; therefore, further characterization of marking and gene expression in different hematopoietic lineages in primate animal model systems is desirable. We use two animal model systems for gene therapy to test the efficiency of transduction and marking, as web as the safety of these vectors. The first utilizes the rhesus animal model for cytokine-mobilized autologous peripheral blood CD34(+) cell transplantation. The second uses the SCID-human (SCID-hu) thymus/liver chimeric graft animal model useful specifically for human T-lymphoid progenitor cell reconstitution. In the rhesus macaques, detectable levels of vector were observed in granulocytes, lymphocytes, monocytes, and, in one animal with the highest levels of marking, erythrocytes and platelets. In transplanted SCID-hu mice, we directly compared marking and gene expression of the lentivirus vector and a murine leukemia virus-derived vector in thymocytes. Marking was observed at comparable levels, but the lentivirus vector bearing an internal cytomegalovirus promoter expressed less efficiently than did the murine retroviral vector expressed from its own long terminal repeats. In assays for infectious HIV type 1 (HIV-1), no replication-competent HIV-1 was detected in either animal model system. Thus, these results indicate that while lentivirus vectors have no apparent deleterious effects and may have advantages over murine retroviral vectors, further study of the requirements for optimal use are warranted. C1 NHLBI, Hematol Branch, Rockville, MD USA. Univ Calif Los Angeles, AIDS Inst, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Microbiol & Immunol & Mol Genet, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Chen, ISY (reprint author), 10833 LeConte Ave,11-934 Factor Bldg, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [AI36555, AI39975, R01 AI039975] NR 60 TC 91 Z9 93 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 3 BP 1286 EP 1295 DI 10.1128/JVI.74.3.1286-1295.2000 PG 10 WC Virology SC Virology GA 273YZ UT WOS:000084738100025 PM 10627539 ER PT J AU Belnap, DM Filman, DJ Trus, BL Cheng, NQ Booy, FP Conway, JF Curry, S Hiremath, CN Tsang, SK Steven, AC Hogle, JM AF Belnap, DM Filman, DJ Trus, BL Cheng, NQ Booy, FP Conway, JF Curry, S Hiremath, CN Tsang, SK Steven, AC Hogle, JM TI Molecular tectonic model of virus structural transitions: the putative cell entry states of poliovirus SO JOURNAL OF VIROLOGY LA English DT Article ID X-RAY CRYSTALLOGRAPHY; CRYOELECTRON MICROSCOPY; CONFORMATIONAL ALTERATION; 3-DIMENSIONAL STRUCTURE; CAPSID RESIDUES; RECEPTOR; PROTEIN; MUTANTS; VP1; RESOLUTION AB Upon interacting with its receptor, poliovirus undergoes conformational changes that are implicated in cell entry, including the externalization of the viral protein VP4 and the N terminus of VP1. We have determined the structures of native virions and of two putative cell entry intermediates, the 135S and 80S particles, at similar to 22-Angstrom resolution by cryo-electron microscopy. The 135S and 80S particles are both similar to 4% larger than the virion. Pseudoatomic models were constructed by adjusting the beta-barrel domains of the three capsid proteins VP1, VP2, and VP3 from their known positions in the virion to fit the 135S and 80S reconstructions. Domain movements of up to 9 Angstrom were detected, analogous to the shifting of tec tonic plates. These movements create gaps between adjacent subunits. The gaps at the sites ct-here VP1, VP3, and VP3 subunits meet are plausible candidates for the emergence of VP4 and the N terminus of VP1. The implications of these observations are discussed for models in which the externalized components form a transmembrane pore through which viral RNA enters the infected cell. C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA. RP Hogle, JM (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RI Conway, James/A-2296-2010; OI Conway, James/0000-0002-6581-4748; Curry, Stephen/0000-0002-0552-8870 FU NIAID NIH HHS [AI20566, R01 AI020566, R21 AI020566, R37 AI020566] NR 63 TC 166 Z9 172 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 3 BP 1342 EP 1354 DI 10.1128/JVI.74.3.1342-1354.2000 PG 13 WC Virology SC Virology GA 273YZ UT WOS:000084738100031 PM 10627545 ER PT J AU Greensill, J Sheldon, JA Renwick, NM Beer, BE Norley, S Goudsmit, J Schulz, TF AF Greensill, J Sheldon, JA Renwick, NM Beer, BE Norley, S Goudsmit, J Schulz, TF TI Two distinct gamma-2 herpesviruses in African green monkeys: A second gamma-2 herpesvirus lineage among old world primates? SO JOURNAL OF VIROLOGY LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; ANTIBODIES; SAIMIRI; VIRUS AB Primate gamma-2 herpesviruses (rhadinoviruses) have so far been found in humans (Kaposi's sarcoma-associated herpesvirus [KSHV], also called human herpesvirus 8), macaques (Macaca spp.) (rhesus rhadinovirus [RRV] and retroperitoneal fibromatosis herpesvirus [RFHV]), squirrel monkeys (Saimiri sciureus) (herpesvirus saimiri), and spider monkeys (Ateles spp.) (herpesvirus ateles), Using serological screening and degenerate consensus primer PCR for the viral DNA polymerase gene, we have detected sequences from two distinct gamma-2 herpesviruses, termed Chlorocebus rhadinovirus 1 (ChRV1) and ChRV2, in African green monkeys. ChRV1 is more closely related to KSHV and RFHV, whereas ChRV2 is closest to RRV. Our findings suggest the existence of two distinct rhadinovirus lineages, represented by the KSHV/RFHV/ChRV1 group and the RRV/ChRV2 group, respectively, in at least two Old World monkey species. Antibodies to members of the RRV/ChRV2 lineage may cross-react in an immunofluorescence assay for early and late KSHV antigens. C1 Univ Liverpool, Dept Med Microbiol & Genitourinary Med, Mol Virol Grp, Liverpool L69 3GA, Merseyside, England. Univ Amsterdam, Acad Med Ctr, Dept Human Retrovirol, NL-1105 AZ Amsterdam, Netherlands. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD USA. Paul Ehrlich Inst, D-6070 Langen, Germany. RP Schulz, TF (reprint author), Univ Liverpool, Dept Med Microbiol & GU Med, Duncan Bldg,Daulby St, Liverpool L69 3GA, Merseyside, England. OI Sheldon, Julie/0000-0002-8240-0010 NR 32 TC 61 Z9 63 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 3 BP 1572 EP 1577 DI 10.1128/JVI.74.3.1572-1577.2000 PG 6 WC Virology SC Virology GA 273YZ UT WOS:000084738100058 PM 10627572 ER PT J AU Newcomb, WW Trus, BL Cheng, NQ Steven, AC Sheaffer, AK Tenney, DJ Weller, SK Brown, JC AF Newcomb, WW Trus, BL Cheng, NQ Steven, AC Sheaffer, AK Tenney, DJ Weller, SK Brown, JC TI Isolation of herpes simplex virus procapsids from cells infected with a protease-deficient mutant virus SO JOURNAL OF VIROLOGY LA English DT Article ID RECOMBINANT BACULOVIRUSES; 3-DIMENSIONAL RECONSTRUCTION; ELECTRON-MICROSCOPY; CAPSID FORMATION; DNA; TYPE-1; PROTEINS; VP26; BACTERIOPHAGE-T4; CLEAVAGE AB Herpes simplex virus type 1 (HSV-1) capsid proteins assemble in vitro into spherical procapsids that differ markedly in structure and stability from mature polyhedral capsids but can be converted to the mature form. Circumstantial evidence suggests that assembly in vivo follows a similar pathway of procapsid assembly and maturation, a pathway that resembles those of double-stranded DNA bacteriophages. We have confirmed the above pathway by isolating procapsids from HSV-1-infected cells and characterizing their morphology, thermal sensitivity, and protein composition. Experiments were carried out with an HSV-1 mutant (m100) deficient in the maturational protease for which it was expected that procapsids-normally, short-lived intermediates-would accumulate in infected cells. Particles isolated from m100-infected cells were found to share the defining properties of procapsids assembled in vitro. For example, by electron microscopy, they were found to be spherical rather than polyhedral in shape, and they disassembled at 0 degrees C, unlike mature capsids, which are stable at this temperature. A three-dimensional reconstruction computed at 18-Angstrom resolution from cryoelectron micrographs showed m100 procapsids to be structurally indistinguishable from procapsids assembled in vitro. In both cases, their predominant components are the four essential capsid proteins: the major capsid protein (VP5), the scaffolding protein (pre-VP22a), and the tripler proteins (VP19C and VP23). VP26, a small, abundant but dispensable capsid protein, was not found associated with m100 procapsids, suggesting that it binds to capsids only after they have matured into the polyhedral form. Procapsids were also isolated from cells infected at the nonpermissive temperature with the HSV-1 mutant tsProt.A (a mutant with a thermoreversible lesion in the protease), and their identity as procapsids was confirmed by cryoelectron microscopy. This analysis revealed density on the inner surface of the procapsid scaffolding core that may correspond to the location of the maturational protease. Upon incubation at the permissive temperature, tsProt.A procapsids transformed into polyhedral, mature capsids, providing further confirmation of their status as precursors. C1 Univ Virginia, Hlth Sci Ctr, Dept Microbiol, Charlottesville, VA 22908 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Wallingford, CT 06492 USA. Univ Connecticut, Ctr Hlth, Dept Microbiol, Farmington, CT 06030 USA. RP Brown, JC (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Microbiol, Box 441, Charlottesville, VA 22908 USA. OI Weller, Sandra/0000-0002-4519-6276 FU NIAID NIH HHS [R56 AI037549, AI37549, AI41644, R01 AI037549, R01 AI041644, R56 AI041644] NR 52 TC 89 Z9 91 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 4 BP 1663 EP 1673 DI 10.1128/JVI.74.4.1663-1673.2000 PG 11 WC Virology SC Virology GA 277XC UT WOS:000084958000009 PM 10644336 ER PT J AU Shishido-Hara, Y Hara, Y Larson, T Yasui, K Nagashima, K Stoner, GL AF Shishido-Hara, Y Hara, Y Larson, T Yasui, K Nagashima, K Stoner, GL TI Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system: Splicing of late RNAs, translation and nuclear transport of major capsid protein VPI, and capsid assembly SO JOURNAL OF VIROLOGY LA English DT Article ID OPEN READING FRAMES; LATE MESSENGER-RNA; SIMIAN VIRUS-40; STRUCTURAL PROTEINS; BRAIN-TUMORS; LOCALIZATION SEQUENCE; MISSENSE MUTATIONS; VIRAL AGNOGENE; DNA-SEQUENCE; INSECT CELLS AB Human polyomavirus JC (JCV) can encode the three capsid proteins VP1, VP2, and VP3, downstream of the agnoprotein in the late region. JCV virions are identified in the nucleus of infected cells. in this study, we have elucidated unique features of JCV capsid formation by using a eukaryotic expression system. Structures of JCV polycistronic late RNAs (M1 to M4 and possibly M5 and M6) generated by alternative splicing were determined. VP1 would be synthesized from M2 RNA, and VP2 and VP3 would be synthesized from M1 RNA. The presence of the open reading frame of the agnoprotein or the leader sequence (nucleotides 275 to 409) can decrease the expression level of VP1. VP1 was efficiently transported to the nucleus in the presence of VP2 and VP3 but distributed both in the cytoplasm and in the nucleus in their absence, Mutation analysis indicated that inefficiency in nuclear transport of VP1 is due to the unique structure in the N-terminal sequence, KRKGERK, Within the nucleus, VP1 was localized discretely and identified as speckles in the presence of VP2; and VP3 but distributed diffusely in their absence. These results suggest that VP1 was efficiently transported to the nucleus and localized in the discrete subnuclear regions, possibly with VP2 and VP3, By electron microscopy, recombinant virus particles were identified in the nucleus, and their intranuclear distribution was consistent with distribution of speckles. This system provides a useful model with which to understand JCV capsid formation and the structures and functions of the JCV capsid proteins. C1 Tokyo Med & Dent Univ, Mol Neurobiol Lab, Human Gene Sci Ctr, Bunkyo Ku, Tokyo 1138519, Japan. Tokyo Metropolitan Inst Neurosci, Dept Microbiol & Immunol, Tokyo, Japan. Hokkaido Univ, Sch Med, Lab Mol & Cellular Pathol, CREST,Japan Sci & Technol Corp, Sapporo, Hokkaido 060, Japan. NINDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. RP Shishido-Hara, Y (reprint author), Tokyo Med & Dent Univ, Mol Neurobiol Lab, Human Gene Sci Ctr, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138519, Japan. NR 68 TC 29 Z9 31 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 4 BP 1840 EP 1853 DI 10.1128/JVI.74.4.1840-1853.2000 PG 14 WC Virology SC Virology GA 277XC UT WOS:000084958000030 PM 10644357 ER PT J AU Soong, W Schultz, JC Patera, AC Sommer, MH Cohen, JI AF Soong, W Schultz, JC Patera, AC Sommer, MH Cohen, JI TI Infection of human T lymphocytes with varicella-zoster virus: An analysis with viral mutants and clinical isolates SO JOURNAL OF VIROLOGY LA English DT Article ID ORF47 PROTEIN-KINASE; SCID-HU MOUSE; IN-VITRO; REPLICATION; VIREMIA; VZV; VACCINE; CHILDREN; ENCODES; HOMOLOG AB Varicella-zoster virus (VZV) disseminates in the body in peripheral blood mononuclear cells during chickenpox, Up to 1 in 10,000 mononuclear cells are infected during the viremic phase of the disease. We developed an in vitro system to infect human mononuclear cells with VZV by using umbilical cord blood, In this system, 3 to 4% of T cells were infected with VZV. VZV mutants unable to express certain genes, such as open reading frame 47 (ORF47) or ORF66, were impaired for growth in T cells, while other mutants showed little difference from parental virus. VZV unable to express ORF47 was even more impaired for spread from umbilical cord blood cells to melanoma cells in vitro. Early-passage clinical isolates of VZV infected T cells at a similar rate to the Oka vaccine strain; however, the clinical isolates were more efficient in spreading from infected T cells to melanoma cells, This in vitro system for infecting human T cells with VZV should be useful for identifying cellular and viral proteins that are important far virus replication in T cells and for the spread of virus from T cells to other cells. C1 NIAID, Clin Invest Lab, Med Virol Sect, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. RP Cohen, JI (reprint author), NIH, Bldg 10,Rm 11N214, Bethesda, MD 20892 USA. NR 21 TC 60 Z9 62 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 4 BP 1864 EP 1870 DI 10.1128/JVI.74.4.1864-1870.2000 PG 7 WC Virology SC Virology GA 277XC UT WOS:000084958000032 PM 10644359 ER PT J AU de Quiros, JCLB Shupert, WL McNeil, AC Gea-Banacloche, JC Flanigan, M Savage, A Martino, L Weiskopf, EE Imamichi, H Zhang, YM Adelsburger, J Stevens, R Murphy, PM Zimmerman, PA Hallahan, CW Davey, RT Connors, M AF de Quiros, JCLB Shupert, WL McNeil, AC Gea-Banacloche, JC Flanigan, M Savage, A Martino, L Weiskopf, EE Imamichi, H Zhang, YM Adelsburger, J Stevens, R Murphy, PM Zimmerman, PA Hallahan, CW Davey, RT Connors, M TI Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODY-RESPONSES; LONG-TERM NONPROGRESSORS; HIV TYPE-1 INFECTION; IMMUNE-RESPONSE; LYMPHOCYTE; CD4(+); INDIVIDUALS; PROGRESSION; DELETION; DISEASE AB High levels of resistance to challenge with human immunodeficiency virus type 1 SF162 were observed in animals engrafted with peripheral blood mononuclear cells of four long-term nonprogressors (LTNPs). Resistance was abrogated by depletion of CD8(+) T cells in vivo and was observed only in LTNPs with proliferative responses to p24. In a subgroup of nonprogressors, CD8(+) T cells mediated restriction of challenge viruses, and this response was associated with strong proliferative responses to p24 antigen. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Autonoma Madrid, Clin Puerta Hierro, Serv Med Interna 1, Madrid, Spain. Hosp Gen Gregorio Maranon, Microbiol Serv, Madrid, Spain. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD USA. RP Connors, M (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B-09,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. NR 37 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2000 VL 74 IS 4 BP 2023 EP 2028 DI 10.1128/JVI.74.4.2023-2028.2000 PG 6 WC Virology SC Virology GA 277XC UT WOS:000084958000049 PM 10644376 ER PT J AU Carmelli, D DeCarli, C Swan, GE Kelly-Hayes, M Wolf, PA Reed, T Guralnik, JM AF Carmelli, D DeCarli, C Swan, GE Kelly-Hayes, M Wolf, PA Reed, T Guralnik, JM TI The joint effect of apolipoprotein E epsilon 4 and MRI findings on lower-extremity function and decline in cognitive function SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID MATTER HYPERINTENSITY VOLUME; HEALTHY ELDERLY SUBJECTS; ALZHEIMERS-DISEASE; WHITE-MATTER; NHLBI TWIN; CARDIOVASCULAR HEALTH; OLDER ADULTS; BRAIN; DISABILITY; ALLELE AB Background. Cognitive decline and poor physical function are risk factors for disability in old age and may occur more often in subjects with the apolipoprotein E epsilon 3 (ApoE-epsilon 4) allele. The objective of this study was to investigate the joint effect of ApoE-epsilon 4 and structural changes detected on MRI br ain scans on cognitive decline and lower-extremity function. Methods. Brain MRI (1.5 T), neuropsychological tests, and lower-extremity physical function tests were administered to World War II male veteran twins ages 69 to 80. Quantification of MRI scans used a previously published algorithm to segment brain images into total cerebral brain (TCB), cerebrospinal fluid (CSF), and white-matter hyperintensity (WMH) volumes. A short battery of physical performance tests was used to assess lower-extremity function. Ten-year changes in performance on the Mini-Mental State Exam (MMSE), the Benton Visual Retention Test (BVRT), and the Digit Symbol Substitution (DSS) test were used to assess cognitive decline. Results. For the sample as a whole, the comparison of subjects by median split of total cerebral brain volume found that those with brain volumes below the median performed worse on tests of gait and balance (p < .01) and experienced greater cognitive decline on the MMSE and BVRT cognitive test batteries (both p < .01). In addition, subjects with WMH volumes above the median had poor performance on the standing balance tasks and experienced greater decline on the DSS test (p < .01). Stratified analyses revealed that the joint effect of radiological findings and the ApoE-epsilon 4 allele on cognitive decline and lower-extremity function was often greater than that expected from the separate effects combined. Conclusions. We conclude that radiological findings in conjunction with ApoE-epsilon 4 may single out a group at higher risk for dementia. We speculate that the observed interaction effect may be due to increased susceptibility to brain injury or impaired repair mechanisms in subjects with ApoE-epsilon 4. C1 SRI Int, Hlth Sci Ctr, Menlo Pk, CA 94025 USA. Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. Boston Univ, Dept Neurol, Boston, MA 02215 USA. Indiana Univ, Sch Med, Dept Med Genet, Indianapolis, IN 46202 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Carmelli, D (reprint author), SRI Int, Hlth Sci Ctr, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM doritc@unix.sri.com RI DeCarli, Charles/B-5541-2009 FU NHLBI NIH HHS [HL51429] NR 44 TC 50 Z9 51 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2000 VL 55 IS 2 BP M103 EP M109 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XP UT WOS:000088044200018 PM 10737693 ER PT J AU Fillenbaum, GG Pieper, CF Cohen, HJ Cornoni-Huntley, JC Guralnik, JM AF Fillenbaum, GG Pieper, CF Cohen, HJ Cornoni-Huntley, JC Guralnik, JM TI Comorbidity of five chronic health conditions in elderly community residents: Determinants and impact on mortality SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; GENERAL-PRACTICE; OLDER ADULTS; RISK; HYPERTENSION; STROKE; PREVALENCE; WOMEN; LIFE AB Background. Comorbidity is common in elderly persons. Its extent, correlates, and life-threatening impact in representative community residents are unclear. Methods. Self-reported information of physician-diagnosed coronary artery disease (CAD), cerebrovascular disease (CVD, diabetes, and cancer was obtained annually between 1986-87 and 1992-93, and hypertension was obtained triennially from the participants of the Duke Established Populations for Epidemiologic Studies of the Elderly, a stratified multistage sample of 4126 Black and White community residents aged 65-100, living in a five-county area of North Carolina. Date of death was obtained from death certificates identified through search of the National Death Index. Statistical procedures included descriptive statistics, logistic regression, and survival analysis. Results. Of this sample, 57% reported hypertension, 20% diabetes, 15% CAD, 9% cancer, and 9% CVD; 29% reported none of these conditions, whereas 29% reported two or more. Demographic characteristics were not related to comorbidity with CVD or cancer. Increased education tended to be protective. The effect of age, gender, and race varied with condition. At baseline there was substantial comorbidity among hypertension, CAD, CVD, and diabetes, but not with cancer. Hypertension, CVD, and diabetes were risk factors for CAD, whereas diabetes was a risk factor for CVD. After controlling for demographic characteristics, all health conditions except hypertension were predictive of B-year mortality, as was the presence of comorbidity. Conclusion. We found significant comorbidity in older persons who have hypertension, CAD, CVD, or diabetes; particular risk of developing comorbidity, particularly CAD, among those with hypertension, CVD, and diabetes; and risk of CVD in those with diabetes. With the exception of hypertension, these conditions, and comorbidity per se, are life-threatening. C1 Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA. Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Durham, NC 27705 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Fillenbaum, GG (reprint author), Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Box 3003, Durham, NC 27710 USA. FU NIA NIH HHS [N01-AG-12102] NR 38 TC 80 Z9 81 U1 1 U2 7 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 FEB PY 2000 VL 55 IS 2 BP M84 EP M89 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XP UT WOS:000088044200015 PM 10737690 ER PT J AU Komhoff, M Wang, JL Cheng, HF Langenbach, R McKanna, JA Harris, RC Breyer, MD AF Komhoff, M Wang, JL Cheng, HF Langenbach, R McKanna, JA Harris, RC Breyer, MD TI Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development SO KIDNEY INTERNATIONAL LA English DT Article DE cyclooxygenase; NSAIDs; nephrogenesis; prostaglandins; macula densa ID GENE DISRUPTION; INDOMETHACIN; INFLAMMATION; ISOFORMS; KIDNEY AB Background Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with renal dysgenesis in humans. Methods. These studies characterized cyclooxygenase-2 (COX-2) versus COX-1-selective inhibition on nephrogenesis in the rodent using histomorphometry immunohistology, and in situ hybridization. Results. Administration of a COX-2-selective inhibitor (SC58236), started during pregnancy until weaning, significantly impaired development of the renal cortex and reduced glomerular diameter in both mice and rats. An identical phenotype was demonstrated in COX-2 -/- mice. In contrast to its effects on the developing kidney, a COX-2 inhibitor had no effect on glomerular volume in adult mice. This effect was specific for COX-2 because maternal administration of a COX-1-selective inhibitor (SC58560) did not affect renal development despite significantly inhibiting gastric mucosal prostaglandin E-2 (PGE(2)) synthesis in pups. The expression of COX-2 immunoreactivity peaked in the first postnatal week and was localized to S-shaped bodies and the macula densa in the cortex. Treatment with a COX-2 inhibitor during this period (from postnatal day 0 to day 21) severely reduced glomerular diameter, whereas treatment limited to pregnancy did not affect glomerular size. Conclusion. These data demonstrate an important role for COX-2 activity in nephrogenesis in the rodent, and define a specific time period of susceptibility to these effects. C1 Vet Adm Med Ctr, Nashville, TN 37212 USA. Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Div Nephrol, Dept Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Cell Biol, Vanderbilt George M OBrien Kidney & Urol Dis Ctr, Nashville, TN 37212 USA. Natl Inst Environm Hlth Sci, Lab Expt Carcinogenesis & Mutagenesis, Res Triangle Pk, NC USA. RP Breyer, MD (reprint author), Vet Adm Med Ctr, F-427 ACRE Bldg, Nashville, TN 37212 USA. FU NIDDK NIH HHS [1-P50-DK-39261, DK-37097] NR 25 TC 139 Z9 141 U1 0 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2000 VL 57 IS 2 BP 414 EP 422 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 282WG UT WOS:000085243000005 PM 10652018 ER PT J AU Abe, A Arend, LJ Lee, L Lingwood, C Brady, RO Shayman, JA AF Abe, A Arend, LJ Lee, L Lingwood, C Brady, RO Shayman, JA TI Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase SO KIDNEY INTERNATIONAL LA English DT Article DE X-linked disorder; globotriaosylceramide; alpha-galactosidase A; Fabry cell lines; verotoxin ID N-BUTYLDEOXYNOJIRIMYCIN; RECEPTOR AB Background. Fabry disease is an inherited X-linked disorder resulting in the loss of activity of the lysosomal hydrolase alpha-galactosidase A and causing the clinical manifestations of renal failure, cerebral vascular disease, and myocardial infarction. The phenotypic expression of this disorder is manifest by the accumulation of glycosphingolipids containing alpha-galactosyl linkages, most prominently globotriaosylceramide. Methods. Based on quantitative structure activity studies, we recently reported two newly designed glucosylceramide synthase inhibitors based on 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4). These inhibitors, 4'-hydroxy-P4 and ethylenedioxy-P4, were evaluated for their ability to deplete globotriaosylceramide and other glucosylceramide-based lipids in Fabry lymphocytes and were compared with N-butyldeoxynojirimycin another reported glucosylceramide synthase inhibitor. Results. Concentrations as low as 10 nmol/L of 4'-hydroxy-P4 and ethylenedioxy-P4 resulted in 70 and 80% depletion, respectively, of globotriaosylceramide, with maximal depletion occurring at three days of treatment. There was no impairment of cell growth. In contrast, N-butyldeoxynojirimycin only minimally lowered globotriaosylceramide levels, even at concentrations as high as 10 mu mol/L. Globotriaosylceramide depletion was confirmed by the loss of binding of FITC-conjugated verotoxin B subunit to the lymphoblasts. Conclusions. These findings suggest that selective glucosylceramide synthase inhibitors are highly effective in the depletion of globotriaosylceramide from Fabry cell lines. We suggest that these compounds have potential therapeutic utility in the treatment of Fabry disease. C1 Univ Michigan, Dept Internal Med, Div Nephrol, Med Ctr, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pathol, Med Ctr, Ann Arbor, MI 48109 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NINDS, NIH, Bethesda, MD 20892 USA. RP Shayman, JA (reprint author), Univ Michigan, Dept Internal Med, Div Nephrol, Med Ctr, Box 0676,Room 1560 MSRBII,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 19 TC 41 Z9 42 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2000 VL 57 IS 2 BP 446 EP 454 DI 10.1046/j.1523-1755.2000.00864.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 282WG UT WOS:000085243000008 PM 10652021 ER PT J AU Hartley, JW Chattopadhyay, SK Lander, MR Taddesse-Heath, L Naghashfar, Z Morse, HC Fredrickson, TN AF Hartley, JW Chattopadhyay, SK Lander, MR Taddesse-Heath, L Naghashfar, Z Morse, HC Fredrickson, TN TI Accelerated appearance of multiple B cell lymphoma types in NFS/N mice congenic for ecotropic murine leukemia viruses SO LABORATORY INVESTIGATION LA English DT Article ID FOCUS-FORMING VIRUSES; INBRED MOUSE STRAINS; HRS-J MICE; AKR MICE; GENE REARRANGEMENTS; THYMIC LYMPHOMAS; REGION SEQUENCES; CHAIN GENE; CWD MICE; V-MYC AB Spontaneous lymphomas occur at high frequency in NFS.V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS.V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor beta chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS.V+) or absence (NFS.V-) of functional ecotropic MuLV genomes showed that NFS.V- clonal lymphomas developed at about one-half the rate of those occurring in NFS.V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS.V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis. C1 NCI, Registry Expt Canc, NIH, Bethesda, MD USA. RP Hartley, JW (reprint author), NIAID, LIP, Immunopathol Lab, NIH, 7 Ctr Dr,Room 7-304,MSC-0760, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 FU NIAID NIH HHS [N01-AI-45203] NR 75 TC 43 Z9 45 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2000 VL 80 IS 2 BP 159 EP 169 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 288BQ UT WOS:000085542300005 PM 10701686 ER PT J AU Ondrey, FG Greig, JR Herscher, L AF Ondrey, FG Greig, JR Herscher, L TI Radiation dose to otologic structures during head and neck cancer radiation therapy SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Meeting of the Middle Section of the American-Laryngological-Rhinological-and-Otological-Society CY JAN 23-25, 1998 CL MINNEAPOLIS, MINNESOTA SP Amer Laryngol Rhinol & Otol Soc Inc, Middle Sect DE radiation; dosimetry; cochlea; ear; hearing ID SENSORINEURAL HEARING-LOSS; NASOPHARYNGEAL CARCINOMA; CISPLATIN; IRRADIATION; NEUROPATHY AB Background Otologic structures are often contained within head and neck cancer radiation treatment ports. The dosimetry to otologic structures has not been routinely analyzed and radiation treatment planning does not currently attempt to specifically avoid the inner ear structures when dosimetry is calculated. Recent studies demonstrate that up to 30% of patients experience sensorineural hearing loss on multimodality therapy with cisplatin and radiation. Methods: In the current case series, radiation dosimetry to otologic structures was calculated from computed tomogram treatment plans on patients. Fifteen nasopharyngeal, oral cavity, oropharyngeal, and hypopharyngeal cancer patients were analyzed. Results: Between 8% and 102% of the total dose is delivered to the petrous bone/cochlea, with 4 of 15 patients getting more than 50% of the dose to at least one cochlea, The mastoid air cells received between 3% and 75% of the total dose, with higher doses being delivered to patients with bulky high neck metastases or nasopharyngeal tumors, The eustachian tubes received between 2% and 102% of the total dose, with 10 of 15 patients receiving more than 50% of the dose to this anatomic site, Conclusion: We conclude that the cochlea and eustachian tubes receive significant radiation during treatment, particularly in nasopharyngeal cancer patients. Careful design of radiation treatment ports may allow for the reduction of radiation to hearing structures. C1 NIDOCD, Head & Neck Surg Branch, NIH, Bethesda, MD USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Ondrey, FG (reprint author), Univ Minnesota, Dept Otolaryngol, Box 396,420 Delaware St SE, Minneapolis, MN 55455 USA. NR 19 TC 36 Z9 45 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2000 VL 110 IS 2 BP 217 EP 221 DI 10.1097/00005537-200002010-00006 PN 1 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 282ND UT WOS:000085224200006 PM 10680919 ER PT J AU Kim, SS Kim, KS Lee, JG Park, IY Koo, JS Yoon, JH AF Kim, SS Kim, KS Lee, JG Park, IY Koo, JS Yoon, JH TI Levels of intracellular protein and messenger RNA of mucin and lysozyme in normal human nasal and polyp epithelium SO LARYNGOSCOPE LA English DT Article DE mucin; lysozyme; nasal epithelium; polyp ID HUMAN BRONCHIAL GLANDS; IMMUNOCYTOCHEMICAL LOCALIZATION; RESPIRATORY-TRACT; SECRETORY-CELLS; GENES AB Objectives: Mucus hypersecretion is a characteristic feature in chronic sinusitis with nasal polyps, The objective of this study is to examine whether the polyp epithelium itself contributes to a certain extent to the increased mucous secretions in chronic sinusitis with nasal polyps, and if it does, to determine which mucin genes are responsible for the increased mucin secretion. Methods: Three pooled samples of normal nasal epithelial cells from each subject were obtained by scrapings from the inferior turbinates of 30 healthy adult volunteers and nasal polyps from 6 patients who underwent intranasal ethmoidectomy and polypectomy, Isolated epithelial cells were used for total RNA isolation for reverse transcriptase polymerase chain reaction and cell lysates for immuno blotting. Results: The intracellular level of mucin from polyp epithelium was 2.9 times higher than that of normal nasal epithelium (P <.05). Interestingly, MUC2 and MUC8 messenger RNA (mRNA) levels were clearly upregulated in polyp epithelium compared with those of normal turbinate epithelium. Conclusions: Polyp epithelium can be considered to contribute in part to increased secretion in chronic sinusitis with polyps, and increased mucous secretion might be related to the increased mRNA level of MUC2 or MUG8 or both. C1 Yonsei Univ, Coll Med, Dept Otorhinolaryngol, Seodaemun Gu, Seoul 120752, South Korea. Catholic Univ, Coll Med, Seoul, South Korea. NIEHS, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. RP Yoon, JH (reprint author), Yonsei Univ, Coll Med, Dept Otorhinolaryngol, Seodaemun Gu, 134 Shinchon Dong,CPO Box 8044, Seoul 120752, South Korea. RI Yoon, Joo-Heon/E-5781-2016; OI Yoon, Joo-Heon/0000-0003-2404-7156 NR 19 TC 41 Z9 45 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD FEB PY 2000 VL 110 IS 2 BP 276 EP 280 DI 10.1097/00005537-200002010-00017 PN 1 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 282ND UT WOS:000085224200016 PM 10680929 ER PT J AU Steadman, HJ Silver, E Monahan, J Appelbaum, PS Robbins, PC Mulvey, EP Grisso, T Roth, LH Banks, S AF Steadman, HJ Silver, E Monahan, J Appelbaum, PS Robbins, PC Mulvey, EP Grisso, T Roth, LH Banks, S TI A classification tree approach to the development of actuarial violence risk assessment tools SO LAW AND HUMAN BEHAVIOR LA English DT Article ID PREDICTIONS; DANGEROUSNESS; DIMENSIONS; ACCURACY; OTHERS AB Since the 1970s, a wide body of research has suggested that the accuracy of clinical risk assessments of violence might be increased if clinicians used actuarial tools. Despite considerable progress in recent years in the development of such tools for violence risk assessment, they remain primarily research instruments, largely ignored in daily clinical practice. We argue that because most existing actuarial tools are based on a main effects regression approach, they no not adequately reflect the contingent nature of the clinical assessment processes. To enhance the use of actuarial violence risk assessment tools, we propose a classification tree rather than a main effects regression approach. In addition, we suggest that by employing two decision thresholds for identifying high- and low-risk cases-instead of the standard single threshold-the use of actuarial tools to make dichotomous risk classification decisions may be further enhanced. These claims are supported with empirical data from the MacArthur Violence Risk Assessment Study. C1 Policy Res Associates Inc, Delmar, NY 12054 USA. Penn State Univ, University Pk, PA 16802 USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. Natl Inst Hlth, Bethesda, MD 20892 USA. RP Steadman, HJ (reprint author), Policy Res Associates Inc, 262 Delaware Ave, Delmar, NY 12054 USA. FU PHS HHS [R01 49696] NR 35 TC 199 Z9 203 U1 1 U2 15 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-7307 J9 LAW HUMAN BEHAV JI Law Hum. Behav. PD FEB PY 2000 VL 24 IS 1 BP 83 EP 100 DI 10.1023/A:1005478820425 PG 18 WC Law; Psychology, Social SC Government & Law; Psychology GA 282UK UT WOS:000085237200005 PM 10693320 ER PT J AU Fassone, L Bhatia, K Gutierrez, M Capello, D Gloghini, A Dolcetti, R Vivenza, D Ascoli, V Lo Coco, F Pagani, L Dotti, G Rambaldi, A Raphael, M Tirelli, U Saglio, G Magrath, IT Carbone, A Gaidano, G AF Fassone, L Bhatia, K Gutierrez, M Capello, D Gloghini, A Dolcetti, R Vivenza, D Ascoli, V Lo Coco, F Pagani, L Dotti, G Rambaldi, A Raphael, M Tirelli, U Saglio, G Magrath, IT Carbone, A Gaidano, G TI Molecular profile of Epstein-Barr virus infection in HHV-8-positive primary effusion lymphoma SO LEUKEMIA LA English DT Article DE EBV; primary effusion lymphoma; HHV-8; AIDS; transplantation; immunodeficiency ID CAVITY-BASED LYMPHOMAS; LATENT GENE-EXPRESSION; KAPOSIS-SARCOMA; NUCLEAR ANTIGEN-1; DNA-SEQUENCES; CELL-LINES; BURKITTS-LYMPHOMAS; HERPES-VIRUS; NEOPLASIA; DISORDERS AB Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants, A wildtype LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) individual PEL cases consistently harbor a single EBV strain; (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases; (3) no specific EBV genotype preferentially associates with PEL. C1 Amedeo Avogadro Univ Eastern Piedmont, Dept Med Sci, Div Internal Med, I-28100 Novara, Italy. NCI, Pediat Branch, Lymphoma Biol Sect, NIH, Bethesda, MD 20892 USA. Ist Nazl Tumori, Ctr Riferimento Oncol, Div Pathol, Aviano, Italy. Ist Nazl Tumori, Ctr Riferimento Oncol, Div Expt Oncol 1, Aviano, Italy. Ist Nazl Tumori, Ctr Riferimento Oncol, Div Med Oncol A, Aviano, Italy. Univ La Sapienza, Dept Expt Med & Pathol, Rome, Italy. Univ La Sapienza, Dept Cellular Biotechnol & Hematol, Rome, Italy. Azienda Osped Piacenza, Infect Dis Unit, Piacenza, Italy. Osped Riuniti Bergamo, Div Hematol, I-24100 Bergamo, Italy. Univ Paris 13, CHU Avicenne, Serv Hematol Biol, Bobigny, France. Univ Turin, Osped San Luigi, Dept Clin & Biol Sci, Div Hematol & Internal Med, Orbassano, Italy. RP Gaidano, G (reprint author), Amedeo Avogadro Univ Eastern Piedmont, Dept Med Sci, Div Internal Med, Via Solaroli 17, I-28100 Novara, Italy. RI Dolcetti, Riccardo/O-3832-2015; Capello, Daniela/J-4110-2012; Gloghini, Annunziata/C-1992-2017 OI Dolcetti, Riccardo/0000-0003-1625-9853; Capello, Daniela/0000-0001-9157-8753; Gloghini, Annunziata/0000-0002-7226-1942 NR 45 TC 35 Z9 35 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2000 VL 14 IS 2 BP 271 EP 277 DI 10.1038/sj.leu.2401651 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 283NK UT WOS:000085281500009 PM 10673744 ER PT J AU Kim, HY Hamilton, J AF Kim, HY Hamilton, J TI Accumulation of docosahexaenoic acid in phosphatidylserine is selectively inhibited by chronic ethanol exposure in C-6 glioma cells SO LIPIDS LA English DT Article ID FATTY-ACIDS; RAT-BRAIN; MASS-SPECTROMETRY; LIPID-COMPOSITION; MEMBRANE; PHOSPHATIDYLETHANOLAMINE; BIOSYNTHESIS; MOBILIZATION; ARACHIDONATE; CONSUMPTION AB Neuronal membranes are highly enriched with docosahexaenoic acid (22:6n-3), and its content can be altered by ethanol consumption. We have previously reported that the 22:6n-3 status in membrane affects the biosynthesis of phosphatidylserine (PS), a phospholipid class which contains an exceptionally high proportion of 22:6n-3. The aim of the present study is to investigate the effect of chronic ethanol exposure on PS accumulation in relation to the 22:6n-3 status. C-6 glioma cells were enriched with 25 mu M 22:6n-3 for 48 h and the PS accumulation was first evaluated in comparison to nonenriched cells as well as cells enriched with arachidonic acid (20:4n-6). Electrospray liquid chromatography-mass spectrometry analysis revealed that cells treated with 22:6n-3 showed significantly higher accumulation of PS in comparison to nonenriched or 20:4n-6-enriched cells, primarily due to an increase of 1-stearoyl-2-docosahexaenoyl-glycerophosphoserine (18:0,22:6-PS). Chronic ethanol exposure selectively affected the accumulation of PS in 22:6n-3-enriched cells. After cells were exposed to 20 or 50 mM ethanol for 4 wk, accumulation of 18:0,22:6-PS upon 22:6n-3 supplementation was significantly lower, resulting in a drastic reduction of total PS. Concomitantly, ethanol-treated cells showed lower incorporation of serine in comparison to control cells. From these data, it was concluded that supplementation of cells with 22:6n-3 promotes the accumulation of PS and chronic ethanol treatment diminishes this effect at least in part through impaired serine incorporation processes. Attenuated accumulation of 22:6n-3 in PS and the reduction of PS thus may have significant implications in pathophysiological effects of ethanol, especially in tissues with abundant 22:6n-3. C1 NIAAA, LMBB, Sect Mass Spectrometry, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, LMBB, Sect Mass Spectrometry, NIH, 12420 Parklawn Dr,Rm 114, Rockville, MD 20852 USA. NR 42 TC 21 Z9 21 U1 0 U2 0 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD FEB PY 2000 VL 35 IS 2 BP 187 EP 195 DI 10.1007/BF02664769 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 297TV UT WOS:000086099500010 PM 10757550 ER PT J AU Talbot, LA Metter, EJ Fleg, JL AF Talbot, LA Metter, EJ Fleg, JL TI Leisure-time physical activities and their relationship to cardiorespiratory fitness in healthy men and women 18-95 years old SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE MET; peak oxygen consumption; aging; physical activity ID ALL-CAUSE MORTALITY; BODY-COMPOSITION; AEROBIC POWER; AGE; EXERCISE; RISK; POPULATION; SEDENTARY; DECLINE; VO2MAX AB Purpose: We examined leisure-time physical activities (LTPA) and their contribution to peak oxygen consumption ((V) over dot O-2) in healthy men (N = 619) and women (N = 497) aged 18-95 yr (mean 51 +/- 17) who were participants of thr Baltimore Longitudinal study of Aging. Methods: Calculations of LTPA were based on the average self-reported rime spent performing 97 activities and converted into MET-min 24 h(-1). The activities were divided into three levels of LTPA based on absolute intensity. Peak (V) over dot O-2 determined from a maximal treadmill exercise test. Results: Total LTPA was inversely related to age in both sexes (r = -0.26, P < 0.0001 in men and r = -0.23, P < 0.0001 in women), mediated primarily by less high-intensity activities in older subjects, with only minor differences in moderate- and low-intensity activities across age. Peak (V) over dot O-2 correlated positively with LTPA; the correlations were strongest for high-intensity LTPA (r = 0.33 in men and 0.27 in women, each P < 0.0001), intermediate for moderate-intensity activity (r = 0.12, P < 0.004 in men and r = 0.17, P < 0.0001 in women) and minimal for low-intensity activity (r = 0.08, P = 0.05 in men and r = 0.06, P = 0.20 in women). On univariate analysis, total LTPA accounted for 12.9% of peak (V) over dot O-2 variance for men and 10.6% for women. By multivariate analysis, LTPA independently accounted for 1.6% of the peak (V) over dot O-2 variance in men and 1.86 in women after controlling for age and body mass index. Conclusions: In healthy adults across a broad age range, LTPA is a relatively minor independent contributor to aerobic capacity. C1 Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Talbot, LA (reprint author), Johns Hopkins Univ, Sch Nursing, 525 N Wolfe St,Rm 445, Baltimore, MD 21205 USA. FU NIA NIH HHS [1Z01AG 00636-09] NR 40 TC 93 Z9 95 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD FEB PY 2000 VL 32 IS 2 BP 417 EP 425 DI 10.1097/00005768-200002000-00024 PG 9 WC Sport Sciences SC Sport Sciences GA 283TG UT WOS:000085291400024 PM 10694126 ER PT J AU Konkel, ME Tilly, K AF Konkel, ME Tilly, K TI Temperature-regulated expression of bacterial virulence genes SO MICROBES AND INFECTION LA English DT Review DE temperature; virulence; gene regulation ID OUTER SURFACE-PROTEIN; BORRELIA-BURGDORFERI; YERSINIA-PESTIS; LYME-DISEASE; BORDETELLA-PERTUSSIS; SHIGELLA-FLEXNERI; TRANSCRIPTIONAL ACTIVATOR; ENVIRONMENTAL-REGULATION; RELAPSING FEVER; IMMUNE-RESPONSE AB Virulence gene expression in most bacteria is a highly regulated phenomenon, affected by a variety of parameters including osmolarity, pH, ion concentration, iron levels, growth phase, and population density. Virulence genes are also regulated by temperature, which acts as an 'on-off switch in a manner distinct from the more general heat-shock response. Here, we review temperature-responsive expression of virulence genes in four diverse pathogens. (C) 2000 Editions scientifiques et medicales Elsevier SAS. C1 Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NIAID, Rocky Mt Labs, Lab Microbial Struct & Funct, Hamilton, MT 59840 USA. RP Konkel, ME (reprint author), Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. FU NIDDK NIH HHS [DK50567-01A1] NR 69 TC 135 Z9 140 U1 1 U2 17 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2000 VL 2 IS 2 BP 157 EP 166 DI 10.1016/S1286-4579(00)00272-0 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 299VE UT WOS:000086217900007 PM 10742688 ER PT J AU Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J Lister, TA Bloomfield, CD AF Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J Lister, TA Bloomfield, CD TI The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997 SO MODERN PATHOLOGY LA English DT Article DE classification; histiocytic; leukemia; lymphoma; mast cell; myeloid ID AMERICAN AB Since 1995, the European Association of Pathologists and the Society for Hematopathology have been developing a new World Health Organization (WHO) classification of hematologic malignancies. The classification includes lymphoid, myeloid, histiocytic, and mast cell neoplasms. The WHO project involves 10 committees of pathologists, who have developed Lists and definitions of disease entities. A Clinical Advisory Committee of international hematologists and oncologists was formed to ensure that the classification will be useful to clinicians. A meeting was held in November 1997 to discuss clinical issues related to the classification. The WHO has adopted the Revised European-American Classification of Lymphoid Neoplasms, published in 1994 by the International Lymphoma Study Group, as the classification of lymphoid neoplasms. This approach to classification is based on the principle that a classification is a list of "real" disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one "gold standard." The WHO classification has applied the principles of the Revised European-American Classification of Lymphoid Neoplasms to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. The Clinical Advisory Committee meeting, which was organized around a series of clinical questions, was able to reach a consensus on most of the questions posed. The questions and the consensus are discussed in detail in this article. Among other things, the Clinical Advisory Committee concluded that clinical grouping of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors such as the international prognostic index. The experience of developing the WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world. This should facilitate progress in the understanding and treatment of hematologic malignancies. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Hotel Dieu, Paris, France. Hop Necker Enfants Malad, Paris, France. Univ Wurzburg, Wurzburg, Germany. Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. St Bartholomews Hosp, Dept Med Oncol, London, England. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Harris, NL (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,Fruit St, Boston, MA 02114 USA. NR 4 TC 288 Z9 306 U1 1 U2 3 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 FEB PY 2000 VL 13 IS 2 BP 193 EP 207 DI 10.1038/modpathol.3880035 PG 15 WC Pathology SC Pathology GA 286BF UT WOS:000085423200014 PM 10697278 ER PT J AU Sherman, ME Schiffman, M AF Sherman, ME Schiffman, M TI Correspondence Re: Sherman ME, Tabbara SO, Scott DR, Kurman RJ, Glass AG, Manos MM, et al. "Ascus, rule out HSIL": Cytologic features, histologic correlates, and human papillomavirus detection. Mod Pathol 1999;12 : 335-42. - In reply SO MODERN PATHOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Sherman, ME (reprint author), NCI, 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 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2000 VL 13 IS 2 BP 209 EP 209 PG 1 WC Pathology SC Pathology GA 286BF UT WOS:000085423200016 ER PT J AU Wang, WG Furneaux, H Cheng, HM Caldwell, MC Hutter, D Liu, YS Holbrook, N Gorospe, M AF Wang, WG Furneaux, H Cheng, HM Caldwell, MC Hutter, D Liu, YS Holbrook, N Gorospe, M TI HuR regulates p21 mRNA stabilization by UV light SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-BINDING PROTEIN; AU-RICH ELEMENTS; 3' UNTRANSLATED REGION; MESSENGER-RNA; P53-INDEPENDENT INDUCTION; SERUM STIMULATION; LEUKEMIC-CELLS; NUCLEAR EXPORT; ELAV PROTEIN; IN-VITRO AB Expression of the cyclin-dependent kinase inhibitor p21 is highly induced by many stresses, including exposure to short-wavelength UV light (WC), which increases p21 mRNA stability. Investigation into the mechanisms underlying this stabilization process repealed that proteins present in cytoplasmic lysates of human RKO colorectal carcinoma cells formed complexes with p21 mRNA that were inducible by treatment with UVC and other stress agents. The ubiquitous Elav-type RNA-binding protein HuR was identified within the p21 mRNA-protein complexes, as antibodies recognizing HuR supershifted these complexes and revealed HuR-immunoreactive proteins complexing with p21 mRNA on Western blots. Lowering of endogenous HuR levels through expression of antisense HuR decreased p21 RNA-protein complexes, greatly reduced the UVC inducibility and half-life of p21 mRNA, and prevented UVC-mediated induction of luciferase activity in p21 3' untranslated region-containing reporter constructs. Our findings indicate that HuR plays a major role in regulating stress-induced p21 expression by enhancing p21 mRNA stability and that these effects are coupled to HuR's elevated presence in the cytoplasm. C1 NIA, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Therapeut, New York, NY 10021 USA. RP Gorospe, M (reprint author), NIA, Biol Chem Lab, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Liu, Yusen/E-3527-2011 NR 67 TC 384 Z9 389 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2000 VL 20 IS 3 BP 760 EP 769 DI 10.1128/MCB.20.3.760-769.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273XD UT WOS:000084733900004 PM 10629032 ER PT J AU Greenwel, P Tanaka, S Penkov, D Zhang, W Olive, M Moll, J Vinson, C Di Liberto, M Ramirez, F AF Greenwel, P Tanaka, S Penkov, D Zhang, W Olive, M Moll, J Vinson, C Di Liberto, M Ramirez, F TI Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TRANSCRIPTION FACTOR; GENE-EXPRESSION; ACTIVATION; CYTOKINES; PROMOTER; CELLS; C/EBP AB Extracellular matrix (ECM) formation and remodeling are critical processes for proper morphogenesis, organogenesis, and tissue repair. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits ECM accumulation by stimulating the expression of matrix proteolytic enzymes and by downregulating the deposition of structural macromolecules such as type I collagen. Stimulation of ECM degradation has been linked to prolonged activation of jun gene expression by the cytokine. Here we demonstrate that TNF-alpha inhibits transcription of the gene coding for the alpha 2 chain of type I collagen [alpha 2(I) collagen] in cultured fibroblasts by stimulating the synthesis and binding of repressive CCAAT/enhancer proteins (C/EBPs) to a previously identified TNF-alpha-responsive element, This conclusion was based on the concomitant identification of C/EBP beta and C/EBP delta as TNF-alpha-induced factors by biochemical purification and expression library screening. It was further supported by the ability of the C/EBP-specific dominant-negative (DN) protein to block TNF-alpha inhibition of alpha 2(I) collagen but not TNF-alpha stimulation of the MMP-13 protease. The DN protein also blocked TNF-alpha downregulation of the gene coding for the alpha 1 chain of type I collagen. The study therefore implicates repressive C/EBPs in the TNF-alpha-induced signaling pathway that controls ECM formation and remodeling. C1 NYU, Mt Sinai Sch Med, Dept Biochem & Mol Biol, Brookdale Ctr, New York, NY 10029 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA. RP Ramirez, F (reprint author), NYU, Mt Sinai Sch Med, Dept Biochem & Mol Biol, Brookdale Ctr, New York, NY 10029 USA. FU NIAAA NIH HHS [AA12196]; NIAMS NIH HHS [AR38648, R01 AR038648, R37 AR038648] NR 23 TC 112 Z9 114 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2000 VL 20 IS 3 BP 912 EP 918 DI 10.1128/MCB.20.3.912-918.2000 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273XD UT WOS:000084733900020 PM 10629048 ER PT J AU Chen, M Cheng, A Candotti, F Zhou, YJ Hymel, A Fasth, A Notarangelo, LD O'Shea, JJ AF Chen, M Cheng, A Candotti, F Zhou, YJ Hymel, A Fasth, A Notarangelo, LD O'Shea, JJ TI Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: Evidence for interactions between the kinase and pseudokinase domains SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; PROTEIN-TYROSINE KINASES; COMMON GAMMA-CHAIN; MICE LACKING JAK3; IL-2 RECEPTOR; REQUIRES PHOSPHORYLATION; LYMPHOID DEVELOPMENT; SIGNAL-TRANSDUCTION; STAT PATHWAYS; JANUS KINASES AB The structure of Janus kinases (JAKs) is unique among protein tyrosine kinases in having tandem, nonidentical kinase and pseudokinase domains. Despite its conservation in evolution, however, the function of the pseudokinase domain remains poorly understood. Lack of JAK3 expression results in severe combined immunodeficiency (SCID). In this study, we analyze two SCID patients with mutations in the JAK3 pseudokinase domain, which allows for protein expression but disrupts the regulation of the kinase activity. Specifically, these mutant forms of JAK3 had undetectable kinase activity in vitro but were hyperphosphorylated both in patients' Epstein-Barr virus-transformed B cells and when overexpressed in COS7 cells. Moreover, reconstitution of cells with these mutants demonstrated that, although they were constitutively phosphorylated basally, they were unable to transmit cytokine-dependent signals. Further analysis showed that the isolated catalytic domain of JAK3 was functional whereas either the addition of the pseudokinase domain or its deletion from the full-length molecule reduced catalytic activity. Through coimmunoprecipitation of the isolated pseudokinase domain with the isolated catalytic domain, we provide the first evidence that these two domains interact. Furthermore, whereas the wild-type pseudokinase domain modestly inhibited kinase domain-mediated STAT5 phosphorylation, the patient-derived mutants markedly inhibited this phosphorylation. We thus conclude that the JAK3 pseudokinase domain is essential for JAK3 function by regulating its catalytic activity and autophosphorylation. We propose a model in which this occurs via intramolecular interaction with the kinase domain and that increased inhibition of kinase activity by the pseudokinase domain likely contributes to the disease pathogenesis in these two patients. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Univ Brescia, Dept Pediat, I-25123 Brescia, Italy. Univ Gothenburg, Dept Pediat, SE-41685 Gothenburg, Sweden. RP Chen, M (reprint author), NIAMS, LCBS, ARB, NIH, 10-9N262,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. RI Notarangelo, Luigi/F-9718-2016 OI Notarangelo, Luigi/0000-0002-8335-0262 FU Telethon [E.0668] NR 46 TC 80 Z9 84 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2000 VL 20 IS 3 BP 947 EP 956 DI 10.1128/MCB.20.3.947-956.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273XD UT WOS:000084733900024 PM 10629052 ER PT J AU Faruqi, AF Datta, HJ Carroll, D Seidman, MM Glazer, PM AF Faruqi, AF Datta, HJ Carroll, D Seidman, MM Glazer, PM TI Triple-helix formation induces recombination in mammalian cells via a nucleotide excision repair-dependent pathway SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID INTRACHROMOSOMAL HOMOLOGOUS RECOMBINATION; XENOPUS-LAEVIS OOCYTES; DOUBLE-STRAND BREAKS; WILD-TYPE P53; CROSS-LINKS; MISMATCH REPAIR; SHUTTLE VECTOR; EXTRACHROMOSOMAL RECOMBINATION; MICROSATELLITE INSTABILITY; SACCHAROMYCES-CEREVISIAE AB The ability to stimulate recombination in a site-specific manner in mammalian cells may provide a useful tool for gene knockout and a valuable strategy for gene therapy. We previously demonstrated that psoralen adducts targeted by triple-helix-forming oligonucleotides (TFOs) could induce recombination between tandem repeats of a supF reporter gene in a simian virus 40 vector in monkey COS cells. Based on work showing that triple helices, even in the absence of associated psoralen adducts, are able to provoke DNA repair and cause mutations, we asked whether intermolecular triplexes could stimulate recombination. Here, we report that triple-helix formation itself is capable of promoting recombination and that this effect is dependent on a functional nucleotide excision repair (NER) pathway. Transfection of COS cells carrying the dual supF vector with a purine-rich TFO, AG30, designed to bind as a third strand to a region between the two mutant supF genes yielded recombinants at a frequency of 0.37%, fivefold above background, whereas a scrambled sequence control oligomer was ineffective. In human cells deficient in the NER factor XPA, the ability of AG30 to induce recombination was eliminated, but it was restored in a corrected subline expressing the XPA cDNA, In comparison; the ability of tripler-directed psoralen cross-links to induce recombination was only partially reduced in XPA-deficient cells, suggesting that NER is not the only pathway that can metabolize targeted psoralen photoadducts into recombinagenic intermediates. Interestingly, the tripler-induced recombination was unaffected in cells deficient in DNA mismatch repair, challenging our previous model of a heteroduplex intermediate and supporting a model based on end joining. This work demonstrates that oligonucleotide-mediated tripler formation can be recombinagenic, providing the basis fur a potential strategy to direct genome modification by using high-affinity DNA binding ligands. C1 Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84132 USA. NIA, NIH, Baltimore, MD 21224 USA. RP Glazer, PM (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, POB 208040, New Haven, CT 06520 USA. FU NIGMS NIH HHS [GM54731, R01 GM054731] NR 65 TC 100 Z9 102 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2000 VL 20 IS 3 BP 990 EP 1000 DI 10.1128/MCB.20.3.990-1000.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273XD UT WOS:000084733900028 PM 10629056 ER PT J AU Angeloni, D Wei, MH Duh, FM Johnson, BE Lerman, MI AF Angeloni, D Wei, MH Duh, FM Johnson, BE Lerman, MI TI A G-to-A single nucleotide polymorphism in the human Alpha 2 Delta 2 calcium channel subunit gene that maps at chromosome 3p21.3 SO MOLECULAR AND CELLULAR PROBES LA English DT Article DE Alpha 2 Delta subunit 2 calcium channel gene; single nucleotide polymorphism (SNP); loss of heterozygosity LOH; lung cancer C1 Natl Canc Inst, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. USN, Natl Canc Inst, Med Branch, NIH, Bethesda, MD 20892 USA. RP Angeloni, D (reprint author), Natl Canc Inst, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 3 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD FEB PY 2000 VL 14 IS 1 BP 53 EP 54 DI 10.1006/mcpr.1999.0277 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 296XY UT WOS:000086053100008 PM 10722793 ER PT J AU Gonzalez, DS Jordan, IK AF Gonzalez, DS Jordan, IK TI The alpha-mannosidases: Phylogeny and adaptive diversification SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE alpha-mannosidase; glycoside hydrolase; gene duplication; positive selection; adaptation ID SEQUENCE-BASED CLASSIFICATION; GLYCOSYL HYDROLASES; GENE DUPLICATION; GLYCOPROTEIN-BIOSYNTHESIS; MOLECULAR EVOLUTION; GOLGI MEMBRANES; FAMILIES; DROSOPHILA; EXPRESSION; SELECTION AB alpha-Mannosidase enzymes comprise a class of gylcoside hydrolases involved in the maturation and degradation of glycoprotein-linked oligosaccharides. Various alpha-mannosidase enzymatic activities are encoded by an ancient and ubiquitous gene superfamily. A comparative sequence analysis was employed here to characterize the evolutionary relationships and dynamics of the alpha-mannosidase superfamily. A series of lineage-specific BLAST searches recovered the first ever recognized archaean and eubacterial alpha-mannosidase sequences, in addition to numerous eukaryotic sequences. Motif-based alignment and subsequent phylogenetic analysis of the entire superfamily revealed the presence of three well-supported monophyletic clades that represent discrete alpha-mannosidase families. The comparative method was used to evaluate the phylogenetic distribution of alpha-mannosidase functional variants within families. Results of this analysis demonstrate a pattern of functional diversification of alpha-mannosidase paralogs followed by conservation of function among orthologs. Nucleotide polymorphism among the most closely related pair of duplicated genes was analyzed to evaluate the role of natural selection in the functional diversification of alpha-mannosidase paralogs. Ratios of nonsynonymous and synonymous variation show an increase in the rate of nonsynonymous change after duplication and a relative excess of fixed nonsynonymous changes between the two groups of paralogs. These data point to a possible role for positive Darwinian selection in the evolution of alpha-mannosidase functional diversification following gene duplication. C1 Univ Georgia, Dept Med Microbiol, Athens, GA 30602 USA. Univ Nevada, Dept Biol Sci, Las Vegas, NV 89154 USA. RP Jordan, IK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A, Bethesda, MD 20894 USA. NR 50 TC 25 Z9 27 U1 3 U2 5 PU SOC MOLECULAR BIOLOGY EVOLUTION PI LAWRENCE PA PO BOX 1897, LAWRENCE, KS 66044-8897 USA SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD FEB PY 2000 VL 17 IS 2 BP 292 EP 300 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 281BX UT WOS:000085139200009 PM 10677852 ER PT J AU Yu, MS Ryu, DY Snyderwine, EG AF Yu, MS Ryu, DY Snyderwine, EG TI Genomic imbalance in rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine SO MOLECULAR CARCINOGENESIS LA English DT Article DE PhIP; mammary gland; rat ID SPRAGUE-DAWLEY RATS; LOBULAR BREAST CANCERS; MICROSATELLITE INSTABILITY; HETEROCYCLIC AMINES; E-CADHERIN; MUTATOR PHENOTYPE; SUPPRESSOR GENE; BETA-CATENIN; DIETARY-FAT; APC GENE AB 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhlP), a compound found in cooked meat, is a mammary gland carcinogen in female Sprague-Dawley rats. PhlP-induced rat mammary gland carcinomas were examined for mutations in several genes (exons) known to regulate cell growth and apoptosis, including p53 (4-8), p21(Waf1) (coding region), Apc(14, 15), B-catenin (3), E-cadherin (9,13,15), Bcl-x(coding region), Bar (3), IGFIIR (28), and TGFBIIR (3). DNA from 30 carcinomas was examined by single-strand conformation polymorphism analysis, but no mutations were detected in these genes or gene regions. DNA from carcinomas and matching normal tissue were further screened for allelic imbalance by using a polymerase chain reaction-based approach with primers to known microsatellite regions located throughout the rat genome. Of 53 markers examined, 12 revealed allelic imbalance. Microsatellite instability (MSI) was detected at two markers, one an chromosome 4 and one on chromosome 6. Sixty-five percent and 96% of all carcinomas examined (N=23) showed MSI at these loci on chromosomes 4 and 6, respectively, supporting the notion that MSI plays a role in PhlP-induced mammary carcinogenesis. Loss of heterozygosity (LOH), an indication of a possible tumor suppressor gene, was observed at 10 markers distributed on chromosomes 3, 10, 11, 14, and X. The frequency of LOH at these markers was 75-94%, supporting that the regions of allelic imbalance were largely similar for the PhlP-induced carcinomas examined in this study. When PhlP-induced carcinomas from rats placed on high-fat and low-fat diet were compared, no unique regions of allelic imbalance or statistical differences in the frequency of allelic imbalance were observed. Therefore, the high-fat diet, known to be a promoter of PhlP-induced rat mammary carcinogenesis, did not appear to influence allelic imbalance in the carcinomas. Interestingly, 7,12-dimethylbenz[a]anthracene-induced mammary carcinomas did not show allelic imbalance at 11 of the 12 loci that showed allelic imbalance in PhlP-induced carcinomas. These findings suggest that distinct chemical carcinogens induce different patterns of allelic imbalance during rat mammary carcinogenesis. Since several of the known genes involved in carcinogenesis did not harbor mutations in PhlP-induced carcinomas, further studies are needed to clarify the critical genes involved in PhlP-induced mammary carcinogenesis and to determine whether regions of LOH harbor potentially novel tumor suppressor genes involved in this disease. (C) 2000 Wiley-Liss, Inc. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Bldg 37,Room 3C28,37 Convent Dr MSC-4255, Bethesda, MD 20892 USA. NR 53 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2000 VL 27 IS 2 BP 76 EP 83 DI 10.1002/(SICI)1098-2744(200002)27:2<76::AID-MC3>3.0.CO;2-7 PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 282TG UT WOS:000085234300003 PM 10657900 ER PT J AU Gaiotti, D Chung, J Iglesias, M Nees, M Baker, PD Evans, CH Woodworth, CD AF Gaiotti, D Chung, J Iglesias, M Nees, M Baker, PD Evans, CH Woodworth, CD TI Tumor necrosis factor-alpha promotes human papillomavirus (HPV) E6/E7 RNA expression and cyclin-dependent kinase activity in HPV-immortalized keratinocytes by a ras-dependent pathway SO MOLECULAR CARCINOGENESIS LA English DT Article DE tumor necrosis factor; human papillomavirus; keratinocyte; ras; epidermal growth factor receptor ID GROWTH-FACTOR RECEPTOR; NIH 3T3 CELLS; EPITHELIAL-CELLS; CERVICAL-CARCINOMA; AUTONOMOUS GROWTH; GENE-MUTATIONS; UTERINE CERVIX; OVARIAN-CANCER; TYPE-18 E6; PROLIFERATION AB Tumor necrosis factor-alpha (TNF-alpha) inhibits growth of normal cervical keratinocytes but stimulates proliferation of human papillomavirus (HPV)-immortalized and cervical carcinoma-derived cell lines when mitogens such as epidermal growth factor (EGF) or serum are depleted. Current work identifies the mechanism of growth stimulation. TNF-alpha promoted cell cycle progression by increasing expression of HPV-16 E6/E7 RNA5 and enhancing activity of cyclin-dependent kinase (cdk)2 and cdc2 after 3 d. Increased kinase activity was mediated by upregulation of cyclins A and B and decreases in cdk inhibitors p21(Waf) and p27(kip). TNF-alpha stimulated these changes in part by increasing transcription and stabilization of RNA for amphiregulin, an EGF receptor ligand, and amphiregulin directly increased HPV-16 E6/E7 and cyclin A RNAs. To define which components of the EGF receptor signaling pathway were important, HPV-immortalized cells were transfected with activated or dominant negative mutants of Ha-ras, raf, or MAPKK. Expression of activated Ha-ras maintained HPV-16 and cyclin gene expression and promoted rapid growth in the absence of EGF. Furthermore, ras activation was necessary for TNF-alpha mitogenesis as transfection with a dominant negative ras mutant (Asn-17) strongly inhibited growth. Thus, activation of ras promotes expression of HPV-16 E6/E7 RNAs, induces cyclins A and B, and mediates growth stimulation of immortal keratinocytes by TNF-alpha. These studies define a pathway by which ras mutations, which occur in a subset of cervical cancers, may contribute to pathogenesis. Published by Wiley-Liss, Inc. C1 NCI, Biol Lab, Bethesda, MD 20892 USA. RP Woodworth, CD (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37-3B26,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 55 TC 42 Z9 45 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2000 VL 27 IS 2 BP 97 EP 109 DI 10.1002/(SICI)1098-2744(200002)27:2<97::AID-MC5>3.0.CO;2-V PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 282TG UT WOS:000085234300005 PM 10657902 ER PT J AU Liu, JH He, LS Collins, I Ge, H Libutti, D Li, JF Egly, JM Levens, D AF Liu, JH He, LS Collins, I Ge, H Libutti, D Li, JF Egly, JM Levens, D TI The FBP interacting repressor targets TFIIH to inhibit activated transcription SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; FAR UPSTREAM ELEMENT; BARR-VIRUS NUCLEAR-PROTEIN-2; TATA-BINDING PROTEIN; C-MYC; BASAL TRANSCRIPTION; TERMINAL DOMAIN; IN-VIVO; DNA; TRANSACTIVATOR AB FUSE-binding protein (FBP) binds the single-stranded far upstream element of active c-myc genes, possesses potent transcription activation and repression domains, and is necessary for c-myc expression. A novel 60 kDa protein, the FBP interacting repressor (FIR), blocked activator-dependent, but not basal, transcription through TFIIH. Recruited through FBP's nucleic acid-binding domain, FIR formed a ternary complex with FBP and FUSE. FIR repressed a c-myc reporter via the FUSE. The amino terminus of FIR contained an activator-selective repression domain capable of acting in cis or even in trans in vivo and in vitro. The repression domain of FIR targeted only TFIIH's p89/XPB helicase, required at several stages in transcription, but not factors required for promoter selection. Thus, FIR locks TFIIH in an activation-resistant configuration that still supports basal transcription. C1 NCI, Gene Regulat Sect, Pathol Lab, Bethesda, MD 20892 USA. NICHHD, Mol Embryol Lab, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, Metab Regulat Sect, Bethesda, MD 20892 USA. ULP, CNRS, INSERM, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch, France. RP Levens, D (reprint author), NCI, Gene Regulat Sect, Pathol Lab, Bethesda, MD 20892 USA. RI Levens, David/C-9216-2009; OI Levens, David/0000-0002-7616-922X; Li, Junfa/0000-0002-1930-9724 NR 60 TC 100 Z9 108 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD FEB PY 2000 VL 5 IS 2 BP 331 EP 341 DI 10.1016/S1097-2765(00)80428-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 289WN UT WOS:000085645100013 PM 10882074 ER PT J AU Deuring, R Fanti, L Armstrong, JA Sarte, M Papoulas, O Prestel, M Daubresse, G Verardo, M Moseley, SL Berloco, M Tsukiyama, T Wu, C Pimpinelli, S Tamkun, JW AF Deuring, R Fanti, L Armstrong, JA Sarte, M Papoulas, O Prestel, M Daubresse, G Verardo, M Moseley, SL Berloco, M Tsukiyama, T Wu, C Pimpinelli, S Tamkun, JW TI The ISWI chromatin-remodeling protein is required for gene expression and the maintenance of higher order chromatin structure in vivo SO MOLECULAR CELL LA English DT Article ID DROSOPHILA GAGA FACTOR; RNA-POLYMERASE-II; DOSAGE COMPENSATION; BINDING PROTEIN; IN-VITRO; TRANSCRIPTION; YEAST; MELANOGASTER; ENCODES; ACTIVATOR AB Drosophila ISWI, a highly conserved member of the SW12/SNF2 family of ATPases, is the catalytic subunit of three chromatin-remodeling complexes: NURF, CHRAC, and ACF. To clarify the biological functions of ISWI, we generated and characterized null and dominant-negative ISWI mutations. We found that ISWI mutations affect both cell viability and gene expression during Drosophila development. ISWI mutations also cause striking alterations in the structure of the male X chromosome. The ISWI protein does not colocalize with RNA Pol II on salivary gland polytene chromosomes, suggesting a possible role for ISWI in transcriptional repression. These findings reveal novel functions for the ISWI ATPase and underscore its importance in chromatin remodeling in vivo. C1 Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ La Sapienza, Fdn Cenci Bolognetti, Ist Pasteur, I-00185 Rome, Italy. Univ La Sapienza, Dipartimento Genet & Biol Mol, I-00185 Rome, Italy. Univ Bari, Ist Genet, I-70126 Bari, Italy. RP Tamkun, JW (reprint author), Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA. OI Berloco, Maria/0000-0003-3826-8427 FU NIGMS NIH HHS [GM49883] NR 58 TC 260 Z9 266 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD FEB PY 2000 VL 5 IS 2 BP 355 EP 365 DI 10.1016/S1097-2765(00)80430-X PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 289WN UT WOS:000085645100015 PM 10882076 ER PT J AU Maor, SB Abramovitch, S Erdos, MR Brody, LC Werner, H AF Maor, SB Abramovitch, S Erdos, MR Brody, LC Werner, H TI BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: Potential interaction between BRCA1 and Sp1 SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE IGF-I receptor; BRCA1; tumor suppressor; Sp1 ID HUMAN-BREAST-CANCER; GENE-PRODUCT; TRANSCRIPTIONAL ACTIVATION; SOMATOMEDIN RECEPTOR; WILMS-TUMOR; CELL-CYCLE; EXPRESSION; INHIBITION; REGION; WT1 AB The insulin-like growth factor I receptor (IGF-I-R) has an important role in breast cancer etiology. The receptor is overexpressed by most breast cancers, where it functions as a potent antiapoptotic agent. BRCA1 is a tumor suppressor gene that is mutated in a large fraction of familial breast and ovarian cancers. Cotransfection of Saos-2, MCF7, and CHO cells with IGF-I-R promoter constructs driving luciferase reporter genes, and with a BRCA1 expression vector, suppressed promoter activity in a dose-dependent manner. Functional interactions between BRCA1 and Sp1 in the regulation of the IGF-I-R gene were studied in Schneider cells, a Drosophila cell line which lacks endogenous Spl. In these cells BRCA1 suppressed 45% of the Spl-induced trans-activation of the IGF-I-R promoter. These results suggest that BRCA1 is capable of suppressing the IGF-I-B promoter in a number of cell lines, thus resulting in low levels of receptor mRNA and protein. Mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF-I-R promoter. Activation of the over-expressed receptor by locally produced or circulating IGFs mag be a crucial step in breast and ovarian cancer progression. (C) 2000 Academic Press. C1 Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Werner, H (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. NR 47 TC 56 Z9 58 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 FEB PY 2000 VL 69 IS 2 BP 130 EP 136 DI 10.1006/mgme.1999.2958 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 299TF UT WOS:000086213400006 PM 10720440 ER PT J AU Winter, DB Phung, QH Wood, RD Gearhart, PJ AF Winter, DB Phung, QH Wood, RD Gearhart, PJ TI Differential expression of DNA polymerase epsilon in resting and activated B lymphocytes is consistent with an in vivo role in replication and not repair SO MOLECULAR IMMUNOLOGY LA English DT Article DE B lymphocytes; resting; activated; DNA polymerases; replication; repair ID BASE-EXCISION-REPAIR; FULL-LENGTH CDNA; SACCHAROMYCES-CEREVISIAE; CATALYTIC SUBUNIT; MOLECULAR-CLONING; CHROMOSOMAL LOCALIZATION; NUCLEOTIDE-SEQUENCE; INDUCED MUTAGENESIS; GERMINAL-CENTERS; MESSENGER-RNA AB DNA polymerases may be differentially expressed by cells during periods of quiescence and proliferation. Murine B cells are an ideal population to study because their division time varies widely in vivo, and different subsets can be easily isolated. Consequently, we analyzed RNA from resting cells (B220(+) peanut agglutinin(-)) and activated germinal center cells (B220(+) peanut agglutinin(+)) from spleens by reverse transcriptase-PCR using primers for five nuclear polymerases and their associated subunits. Gel analyses of the amplified products showed that the rapidly-dividing germinal center B cells expressed DNA polymerases alpha, beta, delta, epsilon, and zeta. The resting B cells did not express polymerases alpha or epsilon at detectable levels, although they did express polymerases beta, delta, and zeta. Thus, polymerase epsilon, as well as alpha, appears to have a primary role in chromosomal replication of murine B lymphocytes. Further, the lack of expression of polymerase epsilon in resting cells indicates that this enzyme is not used in any DNA repair pathways by these cells. The expression of polymerase zeta by resting cells suggests that it has another role in DNA repair, perhaps recombination, in addition to its function of bypassing damage during chromosomal replication. Published by Elsevier Science Ltd. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD 21205 USA. Imperial Canc Res Fund, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. RP Gearhart, PJ (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Wood, Richard/E-7855-2011 OI Wood, Richard/0000-0002-9495-6892 NR 39 TC 10 Z9 10 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB-MAR PY 2000 VL 37 IS 3-4 BP 125 EP 131 DI 10.1016/S0161-5890(00)00040-7 PG 7 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 329JK UT WOS:000087903700004 PM 10865111 ER PT J AU Ippolito, G Rezza, G Girardi, E Malkovsky, M Cairns, JD AF Ippolito, G Rezza, G Girardi, E Malkovsky, M Cairns, JD TI HIV infections: The global epidemiology and goals for vaccine research SO MOLECULAR MEDICINE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; SHORT-COURSE ZIDOVUDINE; NEUTRALIZING ANTIBODIES; SEXUAL TRANSMISSION; IMMUNE-RESPONSE; CELL RESPONSES; AIDS VACCINES; ANTIRETROVIRAL THERAPY; UNINFECTED VOLUNTEERS C1 Univ Wisconsin, Sch Med, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. IRCCS Osped Lazzaro Spallanzani, Serv Epidemiol Malattie Infett, Ctr Riferimento AIDS, Rome, Italy. Ist Super Sanita, Ctr Operat AIDS, I-00161 Rome, Italy. NIAID, Targeted Intervent Branch, Div AIDS, Bethesda, MD 20892 USA. RP Malkovsky, M (reprint author), Univ Wisconsin, Sch Med, Dept Med Microbiol & Immunol, 1300 univ Ave, Madison, WI 53706 USA. RI REZZA, GIOVANNI/D-4393-2016 OI REZZA, GIOVANNI/0000-0003-0268-6790 NR 108 TC 2 Z9 2 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD FEB PY 2000 VL 6 IS 2 BP 69 EP 85 PG 17 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 315JQ UT WOS:000087110900002 PM 10859024 ER PT J AU Casjens, S Palmer, N van Vugt, R Huang, WM Stevenson, B Rosa, P Lathigra, R Sutton, G Peterson, J Dodson, RJ Haft, D Hickey, E Gwinn, M White, O Fraser, CM AF Casjens, S Palmer, N van Vugt, R Huang, WM Stevenson, B Rosa, P Lathigra, R Sutton, G Peterson, J Dodson, RJ Haft, D Hickey, E Gwinn, M White, O Fraser, CM TI A bacterial genome in flux: the twelve linear and nine circular extrachromosomal DNAs in an infectious isolate of the Lyme disease spirochete Borrelia burgdorferi SO MOLECULAR MICROBIOLOGY LA English DT Review ID SURFACE PROTEIN-C; RIBOSOMAL-RNA GENES; FIELD GEL-ELECTROPHORESIS; OPEN READING FRAMES; SENSU LATE STRAINS; SEQUENCE-ANALYSIS; NUCLEOTIDE-SEQUENCE; ANTIGENIC VARIATION; UNITED-STATES; OSPC GENE AB We have determined that Borrelia burgdorferi strain B31 MI carries 21 extrachromosomal DNA elements, the largest number known for any bacterium. Among these are 12 linear and nine circular plasmids, whose sequences total 610 694 bp, We report here the nucleotide sequence of three linear and seven circular plasmids (comprising 290 546 bp) in this infectious isolate. This completes the genome sequencing project for this organism; its genome size is 1 521 419 bp (plus about 2000 bp of undetermined telomeric sequences). Analysis of the sequence implies that there has been extensive and sometimes rather recent DNA rearrangement among a number of the linear plasmids, Many of these events appear to have been mediated by recombinational processes that formed duplications. These many regions of similarity are reflected in the fact that most plasmid genes are members of one of the genome's 161 paralogous gene families; 107 of these gene families, which vary in size from two to 41 members, contain at least one plasmid gene. These rearrangements appear to have contributed to a surprisingly large number of apparently non-functional pseudogenes, a very unusual feature for a prokaryotic genome. The presence of these damaged genes suggests that some of the plasmids may be in a period of rapid evolution. The sequence predicts 535 plasmid genes greater than or equal to 300 bp in length that may be intact and 167 apparently mutationally damaged and/or unexpressed genes (pseudogenes), The large majority, over 90%, of genes on these plasmids have no convincing similarity to genes outside Borrelia, suggesting that they perform specialized functions. C1 Univ Utah, Sch Med, Dept Oncol Sci, Div Mol Biol & Genet, Salt Lake City, UT 84132 USA. Univ Kentucky, Coll Med, Dept Microbiol & Immunol, Lexington, KY 40536 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. Medimmune Inc, Gaithersburg, MD 20878 USA. Inst Genom Res, Rockville, MD 20850 USA. RP Casjens, S (reprint author), Univ Utah, Sch Med, Dept Oncol Sci, Div Mol Biol & Genet, Salt Lake City, UT 84132 USA. EM sherwood.casjens@hci.utah.edu OI Fraser, Claire/0000-0003-1462-2428 NR 143 TC 500 Z9 514 U1 3 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2000 VL 35 IS 3 BP 490 EP 516 DI 10.1046/j.1365-2958.2000.01698.x PG 27 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 285BF UT WOS:000085367800002 PM 10672174 ER PT J AU Martin, RG Gillette, WK Rosner, JL AF Martin, RG Gillette, WK Rosner, JL TI Promoter discrimination by the related transcriptional activators MarA and SoxS: differential regulation by differential binding SO MOLECULAR MICROBIOLOGY LA English DT Article ID MULTIPLE-ANTIBIOTIC-RESISTANCE; SUPEROXIDE RESPONSE REGULON; ESCHERICHIA-COLI K-12; DNA-BINDING; INDUCIBLE GENES; STRESS GENES; EFFLUX PUMP; PROTEIN; OPERON; LOCUS AB MarA and SoxS are closely related proteins (approximate to 45% identical) that transcriptionally activate a common set of unlinked genes, resulting in multiple antibiotic and superoxide resistance in Escherichia coli. Both proteins bind as monomers to a 20 bp degenerate asymmetric recognition sequence, the 'marbox', located upstream of the promoter. However, the proteins differ widely in the extents to which they activate particular promoters, with the consequence that overexpression of SoxS leads to greater superoxide resistance than does overexpression of MarA, This 'discrimination' between activators by promoters was demonstrated in vivo, using promoters fused to lacZ, and in vitro, using purified RNA polymerase, promoter DNA and MarA or SoxS, The marbox was found to be a critical element in discrimination by in vivo and in vitro assays of hybrid promoters containing the marbox from one gene and the core promoter from another. Furthermore, by sequential mutation of its marbox, a promoter that discriminated 35-fold in favour of SoxS was converted into one that did not discriminate. The relative activation of a promoter by MarA or SoxS was paralleled by the relative binding of the two activators to the promoter's marbox as assayed by band shift experiments. Thus, differential recognition of closely related marbox sequences by the closely related activators is the primary basis for promoter discrimination. Discrimination enables the cell to customize its response to the stresses that trigger synthesis of the activators. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, RG (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Rm 333, Bethesda, MD 20892 USA. EM rgmartin@helix.nih.gov NR 36 TC 73 Z9 75 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2000 VL 35 IS 3 BP 623 EP 634 DI 10.1046/j.1365-2958.2000.01732.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 285BF UT WOS:000085367800012 PM 10672184 ER PT J AU Meng, RD McDonald, ER Sheikh, MS Fornace, AJ El-Deiry, WS AF Meng, RD McDonald, ER Sheikh, MS Fornace, AJ El-Deiry, WS TI The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis SO MOLECULAR THERAPY LA English DT Article DE KILLER/DR5; TRUNDD (DcR2, TRAIL-R4); TRID; TRAIL; p53; apoptosis ID NF-KAPPA-B; FADD-DEPENDENT APOPTOSIS; DEATH RECEPTOR; LIGAND TRAIL; CELL-DEATH; MEDIATED APOPTOSIS; MOLECULAR-CLONING; DOMAIN; GROWTH; GENE AB The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p27(WAF1/CIP1). Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments. C1 Univ Penn, Sch Med, Dept Med,Lab Mol Oncol & Cell Cycle Regulat, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Canc, Philadelphia, PA 19104 USA. SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA. NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP El-Deiry, WS (reprint author), Univ Penn, Sch Med, Dept Med,Lab Mol Oncol & Cell Cycle Regulat, Howard Hughes Med Inst, 415 Curie Blvd,CRB 437A, Philadelphia, PA 19104 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X FU NCI NIH HHS [CA09677-06] NR 47 TC 87 Z9 91 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 FEB PY 2000 VL 1 IS 2 BP 130 EP 144 DI 10.1006/mthe.2000.0025 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 366RN UT WOS:000090018500005 PM 10933923 ER PT J AU Otsu, M Anderson, SM Bodine, DM Puck, JM O'Shea, JJ Candotti, F AF Otsu, M Anderson, SM Bodine, DM Puck, JM O'Shea, JJ Candotti, F TI Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem cell gene therapy SO MOLECULAR THERAPY LA English DT Article DE common gamma chain; XSCID; retroviral vector; gene therapy ID RECEPTOR-GAMMA-CHAIN; CHRONIC GRANULOMATOUS-DISEASE; BONE-MARROW CELLS; HEMATOPOIETIC PROGENITOR CELLS; MESSENGER-RNA EXPRESSION; CHROMOSOME INACTIVATION; RETROVIRAL VECTORS; HOST-DEFENSE; T-LYMPHOCYTE; TRANSPLANTATION AB Mutations of the common gamma chain (gammac) of cytokine receptors cause X-linked severe combined immunodeficiency (XSCID), a candidate disease for gene therapy. Using an XSCID murine model, we have tested the feasibility of stem cell gene correction. XSCID bone marrow (BM) cells were transduced with a retroviral vector expressing the murine gammac (m gammac) and engrafted in irradiated XSCID animals. Transplanted mice developed mature B cells, naive T cells, and mature natural killer (NK) cells, all of which were virtually absent in untreated mice. The m gammac transgene was detected in all treated mice, and we could demonstrate m gammac expression in newly developed lymphocytes at both the RNA and protein level. In addition, treated mice showed T cell proliferation responses to mitogens and production of antigen-specific antibodies upon immunization. Four of seven treated animals showed a clear increase of the transgene positive cells, suggesting in vivo selective advantage for gene-corrected cells. Altogether, these results show that retroviral-mediated gene transfer can improve murine XSCID and suggest that similar strategies may prove beneficial in human clinical trials. C1 NIH, NHGRI, Clin Gene Therapy Branch, Bethesda, MD 20892 USA. NIH, NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NIH, NHGRI, Clin Gene Therapy Branch, 10 Ctr Dr,Bldg 10,Rm 10C103,MSC 1851, Bethesda, MD 20892 USA. OI Otsu, Makoto/0000-0002-9769-0217 NR 37 TC 48 Z9 50 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 FEB PY 2000 VL 1 IS 2 BP 145 EP 153 DI 10.1006/mthe.1999.0020 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 366RN UT WOS:000090018500006 PM 10933924 ER PT J AU Bagnato, F Tancredi, A Richert, N Gasperini, C Bastianello, S Bash, C McFarland, H Pozzilli, C Frank, JA AF Bagnato, F Tancredi, A Richert, N Gasperini, C Bastianello, S Bash, C McFarland, H Pozzilli, C Frank, JA TI Contrast-enhanced magnetic resonance activity in relapsing remitting multiple sclerosis patients: a short term natural history study SO MULTIPLE SCLEROSIS LA English DT Article DE relapsing-remitting multiple sclerosis; Gadolinium-enhancing lesions; natural history; treatment trials ID DISEASE-ACTIVITY; GADOLINIUM-DTPA; CLINICAL-TRIALS; MRI; MULTICENTER; METHYLPREDNISOLONE; SENSITIVITY; GUIDELINES; BREAKDOWN; CRITERIA AB Magnetic resonance imaging (MRI) has been used to study the history of multiple sclerosis (MS). We analyze the relationship between MRI activity in the first scan compared to the subsequent five scans, and we evaluate whether a shorter observation period of 3 months may predict the subsequent 3 months. Monthly enhanced MRI was Performed in 103 relapsing remitting (RR) MS patients for 6 months. Thirty-five per cent of patients had on inactive scan on the initial examination. More than 80% of them developed MRI activity during the following 5 months. Eighteen per cent of patients had three consecutive inactive scans; 65% of them had at least one active scan on the subsequent 3 monthly MRI's. The relationship between the first scan and oil subsequent scans demonstrates a clear weakening over time. Eighty-two per cent of patients had at least one active scan during the initial 3 consecutive months, the chance of becoming inactive decreased from 23% to 0% over the subsequent 3 months, according with the mean number of enhancing lesions during the first 3 months. These results suggest that neither a single scan nor a short baseline of 3 months may adequately describe the natural history of disease in on individual RRMS patient. C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Univ Rome La Sapienza, Dept Neurol Sci, Rome, Italy. Univ Padua, Dept Stat Sci, I-35100 Padua, Italy. NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. S Camillo Hosp, Rome, Italy. RP Frank, JA (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. RI Bastianello, Stefano/A-9001-2012; gasperini, claudio/K-5093-2016; OI gasperini, claudio/0000-0002-3959-4067; Bastianello, Stefano/0000-0002-8414-9077 NR 27 TC 5 Z9 5 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2000 VL 6 IS 1 BP 43 EP 49 DI 10.1191/135245800678827437 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 292KZ UT WOS:000085794400008 PM 10694845 ER PT J AU Fritsche, E Pittman, GS Bell, DA AF Fritsche, E Pittman, GS Bell, DA TI Localization, sequence analysis, and ethnic distribution of a 96-bp insertion in the promoter of the human CYP2E1 gene SO MUTATION RESEARCH-GENOMICS LA English DT Article DE cytochrome P450; CYP2E1; promoter region; polymorphism; insertion ID CHLORZOXAZONE HYDROXYLATION; TRICHLOROETHYLENE; 6-HYDROXYLATION; POLYMORPHISMS; METHYLATION; EXPRESSION; ETHANOL; OBESITY; 2E1 C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Bell, DA (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 34 Z9 38 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5726 J9 MUTAT RES-GENOMICS JI Mutat. Res.-Genomics PD FEB PY 2000 VL 432 IS 1-2 BP 1 EP 5 DI 10.1016/S1383-5726(99)00009-6 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 408AA UT WOS:000167303300002 PM 10729706 ER PT J AU Zheng, CY Baum, BJ Iadarola, MJ O'Connell, BC AF Zheng, CY Baum, BJ Iadarola, MJ O'Connell, BC TI Genomic integration and gene expression by a modified adenoviral vector SO NATURE BIOTECHNOLOGY LA English DT Article DE gene therapy; adeno-retrovirus vector ID MURINE LEUKEMIA-VIRUS; NUCLEAR-PORE COMPLEX; RECOMBINANT ADENOVIRUS; RETROVIRAL DNA; CELL-LINE; POL GENE; IN-VIVO; INFECTION; THERAPY; ASSOCIATION AB A replication-deficient recombinant adenovirus encoding luciferase was constructed using 5' and 3' long terminal repeat (LTR) sequences of the Moloney murine leukemia virus, Gene expression was observed in cultured cells in vitro and in submandibular gland, cortex, and caudate nucleus for as long as three months in vivo. The vector integrated randomly into the genome of both dividing and nondividing cells as determined by fluorescence in situ hybridization (FISH) (10-15% of cells in vitro and 5% in rat spleen in vivo), gene walking, Southern hybridization, and polymerase chain reaction (PCR), in the absence of transcomplementing reverse transcriptase or integrase activity. The new vector combines the high titer and versatility of adenoviral vectors with the long-term gene expression and integration of retroviral vectors. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 48 TC 54 Z9 55 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2000 VL 18 IS 2 BP 176 EP 180 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 281FH UT WOS:000085146900024 PM 10657124 ER PT J AU O'Hagan, RC Schreiber-Agus, N Chen, K David, G Engelman, JA Schwab, R Alland, L Thomson, C Ronning, DR Sacchettini, JC Meltzer, P DePinho, RA AF O'Hagan, RC Schreiber-Agus, N Chen, K David, G Engelman, JA Schwab, R Alland, L Thomson, C Ronning, DR Sacchettini, JC Meltzer, P DePinho, RA TI Gene-target recognition among members of the Myc superfamily and implications for oncogenesis SO NATURE GENETICS LA English DT Article ID C-MYC; DNA-BINDING; REPRESSES TRANSCRIPTION; CELL-GROWTH; IN-VIVO; MAX; PROTEIN; DOMAIN; DIFFERENTIATION; NETWORK AB Myc and Mad family proteins regulate multiple biological processes through their capacity to influence gene expression directly. Here we show that the basic regions of Myc and Mad proteins are not functionally equivalent in oncogenesis, have separable E-box-binding activities and engage both common and distinct gene targets. Our data support the view that the opposing biological actions of Myc and Mxi1 extend beyond reciprocal regulation of common gene targets. Identification of differentially regulated gene targets provides a framework for understanding the mechanism through which the Myc superfamily governs the growth, proliferation and survival of normal and neoplastic cells. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NEI NIH HHS [R01EY09300]; NICHD NIH HHS [R01HD28317] NR 37 TC 115 Z9 117 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2000 VL 24 IS 2 BP 113 EP 119 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 280LQ UT WOS:000085104600009 PM 10655054 ER PT J AU Robert-Guroff, M AF Robert-Guroff, M TI IgG surfaces as an important component in mucosal protection SO NATURE MEDICINE LA English DT Editorial Material ID INFECTION C1 NCI, Sect Immune Biol Retroviral Infect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Sect Immune Biol Retroviral Infect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NR 10 TC 47 Z9 47 U1 0 U2 2 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 FEB PY 2000 VL 6 IS 2 BP 129 EP 130 DI 10.1038/72206 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 278YQ UT WOS:000085016900019 PM 10655090 ER PT J AU Nussbaum, R Auburger, G AF Nussbaum, R Auburger, G TI Neurodegeneration in the polyglutamine diseases: Act 1, Scene 1 SO NATURE NEUROSCIENCE LA English DT News Item C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Nussbaum, R (reprint author), Natl Human Genome Res Inst, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2000 VL 3 IS 2 BP 103 EP 104 DI 10.1038/72042 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 292TC UT WOS:000085810300004 PM 10649562 ER PT J AU Li, M Phylip, LH Lees, WE Winther, JR Dunn, BM Wlodaawer, A Kay, J Gustchina, A AF Li, M Phylip, LH Lees, WE Winther, JR Dunn, BM Wlodaawer, A Kay, J Gustchina, A TI The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID HIV PROTEASE INHIBITORS; X-RAY-DIFFRACTION; PLASMODIUM-FALCIPARUM; YEAST; EXPRESSION; SAQUINAVIR; SEQUENCE; CLONING; IA3 AB Aspartic proteinase A from yeast is specifically and potently inhibited by a small protein called IA(3) from Saccharomyces cerevisiae. Although this inhibitor consists of 68 residues, we show that the inhibitory activity resides within the N-terminal half of the molecule. Structures solved at 2.2 and 1.8 Angstrom, respectively, for complexes of proteinase A with full-length IA(3) and with a truncated form consisting only of residues 2-34, reveal an unprecedented mode of inhibitor-enzyme interactions, Neither form of the free inhibitor has detectable intrinsic secondary structure in solution. However, upon contact with the enzyme, residues 2-32 become ordered and adopt a near-perfect alpha-helical conformation. Thus, the proteinase acts as a folding template, stabilizing the helical conformation in the inhibitor, which results in the potent and specific blockage of the proteolytic activity. C1 NCI, FCRDC, Program Struct Biol, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, FCRDC, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. Cardiff Univ, Sch Biosci, Cardiff CF1 3US, S Glam, Wales. Carlsberg Res Lab, Dept Yeast Genet, DK-2500 Copenhagen Valby, Denmark. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Kay, J (reprint author), NCI, FCRDC, Program Struct Biol, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Winther, Jakob/K-4451-2014 OI Winther, Jakob/0000-0001-6995-9154 NR 31 TC 79 Z9 81 U1 2 U2 13 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD FEB PY 2000 VL 7 IS 2 BP 113 EP 117 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 281QV UT WOS:000085173000011 PM 10655612 ER PT J AU Jacobson, L Muglia, LJ Weninger, SC Pacak, K Majzoub, JA AF Jacobson, L Muglia, LJ Weninger, SC Pacak, K Majzoub, JA TI CRH deficiency impairs but does not block pituitary-adrenal responses to diverse stressors SO NEUROENDOCRINOLOGY LA English DT Article DE stress; corticotropin; corticotropin-releasing hormone; adrenal steroids; catecholamines; hypoglycemia; hypovolemia; interleukins ID CORTICOTROPIN-RELEASING FACTOR; PARAVENTRICULAR NUCLEUS; ADRENOCORTICOTROPIN SECRETION; RAT HYPOTHALAMUS; MICE; HORMONE; AXIS; VASOPRESSIN; ACTH; CORTICOSTERONE AB We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress. Copyright (C) 2000 S. Karger AG, Basel. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Program Neurosci, Boston, MA 02115 USA. NINDS, Clin Neurosci Branch, Bethesda, MD 20892 USA. RP Majzoub, JA (reprint author), Childrens Hosp, Div Endocrinol, Enders 4,300 Longwood Ave, Boston, MA 02115 USA. NR 43 TC 46 Z9 46 U1 0 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD FEB PY 2000 VL 71 IS 2 BP 79 EP 87 DI 10.1159/000054524 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 289AQ UT WOS:000085597500001 PM 10686522 ER PT J AU Haxby, JV Petit, L Ungerleider, LG Courtney, SM AF Haxby, JV Petit, L Ungerleider, LG Courtney, SM TI Distinguishing the functional roles of multiple regions in distributed neural systems for visual working memory SO NEUROIMAGE LA English DT Article ID PRIMATE PREFRONTAL CORTEX; POSITRON EMISSION TOMOGRAPHY; SUSTAINED ACTIVITY; FRONTAL-CORTEX; MEDIAL WALL; PET; ACTIVATION; LOCATION; OBJECT; HUMANS AB We have investigated the human neural systems for visual working memory using functional magnetic resonance imaging to distinguish sustained activity during memory delays from transient responses related to perceptual and motor operations. These studies have identified six distinct frontal regions that demonstrate sustained activity during memory delays. These regions could be distinguished from brain regions in extrastriate cortex that participate more in perception and from brain regions in medial and lateral frontal cortex that participate more in motor control. Moreover, the working memory regions could be distinguished from each other based on the relative strength of their participation in spatial and face working memory and on the relative strength of sustained activity during memory delays versus transient activity related to stimulus presentation. These results demonstrate that visual working memory performance involves the concerted activity of multiple regions in a widely distributed system. Distinctions between functions, such as perception versus memory maintenance, or spatial versus face working memory, are a matter of the degree of participation of different regions, not the discrete parcellation of different functions to different modules. (C) 2000 Academic Press. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Psychol, Baltimore, MD 21218 USA. Grp Imagerie Neurofonct, F-14074 Caen, France. RP Haxby, JV (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RI GINSPAN, All/B-8714-2008; Petit, Laurent/D-6583-2011 OI Petit, Laurent/0000-0003-2499-5367 NR 35 TC 84 Z9 87 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2000 VL 11 IS 2 BP 145 EP 156 DI 10.1006/nimg.1999.0527 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 291JE UT WOS:000085730200005 PM 10679186 ER PT J AU Li-Smerin, YY Hackos, DH Swartz, KJ AF Li-Smerin, YY Hackos, DH Swartz, KJ TI A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel SO NEURON LA English DT Article ID SHAKER POTASSIUM CHANNEL; TRYPTOPHAN-SCANNING MUTAGENESIS; GATING CURRENTS; TRANSMEMBRANE SEGMENTS; STREPTOMYCES-LIVIDANS; ELECTROSTATIC INTERACTIONS; SUBUNIT STOICHIOMETRY; MOLECULAR-BASIS; TEA BLOCKADE; S4 SEGMENT AB Voltage-gated K+ channels contain a central pore domain and four surrounding voltage-sensing domains. How and where changes in the structure of the voltage-sensing domains couple to the pore domain so as to gate ion conduction is not understood. The crystal structure of KcsA, a bacterial K+ channel homologous to the pore domain of voltage-gated K+ channels, provides a starting point for addressing this question. Guided by this structure, we used tryptophan-scanning mutagenesis on the transmembrane shell of the pore domain in the Shaker voltage-gated K+ channel to localize potential protein-protein and protein-lipid interfaces. Some mutants cause only minor changes in gating and when mapped onto the KcsA structure cluster away from the interface between pore domain subunits. In contrast, mutants producing large changes in gating tend to cluster near this interface. These results imply that voltage-sensing domains interact with localized regions near the interface between adjacent pore domain subunits. C1 NINDS, Mol Physiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA NS002945-13] NR 62 TC 98 Z9 99 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB PY 2000 VL 25 IS 2 BP 411 EP 423 DI 10.1016/S0896-6273(00)80904-6 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 288EL UT WOS:000085549100018 PM 10719895 ER PT J AU Loda, M Xu, X Pession, A Vortmeyer, A Giangaspero, F AF Loda, M Xu, X Pession, A Vortmeyer, A Giangaspero, F TI Membranous expression of glucose transporter-1 protein (GLUT-1) in embryonal neoplasms of the central nervous system SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Article DE brain neoplasms; embryonal neoplasms; glucose transporter protein; medulloblastoma; PNET ID BLOOD-BRAIN-BARRIER; ATYPICAL TERATOID/RHABDOID TUMOR; PRIMITIVE NEUROECTODERMAL TUMORS; NEURAL TRANSPLANTS; CELL-LINE; IMMUNOPHENOTYPE; LOCALIZATION; ONTOGENY AB The human erythrocyte GLUT-1 is a transmembrane protein which facilitates transport of glucose in the cell in an energy-independent fashion. Neuroectodermal stem cells show strong membrane immunoreactivitry with this marker at early developmental stages in rodents. Membranous expression by undifferentiated neuroectodermal cells gradually decreases while GLUT-1 becomes confined to the endothelial cells, when these acquire blood-brain barrier function. We thus sought to determine whether GLUT-1 expression was limited to embryonal neoplasms of the central nervous system (CNS) which are presumably derived from developmentally arrested neuroectodermal stem cells. Archival material of 40 primary CNS neoplasms were examined for immunoreactivity with anti-GLUT-1. This included both non-embryonal neoplasms (18 astrocytic tumours, one ependymoma and three oligodendroglioma) and embryonal neoplasms (12 cerebellar medulloblastomas, four supratentorial PNETs and two atypical teratoid/rhabdoid tumours (AT/RhT)). In addition, cell lines and nude mice xenografts derived from both undifferentiated and differentiated tumours were assessed for GLUT-1 immunoreactivity by both immunohistochemistry and Western blotting. All embryonal tumours, MBs and PNET xenografts consistently showed GLUT-1 membrane staining. Non-embryonal neoplasms were negative except for vascular staining. Membrane protein fraction of embryonal tumours cell lines immunoreacted by immunoblot with GLUT-1, whereas the glioblastoma cell line was negative. Expression of GLUT-1 supports the stem cell nature of the cells of origin of MBs, supratentorial PNET and AT/RhTs. As a result, GLUT-1 is a useful marker to define the embryonal nature of CNS neoplasms. C1 Osped M Bufalini, Ist Anat Patol, Dept Anat Pathol, I-47023 Cesena, Italy. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. Univ Bologna, Dept Expt Pathol, I-40126 Bologna, Italy. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Giangaspero, F (reprint author), Osped M Bufalini, Ist Anat Patol, Dept Anat Pathol, Viale G Ghirotti 286, I-47023 Cesena, Italy. RI Pession, Annalisa/B-9014-2012; OI Pession, Annalisa/0000-0001-9035-9698 NR 23 TC 15 Z9 15 U1 2 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0305-1846 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD FEB PY 2000 VL 26 IS 1 BP 91 EP 97 DI 10.1046/j.1365-2990.2000.00225.x PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 293HN UT WOS:000085846200010 PM 10736070 ER PT J AU Bertolino, A Breier, A Callicott, JH Adler, C Mattay, VS Shapiro, M Frank, JA Picker, D Weiberger, DR AF Bertolino, A Breier, A Callicott, JH Adler, C Mattay, VS Shapiro, M Frank, JA Picker, D Weiberger, DR TI The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dorsolateral prefrontal cortex; N-acetylaspartate; striatum; dopamine; evoked release; schizophrenia ID MAGNETIC-RESONANCE SPECTROSCOPY; POSITRON EMISSION TOMOGRAPHY; IN-VIVO; ACETYL ASPARTATE; H-1 MRS; CORTEX; LESIONS; RAT; DYSFUNCTION; EXPRESSION AB Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with C-11-raclopride Positron Emission Tomography (PET) in patients wi;fh schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of C-11-raclopride after amphetamine infusions (rho = -0.76, p <.02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function. Published by Elsevier Science Inc. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, OD, Bethesda, MD 20892 USA. RP Weiberger, DR (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 4S235,MSC 1379, Bethesda, MD 20892 USA. RI Callicott, Joseph/C-9102-2009; Bertolino, Alessandro/O-6352-2016 OI Callicott, Joseph/0000-0003-1298-3334; Bertolino, Alessandro/0000-0002-1251-1380 NR 51 TC 105 Z9 107 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2000 VL 22 IS 2 BP 125 EP 132 DI 10.1016/S0893-133X(99)00096-2 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273HY UT WOS:000084702900003 PM 10649825 ER PT J AU Heinz, A Goldman, D Jones, DW Palmour, R Hommer, D Gorey, JG Lee, KS Linnoila, M Winberger, DR AF Heinz, A Goldman, D Jones, DW Palmour, R Hommer, D Gorey, JG Lee, KS Linnoila, M Winberger, DR TI Genotype influences in vivo dopamine transporter availability in human striatum SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine transporter; gene expression; SLC6A3; SPECT; beta-CIT; alcoholism ID HEALTHY-HUMAN SUBJECTS; BETA-CIT BINDING; ALCOHOL-WITHDRAWAL; NONHUMAN-PRIMATES; GENE POLYMORPHISM; ASSOCIATION; ADDICTION; BRAIN; RATS; NEUROBIOLOGY AB In vivo availability of striatal dopamine transporter (DAT) protein has been reported to be reduced among alcoholics, and allelic variation of the DAT gene (SLC6A3) has been associated with severity of alcohol withdrawal. We examined the VNTR polymorphism of the 3' untranslated region of SLC6A3 and DAT protein availability in 14 abstinent alcoholics and II control subjects. Single photon emission computed tomography (SPECT) and plasma levels of the radioligand [I-123]beta-CIT were used to quantify DAT protein availability. Individuals with the 9-repeat/10-repeat genotype had a mean 22% reduction of DAT protein availability in putamen compared with 10-repeat homozygous individuals (t = 2.14, df = 23, p <.05). Consistent with earlier studies, alcoholism, per se, was not significantly associated with either DAT availability or DAT genotype. These findings suggest that the VNTR polymorphism of the DAT gene effects translation of the DAT protein. This effect may explain a variety of clinical associations that have been reported with this polymorphism. Published by Elsevier Science Inc. C1 NIMH, Clin Brain Disorders Branch, DIRP, NIH, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, DICBR, Bethesda, MD USA. RP Winberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, DIRP, NIH, 10 Ctr Dr,4S-235,MSC 1379, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 50 TC 388 Z9 395 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2000 VL 22 IS 2 BP 133 EP 139 DI 10.1016/S0893-133X(99)00099-8 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273HY UT WOS:000084702900004 PM 10649826 ER PT J AU Kirby, LG Rice, KC Valentino, RJ AF Kirby, LG Rice, KC Valentino, RJ TI Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE corticotropin-releasing hormone; 5-hydroxytryptamine; stress; immunohistochemistry; antalarmin; DPheCRF(12-41) ID MESSENGER-RNA EXPRESSION; CENTRAL NERVOUS-SYSTEM; RAT-BRAIN; LOCUS-COERULEUS; PREFRONTAL CORTEX; 5-HYDROXYINDOLEACETIC ACID; TOPOGRAPHICAL DISTRIBUTION; ANTIDEPRESSANT TREATMENTS; IN-VITRO; 5-HYDROXYTRYPTAMINE AB The present study examined the regional localization of: corticotropin-releasing factor (CRF)- and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the effects of CRF, administered intracerebroventricularly (0.2-3.0 mu g) or intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons were quantified using in vivo single unit recording in halothane-anesthetized rats. CRF-IR fibers were present nf all rostrocaudal levels of the DRN and exhibited a topographical distribution. CRF produced predominantly inhibitory effects on DRN discharge at lower doses and these effects diminished or became excitatory; at higher doses. Inhibition of DRN discharge by CRF was attenuated by the nonselective CRF antagonist, DPheCRF(12-41) and the CRF-R1-selective antagonist, antalarmin, implicating the CRF-R1 receptor subtype in these electrophysiological nl effects. The present findings provide anatomical and physiological evidence for an impact of CRF on the DRN-5HT system. Published by Elsevier Science Inc. C1 Med Coll Penn & Hahnemann Univ, Dept Psychiat, Div Stress Neurobiol, Philadelphia, PA 19102 USA. NIMH, Med Chem Lab, NIDDK, Bethesda, MD 20892 USA. RP Kirby, LG (reprint author), Med Coll Penn & Hahnemann Univ, Dept Psychiat, Div Stress Neurobiol, MS 403,Broad & Vine St, Philadelphia, PA 19102 USA. OI Valentino, Rita/0000-0001-6839-6628 FU NIMH NIH HHS [MH 00840, MH 12274, MH 58250] NR 53 TC 221 Z9 224 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2000 VL 22 IS 2 BP 148 EP 162 DI 10.1016/S0893-133X(99)00093-7 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273HY UT WOS:000084702900006 PM 10649828 ER PT J AU Mehlman, PT Westergaard, GC Hoos, BJ Sallee, FR Marsh, S Suomi, SJ Linnoila, M Higley, JD AF Mehlman, PT Westergaard, GC Hoos, BJ Sallee, FR Marsh, S Suomi, SJ Linnoila, M Higley, JD TI CSF5-HIAA and nighttime activity in free-ranging primates SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE sleep; serotonin; impulsivity; primate; aggression ID CERCOPITHECUS-AETHIOPS-SABAEUS; CEREBROSPINAL-FLUID MONOAMINE; CSF 5-HIAA CONCENTRATIONS; IMPULSIVE FIRE SETTERS; VIOLENT OFFENDERS; SOCIAL-BEHAVIOR; RHESUS-MONKEYS; SUPRACHIASMATIC NUCLEUS; NONHUMAN-PRIMATES; SEVERE AGGRESSION AB Men with low CNS serotonin turnover, as measured by cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, exhibit aberrant circadian activity patterns characterized by disrupted sleep rhythms and daytime hyperactivity. To assess whether similar patterns are found in nonhuman primates we examined the relationship between CSF 5-HIAA and nighttime activity in free-ranging monkeys. CSF samples were obtained from 16 adult male rhesus macaques living on a 475 acre, heavily forested sea island. Each subject was captured, fitted with a radio-telemetry motion-detector collar, and then released back into its group. A receiver placed near the sleeping trees of the study subjects recorded activity between 2100 hrs and 0600 hrs. Trained observers recorded a typical diurnal activity pattern, as they were active 74% of the sampled time during the day and 37% of the sampled time during the night. CSF 5-HIAA concentrations were inversely correlated with total duration of nighttime activity as well as mean duration of all active events. Nighttime activity was inversely correlated with daytime activity. CSF 3-methoxy-hydroxyphenylglycol (MHPG) concentrations were positively correlated with total nighttime activity, and inversely correlated with daytime sleep frequency. We conclude that male rhesus with low CSF 5-HIAA concentrations have higher total nighttime activity, longer mean periods of nighttime activity, and sleep more during the day than do males with high CSF 5-HIAA concentrations. This suggests that low serotonergic neurotransmission is associated with aberrant diurnal activity, as evidenced by a disruption of nighttime sleep patterns and a compensatory higher rate of inactivity during the day. Published by Elsevier Science Inc. C1 LABS Virginia Inc, Div Res & Dev, Yemassee, SC USA. NICHHD, Comparat Ethol Lab, Poolesville, MD USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. Tao Tech Inc, Bedford, MA USA. RP Westergaard, GC (reprint author), LABS Virginia Inc, Div Res, POB 557, Yemassee, SC USA. FU PHS HHS [223-92-1101] NR 53 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2000 VL 22 IS 2 BP 210 EP 218 DI 10.1016/S0893-133X(99)00101-3 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 273HY UT WOS:000084702900011 PM 10649833 ER PT J AU Zalc, B Fields, RD AF Zalc, B Fields, RD TI Do action potentials regulate myelination? SO NEUROSCIENTIST LA English DT Article DE myelination; activity-dependent; action potential; oligodendrocyte; Schwann cell; dorsal root ganglion (DRG); optic nerve; cell adhesion molecule; L1; tetrodotoxin (TTX) ID RAT OPTIC-NERVE; SCHWANN-CELL PRECURSORS; OLIGODENDROCYTE DIFFERENTIATION; ELECTRICAL-ACTIVITY; ADHESION MOLECULE; REACTIVE GLIOSIS; BASIC-PROTEIN; PROLIFERATION; EXPRESSION; MEMBRANE AB A variety of anatomical features suggest that functional activity in the nervous system can influence the process of myelination, yet direct evidence of this is lacking. Research by Zalc and colleagues shows that myelination of optic nerve is inhibited by a neurotoxin that blocks action potential activity and is stimulated by a toxin that increases impulse activity, suggesting that impulse activity is necessary for initiating myelination during development of the optic nerve. Research by Fields and colleagues, using electrical stimulation of axons, shows that low frequency impulse activity inhibits myelination of dorsal root ganglion neurons, but high frequency impulse activity has no effect, This results from reduced expression of a cell adhesion molecule on the stimulated axons that is critical for inducing myelination, Together these studies support the conclusion that impulse activity can influence the process of myelination, probably through more than one molecular mechanism operating during discrete steps in the myelination process. C1 Univ Paris 06, INSERM, Hop La Pitie Salpetriere, U495, Paris, France. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HD000713-13] NR 66 TC 38 Z9 38 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD FEB PY 2000 VL 6 IS 1 BP 5 EP 13 DI 10.1177/107385840000600109 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 303NT UT WOS:000086428500009 PM 18461153 ER PT J AU Magata, Y Lang, LX Kiesewetter, DO Jagoda, EM Channing, MA Eckelman, WC AF Magata, Y Lang, LX Kiesewetter, DO Jagoda, EM Channing, MA Eckelman, WC TI Biologically stable [F-18]-labeled benzylfluoride derivatives SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE F-18; defluorination; metabolism; rat ID F-18; SELECTIVITY; METABOLISM AB Use of the [F-18]-fluoromethyl phenyl group is an attractive alternative to direct fluorination of phenyl groups because the fluorination of the methyl group takes place under milder reaction conditions. However, we have found that 4-FMeBWAY showed femur uptake equal to that of fluoride up to 30 min in rat whereas 4-FMeQNB had a significantly lower percent injected dose per gram in femur up to 120 min; For these and other benzylfluoride derivatives, there was no clear in vivo structure-defluorination relationship. Because benzylchlorides (BzCls) are known alkylating agents, benzylfluorides may be alkylating agents as well, which may be the mechanism of defluorination, On this basis, the effects of substitution on chemical stability were evaluated by the 4-(4-nitro-benzyl)-pyridine (NBP) test, which is used to estimate alkylating activity with NBP. The effect of substitution on the alkylating activity was evaluated for nine BzCl derivatives: BzCl; 3- or 4-methoxy (electron donation) substituted BzCl; 2-, 3-, or 4-nitro (electron withdrawing) substituted BzCl; and 2-, 3-, or 4-chloro (electron withdrawing) substituted BzCl. Taken together, the alkylating reactivity of 3-chloro-BzCl was the weakest, This result was then applied to [F-18]-benlylfluoride derivatives and in vivo and in vitro stability were evaluated. Consequently, 3-chloro-[F-18]-benzylfluoride showed a 70-80% decrease of defluorination in both experiments in comparison with [F-18]-benzylfluoride, as expected. Moreover, a good linear relationship between in vivo femur uptake and in vitro hepatocyte metabolism was observed with seven F-18-labeled radiopharmaceuticals, which were benzylfluorides, alkylfluorides, and arylfluorides. Apparently, the [F-18]-fluoride ion is released by metabolism in the liver in vivo. In conclusion, 3-chloro substituted BzCls are the most stable, which suggests that 3-chloro benzylfluorides will be the most chemically stable compound. This result should be important in future design of radioligands labeled with a benzylfluoride moiety. NUCL MED BIOL 27;2:163-168, 2000. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NIH, Warren G Magnuson Clin Ctr, Pet Dept, Bethesda, MD 20892 USA. RP Magata, Y (reprint author), Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Pathofunct Bioanal, Sakyo Ku, Yoshida Shimoadachi-cho, Kyoto 6068501, Japan. NR 21 TC 28 Z9 28 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD FEB PY 2000 VL 27 IS 2 BP 163 EP 168 DI 10.1016/S0969-8051(99)00108-0 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 307XT UT WOS:000086680000008 PM 10773545 ER PT J AU Gelfand, MS Koonin, EV Mironov, AA AF Gelfand, MS Koonin, EV Mironov, AA TI Prediction of transcription regulatory sites in Archaea by a comparative genomic approach SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ARCHAEBACTERIUM HALOFERAX-VOLCANII; TRYPTOPHAN BIOSYNTHESIS; ESCHERICHIA-COLI; METHANOCOCCUS-JANNASCHII; ARCHAEOGLOBUS-FULGIDUS; METHANOSARCINA-MAZEI; PROTEIN SEQUENCES; DNA-BINDING; PSI-BLAST; GENES AB Intragenomic and intergenomic comparisons of upstream nucleotide sequences of archaeal genes were performed with the goal of predicting transcription regulatory sites (operators) and identifying likely regulons, Learning sets for the detection of regulatory sites were constructed using the available experimental data on archaeal transcription regulation or by analogy with known bacterial regulons, and further analysis was performed using iterative profile searches. The information content of the candidate signals detected by this method is insufficient for reliable predictions to be made. Therefore, this approach has to be complemented by examination of evolutionary conservation in different archaeal genomes. This combined strategy resulted in the prediction of a conserved heat shock regulon in all euryarchaea, a nitrogen fixation regulon in the methanogens Methanococcus jannaschii and Methanobacterium thermoautotrophicum and an aromatic amino acid regulon in M. thermoautotrophicum. Unexpectedly, the heat shock regulatory site was detected not only for genes that encode known chaperone proteins but also for archaeal histone genes. This suggests a possible function for archaeal histones in stress-related changes in DNA condensation. In addition, comparative analysis of the genomes of three Pyrococcus species resulted in the prediction of their purine metabolism and transport regulon, The results demonstrate the feasibility of prediction of at least some transcription regulatory sites by comparing poorly characterized prokaryotic genomes, particularly when several closely related genome sequences are available. C1 State Sci Ctr Biotechnol NIIGenet, Moscow 113545, Russia. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Gelfand, MS (reprint author), State Sci Ctr Biotechnol NIIGenet, Moscow 113545, Russia. RI Mironov, Andrey/C-8024-2012; Gelfand, Mikhail/F-3425-2012 NR 56 TC 141 Z9 148 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 1 PY 2000 VL 28 IS 3 BP 695 EP 705 DI 10.1093/nar/28.3.695 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 281FJ UT WOS:000085147000005 PM 10637320 ER PT J AU Murgo, AJ McBee, WL Cheson, BD AF Murgo, AJ McBee, WL Cheson, BD TI Clinical trials - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Murgo, AJ (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 6 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 FEB PY 2000 VL 14 IS 2 BP 206 EP 206 PG 1 WC Oncology SC Oncology GA 368QJ UT WOS:000090128800014 PM 10736809 ER PT J AU Kupfer, C AF Kupfer, C TI The National Eye Institute's Low Vision Education Program: Improving quality of life SO OPHTHALMOLOGY LA English DT Editorial Material C1 NEI, NIH, Bethesda, MD 20892 USA. RP Kupfer, C (reprint author), NEI, NIH, Bethesda, MD 20892 USA. NR 5 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2000 VL 107 IS 2 BP 229 EP 230 DI 10.1016/S0161-6420(99)00094-9 PG 2 WC Ophthalmology SC Ophthalmology GA 279ZY UT WOS:000085078200015 PM 10690816 ER PT J AU O'Connell, AC Puck, JM Grimbacher, B Facchetti, F Majorana, A Gallin, JI Malech, HL Holland, SM AF O'Connell, AC Puck, JM Grimbacher, B Facchetti, F Majorana, A Gallin, JI Malech, HL Holland, SM TI Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS LA English DT Article ID STIMULATING FACTOR-I; SERUM-IGE LEVELS; CLEIDOCRANIAL DYSPLASIA; TOOTH ERUPTION; EPITHELIAL-CELLS; BONE-RESORPTION; JOBS SYNDROME; CHEMOTAXIS; MODALITY; TISSUES AB Objective. To determine the incidence of abnormal tooth eruption in patients with hyperimmunoglobulinemia E (hyper-IgE) syndrome. Study design. This study evaluated 34 individuals with hyper-IgE syndrome (age range, 2-40 years). A comprehensive dental history and a head and neck evaluation were performed on all patients. Dental age was assessed in patients younger than 17 years by 2 methods: (1) clinical assessment of tooth eruption and (2) a radiographic method. Relationships between the chronologic age, dental developmental age, and age at tooth eruption were determined. Other oral or dental anomalies were recorded. Results. Of patients older than 7 years, 75% reported problems with permanent tooth eruption, as evidenced by retained primary teeth or the need for elective extractions of primary teeth to allow eruption of permanent teeth. None of the patients experienced problems with eruption of primary teeth. Eruption of the first and second permanent molars also occurred on time. Dental maturity scores were established for 14 patients 17 years of age or younger. In each case, the difference between chronologic age and the estimated dental developmental age was less than 12 months; however, we found a significant discrepancy between the chronologic age and the mean age of tooth eruption in 80% of these patients when using a particular set of standardized values. Persistence of Hertwig's epithelial root sheath was observed on histologic examination. Chronic multifocal oral candidiasis was a consistent feature in patients with hyper-IgE recurrent infection syndrome. Other oral anomalies were also noted. Conclusion. We confirmed that a disorder of tooth eruption is part of the hyper-IgE syndrome. This problem occurs because of delayed primary tooth exfoliation rather than a developmental delay in the formation of the permanent dentition. The persistence of Hertwig's epithelial root sheath is unusual and may be associated with the lack of resorption of the primary teeth. Dentists should be aware of this feature of hyper-IgE syndrome because timely intervention will allow normal eruption to occur. C1 NIH, Natl Human Genome Res Inst, Genet & Mol Biol Branch, Bethesda, MD USA. Univ Brescia, Dept Pathol, Brescia, Italy. Univ Brescia, Dept Oral Pathol & Med, Brescia, Italy. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP O'Connell, AC (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 10,Rm 1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. RI FACCHETTI, Fabio/E-7190-2010 OI O'Connell, Anne C/0000-0002-1495-3983; FACCHETTI, Fabio/0000-0003-4975-2388 NR 39 TC 39 Z9 43 U1 0 U2 3 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1079-2104 J9 ORAL SURG ORAL MED O JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. PD FEB PY 2000 VL 89 IS 2 BP 177 EP 185 DI 10.1067/moe.2000.103129 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 285CT UT WOS:000085372400013 PM 10673653 ER PT J AU Treede, RD Kenshalo, DR Gracely, RH Jones, AKP AF Treede, RD Kenshalo, DR Gracely, RH Jones, AKP TI Reply to Eccleston and Crombez, reply to Hooper SO PAIN LA English DT Letter ID RESPONSES; ANATOMY; HUMANS; COLOR; FORM C1 Univ Mainz, Inst Physiol & Pathophysiol, D-55099 Mainz, Germany. NIDR, Bethesda, MD 20892 USA. Univ Manchester, Hope Hosp, Ctr Rheumat Dis, Salford M6 8HD, Lancs, England. RP Treede, RD (reprint author), Univ Mainz, Inst Physiol & Pathophysiol, Saarstr 21, D-55099 Mainz, Germany. NR 9 TC 0 Z9 0 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 FEB PY 2000 VL 84 IS 2-3 BP 443 EP 444 DI 10.1016/S0304-3959(99)00199-2 PG 2 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 282ZP UT WOS:000085251900043 ER PT J AU Mericq, V Uyeda, JA Barnes, KM De Luca, F Baron, J AF Mericq, V Uyeda, JA Barnes, KM De Luca, F Baron, J TI Regulation of fetal rat bone growth by C-type natriuretic peptide and cGMP SO PEDIATRIC RESEARCH LA English DT Article ID RECEPTORS; FAMILY; SYSTEM; BRAIN; MICE AB C-type natriuretic peptide (CNP) and its high affinity receptor-B are expressed in fetal bones. Here we show that CNP accelerates longitudinal growth of fetal rat metatarsal bones in organ culture by several mechanisms. First, CNP stimulates chondrocyte proliferation in the proliferative zone as assessed by [H-3]thymidine incorporation. Second, CNP stimulates cell hypertrophy as assessed by quantitative histology. Third, CNP stimulates cartilage matrix production as assessed by incorporation of (SO4)-S-35 into glycosaminoglycans. Natriuretic peptide receptor-B contains an intracellular guanylyl cyclase catalytic domain. We therefore hypothesized that cyclic GMP (cGMP) would reproduce the effects of CNP on fetal bones. Consistent with this hypothesis, we found that 8-Br-cGMP, like CNP, stimulates longitudinal growth and glycosaminoglycan synthesis. However, unlike CNP, cGMP inhibits proliferation of growth plate chondrocytes and has no effect on hypertrophy. We conclude that CNP stimulates longitudinal bone growth by increasing chondrocyte proliferation, chondrocyte hypertrophy, and cartilage matrix production. cGMP, a second messenger for CNP, reproduces some but not all of the effects of CNP, suggesting that other signal transduction mechanisms may also be involved. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Baron, J (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. RI Mericq, Veronica/F-3927-2010 NR 17 TC 41 Z9 43 U1 0 U2 0 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD FEB PY 2000 VL 47 IS 2 BP 189 EP 193 DI 10.1203/00006450-200002000-00007 PG 5 WC Pediatrics SC Pediatrics GA 279RZ UT WOS:000085060100007 PM 10674345 ER PT J AU Bustamante, JO Michelette, ERF Geibel, JP Dean, DA Hanover, JA McDonnell, TJ AF Bustamante, JO Michelette, ERF Geibel, JP Dean, DA Hanover, JA McDonnell, TJ TI Calcium, ATP and nuclear pore channel gating SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE ATP; calcium; calcium ion channels; cancer cells; Dunning G prostate; gene activity; gene expression; gene regulation; nuclear; nuclear envelope; nuclear pores ID ATOMIC-FORCE MICROSCOPY; PATCH-CLAMP DETECTION; ENDOPLASMIC-RETICULUM; CARDIAC MYOCYTES; PROTEIN IMPORT; ION CHANNELS; MITOCHONDRIAL CHANNEL; ENVELOPE; COMPLEX; DEPLETION AB Nuclear envelope (NE) cisternal Ca2+ and cytosolic ATP are required for nuclear-pore-complex (NPC-) mediated transport of DNAs, RNAs, transcription factors and other large molecules. Isolated cardiomyocyte nuclei, capable of macromolecular transport (MMT), have intrinsic NPC ion channel behavior. The large ion conductance (gamma) activity of the NPC channel (NPCC) is blocked by the NPC monoclonal antibody mAb414, known to block MMT, and is also silenced during periods of MMT. In cardiomyocytes, neither cytosolic Ca2+ nor ATP alone directly affects NPCC gating. To test the role of Ca2+ and ATP in NPCC activity, we carried our the present patch-clamp study with the pipette attached to the outer NE membrane of nuclei isolated from cultured Dunning G prostate cancer cells. Our investigations demonstrate that in these isolated nuclei neither cytosolic Ca2+ nor ATP alone directly affects NPCC gating. However, when simultaneously applied to the bath and pipette, they transiently silence NPCC activity through stimulation of MMT by raising the Ca2+ concentration in the NE cisterna ([Ca2+](NE)). Our fluorescence microscopy observations with nuclear-targeted macromolecular fluorochromes (B-phycoerythrin and plasmid for the enhanced green fluorescence protein EGFP, pEGFP-C1) and with FITC-labeled RNA support the view that channel silence accompanies MMT. Repeated Ca2+ loading of the NE with Ca2+ and ATP, after unloading with 1-5 mu M inositol 1,4,5-trisphosphate (IP3), thapsigargin (TSG) or 5 mM BAPTA or EGTA, failed to affect channel gating. This result indicates that other factors are involved in this phenomenon and that they are exhausted during the first cycle of NE Ca2+ loading/unloading - in agreement with current theories of NPC-mediated MMT. The results explain how Ca2+ and IF, waves may convert the NE into an effective Ca2+ barrier and, consequently, affect the regulation of gene activity and expression through their feedback on MMT and NPCC gating. Thus, [Ca2+](NE) regulation by intracellular messengers is an effective mechanism for synchronizing gene activity and expression to the cellular rhythm. C1 Univ Tiradents, Nucl Physiol Lab, BR-49037610 Aracaju, Sergipe, Brazil. Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Surg, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. Univ S Alabama, Coll Med, Dept Microbiol & Immunol, Mobile, AL 36688 USA. NIDDK, Lab Cell Biochem, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA. RP Bustamante, JO (reprint author), Univ Tiradents, Nucl Physiol Lab, Rua B-508, Priara Aruana, BR-49037610 Aracaju, Sergipe, Brazil. FU NHLBI NIH HHS [R01 HL059956] NR 51 TC 33 Z9 33 U1 0 U2 4 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2000 VL 439 IS 4 BP 433 EP 444 DI 10.1007/s004240050960 PG 12 WC Physiology SC Physiology GA 277KZ UT WOS:000084933900004 PM 10678739 ER PT J AU Bilski, P Li, MY Ehrenshaft, M Daub, ME Chignell, CF AF Bilski, P Li, MY Ehrenshaft, M Daub, ME Chignell, CF TI Vitamin B-6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID AQUEOUS-SOLUTION; ROSE-BENGAL; GENERATING PHOTOSENSITIZERS; CERCOSPORIN; RESISTANCE; OXIDATION; MECHANISM; MUTANTS; DECAY; TOXIN AB Vitamin B-6 (pyridoxine, 1) and its derivatives: pyridoxal (2), pyridoxal 5-phosphate (3) and pyridoxamine (4) are important natural compounds involved in numerous biological functions. Pyridoxine appears to play a role in the resistance of the filamentous fungus Cercospora nicotianae to its own abundantly produced strong photosensitizer of singlet molecular oxygen (O-1(2)), cercosporin. We measured the rate constants (k(q)) for the quenching of O-1(2) phosphorescence by 1-4 in D2O. The respective total (physical and chemical quenching) k(q) values are: 5.5 x 10(7) M-1 s(-1) for 1; 7.5 x 10(7) M-1 s(-1) for 2, 6.2 x 10(7) M-1 s(-1) for 3 and 7.5 x 107 M-1 s(-1) for 4, all measured at pD 6.2. The quenching efficacy increased up to five times in alkaline solutions and decreased similar to 10 times in ethanol, Significant contribution to total quenching by chemical reaction(s) is suggested by the degradation of all the vitamin derivatives by O-1(2), which was observed as declining absorption of the pyridoxine moiety upon aerobic irradiation of RE used to photosensitize O-1(2). This photodegradation was completely stopped by azide, a known physical quencher of O-1(2). The pyridoxine moiety can also function as a redox quencher for excited cercosporin by forming the cercosporin radical anion, as observed by electron paramagnetic resonance. All B-6 vitamers fluoresce upon UV excitation. Compounds 1 and 4 emit fluorescence at 400 mn, compound 3, at 450 nm and compound 3 at 550 nm, The fluorescence intensity of 3 increased similar to 10 times in organic solvents such as ethanol and 1,2-propanediol compared to aqueous solutions, suggesting that fluorescence may be used to image the distribution of 1-4 in Cercospora to understand better the interactions of pyridoxine and O-1(2) in the living fungus. C1 NIEHS, Environm Toxicol Program, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Plant Pathol, Raleigh, NC 27695 USA. RP Bilski, P (reprint author), NIEHS, Environm Toxicol Program, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Strid, Ake/E-5309-2012 OI Strid, Ake/0000-0003-3315-8835 NR 26 TC 175 Z9 182 U1 3 U2 30 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD FEB PY 2000 VL 71 IS 2 BP 129 EP 134 DI 10.1562/0031-8655(2000)071<0129:SIPVBP>2.0.CO;2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 283WG UT WOS:000085298600004 PM 10687384 ER PT J AU Daub, ME Li, M Bilski, P Chignell, CF AF Daub, ME Li, M Bilski, P Chignell, CF TI Dihydrocercosporin singlet oxygen production and subcellular localization: A possible defense against cercosporin phototoxicity in Cercospora SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PHOTOSENSITIZING TOXIN; ROSE-BENGAL; RESISTANCE; FUNGI; MECHANISM; KIKUCHII; YIELDS AB Fungi in the genus Cercospora produce cercosporin, a potent singlet oxygen (O-1(2))-generating photosensitizer that plays a critical role in the ability of these fungi to parasitize plants. Although plants, mice, bacteria and many fungi are sensitive to cercosporin, Cercospora species are resistant to its toxicity. The cellular resistance of these fungi to cercosporin has been correlated with fungal cell surface reducing ability and the ability to maintain cercosporin in a chemically reduced state. As a model for reduced cercosporin we employed a reduced, acetylated derivative (hexaacetyl-dihydrocercosporin, HAC) that we tested for O-1(2) production in a range of solvents. We found that as a O-1(2) photosensitizer, HAC was only moderately effective in organic solvents (phi(SO) = 0.14-0.18) and very poor in water (phi(SO) = 0.02-0.04). By contrast, the O-1(2) quantum yield of cercosporin itself was unaffected hy solvent (phi(SO) = 0.84-0.97). To investigate the localization of reduced cercosporin in fungal cells, we developed a fluorescence assay using laser scanning confocal microscopy, This assay showed a uniform green fluorescence, indicative of reduced cercosporin, in the cytoplasm of hyphal cells treated with cercosporin, We hypothesize that the main protection mechanism against cercosporin phototoxicity in the fungus consists of transformation of cercosporin to a reduced state and localization of this reduced form in the aqueous compartment of the cell, thus decreasing intracellular O-1(2) production to levels that can be tolerated by the fungus. In addition, we have, for the first time, directly detected O-1(2) phosphorescence from fungal culture, either stained with the photosensitizer rose bengal or actively synthesizing cercosporin, demonstrating O-1(2) production in vivo and from cercosporin in culture. C1 N Carolina State Univ, Dept Plant Pathol, Raleigh, NC 27695 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Daub, ME (reprint author), N Carolina State Univ, Dept Plant Pathol, Box 7616, Raleigh, NC 27695 USA. NR 27 TC 18 Z9 18 U1 0 U2 7 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD FEB PY 2000 VL 71 IS 2 BP 135 EP 140 DI 10.1562/0031-8655(2000)071<0135:SIPDSO>2.0.CO;2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 283WG UT WOS:000085298600005 PM 10687385 ER PT J AU Bochar, DA Savard, J Wang, WD Lafleur, DW Moore, P Cote, J Shiekhattar, R AF Bochar, DA Savard, J Wang, WD Lafleur, DW Moore, P Cote, J Shiekhattar, R TI A family of chromatin remodeling factors related to Williams syndrome transcription factor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IN-VITRO; SACCHAROMYCES-CEREVISIAE; NUCLEOSOME DISRUPTION; PROTEIN DATABASE; SWI/SNF COMPLEX; FACTOR TFIIH; SWI-SNF; YEAST; DROSOPHILA; BINDING AB Chromatin remodeling complexes have been implicated in the disruption or reformation of nucleosomal arrays resulting in modulation of transcription, DNA replication, and DNA repair. Here we report the isolation of WCRF, a new chromatin-remodeling complex from HeLa cells. WCRF is composed of two subunits, WCRF135, the human homolog of Drosophila ISWI, and WCRF180, a protein related to the Williams syndrome transcription factor. WCRF180 is a member of a family of proteins sharing a putative heterochromatin localization domain, a PHD finger, and a bromodomain, prevalent in factors involved in regulation of chromatin structure. C1 Wistar Inst, Philadelphia, PA 19104 USA. Univ Laval, Hotel Dieu, Ctr Canc Res, Quebec City, PQ G1R 2J6, Canada. NIA, Genet Lab, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. Human Genome Sci Inc, Dept Biol Mol, Rockville, MD 20874 USA. RP Shiekhattar, R (reprint author), Wistar Inst, 3601 Spruce St, Philadelphia, PA 19104 USA. RI Bochar, Daniel/A-9224-2009; Cote, Jacques/I-8901-2014 OI Cote, Jacques/0000-0001-6751-555X NR 45 TC 113 Z9 118 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 1 PY 2000 VL 97 IS 3 BP 1038 EP 1043 DI 10.1073/pnas.97.3.1038 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281BM UT WOS:000085138300018 PM 10655480 ER PT J AU Wassarman, DA Aoyagi, N Pile, LA Schlag, EM AF Wassarman, DA Aoyagi, N Pile, LA Schlag, EM TI TAF250 is required for multiple developmental events in Drosophila SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TATA-BINDING PROTEIN; GENERAL TRANSCRIPTION FACTORS; RNA-POLYMERASE-II; EYE DEVELOPMENT; RECEPTOR GENE; EGF RECEPTOR; G1 MUTANTS; CELL-LINE; SUBUNIT; COMPLEX AB The TFIID transcription initiation complex is composed of TBP and multiple TAFs. Studies in unicellular systems indicate that TAF250 is required for progression through G(1)/S of the cell cycle and repression of apoptosis. Here we extend these in vivo studies by determining the developmental requirements for TAF250 in a multicellular organism, Drosophila. TAF250 mutants were isolated in a genetic screen that also yielded TAF60 and TAF110 mutants, indicating that TAFs function coordinately to regulate transcription. Null alleles of TAF250 are recessive larval lethal. However, combinations of weak loss-of-function TAF250 alleles survive to adulthood and reveal requirements for TAF250 during ovary, eye, ocelli, wing, bristle, and terminalia development as well as overall growth of the fly. These phenotypes suggest roles for TAF250 in regulating the cell cycle, cell differentiation, cell proliferation, and cell survival. Finally, molecular analysis of TAF250 mutants reveals that the observed phenotypes are caused by mutations in a central region of TAF250 that is conserved among metazoan organisms, This region is contained within the TAF250 histone acetyltransferase domain, but the mutations do not alter the histone acetyltransferase activity of TAF250 in vitro, indicating that some other aspect of TAF250 function is affected. Because this region is not conserved in the yeast TAF250 homologue, TAF145, it may define an activity for TAF250 that is unique to higher eukaryotes. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Wassarman, DA (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NR 50 TC 37 Z9 39 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 1 PY 2000 VL 97 IS 3 BP 1154 EP 1159 DI 10.1073/pnas.97.3.1154 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281BM UT WOS:000085138300038 PM 10655500 ER PT J AU Ellsworth, RE Jamison, DC Touchman, JW Chissoe, SL Maduro, VVB Bouffard, GG Dietrich, NL Beckstrom-Sternberg, SM Iyer, LM Weintraub, LA Cotton, M Courtney, L Edwards, J Maupin, R Ozersky, P Rohlfing, T Wohldmann, P Miner, T Kemp, K Kramer, J Korf, I Pepin, K Antonacci-Fulton, L Fulton, RS Minx, P Hillier, LW Wilson, RK Waterston, RH Miller, W Green, ED AF Ellsworth, RE Jamison, DC Touchman, JW Chissoe, SL Maduro, VVB Bouffard, GG Dietrich, NL Beckstrom-Sternberg, SM Iyer, LM Weintraub, LA Cotton, M Courtney, L Edwards, J Maupin, R Ozersky, P Rohlfing, T Wohldmann, P Miner, T Kemp, K Kramer, J Korf, I Pepin, K Antonacci-Fulton, L Fulton, RS Minx, P Hillier, LW Wilson, RK Waterston, RH Miller, W Green, ED TI Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID YEAST ARTIFICIAL CHROMOSOMES; CFTR GENE; PROMOTER REGION; POSITIONAL CLONING; CHLORIDE CHANNEL; MODEL; DNA; IDENTIFICATION; ELEMENT; ALIGNMENTS AB The identification of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in 1989 represents a landmark accomplishment in human genetics. Since that time, there have been numerous advances in elucidating the function of the encoded protein and the physiological basis of cystic fibrosis. However, numerous areas of cystic fibrosis biology require additional investigation, some of which would be facilitated by information about the long-range sequence context of the CFTR gene. For example, the latter might provide clues about the sequence elements responsible for the temporal and spatial regulation of CFTR expression. We thus sought to establish the sequence of the chromosomal segments encompassing the human CFTR and mouse Cftr genes, with the hope of identifying conserved regions of biologic interest by sequence comparison. Bacterial clone-based physical maps of the relevant human and mouse genomic regions were constructed, and minimally overlapping sets of clones were selected and sequenced, eventually yielding approximate to 1.6 Mb and approximate to 358 kb of contiguous human and mouse sequence, respectively. These efforts have produced the complete sequence of the approximate to 189-kb and approximate to 152-kb segments containing the human CFTR and mouse Cftr genes, respectively, as well as significant amounts of flanking DNA. Analyses of the resulting data provide insights about the organization of the CFTR/Cftr genes and potential sequence elements regulating their expression. Furthermore, the generated sequence reveals the precise architecture of genes residing near CFTR/Cftr. including one known gene (WNT2/Wnt2) and two previously unknown genes that immediately flank CFTR/Cftr. C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Genome Sequencing Ctr, Dept Genet, St Louis, MO 63110 USA. Penn State Univ, Dept Comp Sci & Engn, University Pk, PA 16802 USA. RP Natl Human Genome Res Inst, Genome Technol Branch, NIH, 49 Convent Dr,Bldg 49,Room 2A08, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov FU NLM NIH HHS [LM05110] NR 68 TC 44 Z9 46 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 1 PY 2000 VL 97 IS 3 BP 1172 EP 1177 DI 10.1073/pnas.97.3.1172 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281BM UT WOS:000085138300041 PM 10655503 ER PT J AU Cicala, C Arthos, J Rubbert, A Selig, S Wildt, K Cohen, OJ Fauci, AS AF Cicala, C Arthos, J Rubbert, A Selig, S Wildt, K Cohen, OJ Fauci, AS TI HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; FACTOR-ALPHA SECRETION; INFECTED LYMPH-NODES; GLYCOPROTEIN GP120; CHEMOKINE RECEPTOR; CROSS-LINKING; DIFFERENTIAL SUSCEPTIBILITY; AIDS PATHOGENESIS; INDUCED APOPTOSIS; CYCLE ARREST AB Binding of HIV type 1 (HIV-l) envelope glycoproteins to the surface of a CD4(+) T cell transduces intracellular signals through the primary envelope receptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope-CD4(+) cell interactions increase rates of apoptosis in peripheral blood mononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes. recombinant HIV-1 envelope proteins induce the activation of caspase-3 and caspase-6, which belong to a family of cysteine proteases that, upon activation, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizing as well as CXCR4-utilizing envelopes elicited this response. Focal adhesion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inactivation of FAK by these caspases promotes apoptosis, Envelope treatment of lymphocytes led to the cleavage of FAK in a manner consistent with caspase-mediated cleavage. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Cicala, C (reprint author), 10 Ctr Dr,MSC 1876,Bldg 10,Room 11B13, Bethesda, MD 20892 USA. NR 66 TC 95 Z9 100 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 1 PY 2000 VL 97 IS 3 BP 1178 EP 1183 DI 10.1073/pnas.97.3.1178 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281BM UT WOS:000085138300042 PM 10655504 ER PT J AU De Voss, JJ Rutter, K Schroeder, BG Su, H Zhu, YQ Barry, CE AF De Voss, JJ Rutter, K Schroeder, BG Su, H Zhu, YQ Barry, CE TI The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYCLOPROPANATED MYCOLIC ACIDS; EXTRACELLULAR SIDEROPHORE; IRON TRANSPORT; IDENTIFICATION; SYNTHETASE; SMEGMATIS; BIOSYNTHESIS; DISEASE; GENES; MECHANISMS AB Mycobacterium tuberculosis is an important pathogen of mammals that relies on 2-hydroxyphenyloxazoline-containing siderophore molecules called mycobactins for the acquisition of iron in the restrictive environment of the mammalian macrophage, These compounds have been proposed to be biosynthesized through the action of a cluster of genes that include both nonribosomal peptide synthase and polyketide synthase components. One of these genes encodes a protein, MbtB, that putatively couples activated salicylic acid with serine or threonine and then cyclizes this precursor to the phenyloxazoline ring system. We have used gene replacement through homologous recombination to delete the mbtB gene and replace this with a hygromycin-resistance cassette in the virulent strain of M. tuberculosis H37Rv, The resulting mutant is restricted for growth in iron-limited media but grows normally in iron-replete media. Analysis of siderophore production by this organism revealed that the biosynthesis of all salicylate-derived siderophores was interrupted. The mutant was found to be impaired for growth in macrophage-like THP-1 cells, suggesting that siderophore production is required for virulence of M. tuberculosis, These results provide conclusive evidence linking this genetic locus to siderophore production. C1 NIAID, Host Def Lab, TB Res Sect, Sect Head,NIH, Rockville, MD 20852 USA. Univ Queensland, Dept Chem, St Lucia, Qld 4067, Australia. RP Barry, CE (reprint author), NIAID, Host Def Lab, TB Res Sect, Sect Head,NIH, Twinbrook 2,Room 239,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012; OI Rutter, Kerry/0000-0002-1668-6276 FU Intramural NIH HHS [Z01 AI000783-11] NR 39 TC 328 Z9 337 U1 5 U2 21 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 1 PY 2000 VL 97 IS 3 BP 1252 EP 1257 DI 10.1073/pnas.97.3.1252 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 281BM UT WOS:000085138300055 PM 10655517 ER PT J AU Patterson, TA Little, W Cheng, XB Widen, SG Kumar, A Beard, WA Wilson, SH AF Patterson, TA Little, W Cheng, XB Widen, SG Kumar, A Beard, WA Wilson, SH TI Molecular cloning and high-level expression of human polymerase beta cDNA and comparison of the purified recombinant human and rat enzymes SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID ESCHERICHIA-COLI; MESSENGER-RNA; DNA-SYNTHESIS; TRANSCRIPTION TERMINATION; TRANSLATION; SEQUENCE; BINDING; CELLS; VECTORS; PROTEIN AB The cDNA encoding the human polymerase beta from HeLa cells was PCR amplified and cloned, and its nucleotide sequence determined. The DNA sequence is identical to the polymerase beta cDNA sequence from Tera-2 cells. Three expression strategies were employed that were designed to maximize translation initiation of the polymerase beta mRNA in Escherichia coli and all yielded a high level of human polymerase beta. The recombinant protein was purified and its properties were compared with those of the recombinant rat enzyme. The domain structure and kinetic parameters (k(cat) and K-m) were nearly identical. A mouse IgG monoclonal antibody to the rat enzyme (mAb-10S) was approximately 10-fold less reactive with the human enzyme than with the rat enzyme as determined by ELISA. (C) 2000 Academic Press. C1 Dupont Merck Pharmaceut Co, Wilmington, DE 19880 USA. Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Patterson, TA (reprint author), Dupont Merck Pharmaceut Co, Wilmington, DE 19880 USA. NR 40 TC 12 Z9 13 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD FEB PY 2000 VL 18 IS 1 BP 100 EP 110 DI 10.1006/prep.1999.1167 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 281WP UT WOS:000085184700013 PM 10648175 ER PT J AU Munzar, P Goldberg, SR AF Munzar, P Goldberg, SR TI Dopaminergic involvement in the discriminative-stimulus effects of methamphetamine in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE methamphetamine; drug-discrimination; dopamine; cocaine; GBR-12909; nomifensine; bupropion; Chloro-PB; Chloro-APB; NPA; 7-OH-DPAT; SCH-23390; spiperone; cis-flupenthixol; rat ID D-AMPHETAMINE; RECEPTOR AGONISTS; COCAINE; STEREOISOMERS; DEPRENYL; MONKEYS; USERS; CUE AB Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline Methods: In Srague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg) and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine, Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 27 TC 55 Z9 57 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2000 VL 148 IS 2 BP 209 EP 216 DI 10.1007/s002130050044 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 285HJ UT WOS:000085383400013 PM 10663437 ER PT J AU Heishman, SJ Schuh, KJ Schuster, CR Henningfield, JE Goldberg, SR AF Heishman, SJ Schuh, KJ Schuster, CR Henningfield, JE Goldberg, SR TI Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer SO PSYCHOPHARMACOLOGY LA English DT Article DE opioids; self-administration; progressive ratio; drug abuse; human ID CHOICE PROCEDURE; D-AMPHETAMINE; BEHAVIOR; COCAINE; HEROIN; METHYLPHENIDATE; MAINTENANCE; ABSTINENCE; SCHEDULE AB Rationale: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. Objective: We investigated the influence of morphine dose and an alternative non-drug reinforcer an choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. Methods: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single WI injection at the end of the session; money earned was credited to the subject's account. Results: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. Conclusion: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies. C1 NIDA, Clin Pharmacol & Therapeut Branch, Intramural Res Program, Baltimore, MD 21224 USA. Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA. Pinney Associates, Bethesda, MD 20814 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. NIDA, Preclin Pharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Heishman, SJ (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 21 Z9 21 U1 2 U2 3 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2000 VL 148 IS 3 BP 272 EP 280 DI 10.1007/s002130050051 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 298QE UT WOS:000086150000007 PM 10755740 ER PT J AU Doppman, JL Oldfield, EH Heiss, JD AF Doppman, JL Oldfield, EH Heiss, JD TI Symptomatic vertebral hemangiomas: Treatment by means of direct intralesional injection of ethanol SO RADIOLOGY LA English DT Article DE angioma, skeletal system; spinal cord, compression; spine, angiography; spine; spine, interventional procedures; spine ID SPINAL-CORD COMPRESSION; PERCUTANEOUS VERTEBROPLASTY; PREOPERATIVE EMBOLIZATION; METHYL-METHACRYLATE; ABSOLUTE ETHANOL; RESECTION; RELIEF AB PURPOSE: To describe the technique and results of injecting ethanol directly into symptomatic vertebral hemangiomas. MATERIALS AND METHODS: Eleven patients with paraplegia (n = 6) or radiculopathy (n = 5) due to vertebral hemangioma were treated by means of injecting ethanol (5-50 mt) directly into the lesion with computed tomographic (CT) guidance. CT angiograms were essential prior to treatment to identify functional vascular spaces of the hemangioma and direct needle placement. RESULTS: All hemangiomas were obliterated completely at follow-up angiography and gadolinium-enhanced magnetic resonance imaging. Five of six patients with paraplegia recovered completely: One who was treated recently was walking with assistance. Four of five patients with radiculopathy improved. No immediate complications were associated with ethanol injection. The two patients who received the largest volumes of ethanol, 42 and 50 mt, developed pathologic fractures of the involved vertebrae 4 and 16 weeks after treatment. CONCLUSION: Direct injection of ethanol into symptomatic vertebral hemangioma is an effective and safe treatment, provided the dose is less than 15 mL. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Doppman, JL (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 26 TC 86 Z9 91 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2000 VL 214 IS 2 BP 341 EP 348 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 279BL UT WOS:000085023400006 PM 10671579 ER PT J AU Avila, NA Chen, CC Chu, SC Wu, M Jones, EC Neumann, RD Moss, J AF Avila, NA Chen, CC Chu, SC Wu, M Jones, EC Neumann, RD Moss, J TI Pulmonary lymphangioleiomyomatosis: Correlation of ventilation-perfusion scintigraphy, chest radiography, and CT with pulmonary function tests SO RADIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting and Scientific Assembly of the Radiological-Society-of-North-America (RSNA) CY NOV 29-DEC 06, 1998 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE computed tomography (CT), comparative studies; computed tomography (CT), thin section; lung, CT; lung, cysts; lung, diseases; lymphangiomyomatosis; radiography, comparative studies; radionuclide imaging, comparative studies ID HIGH-RESOLUTION CT; HISTIOCYTOSIS-X; LYMPHANGIOMYOMATOSIS; TOMOGRAPHY AB PURPOSE: To determine the findings on ventilation-perfusion (V-P) scintigrams, computed tomographic (CT) scans, and chest radiographs and correlate them with pulmonary function test results in patients with lymphangioleiomyomatosis. MATERIALS AND METHODS: V-P scintigraphy, chest radiography, conventional and thin-section CT, and pulmonary function tests were performed in 39 patients. The images were graded on a scale of 0 (normal) to 3 (severely abnormal). RESULTS: Imaging abnormalities were found on 92% of ventilation scintigrams, 92% of perfusion scintigrams, 79% of chest radiographs, 100% of CT scans, and 100% of thin-section CT scans. On ventilation scintigrams, 28 (72%) patients demonstrated a speckling pattern. On CT scans, all patients had pulmonary cysts. Univariate analysis showed that extent of disease on chest radiographs and CT scans, cyst size, V-P abnormalities, and degree of speckling were inversely correlated with forced expiratory volume in one second (FEV1), diffusing capacity of lung for carbon monoxide, and the ratio of FEV1 to forced vital capacity (FVC) (P < .01) but not with FVC and total lung capacity. Larger cyst size correlated with extent of disease at CT, but not significantly (P = .056). CONCLUSION: Scintigraphic and radiologic abnormalities are seen in a majority of patients with lymphangioleiomyomatosis. On ventilation scintigrams, a frequently seen speckling pattern may be related to accumulation of radionuclide in pulmonary cysts-a hallmark of the disease at CT. Findings with each imaging modality correlate with certain pulmonary functions. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NHLBI, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Avila, NA (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bldg 10,Rm 1C-660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 26 TC 45 Z9 54 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2000 VL 214 IS 2 BP 441 EP 446 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 279BL UT WOS:000085023400019 PM 10671592 ER PT J AU Illei, GG Klippel, JH AF Illei, GG Klippel, JH TI Apheresis SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; THROMBOTIC THROMBOCYTOPENIC PURPURA; CHURG-STRAUSS-SYNDROME; RHEUMATOID-ARTHRITIS; PLASMA-EXCHANGE; RANDOMIZED TRIAL; PLASMAPHERESIS THERAPY; PULSE CYCLOPHOSPHAMIDE; DOUBLE-BLIND; VASCULITIS AB The removal of pathologic humors by various methods is an ancient medical remedy used in the management of diseases whose pathophysiology is poorly understood and whose effective treatment modalities are lacking. The contemporary means for such an approach involves apheresis, which is now possible due to advances in blood banking technologies. Apheresis has been used in most of the major rheumatic diseases, in particular systemic lupus erythematosus and rheumatoid arthritis. Although numerous case reports describe clinical benefits of apheresis in rheumatologic disorders, data from clinical trials are discouraging and suggest a limited role for apheresis in rheumatic disease management. C1 NIAMSD, Arthrit & Rheumat Branch, NIH, Bethesda, MD 20892 USA. Arthrit Fdn, Washington, DC USA. RP Illei, GG (reprint author), NIAMSD, Arthrit & Rheumat Branch, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. NR 50 TC 2 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-857X J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD FEB PY 2000 VL 26 IS 1 BP 63 EP + DI 10.1016/S0889-857X(05)70120-4 PG 12 WC Rheumatology SC Rheumatology GA 279QL UT WOS:000085056600006 PM 10680194 ER PT J AU Pietrini, P Furey, ML Guazzelli, M AF Pietrini, P Furey, ML Guazzelli, M TI In vivo study of the neurometabolic bases of normal and pathological brain function in humans - Clinical implications SO RIVISTA DI NEURORADIOLOGIA LA Italian DT Article; Proceedings Paper CT National Convention on Physics and Neuroradiology - Spectroscopy in Vivo and Functional MR Imaging CY MAY 06-07, 2000 CL PERUGIA, ITALY DE fMRI; PET; brain function ID STIMULATION C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Pisa, Dept Human & Environm Sci, I-56100 Pisa, Italy. Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56100 Pisa, Italy. NR 2 TC 0 Z9 0 U1 0 U2 0 PU EDIZIONI CENTAURO PI BOLOGNA PA VIA DEL PRATELLO, 8, 40122 BOLOGNA, ITALY SN 1120-9976 J9 RIV NEURORADIOL JI Riv. Neuroradiol. PD FEB PY 2000 VL 13 IS 1 BP 93 EP 94 PG 2 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 315TF UT WOS:000087128500016 ER PT J AU Stewart, PA Carel, R Schairer, C Blair, A AF Stewart, PA Carel, R Schairer, C Blair, A TI Comparison of industrial hygienists' exposure evaluations for an epidemiologic study SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE exposure assessment; formaldehyde ID AGREEMENT AB Objectives A study was conducted to determine what level of information is required by industrial hygienists before they can develop exposure estimates comparable with those developed from a more in-depth evaluation. Methods Three industrial hygienists evaluated formaldehyde exposures of 300 jobs selected from an earlier epidemiologic study. The jobs were evaluated over the following 6 cycles: (i) job title and industry; (ii) job title, industry, dates; (iii) job and department title and industry; (iv) cycle 3 information with dates; (iv) cycle 3 information with a plant report; and (vi) job and department title, industry, dates, and the report. Each hygienist assigned jobs to 1 of 4 exposure categories, which were compared with the categories in the original epidemiologic study. Results Overall, the mean differences between the hygienists' evaluations and the standard, although small, changed little over the cycles. The kappa statistic was poor to moderate for all the cycles, but the agreement was greater than expected due to chance. There was moderate improvement in overall agreement over the cycles using the weighted kappa statistic, but little improvement in the intraclass correlation coefficients of the hygienists' evaluations, which ranged from 0.4 to 0.5. Department information improved the agreement with the standard by 5-10%, but dates did not the improve agreement. There were some differences by type of plant, job function, exposure level, and date of the estimate. Using a hypothetical exposure-response scenario, this level of misclassification would have resulted in missing an association. Conclusions Although there was slight improvement with increasing levels of information, these findings suggest that the subjective categorical assessment of exposures by industrial hygienists will not produce exposure estimates comparable to more in-depth evaluations of exposure. C1 NCI, Environm Epidemiol Program, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Fac Hlth Sci, Div Community Hlth, Dept Occupat Med, Beer Sheva, Israel. RP Stewart, PA (reprint author), NCI, Environm Epidemiol Program, 6120 Execut Blvd,Room 8102 MSC 7240, Bethesda, MD 20892 USA. NR 15 TC 24 Z9 24 U1 0 U2 2 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD FEB PY 2000 VL 26 IS 1 BP 44 EP 51 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 291AU UT WOS:000085711200008 PM 10744177 ER PT J AU Zhang, WG Samelson, LE AF Zhang, WG Samelson, LE TI The role of membrane-associated adaptors in T cell receptor signalling SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Gads; Grb2; PLC-gamma 1 ID PROTEIN-TYROSINE KINASES; NATURAL-KILLER-CELLS; ANTIGEN RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOLIPASE C-GAMMA-1; SIGNALING PROTEINS; RAS PATHWAY; P85 SUBUNIT; SH3 DOMAIN; ACTIVATION AB Engagement of the T cell receptor lends to activation of several tyrosine kinases and phosphorylation of many intracellular;proteins. This is followed by Ca2+ mobilization and activation of multiple biochemical pathways, including the Ras/MAPK cascade, and several downstream serine/ threonine kinases. Membrane-associated adaptor proteins play an important role in T cell activation by coupling TCR ligation at the membrane to distal signalling cascades. Several new membrane associated adaptors have been identified in recent years. LAT (linker for activation of T cells) is an adaptor molecule, which following its phosphorylation associates with Grb2, Gads, PLC-gamma 1, and other signalling molecules. The functional importance of this molecule has been demonstrated by the study of LAT-deficient cell lines and LAT-deficient mice. Two other recently identified adaptor proteins, TRIM (T cell receptor interacting molecule) and SIT (SHP2-interacting transmembrane adaptor protein), which constitutively associate with several surface molecules, bind to PI3K and SHP2, respectively, after T cell activation and might also function in the TCR signalling pathway. C1 NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 42 TC 100 Z9 101 U1 0 U2 5 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2000 VL 12 IS 1 BP 35 EP 41 DI 10.1006/smim.2000.0205 PG 7 WC Immunology SC Immunology GA 286VG UT WOS:000085469100004 PM 10723796 ER PT J AU Wink, DA Miranda, KM Espey, MG AF Wink, DA Miranda, KM Espey, MG TI Effects of oxidative and nitrosative stress in cytotoxicity SO SEMINARS IN PERINATOLOGY LA English DT Review ID NITRIC-OXIDE PROTECTS; SUPEROXIDE; INSIGHTS; METALLOTHIONEIN; MECHANISMS; INHIBITION; BIOLOGY; INJURY C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 23 TC 17 Z9 18 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 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD FEB PY 2000 VL 24 IS 1 BP 20 EP 23 DI 10.1016/S0146-0005(00)80049-X PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 288FR UT WOS:000085552400006 PM 10709853 ER PT J AU Fishbein, M Pequegnat, W AF Fishbein, M Pequegnat, W TI Evaluating AIDS prevention interventions using behavioral and biological outcome measures SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED DISEASES; RANDOMIZED CONTROLLED TRIAL; HIV-INFECTION; SELF-REPORTS; CONDOM USE; EFFICACY; VALIDITY; IMPACT; BIAS AB Objective: To begin a dialogue on the role of behavioral and biological outcome measures in evaluating the effectiveness of behavior change interventions to reduce the risk of transmitting and acquiring HIV and other sexually transmitted diseases (STDs), Methods: A selective review of the literature was undertaken to identify issues and problems associated with the use of behavioral and biological outcome measures. In particular, the article considers the validity of self-reports and the theoretical relationships between behavioral and biological measures. Results: Available data suggest that when proper care is taken, behavioral self-reports are valid. Similarly, sensitive and specific diagnostic tests are available, particularly for bacterial STDs, However, even when diagnostic tests and behavioral self-reports provide valid data, one should not expect a simple relationship between behavioral and biological measures. Conclusion: Both behavioral and biological measures are important outcomes for studying the efficacy and effectiveness of behavior-change interventions. However, one measure cannot substitute for or validate the other, and neither serves as a true surrogate for HIV prevalence or incidence. Therefore, it is important to better understand the relationship among STDs, HIV, and self-reported condom use. To do this, it will first be use. C1 Univ Penn, Annenberg Sch Commun, Annenberg Publ Policy Ctr, Philadelphia, PA 19104 USA. NIMH, Off AIDS Res, Bethesda, MD 20892 USA. RP Fishbein, M (reprint author), Univ Penn, Annenberg Sch Commun, Annenberg Publ Policy Ctr, 3620 Walnut St, Philadelphia, PA 19104 USA. NR 28 TC 135 Z9 137 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD FEB PY 2000 VL 27 IS 2 BP 101 EP 110 DI 10.1097/00007435-200002000-00008 PG 10 WC Infectious Diseases SC Infectious Diseases GA 281RX UT WOS:000085175500008 PM 10676977 ER PT J AU Kibur, M af Geijerstamm, V Pukkala, E Koskela, P Luostarinen, T Paavonen, J Schiller, J Wang, Z Dillner, J Lehtinen, M AF Kibur, M af Geijerstamm, V Pukkala, E Koskela, P Luostarinen, T Paavonen, J Schiller, J Wang, Z Dillner, J Lehtinen, M TI Attack rates of human papillomavirus type 16 and cervical neoplasia in primiparous women and field trial designs for HPV16 vaccination SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article DE attack rate; cervical neoplasia; human papillomavirus; vaccination ID VIRUS-LIKE PARTICLES; POLYMERASE CHAIN-REACTION; HEPATITIS-B VACCINE; SERUM ANTIBODIES; NATURAL-HISTORY; INFECTION; CANCER; IMMUNIZATION; POPULATION; COHORT AB Background: Identification of human papillomavirus type 16 (HPV16) as the major risk factor for cervical neoplasia, and mass production of DNA free HPV capsids have paved the way to preventive vaccination trials. Design of such trials requires reliable attack rate data. Objective: Determination of (1) HPV16 and (2) cervical neoplasia attack rates in primiparous women. Estimation of actuarial sample sizes for HPV16 vaccination phase IV trials. Design: A longitudinal cohort study. Methods: Population based Finnish Maternity Cohort (FMC) and Finnish Cancer Registry (FCR) were linked for the identification of two cohorts of primiparous women: (1) a random subsample of the FMC: 1656 women with two pregnancies between 1983-9 or 1990-6 and living in the Helsinki metropolitan area, and (2) all 72 791 primiparous women living in the same area during 1983-94. Attack rate for persistent HPV16 infection (1) was estimated in 1279 seronegative women by proportion of seroconversions between the first and the second pregnancy. Comparable 10 year cumulative incidence rate (CR) of cervical intraepithelial neoplasia grade III and cervical cancer (CIN III+) (2) was estimated based on cases registered at the FCR during 1991-4. Results: The HPV16 attack rates were 13.8% (<18 years), 7.0% (18-19 years), 2.3% (21 years), 2.4% (23 years), and 4.5% (<25 years). Number of vaccinees required for a 5 year efficacy trial with persistent HPV16 infection as the end point ranged between 1000 and 3900, assuming 80% power, 90%-70% vaccine efficacy (VE), and misclassification. The CRs of CIN III+ were 0.33% (<18 years), 0.44% (18-19 years), 0.21% (20-24 years), and 0.28% (<25 years). Number of vaccinees required for a 10 year efficacy trial with HPV16 positive; CIN III+ as the end point was 15 000 assuming 80% power, 90% VE, and 75% aetiological fraction of CIN III+ for HPV16. Conclusions: The attack rates of HPV16 and CIN III+ identify primiparous women under 25 years of age among target populations for postnatal HPV vaccination at phase II/III trials. C1 Natl Publ Hlth Inst, Dept Infect Dis Epidemiol, SF-00300 Helsinki, Finland. Inst Clin & Expt Med, Dept Epidemiol & Biostat, Tallinn, Estonia. Karolinska Inst, Ctr Microbiol & Tumor Biol, Stockholm, Sweden. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Univ Helsinki, Helsinki, Finland. Natl Publ Hlth Inst, Dept Infect Dis & Epidemiol, Oulu, Finland. Univ Tampere, Sch Publ Hlth, FIN-33101 Tampere, Finland. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Lehtinen, M (reprint author), Natl Publ Hlth Inst, Dept Infect Dis Epidemiol, Mannerheimintie 166, SF-00300 Helsinki, Finland. NR 37 TC 20 Z9 20 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD FEB PY 2000 VL 76 IS 1 BP 13 EP 17 DI 10.1136/sti.76.1.13 PG 5 WC Infectious Diseases SC Infectious Diseases GA 293RM UT WOS:000085866900006 PM 10817062 ER PT J AU Albensi, BC Mattson, MP AF Albensi, BC Mattson, MP TI Evidence for the involvement of TNF and NF-kappa B in hippocampal synaptic plasticity SO SYNAPSE LA English DT Article DE long-term potentiation; long-term depression; hippocampal slice; synaptic plasticity; transcription; tumor necrosis factor ID TUMOR-NECROSIS-FACTOR; LONG-TERM POTENTIATION; BETA-AMYLOID-PRECURSOR; RAT DENTATE GYRUS; FACTOR-ALPHA; PEPTIDE TOXICITY; PROTECT NEURONS; GENE-EXPRESSION; BRAIN INJURY; MICE LACKING AB The cytokine tumor necrosis factor-alpha (TNF), well-known for its roles in cellular responses to tissue injury, has recently been shown to be produced in response to physiological activity in neuronal circuits. TNF stimulates receptors in neurons linked to the activation of the transcription factor NF-kappa B, and recent findings suggest that this signaling pathway can modulate neuronal excitability and vulnerability of neurons to excitotoxicity. Because data indicate that TNF is produced, and NF-kappa B activated, under conditions associated with learning and memory, we performed experiments in the hippocampal slice preparation aimed at elucidating roles for TNF and NF-kappa B in modulating synaptic plasticity. Whereas stimulation of Schaffer collateral axons at a frequency of 1 Hz induced long-term depression (LTD) of synaptic transmission in region CA1 of wild-type mice, LTD did not occur in slices from TNF receptor knockout mice. Stimulation at 100 Hz induced long-term potentiation (LTP) in slices from both wild-type mice and mice lacking TNF receptors. Basal transmission was unaltered in mice lacking TNF receptors. Pretreatment of slices from wild-type mice with kappa B decoy DNA prevented induction of LTD and significantly reduced the magnitude of LTP. Collectively, these data suggest important roles for TNF and signaling pathways that modulate NF-kappa B activity in regulation of hippocampal synaptic plasticity. (C) 2000 Wiley-Liss, Inc. C1 Univ Kentucky, Sanders Brown Res Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, GRC-4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Albensi, Benedict/F-7304-2010; Mattson, Mark/F-6038-2012 NR 49 TC 294 Z9 306 U1 0 U2 13 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2000 VL 35 IS 2 BP 151 EP 159 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 270UV UT WOS:000084556300008 PM 10611641 ER PT J AU Andersen, ME Meek, ME Boorman, GA Brusick, DJ Cohen, SM Dragan, YP Frederick, CB Goodman, JI Hard, GC O'Flaherty, EJ Robinson, DE AF Andersen, ME Meek, ME Boorman, GA Brusick, DJ Cohen, SM Dragan, YP Frederick, CB Goodman, JI Hard, GC O'Flaherty, EJ Robinson, DE TI Lessons learned in applying the US EPA proposed cancer guidelines to specific compounds SO TOXICOLOGICAL SCIENCES LA English DT Article DE chloroform; dichloroacetic acid; proposed cancer guidelines, US EPA; mode of action; margin of exposure; harmonization; modeling, toxicokinetic; evidence, preponderance of; risk assessment ID NONCANCER RISK ASSESSMENT; CHLORINATION BY-PRODUCTS; DRINKING-WATER SOURCE; GENOTOXICITY TEST DATA; RAT-LIVER MICROSOMES; FEMALE B6C3F(1) MICE; MALE F344 RATS; BLADDER-CANCER; SALMONELLA-TYPHIMURIUM; DICHLOROACETIC ACID AB An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted. C1 ILSI Hlth & Environm Sci Inst, Washington, DC 20036 USA. Colorado State Univ, Dept Environm Hlth, Ft Collins, CO 80523 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Covance Labs, Harrogate, England. Univ Nebraska, Med Ctr, Lincoln, NE 68583 USA. Ohio State Univ, Columbus, OH 43210 USA. Rohm & Haas Co, Philadelphia, PA 19105 USA. Michigan State Univ, E Lansing, MI 48824 USA. Amer Hlth Fdn, New York, NY 10017 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. RP Robinson, DE (reprint author), ILSI Hlth & Environm Sci Inst, 1126 16th St NW, Washington, DC 20036 USA. OI Andersen, Melvin/0000-0002-3894-4811 NR 86 TC 36 Z9 38 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2000 VL 53 IS 2 BP 159 EP 172 DI 10.1093/toxsci/53.2.159 PG 14 WC Toxicology SC Toxicology GA 283ZP UT WOS:000085306200002 PM 10696764 ER PT J AU Spalding, JW French, JE Stasiewicz, S Furedi-Machacek, M Conner, F Tice, RR Tennant, RW AF Spalding, JW French, JE Stasiewicz, S Furedi-Machacek, M Conner, F Tice, RR Tennant, RW TI Responses of transgenic mouse lines p53(+/-) and Tg center dot AC to agents tested in conventional carcinogenicity bioassays SO TOXICOLOGICAL SCIENCES LA English DT Article DE Tg center dot AC, p53(+/-); transgenic; mouse bioassays; cancer ID MICE; TUMORIGENESIS AB The haplo-insufficient p53 knockout (p53(+/-)) and zetaglobin v-Ha-ras (Tg.AC) transgenic mouse models were compared to the conventional two rodent species carcinogen bioassay by prospectively testing nine chemicals. Seven of the chemicals classified as carcinogens in the conventional bioassay induced tumors in the liver or kidneys of B6C3F(1) mice, and one (pentachlorophenol) also induced tumors in other tissues. Only three chemicals, furfuryl alcohol, pyridine, and pentachlorophenol, induced tumors in rats. The tumorigenic effect of pyridine was seen in F344 rats but not in Wistar strain rats. None of the chemicals induced tumors in the p53(+/-) transgenic mice, which is consistent with the absence of genotoxicity of these chemicals. Only two of the seven nongenotoxic carcinogens were positive in the Tg.AC model (lauric acid diethanolamine and pentachlorophenol). These results show that these transgenic models do not respond to many chemicals that show strain- or species-specific responses in conventional bioassays. C1 NIEHS, Lab Envirom Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Integrated Lab Syst, Res Triangle Pk, NC 27709 USA. RP Spalding, JW (reprint author), NIEHS, Lab Envirom Carcinogenesis & Mutagenesis, POB 12233, Res Triangle Pk, NC 27709 USA. EM spalding@niehs.nih.gov NR 24 TC 51 Z9 51 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2000 VL 53 IS 2 BP 213 EP 223 DI 10.1093/toxsci/53.2.213 PG 11 WC Toxicology SC Toxicology GA 283ZP UT WOS:000085306200007 PM 10696769 ER PT J AU Hard, GC Boorman, GA Wolf, DC AF Hard, GC Boorman, GA Wolf, DC TI Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-Mendel rats supports chronic renal tubule injury as the mode of action underlying the renal tumor response SO TOXICOLOGICAL SCIENCES LA English DT Article DE kidney; rat; adenoma; carcinoma; cytotoxicity; simple tubule hyperplasia; regeneration; karyomegaly; risk assessment ID REGENERATIVE CELL-PROLIFERATION; INDUCED NEPHROTOXICITY; RISK ASSESSMENT; B6C3F1 MICE; F344 RATS; TOXICITY; KIDNEYS; METABOLISM; GAVAGE; LIVER AB Chloroform, generally regarded as a non-genotoxic compound, is associated with the induction of liver and/or kidney tumors in laboratory mice and rats. In particular, chloroform produced renal tubule tumors in low incidence in male Osborne-Mendel rats when administered by corn-oil gavage or in the drinking water. There is a lack of data on intermediate endpoints that may be linked to renal cancer development in this strain of rat, in contrast to mice. Specifically, evidence linking chloroform-induced liver and kidney tumors in mice with cytotoxicity and regenerative cell proliferation is very strong, but weak in the rat. In the present study, kidney tissue from a carcinogenicity bioassay of chloroform in Osborne-Mendel rats was re-evaluated for histological evidence of compound-induced cytotoxicity and cell turnover. All rats treated with 1800 ppm (160 mg/kg/day, high-dose group) in the drinking water for 2 years and half the rats treated with 900 ppm (81 mg/kg/day) had mild to moderate changes in proximal convoluted tubules in the mid to deep cortex indicative of chronic cytotoxicity. Tubule alterations specifically associated with chronic chloroform exposure included cytoplasmic basophilia, cytoplasmic vacuolation, and nuclear crowding consistent with simple tubule hyperplasia. Occasional pyknotic cells, mitotic figures in proximal tubules, and prominent karyomegaly of the renal tubule epithelium were present. These alterations were not present in control groups or at the 200-ppm (19 mg/kg/day) or 400-ppm (38 mg/kg/day) dose levels. This new information adds substantially to the weight of evidence that the key events in chloroform-induced carcinogenicity in rat kidney include sustained cellular toxicity and chronic regenerative hyperplasia. C1 Amer Hlth Fdn, Valhalla, NY 10595 USA. NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27711 USA. RP Hard, GC (reprint author), Amer Hlth Fdn, 1 Dana Rd, Valhalla, NY 10595 USA. EM gordonhard@msn.com NR 41 TC 32 Z9 32 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2000 VL 53 IS 2 BP 237 EP 244 DI 10.1093/toxsci/53.2.237 PG 8 WC Toxicology SC Toxicology GA 283ZP UT WOS:000085306200009 PM 10696771 ER PT J AU Shimada, H Funakoshi, T Waalkes, MP AF Shimada, H Funakoshi, T Waalkes, MP TI Acute, nontoxic cadmium exposure inhibits pancreatic protease activities in the mouse SO TOXICOLOGICAL SCIENCES LA English DT Article DE cadmium; pancreas; trypsin; chymotrypsin; carboxypeptidase; mice ID WISTAR RATS; CARCINOGENICITY; CHLORIDE; METALS; MICE AB Toxic effects of cadmium on liver, kidney, lung, and testes have been well established in experimental animals and in cell model systems. However, little is known about the effect of cadmium on pancreas, though the pancreas has been reported to accumulate high concentrations of cadmium. Therefore, in this study we examined the effects of cadmium on the pancreas of mice. A single sc injection of 1 mg Cd/kg to mice had no obvious toxic effects on the liver, kidney, and pancreas at both 1 and 5 days after cadmium treatment. Within the pancreas, however, the activities of trypsin, chymotrypsin, and carboxypeptidase A were significantly decreased at 1 day after cadmium treatment, whereas the activity of carboxypeptidase B was not changed. All pancreatic enzyme activities returned to the control levels by 5 days after cadmium treatment. The concentrations of cadmium in pancreas were very similar at 1 and 5 days after cadmium treatment, indicating a stable deposition of the metal. The concentration of zinc in pancreas was markedly increased at 5 days after cadmium treatment. In order to more fully examine the inhibitory effects of cadmium on these protease activities in pancreas, the direct effects of cadmium on purified proteases were studied in vitro. Contrary to the results in vivo, cadmium increased the activity of purified trypsin in a concentration-dependent manner. Consistent with the in vivo results, the activity of purified carboxypeptidase A was decreased by cadmium treatment in a concentration-dependent fashion in vitro. The activities of chymotrypsin and carboxypeptidase B did not change by the cadmium exposure in vitro. The enhanced activity of trypsin by cadmium was returned to the control levels by subsequent treatment with EDTA, indicating that enhancement was reversible. In addition, the zinc normally contained in purified carboxypeptidase A and carboxypeptidase B was released by the cadmium treatment. These results indicate that cadmium inhibits protease activities within the pancreas in vivo at doses that do not induce overt hepatic, renal, or pancreatic toxicity. Based on in vitro study, the decreases seen in trypsin and chymotrypsin activities might be based on indirect effects of cadmium, whereas the decreases in carboxypeptidase A are probably due to the direct inhibition by the metal. C1 Kumamoto Univ, Fac Pharmaceut Sci, Dept Hyg Chem, Kumamoto 8620973, Japan. Kyushu Univ Nursing & Social Welf, Kumamoto 8650062, Japan. NIEHS, Natl Canc Inst, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Shimada, H (reprint author), Kumamoto Univ, Fac Pharmaceut Sci, Dept Hyg Chem, 5-1 Oe Honmachi, Kumamoto 8620973, Japan. NR 34 TC 18 Z9 20 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2000 VL 53 IS 2 BP 474 EP 480 DI 10.1093/toxsci/53.2.474 PG 7 WC Toxicology SC Toxicology GA 283ZP UT WOS:000085306200034 PM 10696796 ER PT J AU Hackstadt, T AF Hackstadt, T TI Redirection of host vesicle trafficking pathways by intracellular parasites SO TRAFFIC LA English DT Review DE chlamydia; intracellular parasites; vesicle trafficking ID MYCOBACTERIUM-TUBERCULOSIS PHAGOSOME; PARASITOPHOROUS VACUOLE MEMBRANE; CHLAMYDIA-TRACHOMATIS INCLUSION; LEGIONELLA-PNEUMOPHILA; TOXOPLASMA-GONDII; ENDOPLASMIC-RETICULUM; LYSOSOME FUSION; INFECTED-CELLS; SALMONELLA-TYPHIMURIUM; LEGIONNAIRES-DISEASE AB Bacterial and protozooan intracellular parasites have evolved diverse mechanisms for evasion of host cellular defenses associated with adaptations for survival in distinct intracellular compartments. As the reagents identifying discrete steps in vesicle maturation and trafficking have become increasingly available, it has become clear that the vacuoles occupied by intracellular parasites are much more diverse than had been previously appreciated. Many parasites induce selective fusion competence with the vacuoles they occupy, without affecting vesicular trafficking elsewhere in the cell. A likely means of controlling vesicular interactions is modification of the parasitophorous vacuole membrane by the insertion of parasite-specific proteins. A rapidly expanding class of bacterial proteins that modify the vacuolar membrane are the chlamydial inclusion membrane proteins. Although the functions of most of these proteins remain to be defined, the majority are expressed early in the infectious process, suggesting that modification of the vacuole is critical to the outcome of the host-parasite interaction. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Host Parasite Interact Sect, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Host Parasite Interact Sect, Hamilton, MT 59840 USA. NR 76 TC 67 Z9 69 U1 1 U2 2 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 FEB PY 2000 VL 1 IS 2 BP 93 EP 99 DI 10.1034/j.1600-0854.2000.010201.x PG 7 WC Cell Biology SC Cell Biology GA 325YZ UT WOS:000087706000001 PM 11208089 ER PT J AU Bradley, DW Hess, RA Tao, F Sciaba-Lentz, L Remaley, AT Laugharn, JA Manak, M AF Bradley, DW Hess, RA Tao, F Sciaba-Lentz, L Remaley, AT Laugharn, JA Manak, M TI Pressure cycling technology: a novel approach to virus inactivation in plasma SO TRANSFUSION LA English DT Article ID HIGH HYDROSTATIC-PRESSURE; HUMAN PARVOVIRUS B19; IMMUNODEFICIENCY VIRUS; BLOOD-TRANSFUSION; FROZEN PLASMA; PROTEIN; PRODUCTS AB BACKGROUND: Hydrostatic-pressure virus inactivation is a novel approach to the inactivation of pathogens in plasma and blood-derived components, that retains the therapeutic properties of these products. STUDY DESIGN AND METHODS: A custom-built apparatus was used to pressurize human plasma samples spiked with lambda phage. Phage titer and plasma protein activities were monitored after pressure treatment. RESULTS: Pressure-mediated inactivation of lambda phage was found to be an effective means for virus inactivation, particularly when performed at near-zero (0 degrees C) temperatures, rather than at temperatures above 20 degrees C and below -40 degrees C. The efficiency of inactivation was improved by an increase in applied pressure and repeated cycling from atmospheric to high pressure. In contrast, activities of plasma proteins alkaline phosphatase and total amylase did not vary with temperature and remained within 29 percent and 6 percent, respectively, of starting values after the same pressure treatments. By combining cycling, near-zero temperatures, and high pressure, phage titers in serum were reduced approximately 6 log after 10 to 20 minutes of treatment. Activities of plasma proteins IgG, IgM, and factor X were at 104 percent, 89 percent, and 80 percent, respectively, of starting values after 20 minutes of the same temperature and pressure treatment. CONCLUSION: High-pressure procedures may be useful for the inactivation of viruses in blood and other protein-containing components. C1 BBI Biotech Res Labs Inc, Gaithersburg, MD 20877 USA. BBI BioSeq Inc, Woburn, MA USA. BMA Labs, Woburn, MA USA. NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. RP Bradley, DW (reprint author), BBI Biotech Res Labs Inc, 217 Perry Pkwy, Gaithersburg, MD 20877 USA. EM mmanak@bbii.com OI Manak, Mark /0000-0002-9217-9129 NR 38 TC 39 Z9 46 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD FEB PY 2000 VL 40 IS 2 BP 193 EP 200 DI 10.1046/j.1537-2995.2000.40020193.x PG 8 WC Hematology SC Hematology GA 285ZT UT WOS:000085418800008 PM 10686003 ER PT J AU Handa, A Dickstein, B Young, NS Brown, KE AF Handa, A Dickstein, B Young, NS Brown, KE TI Prevalence of the newly described human circovirus, TTV, in United States blood donors SO TRANSFUSION LA English DT Article ID DNA VIRUS TTV; POSTTRANSFUSION HEPATITIS; UNKNOWN ETIOLOGY; INFECTION; SEQUENCES AB BACKGROUND: A novel nonenveloped single-stranded circular DNA virus (TTV) was recently identified. The prevalence of TTV in blood donors in the United States is, however, still unclear. STUDY DESIGN AND METHODS: Viral DNA was detected in US blood donors from five cities by using two sets of TTV primers: NG059/NG061/NG063 primers, which amplified the conserved region of strains 1 and 2, and T801/T935 primers, which amplified the 5' end region of the TTV sequence. A TTV antibody assay system was based on the detection of the truncated open reading frame (ORF)-1 (amino acids 1-411) from type 1b. The truncated ORF-1 was expressed as a fusion protein in Escherichia coli, and the fusion protein was used as the antigen in the antibody assay system. RESULTS: Viremia was detected in 21 (8.4%) of 250 donors by use of NG059/NG061/NG063 primers and 104 (41.6%) of 250 by use of T801/T935 primers. There was little correlation among the assays, which suggests the preferential detection of different strains with the different primers. TTV antibody was detected in 38 of 100 donors: 32 (84%) of 38 with concurrent TTV viremia and 6 (16%) of 38 without TTV viremia. TTV viremia and/or TTV antibody-positive samples were detected in 52 (52%) of 100 of US blood donors. CONCLUSION: Evidence of infection or exposure to TTV appears to be common among blood donors in United States. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Handa, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C218,9000 Rockville Pike, Bethesda, MD 20892 USA. EM handaa@nih.gov NR 25 TC 46 Z9 47 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2000 VL 40 IS 2 BP 245 EP 251 DI 10.1046/j.1537-2995.2000.40020245.x PG 7 WC Hematology SC Hematology GA 285ZT UT WOS:000085418800015 PM 10686010 ER PT J AU Burke, ZD Wells, T Carter, DA Baler, R AF Burke, ZD Wells, T Carter, DA Baler, R TI Use of a cryptic splice donor site in the chloramphenicol acetyltransferase (CAT)-SV40 small-t antigen cassette generates alternative transcripts in transgenic rats SO TRANSGENIC RESEARCH LA English DT Article DE chloramphenicol acetyltransferase (CAT); cryptic splice donor site; alternative splicing; SV40 small-t antigen; transgenic rat; reporter genes; circadian rhythms ID SEROTONIN N-ACETYLTRANSFERASE; PINEAL-GLAND; PROMOTER; RHYTHM AB The bacterial gene chloramphenicol acetyltransferase (CAT) is a widely used reporter in both in-vitro and in-vivo studies of genetic regulation. We have recently generated novel rat transgenic lines carrying an arylalkylamine N-acetyltransferase (AA-NAT) promoter-reporter construct in which CAT (with associated SV40 small-t antigen sequence) is the reporter. In addition to the predicted transgene transcript (1.9 kb), we identified an abundant 1.5 kb transcript which derives from an alternative splicing event that utilises a cryptic splice donor site located within the CAT gene. The native CAT open reading frame (ORF) is lost in the 1.5 kb transcript, and a western analysis has shown that protein deriving from an aberrant open reading frame is not expressed at detectable levels. C1 Univ Wales Coll Cardiff, Sch Biosci, Cardiff CF1 3US, S Glam, Wales. NICHD, Dev Neurobiol Lab, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Burke, ZD (reprint author), Univ Wales Coll Cardiff, Sch Biosci, POB 911,Museum Ave, Cardiff CF1 3US, S Glam, Wales. RI Wells, Timothy/A-6484-2010; Carter, David/A-4479-2010; OI Carter, David/0000-0002-8419-3975; Wells, Timothy/0000-0003-3618-0595 NR 10 TC 1 Z9 1 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD FEB PY 2000 VL 9 IS 1 BP 67 EP 70 DI 10.1023/A:1008928121846 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 322BW UT WOS:000087491200007 PM 10853270 ER PT J AU Ponting, CP AF Ponting, CP TI Novel repeats in ryanodine and IP3 receptors and protein O-mannosyltransferases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID MUSCLE SARCOPLASMIC-RETICULUM; MALIGNANT HYPERTHERMIA; MUTATIONS; ALIGNMENT; DOMAIN C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. RP Ponting, CP (reprint author), Univ Oxford, Dept Human Anat & Genet, MRC, Funct Genet Unit, S Parks Rd, Oxford OX1 3QX, England. NR 25 TC 48 Z9 48 U1 0 U2 4 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 FEB PY 2000 VL 25 IS 2 BP 48 EP 50 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 285ZA UT WOS:000085417200005 PM 10664581 ER PT J AU Makarova, KS Aravind, L Koonin, EV AF Makarova, KS Aravind, L Koonin, EV TI A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID PROTEIN; GENE; OTU; PROTEOLYSIS; CHROMOSOMES; GENERATION; PEPTIDASES; FAMILIES; SEQUENCE C1 Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Makarova, KS (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. NR 24 TC 162 Z9 169 U1 0 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 FEB PY 2000 VL 25 IS 2 BP 50 EP 52 DI 10.1016/S0968-0004(99)01530-3 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 285ZA UT WOS:000085417200006 PM 10664582 ER PT J AU Hobert, O Westphal, H AF Hobert, O Westphal, H TI Functions of LIM-homeobox genes SO TRENDS IN GENETICS LA English DT Review ID NAIL-PATELLA SYNDROME; LMX1B MUTANT MICE; MOUSE SPINAL-CORD; CAENORHABDITIS-ELEGANS; DIFFERENTIAL EXPRESSION; HOMEODOMAIN PROTEINS; VERTEBRATE LIMB; NERVOUS-SYSTEM; CELL LINEAGES; MOTOR-NEURONS AB Homeobox genes play fundamental roles in development. They can be subdivided into several subfamilies, one of which is the LIM-homeobox subfamily. The primary structure of LIM-homeobox genes has been remarkably conserved through evolution. Have their functions similarly been conserved? A host of new data has been derived from mutational analysis in diverse organisms, such as nematodes, flies and vertebrates. These studies have revealed a prominent involvement of LIM-homeodomain proteins in tissue patterning and differentiation, and their function in neural patterning is evident in all organisms studied to date. Here, we summarize the recent findings on LIM-homeobox gene function, compare the function of these genes from different organisms and describe specific cc-factor requirements. C1 Columbia Univ Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA. NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Hobert, O (reprint author), Columbia Univ Coll Phys & Surg, Dept Biochem & Mol Biophys, 701 W 168th St, New York, NY 10032 USA. OI Hobert, Oliver/0000-0002-7634-2854 NR 77 TC 289 Z9 299 U1 1 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2000 VL 16 IS 2 BP 75 EP 83 DI 10.1016/S0168-9525(99)01883-1 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 281AD UT WOS:000085135200012 PM 10652534 ER PT J AU Foster, MW Sharp, RR AF Foster, MW Sharp, RR TI Genetic research and culturally specific risks - one size does not fit all SO TRENDS IN GENETICS LA English DT Article ID INFORMED CONSENT; DIVERSITY; DISCRIMINATION; IDENTITY C1 Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Foster, MW (reprint author), Univ Oklahoma, Dept Anthropol, 455 W Lindsey,Room 515, Norman, OK 73019 USA. FU NHGRI NIH HHS [HG010302] NR 37 TC 28 Z9 28 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2000 VL 16 IS 2 BP 93 EP 95 DI 10.1016/S0168-9525(99)01895-8 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 281AD UT WOS:000085135200015 PM 10652537 ER PT J AU Segal, M Korkotian, E Murphy, DD AF Segal, M Korkotian, E Murphy, DD TI Dendritic spine formation and pruning: common cellular mechanisms? SO TRENDS IN NEUROSCIENCES LA English DT Article ID LONG-TERM POTENTIATION; RAT HIPPOCAMPAL-NEURONS; DENTATE GYRUS; MORPHOLOGICAL PLASTICITY; PYRAMIDAL CELLS; CEREBRAL-CORTEX; DENSITY; ESTRADIOL; SYNAPSES; MODEL AB The recent advent of novel high-resolution imaging methods has created a flurry of exciting observations that address a century-old question: what are biological signals that regulate formation and elimination of dendritic spines? Contrary to the traditional belief that the spine is a stable storage site of long-term neuronal memory, the emerging picture is of a dynamic structure that can undergo fast morphological variations. Recent conflicting reports on the regulation of spine morphology lead to the proposal of a unifying hypothesis for a common mechanism involving changes in postsynaptic intracellular Ca2+ concentration, [Ca2+](i): a moderate rise in [Ca2+](i) causes elongation of dendritic spines, while a very large increase in [Ca2+](i) causes fast shrinkage and eventual collapse of spines. This hypothesis provides a parsimonious explanation for conflicting reports on activity-dependent changes in dendritic spine morphology, and might link these changes to functional plasticity in central neurons. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NIH, Ctr Neurosci, Bethesda, MD 20892 USA. RP Segal, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. OI Korkotian, Eduard/0000-0001-5515-3387 NR 50 TC 106 Z9 107 U1 2 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD FEB PY 2000 VL 23 IS 2 BP 53 EP 57 DI 10.1016/S0166-2236(99)01499-X PG 5 WC Neurosciences SC Neurosciences & Neurology GA 302RJ UT WOS:000086379000003 ER PT J AU Walther, MM AF Walther, MM TI The role of photodynamic therapy in the treatment of recurrent superficial bladder cancer SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; EARLY CLINICAL-EXPERIENCE; LONG-TERM EXPERIENCE; 5-AMINOLEVULINIC ACID; PHOTOFRIN-II; IN-SITU; PHOTORADIATION THERAPY; LIGHT DOSIMETRY; PORFIMER SODIUM; SINGLET OXYGEN AB Photochemical sensitization resulting in cell fluorescence or cell death was first reported at the rum of the century. Subsequent observations of selective uptake of photosensitizing agents by tumors generated interest in the detection and treatment of cancer. In urologic practice, photodynamic therapy has been used as an experimental treatment for superficial bladder cancer. This article reviews the underlying principles of photodynamic therapy and clinical experience in treating superficial bladder tumors. Research currently centers on the development of new photosensitizes and methods of light administration to decrease dermal sensitivity and bladder toxicity. C1 NCI, Urol Oncol Branch, DCS, NIH, Bethesda, MD 20898 USA. RP Walther, MM (reprint author), NCI, Urol Oncol Branch, DCS, NIH, 9000 Rockville Pike,Bldg 10,Room 2B-43,10 Ctr Dr,, Bethesda, MD 20898 USA. NR 65 TC 17 Z9 20 U1 0 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD FEB PY 2000 VL 27 IS 1 BP 163 EP + DI 10.1016/S0094-0143(05)70244-5 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 281TR UT WOS:000085177300017 PM 10696255 ER PT J AU Atala, A Nyberg, LM AF Atala, A Nyberg, LM TI Tissue engineering SO WORLD JOURNAL OF UROLOGY LA English DT Editorial Material C1 Harvard Univ, Childrens Hosp, Sch Med, Dept Urol, Boston, MA 02115 USA. NIDDK, Urol Res Program, NIH, Bethesda, MD USA. RP Atala, A (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dept Urol, 300 Longwood Ave, Boston, MA 02115 USA. NR 3 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD FEB PY 2000 VL 18 IS 1 BP 1 EP 1 DI 10.1007/s003450050001 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 298WD UT WOS:000086161700001 ER PT J AU Yang, YG Chen, AM Garrett, LJ Sergio, JJ Theodore, P Awwad, M VerHalen, J Bodine, DM Sachs, DH Sykes, M AF Yang, YG Chen, AM Garrett, LJ Sergio, JJ Theodore, P Awwad, M VerHalen, J Bodine, DM Sachs, DH Sykes, M TI Development and analysis of transgenic mice expressing porcine hematopoietic cytokines: a model for achieving durable porcine hematopoietic chimerism across an extensive xenogeneic barrier SO XENOTRANSPLANTATION LA English DT Article DE bone marrow transplantation; cytokine; hematopoietic chimerism; transgenics; xenotransplantation ID BONE-MARROW TRANSPLANTATION; IMMUNE-DEFICIENT MICE; NONLETHAL PREPARATIVE REGIMEN; SCID MICE; IMMUNODEFICIENT MICE; ALLOGRAFT TOLERANCE; MIXED CHIMERISM; CELLS; ENGRAFTMENT; SWINE AB The capacity of mixed hematopoietic chimerism to induce tolerance has not been demonstrated in discordant xenogeneic species combinations because of the difficulty in achieving lasting hematopoietic engraftment. In an effort to create a model of long-lasting disparate xenogeneic hematopoietic chimerism, we have developed transgenic (Tg) mice carrying porcine cytokines. Three lines of Tg mice were generated: one carrying porcine IL-3 and GM-CSF genes only (termed IL/GM) and the remaining two lines carrying in addition, the soluble SCF gene (termed IL/GM/sS) or membrane-bound SCF gene (termed IL/GM/mS). Sera from mice with IL/GM and IL/GM/sS transgenes markedly stimulated the proliferation of swine marrow cells in vitro. However, proliferation of swine marrow cells was not induced in cultures containing IL/GM/mS sera. Consistent with these observations, ELISA assays revealed detectable levels of porcine cytokines in the sera of IL/GM and IL/GM/sS, but not in sera of IL/GM/mS Tg mice. Marrow stromal cells prepared from all three kinds of Tg mice, but not those from non-Tg littermates, were capable of supporting the growth of porcine hematopoietic cells in vitro. Immunodeficient Tg mice were generated by crossing Tg founders with C.B-17 SCID mice for five generations. All Tg immunodeficient mice showed improved porcine hematopoietic engraftment compared with non-Tg controls. These Tg mice provide a useful model system for studying porcine hematopoietic stem cells, and for evaluating the feasibility of donor-specific tolerance induction by mixed chimerism across highly disparate xenogeneic barriers. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, Boston, MA 02129 USA. NIH, Natl Ctr Human Genome Res, Lab Gene Transfer, Hematopoiesis Sect, Bethesda, MD 20892 USA. BioTransplant Inc, Charlestown, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [R01 HL 54038, R01 HL49915]; NIAID NIH HHS [P01 AI39755] NR 31 TC 13 Z9 14 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD FEB PY 2000 VL 7 IS 1 BP 58 EP 64 DI 10.1034/j.1399-3089.2000.00044.x PG 7 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 311YA UT WOS:000086912800008 PM 10809058 ER PT J AU Chang, RCC Rota, C Glover, RE Mason, RP Hong, JS AF Chang, RCC Rota, C Glover, RE Mason, RP Hong, JS TI A novel effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by electron paramagnetic resonance spectroscopy SO BRAIN RESEARCH LA English DT Article DE microglia; naloxone; superoxide; non-heme iron-nitrosyl complex; electron paramagnetic resonance ID ASTROCYTE-ENRICHED CULTURES; NITRIC-OXIDE; MIXED GLIA; CYTOKINE PRODUCTION; SUPEROXIDE RELEASE; ENDOTOXIN-SHOCK; CELL-DEATH; IRON; NITROSYLATION; INHIBITION AB Microglia as the first line of defensive cells in the brain produce free radicals including superoxide and nitric oxide (NO), contributing to neurodegeneration. An opioid receptor antagonist, naloxone, has been considered pharmacologically beneficial to endotoxin shock, experimental cerebral ischemia, and spinal cord injury. However, the mechanisms underlying these beneficial effects of naloxone are still not clear. This study explores the effects of naloxone on the production of superoxide and NO by the murine microglial cell line, BV2, stimulated with lipopolysaccharide (LPS) as measured by electron paramagnetic resonance (EPR). The production of superoxide triggered by phobol-12-myristate-13-acetate (PMA) resulted in superoxide dismutase (SOD)-inhibitable, catalase-uninhibitable 5,5-dimethyl-1-pyrroline N-oxide (DMPO) hydroxyl radical adduct formation. LPS enhanced the production of superoxide and triggered the formation of non-heme iron-nitrosyl complex. Cells pre-treated with naloxone showed significant reduction of superoxide production by 35%. However, it could not significantly reduce the formation of non-heme iron-nitrosyl complex and nitrite. Taken together, the results expand our understanding of the neutroprotective effects of naloxone as it decreases superoxide production by microglia. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, NIH, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Free Rad Metabolite Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, NIH, Neuropharmacol Sect, Lab Pharmacol & Chem, MD F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. RI Chang, Raymond Chuen-Chung/C-1107-2009 OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993 NR 26 TC 56 Z9 66 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 31 PY 2000 VL 854 IS 1-2 BP 224 EP 229 DI 10.1016/S0006-8993(99)02267-2 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 280UN UT WOS:000085122300028 PM 10784126 ER PT J AU Tao, T Davoodi, F Cho, CJ Skiadopoulos, MH Durbin, AP Collins, PL Murphy, BR AF Tao, T Davoodi, F Cho, CJ Skiadopoulos, MH Durbin, AP Collins, PL Murphy, BR TI A live attenuated recombinant chimeric parainfluenza virus (PIV) candidate vaccine containing the hemagglutinin-neuraminidase and fusion glycoproteins of PIV1 and the remaining proteins from PIV3 induces resistance to PIV1 even in animals immune to PIV3 SO VACCINE LA English DT Article DE recombinant; chimeric; parainfluenza virus; vaccine; live-attenuated; immunization schedule ID COLD-ADAPTED INFLUENZA; TYPE-3 VIRUSES; HETEROSUBTYPIC IMMUNITY; HEALTHY INFANTS; YOUNG-CHILDREN; BOVINE; INFECTION; MUTATIONS; RECOVERY; AGE AB Using a reverse genetics system for PIV3, we previously recovered recombinant chimeric PIV3-PIV1 virus bearing the major protective antigens of PIV1, the hemaglutinin-neuraminidase and fusion proteins, on a background of PIV3 genes bearing temperature sensitive (ts) and attenuating mutations in the L gene. Immunization of hamsters with this virus, designated rPIV3-1.cp45L, induced a high level of resistance to replication of wild type (wt) PIV1 and, surprisingly, also induced a moderate amount of restriction of the replication of PIV3 challenge virus. This suggested that some immunity is conferred by the internal PIV3 proteins shared by the two viruses. In the present study, we found that the immunity to PIV3 conferred by infection with rPIV3-1.cp45L is short-lived and completely disappeared four months after immunization, whereas resistance to replication of PIV3 induced by prior infection with PIV3 remains high even after an interval of four months. Since a live attenuated PIV1 vaccine such as the chimeric rPIV3-1.cp45L virus will likely be given to infants after a live attenuated PIV3 vaccine in a sequential immunization schedule, we examined the immunogenicity and efficacy of rPIV3-1.cp45L against PIV1 challenge in animals with and without prior immunity to PIV3. rPIV3-1.cp45L efficiently infected hamsters previously infected with wt or attenuated PIV3, but there was approximately a five-fold reduction in replication of rPIV3-1.cp45L virus in the PIV3-immune animals. This reduction in replication of rPIV3-1.cp45L in PIV3-immune animals was accompanied by a significant decrease in efficacy against PIV1 challenge. However, rPIV3-1.cp45L immunization of PIV3-immune animals induced a vigorous serum antibody response to PIV1 and reduced replication of PIV1 challenge virus 1000-fold in the lower respiratory tract and 25 to 200-fold in the upper respiratory tract. This study demonstrated that the recombinant chimeric rPIV3-1.cp45L candidate vaccine can induce immunity to PIV1 even in animals immune to PIV3. This establishes the feasibility of employing a sequential immunization schedule in which a recombinant chimeric rPIV3-1.cp45L vaccine is given following a live attenuated PIV3 vaccine. Published by Elsevier Science Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Tao, T (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. EM ttao@niaid.nih.gov NR 32 TC 38 Z9 38 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 31 PY 2000 VL 18 IS 14 BP 1359 EP 1366 DI 10.1016/S0264-410X(99)00406-5 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 277FY UT WOS:000084923100011 PM 10618533 ER PT J AU Coxon, B Sari, N Batta, G Pozsgay, V AF Coxon, B Sari, N Batta, G Pozsgay, V TI NMR spectroscopy, molecular dynamics, and conformation of a synthetic octasaccharide fragment of the O-specific polysaccharide of Shigella dysenteriae type 1 SO CARBOHYDRATE RESEARCH LA English DT Article DE C-13-labeling; conformation; NMR spectroscopy; octasaccharide; restrained molecular dynamics; Shigella dysenteriae type 1; simulated annealing; TOCSY; T-ROESY ID NUCLEAR-MAGNETIC-RESONANCE; COUPLING-CONSTANTS; ROTATING-FRAME; OLIGOSACCHARIDES; VACCINES; TOCSY AB A synthetic octasaccharide fragment (2) of the O-specific polysaccharide (1) of Shigella dysenteriae type 1 has been studied as its methyl glycoside by one- and two-dimensional homo- and heteronuclear NMR spectroscopy. Complete H-1 and C-13 NMR assignments have been generated, and the C-13 spin-lattice relaxation times have been measured for the octasaccharide 2. A congener (6) of this octasaccharide containing one D-galactose residue with a specific C-13 label at C-1 has been synthesized and used to measure interglycosidic C-13-H-1 coupling by the 2D J-resolved H-1 NMR method. From the NMR data, three types of conformational restraints were developed: (a) 29 inter-residue, distance restraints; (b) 48 intra-residue, ring atom dihedral angle restraints, and (c) one heteronuclear, inter-residue dihedral angle restraint. The use of these restraints in a restrained molecular dynamics computation with simulated annealing yielded a conformation resembling a short, irregular spiral, with methyl substituents on the exterior. Published by Elsevier Science Ltd. C1 Natl Inst Stand & Technol, Div Biotechnol, Gaithersburg, MD 20899 USA. Hungarian Acad Sci, Antibiot Res Grp, H-4010 Debrecen, Hungary. NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Coxon, B (reprint author), Natl Inst Stand & Technol, Div Biotechnol, 100 Bur Dr,Stop 8311, Gaithersburg, MD 20899 USA. RI Batta, Gyula/H-4567-2011 OI Batta, Gyula/0000-0002-0442-1828 NR 37 TC 8 Z9 9 U1 0 U2 0 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 JAN 29 PY 2000 VL 324 IS 1 BP 53 EP 65 DI 10.1016/S0008-6215(99)00278-5 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 283XN UT WOS:000085301500007 PM 10723612 ER PT J AU Lamensdorf, I He, LP Nechushtan, A Harvey-White, J Eisenhofer, G Milan, R Rojas, E Kopin, IJ AF Lamensdorf, I He, LP Nechushtan, A Harvey-White, J Eisenhofer, G Milan, R Rojas, E Kopin, IJ TI Effect of glipizide on dopamine synthesis, release and metabolism in PC12 cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE dopamine; tyrosine hydroxylase; sulfonylurea; glipizide; DOPAC (3,4-dihydroxyphenylacetic acid); HVA (homovalinic acid) ID BINDING CASSETTE TRANSPORTER; SENSITIVE K+ CHANNELS; ATP; SULFONYLUREAS; GLIBENCLAMIDE; MECHANISMS; SECRETION; CALCIUM; ABC1; LINE AB Sulfonylureas block ATP-dependent K+ channels (K/ATP channels) in pancreatic beta cells and brain gamma-aminobutyric acid (GABA) containing neurons causing depolarization-evoked insulin or GABA release. In high concentrations, sulfonylureas also inhibit catecholamine release from bovine adrenal chromaffin cells and isolated guinea pig aorta. In this study, we examined the effect of glipizide, a sulfonylurea, on dopamine release from PC12 cells and found that neither basal nor K+-stimulated dopamine release was affected. Although PC12 cells expressed mRNA for the K/ATP channel, functional K/ATP channels could not be demonstrated electrophysiologically, consistent with the lack of effect of glipizide on dopamine release. Glipizide did, however, increase cytoplasmic retention of the acidic dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), indicating blockade of their outward transport. The cellular accumulation of DOPAC was accompanied by reduced tyrosine hydroxylase activity and reduced formation of dopamine and its metabolites presumably by a negative feedback effect of the increased cytoplasmic concentrations of DOPAC. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, Clin Neurosci Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NINDS, Lab Cell Biochem & Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lamensdorf, I (reprint author), NINDS, Clin Neurosci Branch, Natl Inst Hlth, Bldg 10,Room GN252, Bethesda, MD 20892 USA. NR 29 TC 11 Z9 11 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 28 PY 2000 VL 388 IS 2 BP 147 EP 154 DI 10.1016/S0014-2999(99)00839-0 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 282LT UT WOS:000085220100004 PM 10666506 ER PT J AU Schetz, JA Sibley, DR AF Schetz, JA Sibley, DR TI Tandem sulfur-containing amino acids are epicritical determinants of dopamine D-2 receptor pharmacology SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE mutagenesis; allosteric modulator; catecholamine ID PROTEIN-COUPLED RECEPTORS; BINDING-SITE CREVICE AB The conserved aspartic acid that is required for ligand binding to the dopamine D-2 receptor is followed by three tandem sulfur-containing amino acids. While previous point mutation studies did not reveal any single one of these residues as being critical for ligand binding, we now show that simultaneously substituting all three with isovolumetric, non sulfur-containing amino acids results in large decreases in the binding affinity for dopamine, (-)-raclopride and 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl)butyloxy)-3,4-dihydro-2(1H)-quinolinone (aripiprazole), but not for methylspiperone or allosteric modulators. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, Expt Therapeut Branch, NIH, Bldg 10,Rm 5C-108,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 8 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 28 PY 2000 VL 388 IS 2 BP R5 EP R7 DI 10.1016/S0014-2999(99)00867-5 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 282LT UT WOS:000085220100012 PM 10666514 ER PT J AU Oleksiak, MF Wu, S Parker, C Karchner, SI Stegeman, JJ Zeldin, DC AF Oleksiak, MF Wu, S Parker, C Karchner, SI Stegeman, JJ Zeldin, DC TI Identification, functional characterization, and regulation of a new cytochrome P450 subfamily, the CYP2Ns SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARACHIDONIC-ACID METABOLISM; PROTEIN-KINASE-C; EPOXYEICOSATRIENOIC ACIDS; MOLECULAR-CLONING; 11,12-EPOXYEICOSATRIENOIC ACID; AMINO-ACID; EPOXYGENASE; EXPRESSION; ENZYMES; SEQUENCES AB The screening of liver and heart cDNA libraries from the teleost Fundulus heteroclitus with degenerate oligonucleotide probes to conserved alpha-helical regions in mammalian P450s resulted in the identification of two cDNAs that together represent a novel P450 subfamily, the CYP2Ns. Northern analysis demonstrated that CYP2N1 transcripts are most abundant in liver and intestine, whereas CYP2N2 mRNAs are most abundant in heart and brain. CYP2N1 and CYP2N2 proteins were co-expressed with NADPH cytochrome P450 oxidoreductase in Sf9 insect cells, and their ability to metabolize arachidonic acid and xenobiotic substrates was examined. Both CYP2N1. and CYP2N2 metabolize arachidonic acid to epoxyeicosatrienoic acids. Epoxidation is highly regio- and enantioselective with preferential formation of (8R,9S)-epoxyeicosatrienoic acid (optical purities are 91 and 90% for CYP2N1 and CYP2N2, respectively) and (11R,12S)-epoxyeicosatrienoic acid (optical purities are 92 and 70% for CYP2N1 and CYP2N2, respectively). CYP2N1 and CYP2N2 also catalyze the formation of a variety of hydroxyeicosatetraenoic acids. Both P450s have benzphetamine N-demethylase activities but show minimal alkoxyresorufin O-dealkylase activities. To investigate factors affecting CYP2N expression in vivo, CYP2N transcripts were examined following starvation and/or treatment with 12-O-tetradecanoyl phorbol-13-acetate. Intestinal CYP2N1 mRNAs decrease in starved and/or phorbol ester-treated fish, whereas intestinal CYP2N2 transcripts decrease only following phorbol ester treatment. Interestingly, cardiac CYP2N2 expression decreases following phorbol ester treatment but increases following starvation. These results demonstrate that members of this novel P450 subfamily encode early vertebrate forms of arachidonic acid catalysts that are widely expressed and are regulated by environmental factors. Given the wealth of information on the functional role of P450-derived arachidonate metabolites in mammals, we postulate that CYP2N1 and CYP2N2 products have similar biological functions in early vertebrates. The identity of the mammalian orthologue(s) of the CYP2Ns remains unknown. C1 NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA. RP NIEHS, Pulm Pathobiol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jstegeman@whoi.edu FU CSR NIH HHS [NA46RG0470] NR 76 TC 40 Z9 43 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2000 VL 275 IS 4 BP 2312 EP 2321 DI 10.1074/jbc.275.4.2312 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000012 PM 10644680 ER PT J AU Ritz, D Patel, H Doan, B Zheng, M Aring;slund, F Storz, G Beckwith, J AF Ritz, D Patel, H Doan, B Zheng, M Aring;slund, F Storz, G Beckwith, J TI Thioredoxin 2 is involved in the oxidative stress response in Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALKYL HYDROPEROXIDE REDUCTASE; DISULFIDE BOND FORMATION; SALMONELLA-TYPHIMURIUM; TRANSCRIPTION FACTOR; MUTANT THIOREDOXINS; EXPRESSION; GLUTAREDOXIN; ACTIVATION; CYTOPLASM; SEQUENCE AB Two genes encoding thioredoxin are found on the Escherichia coli genome. Both of them are capable of reducing protein disulfide bonds in vivo and in vitro. The catalytic site contains a Cys-X-1-X-2-Cys motif in a so-called thioredoxin fold. Thioredoxin 2 has two additional pairs of cysteines in a non-conserved N-terminal domain. This domain does not appear to be important for the function of thioredoxin 2 in donating electrons to ribonucleotide reductase, 3'-phosphoadenylsulfate-reductase, or the periplasmic disulfide isomerase DsbC. Our results suggests that the two thioredoxins are equivalent for most of the in vivo functions that were tested. On the other hand, transcriptional regulation is different. The expression of trxC is regulated by the transcriptional activator OxyR in response to oxidative stress. Oxidized OxyR binds directly to the trxC promoter and induces its expression in response to elevated hydrogen peroxide levels or the disruption of one or several of the cytoplasmic redox pathways. Mutants lacking thioredoxins 1 and 2 are more resistant to high levels of hydrogen peroxide, whereas they are more sensitive to diamide, a disulfide bond-inducing agent. C1 Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. NICHHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. EM Jon_Beckwith@hms.harvard.edu OI Storz, Gisela/0000-0001-6698-1241 FU NIGMS NIH HHS [GM41883] NR 36 TC 99 Z9 100 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2000 VL 275 IS 4 BP 2505 EP 2512 DI 10.1074/jbc.275.4.2505 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000038 PM 10644706 ER PT J AU Nemes, Z Demeny, M Marekov, LN Fesus, L Steiner, PM AF Nemes, Z Demeny, M Marekov, LN Fesus, L Steiner, PM TI Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase 1 activity from the formation of cross-links and esters to the hydrolysis of glutamine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN STRATUM-CORNEUM; PROTEIN-KINASE-C; CELL-ENVELOPE; KERATINOCYTE TRANSGLUTAMINASE; LAMELLAR ICHTHYOSIS; SUBSTRATE PROPERTIES; STRUCTURAL PROTEINS; ETA-ISOFORM; SULFATE; GENE AB The loss of transglutaminase 1 enzyme (TGase 1) activity causes lamellar ichthyosis, Recessive X-linked ichthyosis (XI) results from accumulation of excess cholesterol 3-sulfate (CSO4) in the epidermis but the pathomechanism how elevated epidermal CSO4 causes ichthyosis is largely unknown. Here we provide evidence that III is also a consequence of TGase 1 dysfunction. TGase 1 is a key component of barrier formation in keratinocytes: it participates in the cross-linking of cell envelope (CE) structural proteins, and also forms the lipid bound envelope by esterification of long chain omega-hydroxyceramides onto CE proteins. Using involucrin and an epidermal omega-hydroxyceramide analog as substrates, kinetic analyses revealed that at membrane concentrations above 4 mol %, CSO4 caused a marked and dose-dependent inhibitory effect on isopeptide and ester bond formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed a large increase in deamidation of substrate glutamines. me hypothesize that supraphysiological levels of CSO4 in keratinocyte membranes distort the structure of TGase 1 and faoilitate the access of water into its active site causing hydrolysis of substrate glutamine residues. Our findings provide further evidence for the pivotal role of the TGase 1 enzyme in CE formation. C1 NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Debrecen, Sch Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. RP Steiner, PM (reprint author), NIAMS, NIH, Bldg 6,Rm 425, Bethesda, MD 20892 USA. EM pemast@helix.nih.gov NR 55 TC 38 Z9 39 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2000 VL 275 IS 4 BP 2636 EP 2646 DI 10.1074/jbc.275.4.2636 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000056 PM 10644724 ER PT J AU Zhang, Y Dufau, ML AF Zhang, Y Dufau, ML TI Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETINOIC ACID RECEPTOR; COUP-TF; TARGET GENES; SUPERFAMILY; HETERODIMERS; EXPRESSION; PROMOTER; MEMBER; CELLS; IDENTIFICATION AB imperfect estrogen receptor half-site response element direct-repeat, located within the TATA-less promoter of the human luteinizing hormone receptor (hLHR), was identified as an inhibitory site for Sp1/Sp3-driven basal transcription. Isolation of proteins recognizing this site by yeast one-hybrid screening of a human placenta cDNA library revealed three nuclear orphan receptors, EARS, EAR3/COUP-TFI, and TR4. Electrophoresis mobility shift assays demonstrated that the in vitro translated nuclear orphan receptors specifically bound the direct-repeat motif of the hLHR promoter. Also, endogenous EARS and EAR3/COUP-TFI from JAR cell and human testis and TR4 from testes bound this motif in electrophoresis mobility shift assays. Functional analyses in CV-1 cells showed that EARS and EAR3/COUP-TFI repressed the hLHR promoter activity by up to 70% in a dose dependent and sequence-specific manner. Conversely, TR4 activated the hLHR promoter activity up to 2.5-fold through binding to the same cis-element. The stimulation was reversed by coexpression of EARS or EARS/COUP-TFI, indicating their competitive binding for this site. Such recognition of a common cognate site by the proteins with antagonistic functions implies that a net regulation of the hLHR gene may result from the relative availability of repressors and activator in a physiological state. This also may contribute to the differential expression of the hLHR gene in gonadal and non-gonadal tissues. C1 NICHD, Endocrinol & Reprod Res Branch, Sect Mol Endocrinol, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, Endocrinol & Reprod Res Branch, Sect Mol Endocrinol, NIH, Bldg 49,Rm 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. NR 29 TC 38 Z9 42 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 JAN 28 PY 2000 VL 275 IS 4 BP 2763 EP 2770 DI 10.1074/jbc.275.4.2763 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000072 PM 10644740 ER PT J AU MacLachlan, TK Somasundaram, K Sgagias, M Shifman, Y Muschel, RJ Cowan, KH El-Deiry, WS AF MacLachlan, TK Somasundaram, K Sgagias, M Shifman, Y Muschel, RJ Cowan, KH El-Deiry, WS TI BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYMERASE-II HOLOENZYME; TRANSCRIPTIONAL ACTIVATION; DEPENDENT KINASES; CDK INHIBITORS; TNF RECEPTOR-1; GROWTH-ARREST; CANCER-CELLS; P53; PROTEIN; BREAST AB The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase ac cumulation, High density cDNA array screening of colon, lung and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control, Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways. C1 Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regual, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Canc, Philadelphia, PA 19104 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP El-Deiry, WS (reprint author), Univ Penn, Sch Med, Lab Mol Oncol & Cell Cycle Regual, Philadelphia, PA 19104 USA. NR 52 TC 166 Z9 177 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 JAN 28 PY 2000 VL 275 IS 4 BP 2777 EP 2785 DI 10.1074/jbc.275.4.2777 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000074 PM 10644742 ER PT J AU Vogel, K Cabaniols, JP Roche, PA AF Vogel, K Cabaniols, JP Roche, PA TI Targeting of SNAP-25 to membranes is mediated by its association with the target SNARE syntaxin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYNAPTOSOMAL-ASSOCIATED PROTEIN; AXONAL-TRANSPORT; SYNAPTIC VESICLES; PALMITOYLATION; COMPLEX; PALMITOYLTRANSFERASE; MYRISTOYLATION; SYNAPTOBREVIN; INSERTION; MACHINERY AB The docking and fusion of synaptic vesicles with the presynaptic plasma membrane require the interaction of the vesicle-associated membrane protein VAMP with the plasma membrane proteins syntaxin and SNAP-25, Both of these proteins behave as integral membrane proteins, although they are unusual in that they insert into membranes post-translationally. Whereas VAMP and syntaxin possess hydrophobic transmembrane domains, SNAP-25 does not, and it is widely believed that SNAP-25 traffics to and inserts into membranes by posttranslational palmitoylation. In pulse-chase biosynthesis studies, we now show that SNAP-25 and syntaxin rapidly bind to each other while still in the cytosol of neuroendocrine and transfected heterologous cells. Cell fractionation studies revealed that cytosolic SNAP-25 .syntaxin complexes then traffic to and insert into membranes. Furthermore, the association of SNAP-25 with membranes is dramatically enhanced by syntaxin, and the transmembrane domain of syntaxin is essential for this effect. Surprisingly, despite the importance of the SNAP-25 palmitoylation domain for membrane anchoring at steady state, removal of this domain did not inhibit the initial association of newly synthesized SNAP-25 with membranes in the presence of syntaxin. These data demonstrate that the initial attachment of newly synthesized SNAP-25 to membranes is a consequence of its association with syntaxin and that it is only after syntaxin-mediated membrane tethering that SNAP-25 is palmitoylated. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. NR 33 TC 54 Z9 55 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 JAN 28 PY 2000 VL 275 IS 4 BP 2959 EP 2965 DI 10.1074/jbc.275.4.2959 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 280XA UT WOS:000085128000098 PM 10644766 ER PT J AU Borlongan, CV Stahl, CE Keep, MF Elmer, E Watanabe, S AF Borlongan, CV Stahl, CE Keep, MF Elmer, E Watanabe, S TI Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats SO NEUROSCIENCE LETTERS LA English DT Article DE immunosuppression; cholinergic system; septum; Alzheimer's disease; neurotrophic effects; calcineurin; mitochondrial permeability transition pore ID BRAIN; NEURONS; INJECTION; PROTECTS; STRIATUM; ISCHEMIA; INJURY; FK-506; DAMAGE; FK506 AB Cydosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for-the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system. Published by Elsevier Science Ireland Ltd. C1 NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. William Beaumont Army Med Ctr, Dept Internal Med, El Paso, TX 79920 USA. Maas BioIAB LLC, Honolulu, HI 96817 USA. Univ Hawaii, Pacific Biomed Res Ctr, Lab Matrix Pathobiol, Honolulu, HI 96822 USA. Wallenberg Neurosci Ctr, Expt Brain Res Lab, Dept Clin Neurosci, S-22185 Lund, Sweden. Keio Univ, Dept Psychol, Minato Ku, Tokyo 108, Japan. RP Borlongan, CV (reprint author), NIDA, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Elmer, Eskil/F-9341-2014; OI Elmer, Eskil/0000-0001-7901-1826; Borlongan, Cesar/0000-0002-2966-9782 NR 20 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 28 PY 2000 VL 279 IS 2 BP 73 EP 76 DI 10.1016/S0304-3940(99)00962-3 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 281GB UT WOS:000085148600002 PM 10674624 ER PT J AU Park, HC Hong, SK Kim, HS Kim, SH Yoon, EJ Kim, CH Miki, N Huh, TL AF Park, HC Hong, SK Kim, HS Kim, SH Yoon, EJ Kim, CH Miki, N Huh, TL TI Structural comparison of zebrafish elav/Hu and their differential expressions during neurogenesis SO NEUROSCIENCE LETTERS LA English DT Article DE zebrafish; HuA; HuG; HuD; HuC; neural plate; neuronal differentiation; neuronal determination ID RNA-BINDING PROTEIN; ISLET-1; FAMILY AB The present communication reports the isolation and characterization of three new zebrafish elav/Hu (Kim, C.-H., Ueshima, E., Muraoka, O., Tanaka, H., Yeo, S.-Y., Huh, T.-L. and Miki, N., Zebrafish elav/HuC homologue as a very early neuronal marker. Neurosci. Lett., 216 (1996) 109-112) homologues, HUA, HUD and HUG. While HuA and HUG showed weak and ubiquitous expressions, HUD, as well as HuC, were specifically expressed in the neuronal cells. The first expression of HuD was detectable of the 10-somite stage, that is, several hours later than HUG. After 24 h of embryonic development, although HuD and HuC expressions overlapped overall, the cells expressing HUD were restricted to subsets of the HuC-positive neuronal cells in the brain and spinal cord. These differentially regulated spatial and temporal expression patterns implied distinct roles for HUC and HUD in neuronal determination and neuronal differentiation, respectively. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Osaka Univ, Sch Med, Dept Pharmacol, Suita, Osaka 5650871, Japan. RP Huh, TL (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. NR 16 TC 49 Z9 49 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 28 PY 2000 VL 279 IS 2 BP 81 EP 84 DI 10.1016/S0304-3940(99)00940-4 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 281GB UT WOS:000085148600004 PM 10674626 ER PT J AU Schechter, AN Rodgers, GP AF Schechter, AN Rodgers, GP TI Sickle cell anemia therapy: Progress since Pauling SO SCIENCE LA English DT Letter C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 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 JAN 28 PY 2000 VL 287 IS 5453 BP 592 EP 592 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278KR UT WOS:000084989400019 PM 10691539 ER PT J AU Jiang, Y Haxby, JV Martin, A Ungerleider, LG Parasuraman, R AF Jiang, Y Haxby, JV Martin, A Ungerleider, LG Parasuraman, R TI Complementary neural mechanisms for tracking items in human working memory SO SCIENCE LA English DT Article ID PREFRONTAL CORTEX; RETRIEVAL; FMRI AB Recognition of a specific visual target among equally familiar distracters requires neural mechanisms for tracking items in working memory. Event-related functional magnetic resonance imaging revealed evidence for two such mechanisms: (i) Enhanced neural responses, primarily in the frontal cortex, were associated with the target and were maintained across repetitions of the target. (ii) Reduced responses, primarily in the extrastriate visual cortex, were associated with stimulus repetition, regardless of whether the stimulus was a target or a distracter, These complementary neural mechanisms track the status of familiar items in working memory, allowing for the efficient recognition of a currently relevant object and rejection of irrelevant distracters. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. RP Jiang, Y (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RI martin, alex/B-6176-2009 FU NIA NIH HHS [AG07569] NR 21 TC 124 Z9 140 U1 3 U2 10 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 JAN 28 PY 2000 VL 287 IS 5453 BP 643 EP 646 DI 10.1126/science.287.5453.643 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 278KR UT WOS:000084989400045 PM 10649996 ER PT J AU Pozsgay, V AF Pozsgay, V TI A new strategy in oligosaccharide synthesis using lipophilic protecting groups: synthesis of a tetracosasaccharide SO TETRAHEDRON-ASYMMETRY LA English DT Article ID POLYSACCHARIDE; GLYCOSYLATION AB The use of lipophilic, acyl-type protecting groups in the synthesis of higher-membered oligosaccharides is described by the example of oligosaccharides corresponding to the O-specific polysaccharide (O-SP) of Shigella dysenteriae type 1. Thus, O-stearoylated and O-lauroylated L-rhamnose and D-galactose precursors, respectively, were synthesized and were combined together with a 2-azido-2-deoxy-D-glucopyranosyl donor to form a fully protected lipidated repeating unit of the O-SP. This module was condensed with another tetrasaccharide containing conventional blocking groups. The resulting lipidated octasaccharide was isolated in a pure form by adsorption to a reverse phase adsorbent from which it could be selectively desorbed by alcoholic solvents. Subsequent chain elongation using the conventionally protected tetrasaccharide module as glycosyl donor afforded oligosaccharides up to and including a tetracosasaccharide. The proposed approach can substantially alleviate the difficulties associated with the conventional silica gel chromatographic purification of protected oligosaccharide intermediates and utilizes environmentally friendly solvents that are less expensive than the solvents used for silica gel chromatography. A new, highly efficient method is also proposed for the synthesis of carbohydrate acetals and cyclic orthoesters employing scandium trifluoromethanesulfonate as the catalyst. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), NICHHD, NIH, 6 Ctr Dr,MSC 2720, Bethesda, MD 20892 USA. NR 22 TC 28 Z9 28 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0957-4166 J9 TETRAHEDRON-ASYMMETR JI Tetrahedron: Asymmetry PD JAN 28 PY 2000 VL 11 IS 1 BP 151 EP 172 DI 10.1016/S0957-4166(99)00553-4 PG 22 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic; Chemistry, Physical SC Chemistry GA 292ML UT WOS:000085798700012 ER PT J AU Elbaum, D Brzyska, M Bacia, A Alkon, DL AF Elbaum, D Brzyska, M Bacia, A Alkon, DL TI Implication of novel biochemical property of beta-amyloid SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID FREE-RADICAL GENERATION; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; HYDROGEN-PEROXIDE; PEPTIDE; TOXICITY; PROTEOLYSIS; INHIBITORS; FRAGMENTS; MECHANISM AB Alzheimer disease (AD) is a heterogeneous disorder with a variety of molecular pathologies converging predominantly on abnormal amyloid deposition particularly in the brain. beta-Amyloid aggregation into senile plaques is one of the pathological hallmarks of AD. beta-Amyloid is generated by a proteolytic cleavage of a large membrane protein, amyloid precursor protein (APP). We have observed a new property of beta-amyloid. The amyloid 1-42 beta fragment, when aggregated, possesses proteolytic and esterase like activity, in vitro. Three independent methods were used to test the new property of beta-amyloid, While esterase activity involves imidazole catalysis, proteolytic activity is consistent with participation of a serine peptidase triad: catalytic Ser, His and Glu (or Asp). Although the amino acid triad is a necessary requirement for the protease reactivity, it is not sufficient since the secondary structure of the protein significantly contributes to the proteolytic activity. The ability of beta-amyloid to cleave peptide or ester bonds could be thus responsible for either inactivation of other proteins and/or APP proteolysis itself. This property may be responsible for early pathogenesis of AD since there is emerging evidence that non-plaque amyloid is elevated in Alzheimer patients. (C) 2000 Academic Press. C1 M Nencki Inst Expt Biol, Lab Biophys Methods, PAN, PL-02093 Warsaw, Poland. NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Elbaum, D (reprint author), M Nencki Inst Expt Biol, Lab Biophys Methods, PAN, Ul Pasteura 3, PL-02093 Warsaw, Poland. NR 34 TC 7 Z9 7 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 JAN 27 PY 2000 VL 267 IS 3 BP 733 EP 738 DI 10.1006/bbrc.1999.2024 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 280YR UT WOS:000085131800010 PM 10673360 ER PT J AU Mayeux-Portas, V File, SE Stewart, CL Morris, RJ AF Mayeux-Portas, V File, SE Stewart, CL Morris, RJ TI Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food SO CURRENT BIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; ATAXIA-TELANGIECTASIA; DENTATE GYRUS; MUTANT MICE; PRION PROTEIN; IN-VITRO; GENE; MEMORY; INHIBITION; RECEPTORS AB Background: Thy-1 is a major cell-surface glycoprotein of mature neurons and certain other cells, including those of the lymphoreticular system. Despite being the simplest member of the immunoglobulin superfamily, the biological role of Thy-1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively, without any neurological or behavioural effects being apparent. Results: We show here that Thy-1 null mice are unable to make the appropriate dietary choice in the test for social transmission of food preference, despite showing a normal level of social interaction with the demonstrator mouse, normal neophobia, and normal learning in a T-maze using scented food as cues. The mice also performed normally in tests of anxiety, locomotor activity, exploration of a novel environment, habituation to novelty and spatial learning. This phenotype is maintained on two different strain backgrounds, is rescued by transgenic expression of Thy-1 and by administration of the GABA, receptor antagonist pentylenetetrazole. Conclusions: The test for social transmission of food preference is based on the normal ability of mice in a colony to learn from each other which foods are safe to eat. The lack of this key survival behaviour in Thy-1 null mice could act as an evolutionary pressure point to conserve expression of Thy-1. Furthermore, the specific cognitive defect caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to determine the role of Thy-1 in certain human familial forms of mental retardation that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the nearby ataxia telangiectasia locus. C1 GKT Med Sch, Mol Neurobiol Grp, London SE1 1UL, England. GKT Sch Biomed Sci, Psychopharmacol Res Unit, London SE1 1UL, England. NCI, Frederick Canc Res & Dev Ctr, Lab Canc & Dev Biol, Frederick, MD 21710 USA. RP Morris, RJ (reprint author), GKT Med Sch, Mol Neurobiol Grp, Guys Campus, London SE1 1UL, England. NR 48 TC 31 Z9 31 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 27 PY 2000 VL 10 IS 2 BP 68 EP 75 DI 10.1016/S0960-9822(99)00278-X PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 279KC UT WOS:000085042100017 PM 10662668 ER PT J AU Aravind, L Koonin, EV AF Aravind, L Koonin, EV TI The STAS domain - a link between anion transporters and antisigma-factor antagonists SO CURRENT BIOLOGY LA English DT Letter ID DYSPLASIA SULFATE-TRANSPORTER; TRANSCRIPTION FACTOR SIGMA(F); BACILLUS-SUBTILIS; PSI-BLAST; GENE; MUTATIONS; PROTEIN; SPOIIAA; FAMILY C1 Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. NR 21 TC 130 Z9 133 U1 0 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 27 PY 2000 VL 10 IS 2 BP R53 EP R55 DI 10.1016/S0960-9822(00)00335-3 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 279KC UT WOS:000085042100006 PM 10662676 ER PT J AU Zhang, SX Feng, J Kuo, SC Brossi, A Hamel, E Tropsha, A Li, KH AF Zhang, SX Feng, J Kuo, SC Brossi, A Hamel, E Tropsha, A Li, KH TI Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIMITOTIC NATURAL-PRODUCTS; BIOLOGICAL EVALUATION; TUBULIN POLYMERIZATION; ANTITUBULIN ACTIVITY; THIOCOLCHICINE ANALOGS; ESTER ANALOGS; INHIBITION; 2-PHENYL-4-QUINOLONES; ALLOTHIOCOLCHICINOIDS; CONFIGURATION AB Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesis of a number of colchicine site agents, such as thiocolchicinoids and allocolchicinoids, which are colchicine analogues, and 2-phenylquinolones and 2-aryl-naphthyridinones, which are the amino analogue a of cytotoxic antimitotic flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)-GRS CoMFA to identify the essential structural requirements for increasing the ability of these compounds to form tubulin complexes. The CoMFA model for the training set of 51 compounds yielded cross-validated. R-2 (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this model was confirmed by successful activity prediction for a test set of 53 compounds with known potencies as inhibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predictive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546) was analyzed in detail in terms of underlying structure-activity relationships. C1 Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Pharm, Lab Mol Modeling, Chapel Hill, NC 27599 USA. China Med Coll, Grad Inst Pharmaceut Chem, Taichung 400, Taiwan. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Canc Res Ctr, Ft Detrick, MD 21702 USA. RP Tropsha, A (reprint author), Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. RI Tropsha, Alexander/G-6245-2014 FU NCI NIH HHS [CA 17625] NR 41 TC 85 Z9 89 U1 1 U2 8 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 JAN 27 PY 2000 VL 43 IS 2 BP 167 EP 176 DI 10.1021/jm990333a PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 279FP UT WOS:000085034000005 PM 10649972 ER PT J AU Saavedra, JE Shami, PJ Wang, LY Davies, KM Booth, MN Citro, ML Keefer, LK AF Saavedra, JE Shami, PJ Wang, LY Davies, KM Booth, MN Citro, ML Keefer, LK TI Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: In vitro antileukemic activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FLOW-CYTOMETRY; APOPTOSIS; HYPOTENSION; DELIVERY; DESIGN; CELLS; NO AB We have designed a novel prodrug class that is stable in neutral aqueous media but releases bioactive nitric oxide (NO) on metabolism by esterase. Diazeniumdiolates of structure R2N-N(O)=N-OR', in which R' = Na, were reacted with BrCH2OAc to convert the spontaneously NO-releasing salts 1a (R2N = diethylamino) and 1b (R2N = pyrrolidino) to prodrugs 2a (AcOM-DEA/NO) and 2b (AcOM-PYRRO/NO), respectively, where R' = CH2OAc. In contrast to anions la and Ib (half-lives in pH 7.4 phosphate at 37 degrees C of 2 min and 3 s, respectively), 2a and 2b showed only minimal decomposition after 16 h under these conditions. Very rapid hydrolysis occurred in the presence of porcine liver esterase, however, with free anion 1a being observed as an intermediate in the esterase-induced generation of NO from 2a. The potential utility of this prodrug class is illustrated with a comparison of 1 and 2 as antiproliferative agents in NO-sensitive human leukemia cell lines HL-60 and U937. While the 72-h IC50's for 1a and 1b (which generate NO throughout the medium) in HL-60 cell cultures were >600 mu M, those of 2a and 2b were 8.3 and 6.4 mu M, respectively. This result is consistent with our hypothesis that 2 is selectively hydrolyzed to 1 and thence to NO intracellularly. For U937 cells, the 72-h IC50 for both 2a and 2b was 53 mu M. By contrast, relatively high antiproliferative IC50's (>100 mu M in U937 cells) were observed for analogues in which R' = CH2CH2SC(O)Me, from which acetyl and 2-mercaptoethyl groups must be successively cleaved to free the NO-releasing diazeniumdiolate function. Within 24 h at initial concentrations of 50 mu M, 2a and 2b induced apoptosis in 50% and 57% of the HL-60 cells, respectively (35% and 40% of the U937 cells, respectively). The data reveal significant in vitro antileukemic activity on the part of these novel compounds. Moreover, their substantial ease-of-handling advantages over the anionic diazeniumdiolates from which they are derived suggest their use as convenient agents for probing the biological roles of NO. C1 NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. Vet Adm Med Ctr, Salt Lake City, UT 84148 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Frederick Canc Res & Dev Ctr, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Keefer, LK (reprint author), NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 13 TC 89 Z9 92 U1 1 U2 11 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 JAN 27 PY 2000 VL 43 IS 2 BP 261 EP 269 DI 10.1021/jm9903850 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 279FP UT WOS:000085034000014 PM 10649981 ER PT J AU Wickner, RB AF Wickner, RB TI Give credit where it's due (not to me, this time) SO NATURE LA English DT Letter C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 1 U2 1 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 27 PY 2000 VL 403 IS 6768 BP 356 EP 356 DI 10.1038/35000398 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 280UA UT WOS:000085121100017 ER PT J AU Balajee, AS DeSantis, LP Brosh, RM Selzer, R Bohr, VA AF Balajee, AS DeSantis, LP Brosh, RM Selzer, R Bohr, VA TI Role of the ATPase domain of the Cockayne syndrome group B protein in UV induced apoptosis SO ONCOGENE LA English DT Article DE Cockayne syndrome; transcription coupled repair; neurodegeneration; RNA pol II transcription; apoptosis; p53 independent pathway ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; CSB ERCC6 GENE; DNA-DAMAGE; HUMAN FIBROBLASTS; FACTOR CSB/ERCC6; P53 PROTEIN; CELLS; ACCUMULATION; SENSITIVITY AB Cockayne syndrome (CS) is a human autosomal recessive disorder characterized by many neurological and developmental abnormalities, CS cells are defective in the transcription coupled repair (TCR) pathway that removes DNA damage from the transcribed strand of active genes, The individuals suffering from CS do not generally develop cancer but show increased neurodegeneration, Two genetic complementation groups (CS-A and CS-B) have been identified, The lack of cancer formation in CS may be due to selective elimination of cells containing DNA damage by a suicidal pathway. In this study, we have evaluated the role of the CSB gene in UV induced apoptosis in human and hamster cells. The hamster cell line UV61 carries a mutation in the homolog of the human CSB gene, We show that both human CS-B and hamster UV61 cells display increased apoptotic response following UV exposure compared with normal cells, The increased sensitivity of UV61 cells to apoptosis is complemented by the transfection of the wild type human CSB gene, In order to determine which functional domain of the CSB gene participates in the apoptotic pathway, we constructed stable cell lines with different CSB domain disruptions, UV61 cells were stably transfected with the human CSB cDNA containing a point mutation in the highly conserved glutamic acid residue in ATPase motif II, This cell line (UV61/pc3.1-CSBE646Q) showed the same increased apoptosis as the UV61 cells, In contrast, cells containing a deletion in the acidic domain at the N-terminal end of the CSB protein had no effect on apoptosis, This indicates that the integrity of the ATPase domain of CSB protein is critical for preventing the UV induced apoptotic pathway, In primary human CS-B cells, the induction and stabilization of the p53 protein seems to correlate with their increased apoptotic potential, In contrast, no change in the level of either p53 or activation of mdm2 protein by p53 was observed in hamster UV61 cells after UV exposure. This suggests that the CSB dependent apoptotic pathway can occur independently of the transactivation potential of p53 in hamster cells. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 35 Z9 35 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 27 PY 2000 VL 19 IS 4 BP 477 EP 489 DI 10.1038/sj.onc.1203372 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 280LL UT WOS:000085104200001 PM 10698517 ER PT J AU Contreras, JL Eckhoff, DE Cartner, S Bilbao, G Ricordi, C Neville, DM Thomas, FT Thomas, JM AF Contreras, JL Eckhoff, DE Cartner, S Bilbao, G Ricordi, C Neville, DM Thomas, FT Thomas, JM TI Long-term functional islet mass and metabolic function after xenoislet transplantation in primates SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the American-Society-of-Transplant-Surgeons (ASTS) CY MAY 19-21, 1999 CL CHICAGO, ILLINOIS SP Amer Soc Transplant Surg ID DIABETES-MELLITUS; CELL MASS; ALLOGRAFTS; ANTI-CD3-IMMUNOTOXIN; PERITRANSPLANT; TOLERANCE; INDUCTION; MONKEYS AB Background, Pancreatic islet transplantation (PIT) is an attractive alternative for patients with type I diabetes mellitus. PIT is not yet an effective clinical reality due in part to the high incidence of rejection and early loss of functional islet mass. In addition, current immunosuppressive drugs have toxic effects on islets and increase the risk of morbidity and mortality. In the present study, the effects of PIT on glycemic parameters were assessed in spontaneously diabetic primates. Methods, Five insulinopenic nonhuman primates (three Macaccca fascicularis, one Ceropithecus aethiops, and one Macacca mulatta) were studied. All required twice-daily treatment with 4-10 U of insulin. For immunosuppression, the animals received anti-CD3-immunotoxin (100 mu g/kg/initially infused 2 hr before transplantation and again on day +1), cyclosporine (CsA) (20 mg/kg/i.v./2 hr before transplantation), cyclosporine microemulsion (Neoral) 60 mg/kg/b.i.d. on days fl to +3 with dose adjusted by blood levels, and methylprednisolone (15 mg/kg day 0 to +3), Three recipients were given islets from a single donor (M mulatta), The islets were prepared by a semiautomated technique using Liberase, A mean of 13,136 islet equivalents/kg was infused into the portal vein. Two animals (M fascicularis and M mulatta) were used as a diabetic, nontransplanted control. Several metabolic parameters were evaluated. Results. All monkeys that underwent transplantation experienced reversal of diabetes mellitus with normalization of all diabetic glycemic parameters, In the nontransplanted primates given the same immunosuppression but no PIT, diabetic metabolic parameters were unchanged after 9 months of follow-up. In contrast, all three PIT recipients established fasting and nonfasting euglycemia within 1-2 weeks, and none required exogenous insulin after day 10. Normal intravenous glucose tolerance tests were observed at day 15, and no significant differences in the glucose disappearance rate (Kg) were observed at days 15, 45, 190, and 365 days after transplantation. The acute insulin response to glucose indicated no significant reduction of functional islet mass. Conclusions. PIT in severely insulinopenic type I diabetes mellitus primates resulted in restoration of normal glycemic parameters and durable islet mass. Operational tolerance was achieved with only 4 days of drug administration, sparing the animals from chronic exposure to potentially diabetogenic immunosuppressive drugs. These results offer an exciting new potential for type I diabetes mellitus treatment. C1 Univ Alabama, Dept Surg, Div Transplantat Immunol, Birmingham, AL 35294 USA. Univ Alabama, Dept Comparat Med, Birmingham, AL 35294 USA. Univ Alabama, Gene Therapy Ctr, Birmingham, AL 35294 USA. Univ Miami, Diabet Res Inst, Miami, FL 33136 USA. NIMH, Mol Biol Lab, Bethesda, MD 20800 USA. RP Thomas, JM (reprint author), Univ Alabama, Dept Surg, Div Transplantat Immunol, BDB 802,1808 7th Ave S, Birmingham, AL 35294 USA. OI Ricordi, Camillo/0000-0001-8092-7153; Cartner, Samuel/0000-0002-2200-2627 FU NIAID NIH HHS [R0I AI39793, R0I AII22293] NR 22 TC 31 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2000 VL 69 IS 2 BP 195 EP 201 DI 10.1097/00007890-200001270-00001 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 280YZ UT WOS:000085132500001 PM 10670626 ER PT J AU Schairer, C Lubin, J Troisi, R Sturgeon, S Brinton, L Hoover, R AF Schairer, C Lubin, J Troisi, R Sturgeon, S Brinton, L Hoover, R TI Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROLIFERATION; WOMEN AB Context Whether menopausal hormone replacement therapy using a combined estrogen-progestin regimen increases risk of breast cancer beyond that associated with estrogen alone is unknown. Objective To determine whether increases in risk associated with the estrogen-progestin regimen are greater than those associated with estrogen alone. Design Cohort study of follow-up data for 1980-1995 from the Breast Cancer Detection Demonstration Project, a nationwide breast cancer screening program. Setting Twenty-nine screening centers throughout the United States. Participants A total of 46 355 postmenopausal women (mean age at start of followup, 58 years). Main Outcome Measure Incident breast cancers by recency, duration, and type of hormone use. Results During follow-up, 2082 cases of breast cancer were identified. Increases in risk with estrogen only and estrogen-progestin only were restricted to use within the previous 4 years (relative risk [RR], 1.2 [95% confidence interval {CI}, 1.0-1.4] and 1.4 [95% CI, 1.1-1.8], respectively); the relative risk increased by 0.01 (95% CI, 0.002-0.03) with each year of estrogen-only use and by 0.08 (95% CI, 0.02-0.16) with each year of estrogen-progestin-only use among recent users, after adjustment for mammographic screening, age at menopause, body mass index (BMI), education, and age. The P value associated with the test of homogeneity of these estimates was .02. Among women with a BMI of 24.4 kg/m(2) or less, increases in RR with each year of estrogen-only use and estrogen-progestin-only use among recent users were 0.03 (95% CI, 0.01-0.06) and 0.12 (95% CI, 0.02-0.25), respectively. These associations were evident for the majority of invasive tumors with ductal histology and regardless of extent of invasive disease. Risk in heavier women did not increase with use of estrogen only or estrogen-progestin only. Conclusion Our data suggest that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Social & Sci Syst Inc, Bethesda, MD USA. Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP Schairer, C (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7080,MSC 7234, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 15 TC 698 Z9 731 U1 3 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 JAN 26 PY 2000 VL 283 IS 4 BP 485 EP 491 DI 10.1001/jama.283.4.485 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 276LT UT WOS:000084879800027 PM 10659874 ER PT J AU Nachman, SA Stanley, K Yogev, R Pelton, S Wiznia, A Lee, S Mofenson, L Fiscus, S Rathore, M Jimenez, E Borkowsky, W Pitt, J Smith, ME Wells, B McIntosh, K AF Nachman, SA Stanley, K Yogev, R Pelton, S Wiznia, A Lee, S Mofenson, L Fiscus, S Rathore, M Jimenez, E Borkowsky, W Pitt, J Smith, ME Wells, B McIntosh, K CA Pediat AIDS Clin Trials Grp 338 Study TI Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID VIRUS TYPE-1 RNA; IMMUNODEFICIENCY; ZIDOVUDINE; DIDANOSINE; PROGRAM; PLASMA AB Context Although protease inhibitors are used routinely in adults with human immunodeficiency virus (HIV) infection, the role of these drugs in the treatment of clinically stable HIV-infected children is not clear. Objective To evaluate the safety, tolerance, and virologic response produced by a change in antiretroviral therapy in HIV-infected children who were clinically and immunologically stable while receiving previous therapy. Design The Pediatric AIDS Clinical Trials Group 338, a multicenter, phase 2, randomized, open-label controlled trial conducted from February 6 to April 30, 1997 (patient entry period); patients were followed up for 48 weeks. Setting Pediatric HIV research clinics in the United States and Puerto Rico. Patients Two hundred ninety-seven antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children aged 2 to 17 years. Interventions Children were randomized to receive zidovudine, 160 mg/m(2) 3 times per day, plus lamivudine, 4 mg/kg 2 times per day (n = 100); the same regimen plus ritonavir, 350 mg/m(2) 2 times per day (n = 100); or ritonavir, 350 mg/m(2) 2 times per day, and stavudine, 4 mg/kg 2 times per day (n = 97). Main Outcome Measure Plasma HIV-1 RNA levels at study weeks 12 and 48, compared among the 3 treatment groups. Results At study week 12, 12% of patients in the zidovudine-lamivudine group had undetectable plasma HIV RNA levels (<400 copies/mL) compared with 52% and 54% of patients in the 2- and 3-drug ritonavir-containing groups, respectively (P<.001). Through study week 48, 70% of children continued receiving their ritonavir-containing regimen. At study week 48, 42% of children receiving ritonavir plus 2 nucleosides compared with 27% of those receiving ritonavir and a single nucleoside had undetectable HIV RNA levels (P =.04); however, similar proportions in each group continuing initial therapy had HIV RNA levels of less than 10 000 copies/mL (58% vs 48%, respectively; P=.19). Conclusions In our study, change in antiretroviral therapy to a ritonavir-containing regimen was associated with superior virologic response at study week 12 compared with change to a dual nucleoside analog regimen. More children receiving ritonavir in combination with 2 compared with 1 nucleoside analog had undetectable HIV RNA levels at study week 48. C1 SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. Albert Einstein Coll Med, Jacobi Med Ctr, New York, NY USA. NYU Med Ctr, New York, NY 10016 USA. Columbia Univ Coll Phys & Surg, Dept Pediat Infect Dis, New York, NY USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Cambridge, MA 02138 USA. Boston Med Ctr, Sect Pediat Infect Dis, Boston, MA USA. Childrens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. Childrens Mem Hosp, Div Infect Dis, Chicago, IL USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. NIAID, Div AIDS, NIH, Bethesda, MD USA. Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. Univ Florida, Hlth Sci Ctr, Dept Pediat, Jacksonville, FL 32209 USA. San Juan City Hosp, Dept Pediat, San Juan, PR USA. Social & Sci Syst, Sect Pediat Infect Dis, Rockville, MD USA. RP Nachman, SA (reprint author), SUNY Stony Brook, Dept Pediat, HSC T11,080, Stony Brook, NY 11794 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI-41110] NR 18 TC 85 Z9 88 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 26 PY 2000 VL 283 IS 4 BP 492 EP 498 DI 10.1001/jama.283.4.492 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 276LT UT WOS:000084879800028 PM 10659875 ER PT J AU List, K Jensen, ON Bugge, TH Lund, LR Ploug, M Dano, K Behrendt, N AF List, K Jensen, ON Bugge, TH Lund, LR Ploug, M Dano, K Behrendt, N TI Plasminogen-independent initiation of the pro-urokinase activation cascade in vivo. Activation of pro-urokinase by glandular kallikrein (mGK-6) in plasminogen-deficient mice SO BIOCHEMISTRY LA English DT Article ID MAMMARY-GLAND; SARCOMA-CELLS; GENE FAMILY; RECEPTOR; MOUSE; GROWTH; PROENZYME; EXPRESSION; BINDING; PROUROKINASE AB The plasminogen activation (PA) system is involved in the degradation of fibrin and various extracellular matrix proteins, taking part in a number of physiological and pathological tissue remodeling processes including cancer invasion. This system is organized as a classical proteolytic cascade, and as for other cascade systems, understanding the physiological initiation mechanism is of central importance. The attempts to identify initiation routes for activation of the preform of the key enzyme urokinase-type plasminogen activator (pro-uPA) in vivo have been hampered by the strong activator potency of the plasmin, that is generated during the progress of the cascade. Using gene-targeted mice deficient in plasminogen (Plg -/- mice) [Bugge, T. H., Flick, M. J., Daugherty, C. C., and Degen, J, L. (1995) Genes Dev, 9, 794-807], we have now demonstrated and identified a component capable of initiating the cascade by activating pro-uPA. The urine from Pig -/- mice contained active two-chain uPA as well as a proteinase capable of activating exogenously added pro-uPA. The active component was purified and identified by mass spectrometry-based peptide mapping as mouse glandular kallikrein mGK-6 (true tissue kallikrein). The pro-uPA converting activity of the mGK-6 enzyme, as well as its ability to cleave a synthetic substrate for glandular kallikrein, was inhibited by the serine proteinase inhibitor leupeptin but not by other serine proteinase inhibitors such as aprotinin, antithrombin III, or alpha(1)-antitrypsin. We suggest that mouse glandular kallikrein mGK-6 is an activator of pro-uPA in the mouse urinary tract in vivo. Since this kallikrein is expressed in a number of tissues and also occurs in plasma, it can also be considered a candidate for a physiological pro-uPA activator in other locations. C1 Rigshosp, Finsen Lab, DK-2100 Copenhagen 0, Denmark. Odense Univ, Dept Biol Mol, DK-5230 Odense, Denmark. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP List, K (reprint author), Rigshosp, Finsen Lab, Strandboulevarden 49, DK-2100 Copenhagen 0, Denmark. RI Jensen, Ole/J-1763-2012 OI Jensen, Ole/0000-0003-1862-8528 NR 52 TC 37 Z9 40 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 25 PY 2000 VL 39 IS 3 BP 508 EP 515 DI 10.1021/bi991701f PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278LG UT WOS:000084990800003 PM 10642175 ER PT J AU Poli, KA Tofler, GH Larson, MG Evans, JC Sutherland, PA Lipinska, I Mittleman, MA Muller, JE D'Agostino, RB Wilson, PWF Levy, D AF Poli, KA Tofler, GH Larson, MG Evans, JC Sutherland, PA Lipinska, I Mittleman, MA Muller, JE D'Agostino, RB Wilson, PWF Levy, D TI Association of blood pressure with fibrinolytic potential in the Framingham Offspring population SO CIRCULATION LA English DT Article DE hypertension; fibrinolysis; cardiovascular diseases ID PLASMINOGEN-ACTIVATOR INHIBITOR; CORONARY-ARTERY DISEASE; LINKED IMMUNOSORBENT-ASSAY; ISCHEMIC-HEART-DISEASE; ESSENTIAL-HYPERTENSION; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; VONWILLEBRAND-FACTOR; HEMOSTATIC FACTORS; PLATELET-FUNCTION AB Background-Hypertension is an established risk factor for acute coronary events. Because fibrinolytic and hemostatic factors are also associated with cardiovascular disease, we examined the relations of systolic and diastolic blood pressures (SBP and DBP) to levels of plasminogen activator inhibitor antigen, tissue plasminogen activator antigen, fibrinogen, factor VII, von Willebrand factor, fibrinogen, and plasma viscosity in subjects of the Framingham Offspring Study. Methods and Results-We studied 1193 men and 1459 women after the exclusion of subjects with known cardiovascular disease and those receiving anticoagulant or antihypertensive therapy. Linear regression models were used to evaluate SBP and DBP as predictors of fibrinolytic and hemostatic factor levels in separate sex models, with adjustment for age, body mass index, smoking, diabetes, total cholesterol, HDL, triglycerides, alcohol intake, and estrogen use (in women). In both sexes, levels of plasminogen activator inhibitor and tissue plasminogen activator antigen were positively related to SBP and DBP (P<0.001). Plasma viscosity was positively related to SBP (P=0.008) and DBP (P=0.001) in women only, There was no association between SBP or DBP and fibrinogen, factor VII, or von Willebrand factor in either sex. Conclusions-These data suggest that impaired fibrinolysis may play; an important role in the pathogenesis of cardiovascular disease in hypertensive patients. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc,Inst Prevent Cardiovasc Dis, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-38038, R01-HL-48157] NR 49 TC 122 Z9 133 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 25 PY 2000 VL 101 IS 3 BP 264 EP 269 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 277WT UT WOS:000084957100024 PM 10645922 ER PT J AU Usui, M Egashira, K Tomita, H Koyanagi, M Katoh, M Shimokawa, H Takeya, M Yoshimura, T Matsushima, K Takeshita, A AF Usui, M Egashira, K Tomita, H Koyanagi, M Katoh, M Shimokawa, H Takeya, M Yoshimura, T Matsushima, K Takeshita, A TI Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats SO CIRCULATION LA English DT Article DE endothelium-derived factors; nitric oxide; remodeling; proteins; cells ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; LONG-TERM BLOCKADE; ENDOTHELIUM-DEPENDENT VASODILATION; CONVERTING ENZYME-INHIBITION; VASCULAR SMOOTH-MUSCLE; KAPPA-B ACTIVATION; ATHEROSCLEROTIC LESIONS; MONOCLONAL-ANTIBODY; CORONARY-ARTERY; RISK-FACTORS AB Background-The chronic inhibition of NO synthesis by N-omega-nitro-L-arginine methyl ester (L-NAME) upregulates the cardiovascular tissue angiotensin II (Ang II)-generating system and induces cardiovascular inflammatory changes in rats. Methods and Results-We used a rat model to investigate the role of local Ang II activity in the pathogenesis of such inflammatory changes. Marked increases in monocyte infiltration into coronary vessels and myocardial interstitial areas, monocyte chemoattractant protein-1 (MCP-1) expression, and nuclear factor-kappa B (NF-kappa B, an important redox-sensitive transcriptional factor that induces MCP-1) activity were observed on day 3 of L-NAME administration. Along with these changes, vascular superoxide anion production was also increased. Treatment with an Ang II type 1 receptor antagonist or with a thiol-containing antioxidant, N-acetylcysteine, prevented all of these changes. Conclusions-Increased Ang II activity mediated via the type 1 receptor may thus be important in the pathogenesis of early cardiovascular inflammatory changes in this model. Endothelium-derived NO may decrease MCP-1 production and oxidative stress-sensitive signals by suppressing localized activity of Ang II. C1 Kyushu Univ, Sch Med, Angiocardiol Res Inst, Higashi Ku, Fukuoka 8128582, Japan. Kumamoto Univ, Sch Med, Dept Pathol 2, Kumamoto 860, Japan. Univ Tokyo, Sch Med, Dept Mol Prevent Med, Tokyo 113, Japan. NCI, Immunopathol Sect, Immunobiol Lab, Frederick, MD 21701 USA. RP Egashira, K (reprint author), Kyushu Univ, Sch Med, Angiocardiol Res Inst, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. RI U-ID, Kyushu/C-5291-2016 NR 38 TC 133 Z9 137 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 25 PY 2000 VL 101 IS 3 BP 305 EP 310 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 277WT UT WOS:000084957100029 PM 10645927 ER PT J AU Bounpheng, MA Melnikova, IN Dodds, SG Chen, HP Copeland, NG Gilbert, DJ Jenkins, NA Christy, BA AF Bounpheng, MA Melnikova, IN Dodds, SG Chen, HP Copeland, NG Gilbert, DJ Jenkins, NA Christy, BA TI Characterization of the mouse JAB1 cDNA and protein SO GENE LA English DT Article DE chromosomal location; mRNA; proteasome; protein expression; subcellular location; ubiquitin ID COP9 COMPLEX; NUCLEAR-LOCALIZATION; PROTEASOME; P53; DIFFERENTIATION; UBIQUITINATION; LACTACYSTIN; THREONINE; SEQUENCES; SUBUNITS AB JAB1 was originally described as a transcriptional coactivator of c-Jun and Jun D. Recent data suggests that JAB1 is a component of a large protein complex, the JAB1 signalosome in mammals and the COP9 complex in plants. The JAB1 signalosome is implicated in the phosphorylation of selected transcription factors, while the COP9 complex is involved in repression of photomorphogenesis in Arabidopsis. In this study, we describe the partial characterization of mouse JAB1 (mJAB1). The murine JAB1 protein is encoded by a gene located on mouse chromosome 1. mJAB1 mRNA is abundantly expressed in a variety of adult tissues as well as in mouse embryos. The JAB1 protein was readily detectable in many cell types and localized to both the nucleus and cytoplasm. Endogenous JAB1 protein is relatively stable and its degradation is not perturbed by blocking 26S proteasome activity, suggesting that this protein is not degraded by the ubiquitin-mediated proteolytic pathway. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78245 USA. NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, ABL Basic Res Program, Frederick, MD 21702 USA. RP Christy, BA (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78245 USA. FU NICHD NIH HHS [R29HD29850] NR 31 TC 27 Z9 30 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 25 PY 2000 VL 242 IS 1-2 BP 41 EP 50 DI 10.1016/S0378-1119(99)00525-9 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 283ME UT WOS:000085278700004 PM 10721695 ER PT J AU Quach, TT Mosinger, B Ricard, D Copeland, NG Gilbert, DJ Jenkins, NA Stankoff, B Honnorat, J Belin, MF Kolattukudy, P AF Quach, TT Mosinger, B Ricard, D Copeland, NG Gilbert, DJ Jenkins, NA Stankoff, B Honnorat, J Belin, MF Kolattukudy, P TI Collapsin response mediator protein-3/unc-33-like protein-4 gene: organization, chromosomal mapping and expression in the developing mouse brain SO GENE LA English DT Article DE collapsin response-mediator protein; neurodegenerative disorders; unc-33-like protein ID PARANEOPLASTIC NEUROLOGICAL SYNDROMES; AXON OUTGROWTH; UNC-33; IDENTIFICATION; GUIDANCE; HOMOLOG; CLONING; CELLS; ULIP; CDNA AB CRMPs (collapsin response mediator proteins)/ULIPs (unc-33-like proteins) are a family of intracytoplasmic proteins that are expressed mainly in the brain. The involvement of CRMP/ULIP members in neuronal differentiation, growth cone motility and axonal collapse has been suggested. We recently found that a member of this family, CRMP3/ULIP4, corresponds to POP66 (paraneoplastic oligodendrocyte protein of 66 kDa), a protein which may be associated with auto-immune induced-neuronal degeneration in paraneoplastic neurological syndromes. However, the physiological functions of these proteins remain to be elucidated. Further studies, including the generation of cell lines and of animals with modified/disrupted CRMP/ULIP gene expression, are necessary to explore the functions of this protein. We have cloned and determined the organization and chromosomal localization of the mouse gene encoding CRMP3/ULIP4. The gene is composed of 14 exons and spans more than 20 kb. We assigned the mouse CRMP3/ULIP4 gene to the distal end of chromosome 7. In mouse brain, in situ hybridization showed that CRMP3/ULIP4 mRNA is expressed mainly in the dentate gyrus of hippocampus, in the granular layers of cerebellum and in the inferior olive of the pens, the nucleus which controls movement and posture, and adjusts the major output of descending motor system. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Ohio State Univ, Neurobiotechnol Ctr, Columbus, OH 43210 USA. Fac Med Laennec, INSERM, U433, F-69008 Lyon, France. NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, Frederick, MD 21702 USA. Grp Hosp Pitie Salpetriere, INSERM, U495, F-75634 Paris, France. RP Kolattukudy, P (reprint author), Ohio State Univ, Neurobiotechnol Ctr, 1060 Carmack Rd, Columbus, OH 43210 USA. RI kolattukudy, pappachan/A-1350-2012 NR 23 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 25 PY 2000 VL 242 IS 1-2 BP 175 EP 182 DI 10.1016/S0378-1119(99)00528-4 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 283ME UT WOS:000085278700019 PM 10721710 ER PT J AU Litvan, I Saposnik, G Maurino, J Gonzalez, L Saizar, R Sica, REP Bartko, JJ AF Litvan, I Saposnik, G Maurino, J Gonzalez, L Saizar, R Sica, REP Bartko, JJ TI Pupillary diameter assessment: Need for a graded scale SO NEUROLOGY LA English DT Article DE reliability; pupil assessment ID RELIABILITY C1 Henry M Jackson Fdn, Def & Vet Head Injury Program, Cognit Neuropharmacol Unit, Bethesda, MD 20814 USA. NINDS, Med Branch, NIH, Bethesda, MD 20892 USA. Hosp Ramos Mejia, Dept Neurol, Buenos Aires, DF, Argentina. RP Litvan, I (reprint author), Henry M Jackson Fdn, Def & Vet Head Injury Program, Cognit Neuropharmacol Unit, Champlain Bldg,Suite 600,6140 Rockledge Dr, Bethesda, MD 20814 USA. OI Saposnik, Gustavo/0000-0002-5950-9886; Litvan, Irene/0000-0002-3485-3445 NR 7 TC 11 Z9 11 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 JAN 25 PY 2000 VL 54 IS 2 BP 530 EP 531 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 279KW UT WOS:000085043800059 PM 10668738 ER PT J AU Oh, JD Chartisathian, K Chase, TN Butcher, LL AF Oh, JD Chartisathian, K Chase, TN Butcher, LL TI Overexpression of neurotrophin receptor p75 contributes to the excitotoxin-induced cholinergic neuronal death in rat basal forebrain SO BRAIN RESEARCH LA English DT Review DE Alzheimer's disease; kainic acid lesion; medial septum; nucleus of basalis of Meynert; apoptosis; nerve growth factor ID NERVE GROWTH-FACTOR; NF-KAPPA-B; AMYLOID PRECURSOR PROTEIN; FIMBRIA-FORNIX TRANSECTION; HUMAN NEUROBLASTOMA-CELLS; ALZHEIMERS-DISEASE; NUCLEUS BASALIS; KAINIC ACID; PC12 CELLS; MEDIATED NEUROTOXICITY AB Both excitotoxicity and altered trophic factor support have been implicated in the pathogenesis of Alzheimer's disease. To determine whether stimulation of p75, the low-affinity receptor for nerve growth factor, contributes to the excitotoxin-induced apoptotic death of cholinergic neurons, we examined the effect of unilateral kainic acid (KA; PBS vehicle, 1.25, 2.5 and 5.0 nmol) administration into rat basal forebrain on neuronal loss and p75 expression. KA (2.5 nmol) destroyed 43% of Nissl-stained neurons and 70% of choline acetyltransferase (ChAT)-positive neurons 5 days after injection. Agarose gel electrophoresis revealed that KA (2.5 nmol) induced local intemucleosomal DNA fragmentation after 6-48 h. Immunohistochemical analysis further showed that KA (2.5 nmol) augmented p75 immunoreactivity at a time when terminal transferase-mediated deoxyuridine trophosphate (d-UTP)-digoxigenin nick end labeling (TUNEL)-positive nuclei were increased. Many fragmented nuclei were co-labeled with ChAT antibody. The chronic administration of anti-rat p75 or the protein synthesis inhibitor, cycloheximide, but not anti-human p75, substantially reduced the KA-induced destruction of cholinergic neurons and the induction of internucleosomal DNA fragmentation. Anti-rat p75, but not cycloheximide, also reversed the spatial memory impairment produced by KA. These findings suggest that overexpression of p75 contributes to the excitotoxin-induced death of rat basal forebrain cholinergic neurons by an apoptotic-like mechanism. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Psychol, Lab Chem Neuroanat, Los Angeles, CA 90024 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103,Room 5C211,90900 Rockville Pik, Bethesda, MD 20892 USA. NR 105 TC 38 Z9 38 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 24 PY 2000 VL 853 IS 2 BP 174 EP 185 DI 10.1016/S0006-8993(99)02054-5 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 282AY UT WOS:000085194700002 PM 10640615 ER PT J AU Kim, HC Bing, GY Jhoo, WK Ko, KH Kim, WK Suh, JH Kim, SJ Kato, K Hong, JS AF Kim, HC Bing, GY Jhoo, WK Ko, KH Kim, WK Suh, JH Kim, SJ Kato, K Hong, JS TI Changes of hippocampal Cu/Zn-superoxide dismutase after kainate treatment in the rat SO BRAIN RESEARCH LA English DT Article DE kainic acid; neurodegeneration; hippocampus; superoxide; Cu,Zn-superoxide dismutase; free radical; astrocyte; microglia ID CENTRAL-NERVOUS-SYSTEM; ACID-INDUCED SEIZURES; KAINIC ACID; TRANSGENIC MICE; COPPER-ZINC; ALPHA-AMINOADIPATE; LIPID-PEROXIDATION; CEREBRAL-ISCHEMIA; OXIDATIVE STRESS; NEURONAL DAMAGE AB In order to evaluate the putative role of Cu,Zn-superoxide dismutase (SOD-1) in the antioxidant defense mechanism during the neurodegenerative process, we examined the level of mRNA, the specific activity and immunocytochemical distribution for SOD-1 in the rat hippocampus after systemic injection of kainic acid (KA). Hippocampal SOD-1 mRNA levels were significantly increased by the seizure intensity 3 and 7 days after KA. These enhanced mRNA levels for SOD-1 were consistent with the increased specific activities for SOD-1, suggesting that the superoxide radical generated in neurotoxic lesion, induced SOD-1 mRNA, The CA1 and CA3 neurons lost their SOD-1-like immunoreactivity, whereas SOD-1-positive glia-like cells mainly proliferated throughout the CAL sector and had an intense immunoreactivity at 3 and 7 days after KA. This immunocytochemical distribution for SOD-1-positive non-neuronal elements was similar to that for glial fibrillary acidic protein (GFAP)-positive cells. Each immunoreactivity for SOD-1-positive non-neuronal cell or GFAP in the layers of CA1 and CA3 disappeared 3 and 7 days after a maximal stage 5 seizure. On the other hand, activated microglial cells as selectively marked with the lectin occurred in the areas affected by KA-induced lesion. Double-labeling immunocytochemical analysis demonstrated the co-localization of SOD-l-positive glia-like cells and reactive astrocytes as labeled by GFAP or S-100 protein immunoreactivity. This finding suggested that the mobilization of astroglial cells for the synthesis of SOD-I protein is a response to the KA insult designed to decrease the neurotoxicity induced by oxygen-derived free radicals. Therefore, these alterations might reflect the regulatory role of SOD-1 against oxygen-derived free radical-induced neuronal degeneration after systemic KA administration. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Kangweon Natl Univ, Coll Pharm, Sect Pharmacol & Toxicol, Dept Pharm, Chunchon 200701, South Korea. Oklahoma Med Res Fdn, Free Rad Biol & Aging Res Program, Oklahoma City, OK 73104 USA. Seoul Natl Univ, Coll Pharm, Ctr Biofunct Mol, Seoul 151741, South Korea. Ewha Womens Univ, Dept Pharmacol, Coll Med, Ewha Med Res Ctr, Seoul 158056, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Aichi Prefectural Colony, Inst Dev Res, Dept Biochem, Aichi 48003, Japan. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Kim, HC (reprint author), Kangweon Natl Univ, Coll Pharm, Sect Pharmacol & Toxicol, Dept Pharm, Chunchon 200701, South Korea. OI Bing, Guoying/0000-0003-0609-8152 NR 61 TC 39 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 24 PY 2000 VL 853 IS 2 BP 215 EP 226 DI 10.1016/S0006-8993(99)02254-4 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 282AY UT WOS:000085194700006 PM 10640619 ER PT J AU Chang, RCC Hudson, P Wilson, B Haddon, L Hong, JS AF Chang, RCC Hudson, P Wilson, B Haddon, L Hong, JS TI Influence of neurons on lipopolysaccharide-stimulated production of nitric oxide and tumor necrosis factor-alpha by cultured glia SO BRAIN RESEARCH LA English DT Article DE lipopolysaccharide; neural cell adhesion molecule; neuron-glia interaction; microglia; astrocyte; cerebral inflammation ID CENTRAL-NERVOUS-SYSTEM; ASTROCYTE-ENRICHED CULTURES; RAT ASTROCYTES; SUBSTANCE-P; MIXED GLIA; IN-VITRO; MICROGLIA; BRAIN; ADHESION; PROLIFERATION AB Cerebral inflammation often originates in a region where neuronal death occurs and thereafter slowly spreads outward. This study aimed to elucidate the roles of neurons in modulating the production of inflammatory factors stimulated by the bacterial endotoxin lipopolysaccharide (LPS). Culturing neurons with mixed glia reduced nitrite and tumor necrosis factor-alpha (TNF-alpha) production compared to cultures with only mixed glia, and shifted the dose-response curve to the right. The decreased nitrite and TNF-alpha production were not due to the cytotoxicity of LPS. Immunocytochemical analysis of glia-neuron co-cultures revealed the morphological changes in the activated microglia. Culturing PC12 cells with rat mixed-glia also reduced nitrite production. The influence of neurons on glial inflammation was partly due to the cell-cell contacts between neurons and glia via neural cell adhesion molecules (NCAM) because NCAM significantly reduced LPS-stimulated nitrite production. These results demonstrate that neurons reduce the production of inflammatory factors by glia. Since cerebral inflammation is important in many neurological disorders, this study might provide insight about the role of glia-neuron interactions in inflammatory responses in the brain. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, MD F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. RI Chang, Raymond Chuen-Chung/C-1107-2009 OI Chang, Raymond Chuen-Chung/0000-0001-8538-7993 NR 27 TC 38 Z9 42 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 24 PY 2000 VL 853 IS 2 BP 236 EP 244 DI 10.1016/S0006-8993(99)02255-6 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 282AY UT WOS:000085194700008 PM 10640621 ER PT J AU Serrano, J Uttenthal, LO Martinez, A Fernandez, AP de Velasco, JM Alonso, D Bentura, ML Santacana, M Gallardo, JR Martinez-Murillo, R Cuttitta, F Rodrigo, J AF Serrano, J Uttenthal, LO Martinez, A Fernandez, AP de Velasco, JM Alonso, D Bentura, ML Santacana, M Gallardo, JR Martinez-Murillo, R Cuttitta, F Rodrigo, J TI Distribution of adrenomedullin-like immunoreactivity in the rat central nervous system by light and electron microscopy SO BRAIN RESEARCH LA English DT Article DE adrenomedullin-like immunoreactivity; rat central nervous system; light and electron microscopy; avidin-biotin peroxidase complex; immunocytochemistry ID NITRIC-OXIDE SYNTHASE; GENE-RELATED PEPTIDE; CALCITONIN-GENE; NEUROPEPTIDE-Y; HYPOTENSIVE PEPTIDE; ENDOTHELIAL-CELLS; CONSCIOUS SHEEP; CEREBRAL-CORTEX; PORCINE TISSUE; HUMAN BRAIN AB Adrenomedullin is a peptide of marked vasodilator activity first isolated from human pheochromocytoma and subsequently demonstrated in other mammalian tissues. Using a polyclonal antiserum against human adrenomedullin-(22-52) amide and the avidin-biotin peroxidase complex technique, we have demonstrated by light and electron microscopy that adrenomedullin-like immunoreactivity is widely distributed in the rat central nervous system. Western blotting of extracts of different brain regions demonstrated the fully processed peptide as the major form in the cerebellum, whereas a 14-kDa molecular species and a small amount of the 18-kDa propeptide were present in other brain regions. Immunoreactive neurons and processes were found in multipolar neurons and pyramidal cells of layers IV-VI of the cerebral cortex and their apical processes, as well as in a large number of telencephalic, diencephalic, mesencephalic, pontine and medullary nuclei. Cerebellar Purkinje cells and mossy terminal nerve fibers as well as neurons of the cerebellar nuclei were immunostained, as were neurons in area 9 of the anterior horn of the spinal cord. Immunoreactivity was also found in some vascular endothelial cells and surrounding processes that probably originated from perivascular glial cells. Electron microscopy confirmed the light microscopy findings and showed the reaction product in relation to neurofilaments and the external membrane of small mitochondria. Immunoreactive terminal boutons were occasionally seen. The distribution of adrenomedullin-like immunoreactivity in the central nervous system suggests that it has a significant role in neuronal function as well as in the regulation of regional blood flow. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 CSIC, Inst Cajal, Dept Neuroanat Comparada, E-28002 Madrid, Spain. NCI, Cell & Canc Biol Dept, Bethesda, MD 20892 USA. RP CSIC, Inst Cajal, Dept Neuroanat Comparada, E-28002 Madrid, Spain. EM rodmart@cajal.csic.es RI Martinez, Alfredo/A-3077-2013; Martinez-Murillo, Ricardo/K-7596-2014 OI Martinez, Alfredo/0000-0003-4882-4044; Martinez-Murillo, Ricardo/0000-0003-3657-3890 NR 67 TC 85 Z9 97 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JAN 24 PY 2000 VL 853 IS 2 BP 245 EP 268 DI 10.1016/S0006-8993(99)02273-8 PG 24 WC Neurosciences SC Neurosciences & Neurology GA 282AY UT WOS:000085194700009 PM 10640622 ER PT J AU Inoue, K Mogi, M Mori, R Naito, J Fukuda, S Creveling, CR AF Inoue, K Mogi, M Mori, R Naito, J Fukuda, S Creveling, CR TI Immunocytochemical localization of serotonin, monoamine oxidase and assessment of monoamine oxidase activity in human dental pulp SO BRAIN RESEARCH LA English DT Article DE serotonin; MAO; dental pulp; human ID TISSUES AB In the present study serotonin (5-hydroxytryptamine, 5-HT) and monoamine oxidase (MAO) were both found localized in the blood vessel walls of human dental pulp. Our discovery of MAO activity in human dental pulp suggests a functional relationship between serotonin and MAO in this region. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Matsumoto Dent Univ, Dept Oral Anat, Nagano 3990781, Japan. Aichi Gakuin Univ, Sch Dent, Dept Pharmacol, Chikusa Ku, Nagoya, Aichi 464, Japan. Matsumoto Dent Univ, Dept Oral & Maxillofacial Surg, Nagano 3990781, Japan. Nagoya Univ, Grad Sch Bioagr Sci, Div Biofunct Dev, Chikusa Ku, Nagoya, Aichi 4648601, Japan. NIDDK, Off Technol Dev, NIH, Bethesda, MD 20892 USA. RP Inoue, K (reprint author), Matsumoto Dent Univ, Dept Oral Anat, Nagano 3990781, Japan. NR 17 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 24 PY 2000 VL 853 IS 2 BP 374 EP 376 DI 10.1016/S0006-8993(99)02170-8 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 282AY UT WOS:000085194700023 PM 10640636 ER PT J AU Kubota, R Kawanishi, T Matsubara, H Manns, A Jacobson, S AF Kubota, R Kawanishi, T Matsubara, H Manns, A Jacobson, S TI HTLV-I specific IFN-gamma+CD8+lymphocytes correlate with the proviral load in peripheral blood of infected individuals SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE human T lymphotropic virus type I (HTLV-I); HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP); proviral load; CD8+lymphocytes ID VIRUS TYPE-I; TROPICAL SPASTIC PARAPARESIS; CELL LEUKEMIA-VIRUS; CYTOTOXIC T-LYMPHOCYTES; CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD LESIONS; MYELOPATHY HAM-TSP; NEUROLOGICAL DISEASE; CEREBROSPINAL-FLUID; SURFACE PHENOTYPE AB Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurological disease caused by HTLV-I infection. It has been shown that HAM/TSP patients have high proviral loads and an extraordinarily high frequency of circulating CD8 + cytotoxic T lymphocytes specific for HTLV-I in their peripheral blood when compared to asymptomatic HTLV-I carriers (AC). We have previously described an intracellular cytokine detection assay, in which interferon-gamma (IFN-gamma)+ CD8 + lymphocytes are specific for HTLV-I in infected individuals, Here, we have established a competitive polymerase chain reaction assay to measure the proviral load of patients and investigate a potential relationship between proviral load and virus-specific CD8 + lymphocytes. Genomic DNA was extracted from peripheral blood lymphocytes (PBL) from eight HAM/TSP patients and seven AC for the measurement of HTLV-I measuring proviral loads, The same PBL were analyzed for intracellular IFN-gamma expression by flow cytometry. In the HAM/TSP patients and AC, the average proviral lends were 34,482 and 9784 copy/mu g DNA (P = 0.021), and the average of IFN-gamma + CD8 + lymphocytes in total PBL were 1.47 and 0.08% (P = 0.001), respectively. It was confirmed that HAM/TSP patients have both high proviral loads and increased HTLV-I-specific CD8 + lymphocytes. Furthermore, we found a positive correlation between both factors in the patients with HAM/TSP (P = 0.044) but not in the AC (P = 0.508). These findings suggest that the high number of HTLV-I-specific lymphocytes may result from the increased proviral load in HAM/TSP patients. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 NINDS, Viral Immunol Sect, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 40 TC 61 Z9 62 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JAN 24 PY 2000 VL 102 IS 2 BP 208 EP 215 DI 10.1016/S0165-5728(99)00175-7 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 272FB UT WOS:000084638900012 PM 10636490 ER PT J AU Star, RA Kimmel, PL AF Star, RA Kimmel, PL TI Biocompatibility and acute renal failure SO LANCET LA English DT Letter ID MEMBRANES C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Texas, Dallas, TX 75230 USA. RP Star, RA (reprint author), NIDDKD, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 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 JAN 22 PY 2000 VL 355 IS 9200 BP 314 EP 314 DI 10.1016/S0140-6736(05)72307-2 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 279LQ UT WOS:000085045600045 PM 10675092 ER PT J AU Idle, JR Corchero, J Gonzalez, FJ AF Idle, JR Corchero, J Gonzalez, FJ TI Medical implications of HGP's sequence of chromosome 22 SO LANCET LA English DT Letter ID DEBRISOQUINE C1 NCI, NIH, Lab Metab, Bethesda, MD 20892 USA. RP Idle, JR (reprint author), Zlata Ul 34, Karlovy Vary 36005, Czech Republic. NR 5 TC 15 Z9 16 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 JAN 22 PY 2000 VL 355 IS 9200 BP 319 EP 319 DI 10.1016/S0140-6736(05)72317-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 279LQ UT WOS:000085045600055 PM 10675100 ER PT J AU Ducy, P Amling, M Takeda, S Priemel, M Schilling, AF Beil, FT Shen, JH Vinson, C Rueger, JM Karsenty, G AF Ducy, P Amling, M Takeda, S Priemel, M Schilling, AF Beil, FT Shen, JH Vinson, C Rueger, JM Karsenty, G TI Leptin inhibits bone formation through a hypothalamic relay: A central control of bone mass SO CELL LA English DT Article ID OSTEOCLAST DIFFERENTIATION; INVOLUTIONAL OSTEOPOROSIS; POSTMENOPAUSAL WOMEN; RECEPTOR GENE; DIABETIC MICE; FEMALE MICE; DB/DB MICE; OB/OB MICE; OBESITY; MOUSE AB Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ Hamburg, Dept Trauma Surg, D-20246 Hamburg, Germany. NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Karsenty, G (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RI takeda, shu/B-5195-2012 FU NIAMS NIH HHS [AR45548]; NIDCR NIH HHS [DE11290] NR 50 TC 1216 Z9 1305 U1 7 U2 29 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 21 PY 2000 VL 100 IS 2 BP 197 EP 207 DI 10.1016/S0092-8674(00)81558-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 277KF UT WOS:000084932200004 PM 10660043 ER PT J AU Lata, R Conway, JF Cheng, NQ Duda, RL Hendrix, RW Wikoff, WR Johnson, JE Tsuruta, H Steven, AC AF Lata, R Conway, JF Cheng, NQ Duda, RL Hendrix, RW Wikoff, WR Johnson, JE Tsuruta, H Steven, AC TI Maturation dynamics of a viral capsid: Visualization of transitional intermediate states SO CELL LA English DT Article ID CRYOELECTRON MICROSCOPY; STRUCTURAL TRANSITIONS; BIOLOGICAL MACROMOLECULES; ELECTRON CRYOMICROSCOPY; CONFORMATIONAL-CHANGES; BACTERIAL-VIRUS; IN-VITRO; PROTEIN; DNA; BACTERIOPHAGE-T4 AB Typical of DNA bacteriophages and herpesviruses, HK97 assembles in two stages: polymerization and maturation. First, capsid protein polymerizes into closed shells; then, these precursors mature into larger, stabler particles. Maturation is initiated by proteolysis, producing a metastable particle primed for expansion-the major structural transition. We induced expansion in vitro by acidic pH and monitored the resulting changes by time-resolved X-ray diffraction and cryo-electron microscopy. The transition, which is not synchronized over the population, proceeds in a series of stochastically triggered subtransitions. Three distinct intermediates were identified, which are comparable to transitional states in protein folding. The intermediates' structures reveal the molecular events occurring during expansion. Integrated into a movie (see Dynamic Visualization below), they show capsid maturation as a dynamic process. C1 NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Stanford Univ, Stanford Linear Accelerator Ctr, SSRL, Palo Alto, CA 94309 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 FU NCRR NIH HHS [P41 RR01209]; NIAID NIH HHS [R01 AI40101]; NIGMS NIH HHS [R01 GM47795] NR 46 TC 109 Z9 110 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 21 PY 2000 VL 100 IS 2 BP 253 EP 263 DI 10.1016/S0092-8674(00)81563-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 277KF UT WOS:000084932200009 PM 10660048 ER PT J AU Tsuchiya, K Yoshizumi, M Houchi, H Mason, RP AF Tsuchiya, K Yoshizumi, M Houchi, H Mason, RP TI Nitric oxide-forming reaction between the iron-N-methyl-D-glucamine dithiocarbamate complex and nitrite SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; MICE IN-VIVO; BAND EPR SPECTROSCOPY; SEPTIC-SHOCK MICE; L-ARGININE; RELAXING FACTOR; REPERFUSION INJURY; ANIMAL-TISSUES; RAT; GENERATION AB The objective of this study was to elucidate the origin of the nitric oxide-forming reactions from nitrite in the presence of the iron-N-methyl-D-glucamine dithiocarbamate complex ((MGD)(2)Fe2+). The (MGD)(2)Fe2+ complex is commonly used in electron paramagnetic resonance (EPR) spectroscopic detection of NO both in vivo and in vitro. Although it is widely believed that only NO can react with (MGD)(2)Fe2+ complex to form the (MGD)(2)Fe2+. NO complex, a recent article reported that the (MGD)(2)Fe2+ complex can react not only with NO, but also with nitrite to produce the characteristic triplet EPR signal of (MGD)(2)Fe2+. NO (Hiramoto, K., Tomiyama, S., and Kikugawa, K. (1997) Free Radical Res, 27, 505-509). However, no detailed reaction mechanisms were given. Alternatively, nitrite is considered to be a spontaneous NO donor, especially at acidic pH values (Samouilov, A, Kuppusamy, P., and Zweier, J. L. (1998) Arch Biochem, Biophys. 357, 1-7). However, its production of nitric oxide at physiological pH is unclear. In this report, we demonstrate that the (MGD)(2)Fe2+ complex and nitrite reacted to form NO as follows: 1) (MGD)(2)Fe2+. NO complex was produced at pH 7.4; 2) concomitantly, the (MGD)(2)Fe3+ complex, which is the oxidized form of (MGD)Fe-2(2+), was formed; 3) the rate of formation of the (MGD)(2)Fe2+. NO complex was a function of the concentration of [Fe2+](2), [MGD], [H+] and [nitrite]. C1 NIEHS, Free Rad Metabolite Sect, Lab Pharmacol & Chem, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. Univ Tokushima, Sch Med, Dept Pharmacol, Tokushima 770, Japan. Univ Tokushima, Sch Med, Dept Pharm, Tokushima 770, Japan. RP Tsuchiya, K (reprint author), NIEHS, Free Rad Metabolite Sect, Lab Pharmacol & Chem, Natl Inst Hlth, FO-02, Res Triangle Pk, NC 27709 USA. NR 68 TC 54 Z9 57 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 JAN 21 PY 2000 VL 275 IS 3 BP 1551 EP 1556 DI 10.1074/jbc.275.3.1551 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277NQ UT WOS:000084940000006 PM 10636843 ER PT J AU de Caestecker, MP Yahata, T Wang, D Parks, WT Huang, SX Hill, CS Shioda, T Roberts, AB Lechleider, RJ AF de Caestecker, MP Yahata, T Wang, D Parks, WT Huang, SX Hill, CS Shioda, T Roberts, AB Lechleider, RJ TI The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TGF-BETA; TUMOR-SUPPRESSOR; HETERO-OLIGOMERIZATION; BINDING-PROTEIN; DNA-BINDING; COACTIVATOR; CELLS; PHOSPHORYLATION; DOWNSTREAM; RESPONSES AB Transforming growth factor-p (TGF-P) family members signal through a unique set of intracellular proteins called Smads, Smad4, previously identified as the tumor suppressor DPC4, is functionally distinct among the Smad family, and is required for the assembly and transcriptional activation of diverse, Smad-DNA complexes. We previously identified a 48-amino acid proline-rich regulatory element within the middle linker domain of this molecule, the Smad4 activation domain (SAD), which is essential for mediating these signaling activities. We now characterize the functional activity of the SAD. Mutants lacking the SAD are still able to form complexes with other Smad family members and associated transcription factors, but cannot activate transcription in these complexes. Furthermore, the SAD itself is able to activate transcription in heterologous reporter assays, identifying it as a proline-rich transcriptional activation domain, and indicating that the SAD is both necessary and sufficient to activate Smad-dependent transcriptional responses. We show that transcriptional activation by the SAD is p300-dependent, and demonstrate that this activity is associated with a physical interaction of the SAD with the amino terminus of p300, These data identify a novel function of the middle linker region of Smad4, and define the role of the SAD as an important locus determining the transcriptional activation of the Smad complex. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Ctr Canc, Lab Tumor Biol, Charlestown, MA 02129 USA. Imperial Canc Res Fund, Dev Signaling Lab, London WC2A 3PX, England. RP Lechleider, RJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. OI Parks, W. Tony/0000-0001-7341-3277 NR 38 TC 123 Z9 128 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 JAN 21 PY 2000 VL 275 IS 3 BP 2115 EP 2122 DI 10.1074/jbc.275.3.2115 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277NQ UT WOS:000084940000079 PM 10636916 ER PT J AU Horton, JK Prasad, R Hou, E Wilson, SH AF Horton, JK Prasad, R Hou, E Wilson, SH TI Protection against methylation-induced cytotoxicity by DNA polymerase beta-dependent long patch base excision repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; ABASIC SITES; OXYGEN ALKYLATION; MAMMALIAN-CELLS; BOVINE TESTIS; CHO CELLS; PATHWAY; METHOXYAMINE; GLYCOSYLASE; AGENTS AB Using a plasmid-based uracil-containing DNA substrate, we found that the long patch base excision repair (BER) activity of a wild-type mouse fibroblast extract was partially inhibited by an antibody to DNA polymerase beta (beta-pol), This suggests that beta-pol participates in long patch BER, in addition to single-nucleotide BER. In single-nucleotide BER, the deoxyribose phosphate (dRP) in the abasic site is removed by the lyase activity of beta-pol. Methoxyamine (MX) can react with the aldehyde of an abasic site, making it refractory to the beta-elimination step of the dRP lyase mechanism, thus blocking single-nucleotide BER. MX exposure sensitizes wildtype, but not beta-pol null mouse embryonic fibroblasts, to the cytotoxic effects of methyl methanesulfonate (MMS) and methylnitrosourea. Expression of beta-pol in the null cells restores the ability of MX to modulate sensitivity to MMS. The beta-pol null cells are known to be hypersensitive to MMS and methylnitrosourea, and in the presence of MX (i.e. under conditions where single-nucleotide BER is blocked) the null cells are still considerably more sensitive than wild-type. The data are consistent with a role of beta-pol in long patch BER, which helps protect cells against methylation damage-induced cytotoxicity. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 44 TC 111 Z9 115 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 JAN 21 PY 2000 VL 275 IS 3 BP 2211 EP 2218 DI 10.1074/jbc.275.3.2211 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277NQ UT WOS:000084940000091 PM 10636928 ER PT J AU Clair, T AF Clair, T TI Societal responsibilities SO SCIENCE LA English DT Letter C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Clair, T (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JAN 21 PY 2000 VL 287 IS 5452 BP 428 EP 428 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 277JF UT WOS:000084929900020 PM 10671169 ER PT J AU Romano-Spica, V Ianni, A Arzani, D Cattarini, L Majore, S Dean, M AF Romano-Spica, V Ianni, A Arzani, D Cattarini, L Majore, S Dean, M TI Allelic distribution of CCR5 and CCR2 genes in an Italian population sample SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CHEMOKINE RECEPTOR; HIV-1 INFECTION; DISEASE PROGRESSION; FUSION COFACTORS; DELETION ALLELE; RESISTANCE; AIDS; TRANSMISSION; INDIVIDUALS; CORECEPTOR AB Genetic polymorphisms of CCR5 and CCR2 human chemokine receptors have been associated with resistance during HIV-1 infection and disease progression. The protective effect of mutant alleles at these loci has important implications: in AIDS pathogenesis. Chemokine receptors have a role in viral entry into target cells as well as in immune response modulation. In the present report, me studied the frequency of CCR5 Delta 32 and CCR264I allelic variants among a representative sample of the Italian population. Observed allelic frequencies were 0.0454 and 0.0655, respectively. In both cases, genotype distribution was in equilibrium as predicted by the Hardy-Weinberg equation. Taken as a whole, about 21% of the population sample was found to be heterozygous for one or another of those two mutated alleles, Distribution of CCR5 Delta 32 and CCR264I allelic variants within a population can be considered as a measure of genetic susceptibility to HIV infection and disease progression. C1 Catholic Univ, Fac Med, Inst Hyg & Publ Hlth, I-00168 Rome, Italy. Univ Rome La Sapienza, Fac Med, Inst Med Genet, Rome, Italy. NCI, Lab Genomic Divers, Frederick, MD 21702 USA. RP Romano-Spica, V (reprint author), Catholic Univ, Fac Med, Inst Hyg & Publ Hlth, Lgo F Vito 1, I-00168 Rome, Italy. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 28 TC 17 Z9 17 U1 0 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 20 PY 2000 VL 16 IS 2 BP 99 EP 101 DI 10.1089/088922200309430 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 309QR UT WOS:000086781200001 PM 10659048 ER PT J AU Daly, JW Harper, J AF Daly, JW Harper, J TI Loperamide: novel effects on capacitative calcium influx SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE loperamide; calcium channels; calcium stores; maitotoxin; inositol trisphosphate; thapsigargin; ATP ID INTRACELLULAR CA2+ STORES; PLASMA-MEMBRANE; HL-60 CELLS; CYCLOPIAZONIC ACID; THYMIC LYMPHOCYTES; INOSITOL PHOSPHATE; CHANNEL BLOCKERS; ENTRY; CALMODULIN; RAT AB Loperamide is a widely used antidiarrheal that primarily acts at nanomolar concentrations through activation of opioid receptors in the gastrointestinal tract. At somewhat higher concentrations, loperamide blocks calmodulin activity, calcium channels, N-methyl-D-aspartate-receptor channels, and maitotoxin-elicited calcium influx. Loperamide at micromolar concentrations has now been shown to have a remarkable stimulatory effect on the capacitative calcium influx that is triggered in many cells by depletion of the inositol-trisphosphate-sensitive stores of calcium in the endoplasmic reticulum. The mechanism whereby loperamide enhances levels of intracellular calcium elevated by capacitative calcium influx is, as yet, undefined. C1 Natl Inst Hlth, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), Natl Inst Hlth, Bioorgan Chem Lab, Bldg 8,Rm 1A17, Bethesda, MD 20892 USA. RI Harper, Jacquie/A-8920-2014 NR 57 TC 14 Z9 14 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JAN 20 PY 2000 VL 57 IS 1 BP 149 EP 157 DI 10.1007/s000180050504 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 288PU UT WOS:000085572900011 PM 10949586 ER PT J AU Thompson, PA Munoz, V Jas, GS Henry, ER Eaton, WA Hofrichter, J AF Thompson, PA Munoz, V Jas, GS Henry, ER Eaton, WA Hofrichter, J TI The helix-coil kinetics of a heteropeptide SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; LASER TEMPERATURE-JUMP; ALANINE-BASED PEPTIDES; CIRCULAR-DICHROISM; ALPHA-HELICES; WATER; STABILITY; MECHANISM; THERMODYNAMICS; POLYPEPTIDE AB We have measured the kinetics of the helix-coil transition for the synthetic 21-residue peptide Ac-WAAAH(+) (AAAR(+)A)(3)A-NH(2) initiated by nanosecond laser temperature jumps. This peptide was designed with tryptophan in position 1 and histidine in position 5 so that the side chains interact when the backbone of residues 1-5 is alpha-helical. Histidine, when protonated, efficiently quenches tryptophan fluorescence providing a probe for the presence of helical structure. The kinetics measured throughout the melting transition are well-described by a single-exponential relaxation, with a rate of 3.3 x 10(6) s(-1) at 301 K, the midpoint of the helix-coil transition. The rate increases with increasing temperature with an apparent activation energy of approximately 8 kcal/mol. To interpret these results we have fitted the equilibrium and kinetic data with the statistical mechanical model of Munoz et al. (Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 5872-5879). This model includes both variable helix propensities and side chain-side chain interactions. The model accounts for the single-exponential kinetics by predicting that approximately 90% of the change in the tryptophan fluorescence results from melting of stretches of helix which include residues 1-5 by passage over a nucleation free energy barrier. The measured temperature dependence is reproduced by introducing damping from solvent friction and an activation barrier for the individual helix propagation and melting steps. This barrier is somewhat larger than that which results from the loss in conformational entropy or breaking of hydrogen bonds. The model provides a description of the kinetics of the helix-coil transition which is consistent with the results of other experimental studies as well as molecular dynamics simulations. C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Hofrichter, J (reprint author), NIH, Chem Phys Lab, Bldg 5, Bethesda, MD 20892 USA. RI Henry, Eric/J-3414-2013 OI Henry, Eric/0000-0002-5648-8696 NR 45 TC 139 Z9 141 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JAN 20 PY 2000 VL 104 IS 2 BP 378 EP 389 DI 10.1021/jp990292u PG 12 WC Chemistry, Physical SC Chemistry GA 278TT UT WOS:000085005600026 ER PT J AU Pestova, TV Lomakin, IB Lee, JH Choi, SK Dever, TE Hellen, CUT AF Pestova, TV Lomakin, IB Lee, JH Choi, SK Dever, TE Hellen, CUT TI The joining of ribosomal subunits in eukaryotes requires eIF5B SO NATURE LA English DT Article ID TRANSLATION INITIATION; PROTEIN-SYNTHESIS; RABBIT RETICULOCYTES; FACTOR-5; PURIFICATION; COMPLEX; BINDING; CODON AB Initiation of eukaryotic protein synthesis begins with the ribosome separated into its 40S and 60S subunits(1). The 40S subunit first binds eukaryotic initiation factor (eIF) 3 and an eIF2-GTP-initiator transfer RNA ternary complex. The resulting complex requires eIF1, eIF1A, eIF4A, eIF4B and eIF4F to bind to a messenger RNA and to scan to the initiation codon(2). eIF5 stimulates hydrolysis of eIF2-bound GTP and eIF2 is released from the 48S complex formed at the initiation codon before it is joined by a 60S subunit to form an active 80S ribosome(3-8). Here we show that hydrolysis of eIF2-bound GTP induced by eIF5 in 48S complexes is necessary but not sufficient for the subunits to join. A second factor termed eIF5B (relative molecular mass 175,000) is essential for this process. It is a homologue of the prokaryotic initiation factor IF2 (refs 6, 7) and, like it(8-12), mediates joining of subunits and has a ribosome-dependent GTPase activity that is essential for its function. C1 SUNY Hlth Sci Ctr, Dept Microbiol & Immunol, Brooklyn, NY 11203 USA. Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119899, Russia. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Pestova, TV (reprint author), SUNY Hlth Sci Ctr, Dept Microbiol & Immunol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. NR 17 TC 246 Z9 249 U1 1 U2 18 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 20 PY 2000 VL 403 IS 6767 BP 332 EP 335 DI 10.1038/35002118 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276VU UT WOS:000084899700058 PM 10659855 ER PT J AU Park, JB Levine, M AF Park, JB Levine, M TI Characterization of the promoter of the human ribonucleotide reductase R2 gene SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID GLUTAREDOXIN; EXPRESSION; IDENTIFICATION; CLONING AB We describe here cloning and characterization of the promoter region of the human ribonucleotide reductase R2 gene. Primer extension and sequence data indicated that two different transcripts were produced via using two different promoter regions, Promoter activity of the 5' flanking region of the first transcript was approximately 100-fold higher than controls, and that of the second transcript was approximately 30-fold higher than controls, Particularly, the proximal region of the first transcript, -125 to +1 bp, was responsible for approximately a 50-fold increase in promoter activity, compared to controls. This region had three CCAAT sequences, each of which contributed similarly to promoter activity. When all three CCAAT sequences were mutated, promoter activity declined 80%. In addition, the promoter region -125 to fl bp was responsible for cell-cycle-specific expression. These data provided essential information concerning regulatory mechanisms of cell-cycle-specific expression of human ribonucleotide reductase R2. (C) 2000 Academic Press. C1 ARS, USDA, BHNRC, Phytonutrients Lab,Bldg 307,Room 313, Beltsville, MD 20705 USA. NIH, Mol & Clin Nutr Sect, Digest Dis Branch, Bethesda, MD 20892 USA. RP Park, JB (reprint author), ARS, USDA, BHNRC, Phytonutrients Lab,Bldg 307,Room 313, Beltsville, MD 20705 USA. NR 20 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 19 PY 2000 VL 267 IS 2 BP 651 EP 657 DI 10.1006/bbrc.1999.1980 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 278XE UT WOS:000085013600032 PM 10631117 ER PT J AU Hisada, M Rabkin, CS Strickler, HD Wright, WE Christianson, RE van den Berg, BJ AF Hisada, M Rabkin, CS Strickler, HD Wright, WE Christianson, RE van den Berg, BJ TI Human papillomavirus antibody and risk of prostate cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Dept Hlth Serv, Sacramento, CA USA. Child Hlth & Dev Studies, Berkeley, CA USA. RP Hisada, M (reprint author), NCI, Bethesda, MD 20892 USA. NR 6 TC 31 Z9 32 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 JAN 19 PY 2000 VL 283 IS 3 BP 340 EP 341 DI 10.1001/jama.283.3.340-a PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 273WM UT WOS:000084732400023 PM 10647795 ER PT J AU Stanford, JL Feng, ZD Hamilton, AS Gilliland, FD Stephenson, RA Eley, JW Albertsen, PC Harlan, LC Potosky, AL AF Stanford, JL Feng, ZD Hamilton, AS Gilliland, FD Stephenson, RA Eley, JW Albertsen, PC Harlan, LC Potosky, AL TI Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer - The prostate cancer outcomes study SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; EXPERIENCE; THERAPY; MEN AB Context Patients with prostate cancer and their physicians need knowledge of treatment options and their potential complications, but limited data on complications are available in unselected population-based cohorts of patients. Objective To measure changes in urinary and sexual function in men who have undergone radical prostatectomy for clinically localized prostate cancer. Design The Prostate Cancer Outcomes Study, a population-based longitudinal cohort study with up to 24 months of follow-up. Setting Population-based cancer registries in 6 geographic regions of the United States. Participants A total of 1291 black, white, and Hispanic men aged 39 to 79 years who were diagnosed as having primary prostate cancer between October 1, 1994, and October 31, 1995, and who underwent radical prostatectomy within 6 months of diagnosis for clinically localized disease. Main Outcome Measures Distribution of and change in urinary and sexual function measures reported by patients at baseline and 6, 12, and 24 months after diagnosis. Results At 18 or more months following radical prostatectomy, 8.4% of men were incontinent and 59.9% were impotent. Among men who were potent before surgery, the proportion of men reporting impotence at 18 or more months after surgery varied according to whether the procedure was nerve sparing (65.6% of non-nerve-sparing, 58.6% of unilateral, and 56.0% of bilateral nerve-sparing). At 18 or more months after surgery, 41.9% reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age (39.0% of men aged <60 years vs 15.3%-21.7% of older men were potent at greater than or equal to 18 months [P<.001]; 13.8% of men aged 75-79 years vs 0.7%-3.6% of younger men experienced the highest level of incontinence at greater than or equal to 18 months [P =.03]), and sexual function also varied by race (38.4% of black men reported firm erections at greater than or equal to 18 months vs 25.9% of Hispanic and 21.3% of white men; P =.001), Conclusions Our study suggests that radical prostatectomy is associated with significant erectile dysfunction and some decline in urinary function. These results may be particularly helpful to community-based physicians and their patients with prostate cancer who face difficult treatment decisions. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. Univ New Mexico, Hlth Sci Ctr, New Mexico Tumor Registry, Albuquerque, NM USA. Univ Utah, Sch Med, Utah Canc Registry, Salt Lake City, UT USA. Univ Utah, Sch Med, Div Urol, Salt Lake City, UT USA. Emory Univ, Rollins Sch Publ Hlth, Georgia Ctr Canc Stat, Atlanta, GA USA. Univ Connecticut, Hlth Sci Ctr, Div Urol, Farmington, CT USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,MW 814, Seattle, WA 98109 USA. FU NCI NIH HHS [N01-PC-67009, N01-PC-67007, N01-PC-67010] NR 20 TC 668 Z9 689 U1 0 U2 27 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 JAN 19 PY 2000 VL 283 IS 3 BP 354 EP 360 DI 10.1001/jama.283.3.354 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 273WM UT WOS:000084732400027 PM 10647798 ER PT J AU Kirk, GD Camus-Randon, AM Mendy, M Goedert, JJ Merle, P Trepo, C Brechot, C Hainaut, P Montesano, R AF Kirk, GD Camus-Randon, AM Mendy, M Goedert, JJ Merle, P Trepo, C Brechot, C Hainaut, P Montesano, R TI Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from the Gambia SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HEPATITIS-B VIRUS; CANCER-PATIENTS; MICROSATELLITE ALTERATIONS; AFLATOXIN EXPOSURE; RAS MUTATIONS; CELL-LINES; GENE; HOTSPOT; RISK; CODON-249 AB Background: A selective mutation, an arginine-to-serine substitution in codon 249, of the p53 gene has been identified as a "hotspot" mutation in hepatocellular carcinoma (HCC), This mutation occurs in populations that are exposed to aflatoxins and have a high prevalence of hepatitis B virus carriers. We evaluated whether this mutation could be detected in cell-free DNA isolated from the plasma of subjects from The Gambia to detect this mutation that is strongly associated with HCC. Methods: Fifty-three patients with HCC, 13 patients with cirrhosis, and 53 control subjects were prospectively recruited from The Gambia, Sixty patients, of non-African origin, with various liver pathologies were also selected from France. DNA was extracted and purified from 200-mu L aliquots of plasma. The Ser-249 p53 mutation was detected by restriction endonuclease digestion of polymerase chain reaction products from exon 7 and was confirmed by direct sequencing of the amplified DNA, Results: The Ser-249 p53 mutation was detected in plasma DNA from 19 (36%) of the 53 patients with HCC, two (15%) of the 13 patients with cirrhosis, and three (6%) of the 53 control subjects. This mutation was not detected in any plasma DNA from the European patients. The adjusted odds ratio for having the mutation was 16.4 (95% confidence interval = 3.0-90.5) for patients with HCC compared with the control subjects. Conclusion: The Ser-249 p53 mutation in plasma DNA is strongly associated with HCC in Gambian patients, This mutation was also detected at a much lower prevalence in plasma DNA from Gambian patients with cirrhosis and in Gambian control subjects, findings that may lead to the earlier detection of HCC. Use of the Ser-249 p53 mutation should facilitate further molecular epidemiologic studies on the development of HCC. C1 Int Agcy Res Canc, Unit Mechanisms Carcinogenesis, F-69372 Lyon 08, France. Int Agcy Res Canc, Banjul, Gambia. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Med Res Council Labs, Banjul, Gambia. INSERM U271, Lyon, France. Necker Hosp, Hepatol Unit, Paris, France. RP Montesano, R (reprint author), Int Agcy Res Canc, Unit Mechanisms Carcinogenesis, 150 Cours Albert Thomas, F-69372 Lyon 08, France. RI Kirk, Gregory/A-8484-2009; Hainaut, Pierre /B-6018-2012 OI Hainaut, Pierre /0000-0002-1303-1610 NR 45 TC 97 Z9 107 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 JAN 19 PY 2000 VL 92 IS 2 BP 148 EP 153 DI 10.1093/jnci/92.2.148 PG 6 WC Oncology SC Oncology GA 275KQ UT WOS:000084819700013 PM 10639517 ER PT J AU Seeff, LB Miller, RN Rabkin, CS Buskell-Bales, Z Straley-Eason, KD Smoak, BL Johnson, LD Lee, SR Kaplan, EL AF Seeff, LB Miller, RN Rabkin, CS Buskell-Bales, Z Straley-Eason, KD Smoak, BL Johnson, LD Lee, SR Kaplan, EL TI 45-year follow-up of hepatitis C virus infection in healthy young adults SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NON-B-HEPATITIS; POST-TRANSFUSION HEPATITIS; VOLUNTEER BLOOD-DONORS; NON-A; HEPATOCELLULAR-CARCINOMA; POSTTRANSFUSION HEPATITIS; ALANINE AMINOTRANSFERASE; ANTIBODIES; PREVALENCE; EPIDEMIOLOGY AB Background: The sequelae during the first two decades after acute hepatitis C virus (HCV) infection have been well studied, but the outcome thereafter is unknown. Objective: To conduct an extended study of the natural history of HCV infection by using archived serum specimens originally collected between 1948 and 1954. Design: Retrospective cohort study. Setting: A university, a Veterans Affairs medical center, and a medical follow-up agency that had access to the serum specimens and accompanying demographic and medical records. Participants: 8568 military recruits who were evaluated for group A streptococcal infection and acute rheumatic fever between 1948 and 1954. Blood samples were taken from the recruits and, after testing, were stored frozen for almost 45 years. Measurements: The presence of antibodies to HCV was determined by enzyme-linked immunoassay, supplementary recombinant immunoblot assay, and polymerase chain reaction for HCV RNA. Morbidity and mortality were also assessed. Results: Of 8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay and recombinant immunoblot assay. The rate was 1.8% among the African-American persons and 0.1% among the white persons in the total sample (relative risk, 25.9 [95% CI, 8.4 to 80.01]). During the 45-year follow-up, liver disease occurred in 205 of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the 17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%) had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to 2.61]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years after the original phlebotomy, 5 (29%) died of non-liver-related disease a median of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes. One hundred nineteen HCV-negative persons (1.4%) died of liver disease. Conclusions: The rate of HCV infection from 1948 to 1954 among a sample of military recruits parallels that among present-day military recruits and volunteer blood donors. During 45 years of follow-up, HCV-positive persons had low liver-related morbidity and mortality rates. This suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought. C1 Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Inst Med, Washington, DC USA. Walter Reed Army Inst Res, Washington, DC USA. NCI, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Ortho Clin Diagnost, Raritan, NJ USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Seeff, LB (reprint author), NIDDKD, NIH, Room 9A-18,31 Ctr Dr, Bethesda, MD 20892 USA. RI Jepsen, Peter/A-2593-2010 OI Jepsen, Peter/0000-0002-6641-1430 NR 42 TC 255 Z9 263 U1 0 U2 2 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 JAN 18 PY 2000 VL 132 IS 2 BP 105 EP 111 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 275ZZ UT WOS:000084852300002 PM 10644270 ER PT J AU Refsgaard, HHF Tsai, L Stadtman, ER AF Refsgaard, HHF Tsai, L Stadtman, ER TI Modifications of proteins by polyunsaturated fatty acid peroxidation products SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OXIDATIVELY MODIFIED PROTEINS; METAL-CATALYZED OXIDATION; GLUTAMINE-SYNTHETASE; IMMUNOCHEMICAL DETECTION; CARBONYL GROUPS; MALONDIALDEHYDE; HYDROPEROXIDES; GENERATION; CHEMISTRY; RESIDUES AB The ability of unsaturated fatty acid methyl esters to modify amino acid residues in bovine serum albumin (BSA), glutamine synthetase, and insulin in the presence of a metal-catalyzed oxidation system [ascorbate/Fe(lll)/O-2] depends on the degree of unsaturation of the fatty acid. The fatty acid-dependent generation of carbonyl groups and loss of lysine residues increased in the order methyl linoleate < methyl linolenate < methyl arachidonate. The amounts of alkyl hydroperoxides, malondialdehyde, and a number of other aldehydes that accumulated when polyunsaturated fatty acids were oxidized in the presence of BSA were significantly lower than that observed in the absence of BSA. Direct treatment of proteins with various lipid hydroperoxides led to a slight increase in the formation of protein carbonyl derivatives, whereas treatment with the hydroperoxides together with Fe(ll) led to a substantial increase in the formation of protein carbonyls, These results are consistent with the proposition that metal-catalyzed oxidation of polyunsaturated fatty acids can contribute to the generation of protein carbonyls by direct interaction of lipid oxidation products (alpha,beta-unsaturated aldehydes) with lysine residues (Michael addition reactions) and also by interactions with alkoxyl radicals obtained by Fe(ll) cleavage of lipid hydroperoxides that are formed, In addition, saturated aldehydes derived from the polyunsaturated fatty acids likely react with lysine residues to form Schiff base adducts. C1 NHLBI, NIH, Biochem Lab, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, NIH, Biochem Lab, Bldg 3,Room 222,3 Ctr Dr,MSC-0342, Bethesda, MD 20892 USA. NR 38 TC 187 Z9 194 U1 1 U2 20 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 JAN 18 PY 2000 VL 97 IS 2 BP 611 EP 616 DI 10.1073/pnas.97.2.611 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HX UT WOS:000084873100019 PM 10639127 ER PT J AU Taylor, GA Collazo, CM Yap, GS Nguyen, K Gregorio, TA Taylor, LS Eagleson, B Secrest, L Southon, EA Reid, SW Tessarollo, L Bray, M McVicar, DW Komschlies, KL Young, HA Biron, CA Sher, A Vande Woude, GF AF Taylor, GA Collazo, CM Yap, GS Nguyen, K Gregorio, TA Taylor, LS Eagleson, B Secrest, L Southon, EA Reid, SW Tessarollo, L Bray, M McVicar, DW Komschlies, KL Young, HA Biron, CA Sher, A Vande Woude, GF TI Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MURINE CYTOMEGALOVIRUS-INFECTION; INTERFERON-GAMMA; TOXOPLASMA-GONDII; GTP-BINDING; EXPRESSED GTPASE; PROTEIN; INTERLEUKIN-12; IDENTIFICATION; RESPONSES; PARASITE AB Interferon-gamma (IFN-gamma) is critical for defense against pathogens, but the molecules that mediate its antimicrobial responses are largely unknown. IGTP is the prototype for a family of IFN-gamma-regulated genes that encode 48-kDa CTP-binding proteins that localize to the endoplasmic reticulum. We have generated IGTP-deficient mice and found that, despite normal immune cell development and normal clearance of Listeria monocytogenes and cytomegalovirus infections, the mice displayed a profound loss of host resistance to acute infections of the protozoan parasite Toxoplasma gondii. By contrast, IFN-gamma receptor-deficient mice have increased susceptibility to all three pathogens. Thus, IGTP defines an IFN-gamma-regulated pathway with a specialized role in antimicrobial resistance. C1 NCI, Frederick Canc Res & Dev Ctr, Adv Biosci Labs, Basic Res Program, Frederick, MD 21702 USA. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Brown Univ, Div Biol & Med, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Cellular & Mol Immunol Sect, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. RP Vande Woude, GF (reprint author), Van Andel Res Inst, 201 Monroe Ave,Suite 400, Grand Rapids, MI 49503 USA. RI Young, Howard/A-6350-2008; McVicar, Daniel/G-1970-2015 OI Young, Howard/0000-0002-3118-5111; FU NCI NIH HHS [N01-CO-46000, R01 CA041268] NR 27 TC 174 Z9 181 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 18 PY 2000 VL 97 IS 2 BP 751 EP 755 DI 10.1073/pnas.97.2.751 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HX UT WOS:000084873100043 PM 10639151 ER PT J AU Klucken, J Buchler, C Orso, E Kaminski, WE Porsch-Ozcurumez, M Liebisch, C Kapinsky, M Diederich, W Drobnik, W Dean, M Allikmets, R Schmitz, G AF Klucken, J Buchler, C Orso, E Kaminski, WE Porsch-Ozcurumez, M Liebisch, C Kapinsky, M Diederich, W Drobnik, W Dean, M Allikmets, R Schmitz, G TI ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; FAMILIAL INTRAHEPATIC CHOLESTASIS; INTRACELLULAR CHOLESTEROL; MULTIDRUG-RESISTANCE; SIGNAL-TRANSDUCTION; BINDING PROTEINS; P-GLYCOPROTEIN; FIBROBLASTS; MEMBRANE; EFFLUX AB Excessive uptake of atherogenic lipoproteins such as modified low-density lipoprotein complexes by vascular macrophages leads to foam cell formation, a critical step in atherogenesis, Cholesterol afflux mediated by high-density lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid overloading. The molecular mechanisms underlying this reverse cholesterol transport process are currently not fully understood. To identify effector proteins that are involved in macrophage lipid uptake and release, we searched for genes that are regulated during lipid influx and efflux in human macrophages using a differential display approach. We report here that the ATP-binding cassette (ABC) transporter ABCG1 (ABC8) is induced in monocyte-derived macrophages during cholesterol influx mediated by acetylated low-density lipoprotein. Conversely, lipid efflux in cholesterol-laden macrophages, mediated by the cholesterol acceptor HDL3, suppresses the expression of ABCG1, Immunocytochemical and flow cytometric analyses revealed that ABCG1 is expressed on the cell surface and in intracellular compartments of cholesterol-laden macrophages. Inhibition of ABCG1 protein expression using an antisense strategy resulted in reduced HDL3-dependent efflux of cholesterol and choline-phospholipids. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified an additional set of ABC genes whose expression is regulated by cholesterol uptake or HDL3-mediated lipid release, suggesting a potential function for these transporters in macrophage lipid homeostasis. Our results demonstrating a regulator function for ABCG1 in cholesterol and phospholipid transport define a biologic activity for ABC transporters in macrophages. C1 Univ Regensburg, Inst Clin Chem & Lab Med, D-93042 Regensburg, Germany. NCI, Lab Genome Divers, Frederick, MD 21702 USA. Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. RP Schmitz, G (reprint author), Univ Regensburg, Inst Clin Chem & Lab Med, Franz Josef Str Allee 11, D-93042 Regensburg, Germany. RI Dean, Michael/G-8172-2012; Liebisch, Gerhard/G-6130-2010; OI Dean, Michael/0000-0003-2234-0631; Liebisch, Gerhard/0000-0003-4886-0811; Schmitz, Gerd/0000-0002-1325-1007 NR 41 TC 387 Z9 409 U1 1 U2 20 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 JAN 18 PY 2000 VL 97 IS 2 BP 817 EP 822 DI 10.1073/pnas.97.2.817 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HX UT WOS:000084873100055 PM 10639163 ER PT J AU Cho, YS Park, YG Lee, YN Kim, MK Bates, S Tan, LZ Cho-Chung, YS AF Cho, YS Park, YG Lee, YN Kim, MK Bates, S Tan, LZ Cho-Chung, YS TI Extracellular protein kinase A as a cancer biomarker: Its expression by tumor cells and reversal by a myristate-lacking C alpha and RII beta subunit overexpression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RII(BETA) REGULATORY SUBUNIT; PROSTATE-SPECIFIC ANTIGEN; CYCLIC-AMP; CATALYTIC SUBUNIT; GROWTH ARREST; DIFFERENTIATION; SITE; FIBROBLASTS; MUTATION AB Overexpression of cAMP-dependent protein kinase (PKA) type I isozyme is associated with cell proliferation and neoplastic transformation. The presence of PKA on the external surface of LS-174T human colon carcinoma cells has been shown. Here, we show that cancer cells of various cell types excrete PKA into the conditioned medium. This extracellular PKA (ECPKA) is present in active, free catalytic subunit (C subunit) form, and its activity is specifically inhibited by PKA inhibitory protein, PKI. Overexpression of the CLY or RI alpha subunit gene of PKA in an expression vector, which upregulates intracellular PKA type I, markedly up-regulates ECPKA expression. In contrast, overexpression of the RII beta subunit, which eliminates PKA type I, up-regulates PKA type II, and reverts the transformed phenotype, down-regulates ECPKA. A mutation in the C alpha gene that prevents myristylation allows the intracellular PKA up-regulation but blocks the ECPKA increase, suggesting that the NH2-terminal myristyl group of C alpha is required for the ECPKA expression. In serum of cancer patients, the ECPKA expression is up-regulated 10-fold as compared with normal serum. These results indicate that the ECPKA expression is an ordered cellular response of a living cell to actively exclude excess intracellular PKA molecules from the cell. This phenomenon is up-regulated in tumor cells and has an inverse relationship with the hormone dependency of breast cancer. Thus, the extracellular PKA may serve as a potential diagnostic and prognostic marker for cancer. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, NIH, Med Branch, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NR 27 TC 72 Z9 76 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 JAN 18 PY 2000 VL 97 IS 2 BP 835 EP 840 DI 10.1073/pnas.97.2.835 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HX UT WOS:000084873100058 PM 10639166 ER PT J AU Barlow, C Ribaut-Barassin, C Zwingman, TA Pope, AJ Brown, KD Owens, JW Larson, D Harrington, EA Haeberle, AM Mariani, J Eckhaus, M Herrup, K Bailly, Y Wynshaw-Boris, A AF Barlow, C Ribaut-Barassin, C Zwingman, TA Pope, AJ Brown, KD Owens, JW Larson, D Harrington, EA Haeberle, AM Mariani, J Eckhaus, M Herrup, K Bailly, Y Wynshaw-Boris, A TI ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ATAXIA-TELANGIECTASIA; DEFICIENT MICE; NERVOUS-SYSTEM; GENE-PRODUCT; NEURONS; EXPRESSION; LOCALIZATION; UBIQUITIN; DEFECTS AB We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm-/-) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hindpaw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm-/- mice analyzed in most laboratories, Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm-/- mice to determine whether there was evidence of neuronal abnormality, We found a significant increase in the number of lysosomes in Atm-/- mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells, The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum, These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers. C1 Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. NIH, Natl Ctr Human Genome Res, Genet Dis Res Branch, Bethesda, MD 20892 USA. CNRS, Ctr Neurochim, Lab Neurobiol Cellulaire, Unite Propre Rech 9009,Ctr Neurochim, F-67084 Strasbourg, France. Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Alzheimers Res Lab, Cleveland, OH 44106 USA. Louisiana State Univ, Med Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. Louisiana State Univ, Med Ctr, Stanley S Scott Canc Ctr, New Orleans, LA 70112 USA. Off Res Serv, Vet Resources Program, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Ctr Canc, Mol Oncol Lab, Charlestown, MA USA. Univ Paris 06, Lab Dev & Vieillissement Syst Nerveux, Unite Mixte Rech 7624, CNRS, F-75005 Paris, France. RP Barlow, C (reprint author), Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NCRR NIH HHS [R25 RR010836, 5R25 RR10836-02]; NINDS NIH HHS [NS18381, NS20591, R01 NS018381, R01 NS020591] NR 26 TC 111 Z9 113 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 18 PY 2000 VL 97 IS 2 BP 871 EP 876 DI 10.1073/pnas.97.2.871 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 276HX UT WOS:000084873100064 PM 10639172 ER PT J AU Sun, JZ Chen, J Cheng, ZY Robbins, JB Battey, JF Gu, XX AF Sun, JZ Chen, J Cheng, ZY Robbins, JB Battey, JF Gu, XX TI Biological activities of antibodies elicited by lipooligosaccharide based-conjugate vaccines of nontypeable Haemophilus influenzae in an otitis media model SO VACCINE LA English DT Article DE lipooligosaccharide; conjugate vaccine; otitis media ID NONTYPABLE HEMOPHILUS-INFLUENZAE; HUMAN EPITHELIAL-CELLS; EAR FLUID ANTIBODY; IMMUNE-RESPONSE; MIDDLE-EAR; DETOXIFIED LIPOOLIGOSACCHARIDE; NASOPHARYNGEAL COLONIZATION; BACTERICIDAL ANTIBODY; SERUM; CHILDREN AB Vaccination of chinchillas with nontypeable Haemophilus influenzae (NTHi) lipooligosaccharide (LOS) conjugates protected against otitis media. Correlations between the levels of conjugate-induced LOS antibodies (Abs) in sera and middle car fluids (MEFs) and Ab-mediated biological functions and protection were examined. Following parenteral vaccination and middle ear challenge, all vaccinated animals, but none of the controls, had high titers of anti-LOS in their sera and MEFs. There was a correlation between the levels of anti-LOS IgG+M, IgG or IgA in the sera and ill the MEFs (P < 0.001). An inverse correlation was found between the level of serum IgG+M and bacterial counts and between the levels of MEF Abs and bacterial counts at the early postchallenge stage (P < 0.05). Of the 39 vaccinated animals, 44% showed complete protection against otitis media, 46% (18/39) of their sera inhibited adherence of NTHi to human epithelial cells, 49% (19/39) demonstrated bactericidal activity and 49% (19/39) showed opsonophagocytic activity. In contrast, none of the controls (19) were protected, none of their sera inhibited bacterial adherence or had bactericidal activity and only 21% showed opsonophagocytosis. Our interpretation is that vaccine-induced LOS Abs transuded into the middle car and conferred immunity to NTHi by binding to LOS of NTHi, inhibition of NTHi adherence to epithelial cells and complement-mediated bacteriolysis (or opsonophagocytosis). Published by Elsevier Science Ltd. C1 Natl Inst Deafness & Other Commun Disorders, Immunol Lab, Rockville, MD 20850 USA. Prince Georges Hosp Ctr, Cheverly, MD 20785 USA. NICHHD, Bethesda, MD 20892 USA. RP Gu, XX (reprint author), Natl Inst Deafness & Other Commun Disorders, Immunol Lab, 5 Res Court,Rm 2A31, Rockville, MD 20850 USA. NR 41 TC 24 Z9 24 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 18 PY 2000 VL 18 IS 13 BP 1264 EP 1272 DI 10.1016/S0264-410X(99)00381-3 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 271NT UT WOS:000084600900014 PM 10649628 ER PT J AU Brasaemle, DL Levin, DM Adler-Wailes, DC Londos, C AF Brasaemle, DL Levin, DM Adler-Wailes, DC Londos, C TI The lipolytic stimulation of 3T3-L1 adipocytes promotes the translocation of hormone-sensitive lipase to the surfaces of lipid storage droplets SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE adipocyte; hormone-sensitive lipase; lipolysis ID DEPENDENT PROTEIN-KINASE; ADIPOSE CONVERSION; MEMBRANE-FUSION; CELLS; TISSUE; PHOSPHORYLATION; DIFFERENTIATION; IDENTIFICATION; NOCODAZOLE; EXPRESSION AB Hormone-sensitive lipase catalyzes the rate-limiting step in the release of fatty acids from triacylglycerol-rich lipid storage droplets of adipocytes, which contain the body's major energy reserves. Hormonal stimulation of cAMP formation and the activation of cAMP-dependent protein kinase leads to the phosphorylation of hormone-sensitive lipase and a large increase in lipolysis in adipocytes. By contrast, phosphorylation of hormone-sensitive lipase by the kinase in vitro results in a comparatively minor increase in catalytic activity. In this study, we investigate the basis for this discrepancy by using immunofluorescence microscopy to locate hormone-sensitive lipase in lipolytically stimulated and unstimulated 3T3-L1 adipocytes. In unstimulated cells, hormone-sensitive lipase is diffusely distributed throughout the cytosol. Upon stimulation of cells with the P-adrenergic receptor agonist, isoproterenol, hormone-sensitive lipase translocates from the cytosol to the surfaces of intracellular lipid droplets concomitant with the onset of lipolysis, as measured by the release of glycerol to the culture medium. Both hormone-sensitive lipase translocation and lipolysis are reversed by the incubation of cells with the beta-adrenergic receptor antagonist. propranolol. The treatment of cells with cycloheximide fails to inhibit lipase translocation or lipolysis, indicating that the synthesis of nascent proteins is not required. Cytochalasin D and nocodazole used singly and in combination also failed to have a major effect, thus suggesting that the polymerization of microfilaments and microtubules and the formation of intermediate filament networks is unnecessary. Hormone-sensitive lipase translocation and lipolysis were inhibited by N-ethylmaleimide and a combination of deoxyglucose and sodium azide. We propose that the major consequence of the phosphorylation of hormone-sensitive lipase following the lipolytic stimulation of adipocytes is the translocation of the lipase from the cytosol to the surfaces of lipid storage droplets. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. OI Brasaemle, Dawn/0000-0002-8553-8285 NR 30 TC 149 Z9 153 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI BBA-Mol. Cell. Biol. Lipids PD JAN 17 PY 2000 VL 1483 IS 2 BP 251 EP 262 DI 10.1016/S1388-1981(99)00179-1 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 277BK UT WOS:000084912700005 PM 10634941 ER PT J AU Copeland, PR Fletcher, JE Carlson, BA Hatfield, DL Driscoll, DM AF Copeland, PR Fletcher, JE Carlson, BA Hatfield, DL Driscoll, DM TI A novel RNA binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs SO EMBO JOURNAL LA English DT Article DE RNA binding protein; SECIS element; selenocysteine; translation; 3 ' UTR ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; MESSENGER-RNA; ESCHERICHIA-COLI; SELENOCYSTEINE INCORPORATION; UGA CODON; FACTOR SELB; INSERTION; ENZYME; MOTIF; GENE AB In eukaryotes, the decoding of the UGA codon as selenocysteine (Sec) requires a Sec insertion sequence (SECIS) element in the 3' untranslated region of the mRNA, We purified a SECIS binding protein, SBP2, and obtained a cDNA clone that encodes this activity. SBP2 is a novel protein containing a putative RNA binding domain found in ribosomal proteins and a yeast suppressor of translation termination. By UV cross-linking and immunoprecipitation, we show that SBP2 specifically binds selenoprotein mRNAs both in vitro and in vivo. Using Se-75-labeled Sec-tRNA(Sec), we developed an in vitro system for analyzing Sec incorporation in which the translation of a selenoprotein mRNA was both SBP2 and SECIS element dependent. Immunodepletion of SBP2 from the lysates abolished Sec insertion, which was restored when recombinant SBP2 was added to the reaction. These results establish that SBP2 is essential for the co-translational insertion of Sec into selenoproteins. We hypothesize that the binding activity of SBP2 may be involved in preventing termination at the UGA/Sec codon. C1 Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44195 USA. NCI, Sect Mol Biol Selenium, Basic Res Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Driscoll, DM (reprint author), Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, 9500 Euclid Ave,NC-10, Cleveland, OH 44195 USA. FU NHLBI NIH HHS [HL29582, P01 HL029582]; NIDDK NIH HHS [F32 DK09878-01, F32 DK009878] NR 34 TC 228 Z9 236 U1 2 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 JAN 17 PY 2000 VL 19 IS 2 BP 306 EP 314 DI 10.1093/emboj/19.2.306 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 277YU UT WOS:000084961800015 PM 10637234 ER PT J AU Staudt, LM AF Staudt, LM TI The molecular and cellular origins of Hodgkin's disease SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Editorial Material ID NF-KAPPA-B; REED-STERNBERG CELLS; TRANSCRIPTION FACTOR; GENE-EXPRESSION; GERMINAL-CENTERS; IN-VIVO; ACTIVATION; DIFFERENTIATION; LYMPHOCYTES; APOPTOSIS C1 NCI, Div Clin Sci, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Div Clin Sci, Metab Branch, NIH, Bldg 10,Rm 4N114,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 60 TC 76 Z9 76 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 JAN 17 PY 2000 VL 191 IS 2 BP 207 EP 212 DI 10.1084/jem.191.2.207 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 276ZJ UT WOS:000084908000002 PM 10637266 ER PT J AU Foltys, H Kemeny, S Krings, T Boroojerdi, B Sparing, R Thron, A Topper, R AF Foltys, H Kemeny, S Krings, T Boroojerdi, B Sparing, R Thron, A Topper, R TI The representation of the plegic hand in the motor cortex: a combined fMRI and TMS study SO NEUROREPORT LA English DT Article DE fMRI; motor cortex; motor imagery; neuroplasticity; TMS ID MAGNETIC STIMULATION; CORTICAL EXCITABILITY; REORGANIZATION; ORGANIZATION; EXECUTION; MOVEMENTS; IMAGERY AB TMS mapping and fMRI were used to investigate changes in the motor cortex representation of the hand in a patient with complete loss of right hand function following traumatic avulsion of the cervical roots C7 and C8. Both TMS and fMRI demonstrated an expansion of the motor representation of the forearm into the hand area contralateral to the injured side. fMRI of the hand area, however, revealed that this area could still be activated when the patient was instructed to imagine finger tapping with his plegic hand. These results indicate that the plegic hand is still represented in the motor cortex, despite the fact that the same cortical area is also now active during movements involving forearm muscles. NeuroReport 11:147-150 (C) 2000 Lippincott Williams & Wilkins. C1 Aachen Tech Univ, Dept Neurol, D-52057 Aachen, Germany. Aachen Tech Univ, Dept Neuroradiol, D-52057 Aachen, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Topper, R (reprint author), Aachen Tech Univ, Dept Neurol, Pauwelsstr 30, D-52057 Aachen, Germany. NR 23 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JAN 17 PY 2000 VL 11 IS 1 BP 147 EP 150 DI 10.1097/00001756-200001170-00029 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 274YA UT WOS:000084791600030 PM 10683847 ER PT J AU Zhu, JH Quyyumi, AA Norman, JE Csako, G Waclawiw, MA Shearer, GM Epstein, SE AF Zhu, JH Quyyumi, AA Norman, JE Csako, G Waclawiw, MA Shearer, GM Epstein, SE TI Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HERPES-SIMPLEX VIRUS; CHLAMYDIA-PNEUMONIAE; HEART-DISEASE; CYTOMEGALOVIRUS-INFECTION; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS; ASSOCIATION; ATHERECTOMY; INFARCTION; SURGERY AB Infection and inflammation have been suggested to play roles in coronary artery disease (CAD). We hypothesized that: (1) CAD risk is associated with the aggregate number of pathogens (pathogen burden), and (2) increased pathogen burden is associated with elevated levels of C-reactive protein (CRP), a marker of inflammation, We evaluated 233 patients for CAD. Blood samples from each patient were tested for immunoglobulin-G (IgG) antibodies to cytomegalovirus (CMV), Chlamydia pneumoniae, hepatitis A virus (HAV), herpes simplex virus type 1 (HSV-IJ and HSV type 2 (HSV-2), and for the CRP levels. Of the 233 study subjects, 68% had evidence of CAD by coronary angiography. Although the prevalence of seropositivity for each pathogen tended to be higher in the patients with CAD than those without, only the association between CAD and seropositivity to HAV was significant in multivariate analysis. Over 75% of study subjects had been exposed to greater than or equal to 3 of the 5 pathogens tested, and analysis determined that increasing pathogen burden was significantly associated with increasing CAD risk, even after adjustment for traditional CAD risk factors. The prevalence of CAD was 48%, 69%, and 85% in individuals with antibodies to less than or equal to 2 pathogens, to 3 or 4 pathogens, and to 5 pathogens, respectively. A similar association between increasing pathogen burden and CRP levels was also found. The pathogen burden remained a significant predictor of CRP levels after multivariate analysis. Our data suggest that infection does play a role in the genesis of atherosclerosis. However, the risk posed by infection is related to the pathogen burden that may contribute to CAD through inflammatory responses. (C) 2000 by Excerpta Medica, Inc. C1 Washington Hosp Ctr, Inst Cardiovasc Res, Washington, DC 20010 USA. Natl Heart Lung & Blood Inst, Nat Inst Hlth, Cardiol Branch, Ctr Clin, Bethesda, MD USA. Natl Heart Lung & Blood Inst, Nat Inst Hlth, Div Epidemiol & Clin Applicat, Ctr Clin, Bethesda, MD USA. NCI, Natl Inst Hlth, Expt Immunol Branch, Bethesda, MD USA. RP Epstein, SE (reprint author), Washington Hosp Ctr, Inst Cardiovasc Res, 110 Irving St,NW,Suite 4B-1, Washington, DC 20010 USA. NR 30 TC 187 Z9 196 U1 1 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2000 VL 85 IS 2 BP 140 EP 146 DI 10.1016/S0002-9149(99)00653-0 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 275CG UT WOS:000084801400002 PM 10955367 ER PT J AU Haydar, ZR Brantley, DA Gittings, NS Wright, JG Fleg, JL AF Haydar, ZR Brantley, DA Gittings, NS Wright, JG Fleg, JL TI Early repolarization: An electrocardiographic predictor of enhanced aerobic fitness SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Baylor Univ, Med Ctr, Div Geriatr, Dallas, TX USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Winston Salem, NC 27103 USA. RP Fleg, JL (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 10 TC 12 Z9 14 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2000 VL 85 IS 2 BP 264 EP 266 DI 10.1016/S0002-9149(99)00632-3 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 275CG UT WOS:000084801400025 PM 10955390 ER PT J AU Hanson, RL Pratley, RE Bogardus, C Narayan, KMV Roumain, JML Imperatore, G Fagot-Campagna, A Pettitt, DJ Bennett, PH Knowler, WC AF Hanson, RL Pratley, RE Bogardus, C Narayan, KMV Roumain, JML Imperatore, G Fagot-Campagna, A Pettitt, DJ Bennett, PH Knowler, WC TI Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diabetes mellitus; non-insulin-dependent; epidemiologic studies; incidence; insulin resistance ID IMPAIRED GLUCOSE-TOLERANCE; DEPENDENT DIABETES-MELLITUS; BETA-CELL FUNCTION; PIMA-INDIANS; CARDIOVASCULAR RISK; RESISTANCE; OBESITY; NIDDM; MODEL; TESTS AB The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures or insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1,731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G(0), G(120)) and insulin (I-0, I-120) concentrations obtained during an oral glucose tolerance test. Pasting serum insulin concentration and the insulin sensitivity index (10(4)/(I-0 x G(0))) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemiceuglycemic cramp (\r\ approximate to 0.60) They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups approximate to 3.0), Corrected insulin response (I-120/(G(120) x (G(120) - 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35), Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be reasonable surrogates for more sophisticated measures in epidemiologic studies. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Hanson, RL (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RI Narayan, K.M. Venkat /J-9819-2012; Hanson, Robert/O-3238-2015 OI Narayan, K.M. Venkat /0000-0001-8621-5405; Hanson, Robert/0000-0002-4252-7068 NR 35 TC 310 Z9 328 U1 1 U2 7 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2000 VL 151 IS 2 BP 190 EP 198 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 275LE UT WOS:000084821000013 PM 10645822 ER PT J AU Harty, LC Shields, PG Winn, DM Caporaso, NE Hayes, RB AF Harty, LC Shields, PG Winn, DM Caporaso, NE Hayes, RB TI Self-collection of oral epithelial cell DNA under instruction from epidemiologic interviewers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE DNA; epidemiologic methods; epidemiology, molecular; mouth mucosa; mouthwashes; polymerase chain reaction ID ENZYMATIC AMPLIFICATION; RISK; POPULATION; CANCER; PCR AB Oral epithelial cells provide an easily accessible source of germline DNA. Two methods for collection were compared in a 1992-1995 case-control study of oral cancer in Puerto Rico. One group of subjects (55 controls without oral cancer) collected oral rinse samples at home or work under the direction of a nonmedically trained interviewer ("self-collection"); the other group (94 controls) participated in a clinic-based collection, which also included blood and urine samples, conducted by a medical technician ("clinic collection"). Participation was higher for self-collection (98.2%) than for clinic collection (70.7%) (p < 0.001). DNA yields ranged from 2.0 to 204.5 mu g (median, 25.9 mu g) and did not differ by collection method, although yields varied by interviewer among self-collected samples (p = 0.02). Success rates for polymerase chain reaction amplification of the ADH3, NAT1, and multiplex CYP1A1/GSTT1/GSTM1 genotyping assays ranged from 76.4% (NAT1) to 98.2% (ADH3) for self-collected samples and were similar to those for clinic-collected samples (87.2-97.9%). Failure to amplify was associated with low DNA content (p = 0.015). Similar results were observed among cases (91 self-collected, 66 clinic collected), except that DNA yields did not vary by interviewer and a larger fraction (10.2%) of samples contained less than 5 mu g of DNA, perhaps because of disease-related oral impairment. Self-collection of oral epithelial DNA samples appears satisfactory and efficient for many epidemiologic studies. C1 NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NIDR, Oral Hlth Promot Risk Factors & Mol Epidemiol Bra, Bethesda, MD 20892 USA. NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. RP Caporaso, NE (reprint author), NCI, Genet Epidemiol Branch, Execut Plaza S Suite 7116,MSC 7236, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 NR 15 TC 29 Z9 31 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2000 VL 151 IS 2 BP 199 EP 205 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 275LE UT WOS:000084821000014 PM 10645823 ER PT J AU Kim, YS Zhang, HJ Kim, HY AF Kim, YS Zhang, HJ Kim, HY TI Profiling neurosteroids in cerebrospinal fluids and plasma by gas chromatography/electron capture negative chemical ionization mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE neurosteroids; allopregnanolone; pregnanolone; isopregnanolone; epipregnanolone; gas chromatography/mass spectrometry; electron capture negative ion chemical ionization; cerebrospinal fluids; plasma ID STEROID-HORMONE METABOLITES; GABA-A RECEPTOR; RAT-BRAIN; NEUROACTIVE STEROIDS; MAJOR DEPRESSION; CORTISOL; RADIOIMMUNOASSAY; MODULATORS; FLUOXETINE; BINDING AB A quantitative method for the determination of allopregnanolone (5 alpha,3 alpha-THP) and related neurosteroids in CSF and plasma was established using gas chromatography/electron capture negative chemical ionization mass spectrometry (GC/ECNCI/MS). Neurosteroids were converted to carboxymethoxime, pentafluorobenzyl and trimethylsilyl derivatives and detected as intense (M-181)(-) fragment ions generated under the negative ion chemical ionization process. The response curves constructed using d(4)-dihydrotestosterone (DHT) and d(4)-5 alpha,3 alpha-THP as internal standards showed linearity in the concentration range of 10-1000 pg/ml, The variation of response ratios determined against internal standards over a a-month period was less than 10%, Instrumental detection limits for most neurosteroids were in the low picogram range with the exception of progesterone and dihydroprogesterone (DHP) which were detected with approximately 10 times less sensitivity in comparison to other steroids. In conjunction with solid-phase extraction, this method allowed the quantification of at least four neurosteroids, including androsterone, testosterone, 5 alpha,3 alpha-THP, and pregnenolone in 1-2 ml of human cerebrospinal fluid (CSF), While the level of 5 alpha,3 alpha-THP in human CSF was comparable to that in the human plasma, other steroid levels were significantly lower. Although individual CSF and plasma samples showed widely varying neurosteroid levels, species specificity appeared to exist. The levels of 5 alpha,3 alpha-THP and pregnenolone in human CSF were higher than those of monkey CSF where these steroids were often not detected with our current detection limit, In comparison to human plasma, rat plasma samples contained considerably lower levels of androsterone and pregnenolone, Among THP stereoisomers, 5 beta,3 alpha-THP and 5 alpha,3 beta-THP were observed only in human plasma, while 5 beta,3 beta-THP was detected only in rat plasma. (C) 2000 Academic Press. C1 NIAAA, Sect Mass Spectrometry, LMBB, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, LMBB, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. NR 30 TC 57 Z9 59 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JAN 15 PY 2000 VL 277 IS 2 BP 187 EP 195 DI 10.1006/abio.1999.4384 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 282QX UT WOS:000085230700003 PM 10625505 ER PT J AU Cai, RR Carpick, B Chun, RF Jeang, KT Williams, BRG AF Cai, RR Carpick, B Chun, RF Jeang, KT Williams, BRG TI HIV-I TAT inhibits PKR activity by both RNA-dependent and RNA-independent mechanisms SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID DOUBLE-STRANDED-RNA; HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVATED PROTEIN-KINASE; MUTATIONAL ANALYSIS; CELLULAR INHIBITOR; CATALYTIC SUBUNIT; PROMOTER ACTIVITY; MESSENGER-RNA; REGION RNA; INTERFERON AB Replication of the human immunodeficiency virus type 1 (HIV-1) is inhibited by interferons (IFNs), in part through activity of the IFN-inducible protein kinase PKR, To escape this antiviral effect, HIV-1 has developed strategies for blocking PKR function. We have previously shown that the HIV-1 Tat protein can associate with PKR in vitro and in vivo and inhibit PKR activity. Here we present evidence that Tat can inhibit PKR activity by both RNA-dependent and RNA-independent mechanisms. Tat inhibited PKR activation by the non-RNA activator heparin, and also suppressed PKR basal level autophosphorylation in the absence of RNA. However, when Tat and dsRNA were preincubated, the amount of Tat required to inhibit PKR activation by dsRNA depended on the dsRNA concentration. In addition to its function in vitro, Tat can also reverse translation inhibition mediated by PKR in COS cells. The Tat amino acid sequence required for interaction with PKR was mapped to residues 40-58, overlapping the hydrophobic core and basic region of HIV-1 Tat. Alignment of amino acid sequences of Tat and eIF-2 alpha indicates similarity between the Tat-PKR binding region and the residues around the eIF-2 alpha phosphorylation site, suggesting that Tat and eIF-2 alpha may bind to the same site on PKR. (C) 2000 Academic Press. C1 Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Mol Virol Program, Cleveland, OH 44106 USA. NIAID, Mol Microbiol Lab, Mol Virol Sect, Bethesda, MD 20892 USA. RP Williams, BRG (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, NB40,9500 Euclid Ave, Cleveland, OH 44195 USA. RI Jeang, Kuan-Teh/A-2424-2008; Williams, Bryan/A-5021-2009; Chun, Rene/A-9415-2010 OI Williams, Bryan/0000-0002-4969-1151; Chun, Rene/0000-0002-0190-0807 FU NIAID NIH HHS [AI-34039] NR 54 TC 57 Z9 57 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2000 VL 373 IS 2 BP 361 EP 367 DI 10.1006/abbi.1999.1583 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 279FD UT WOS:000085033000007 PM 10620360 ER PT J AU Davis, BR Yannariello-Brown, J Prokopishyn, NL Luo, ZJ Smith, MR Wang, J Carsrud, NDV Brown, DB AF Davis, BR Yannariello-Brown, J Prokopishyn, NL Luo, ZJ Smith, MR Wang, J Carsrud, NDV Brown, DB TI Glass needle-mediated microinjection of macromolecules and transgenes into primary human blood stem/progenitor cells SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; UMBILICAL-CORD BLOOD; IMMUNE-DEFICIENT MICE; REPOPULATING ACTIVITY; SCID/SCID MICE; GENE-TRANSFER; BONE-MARROW; IN-VITRO; ENGRAFTMENT; EXPANSION AB A novel glass needle-mediated microinjection method for delivery of macromolecules,including proteins and larger transgene DNAs, into the nuclei of blood stem/progenitor cells was developed. Temporary immobilization of cells to extracellular matrix-coated dishes has enabled rapid and consistent injection of macromolecules into nuclei of CD34(+), CD34(+)/CD38(-), and CD34(+)/CD38(-)/Thy-1(lo) human cord blood cells. Immobilization and detachment protocols were identified, which had no adverse effect on cell survival, progenitor cell function (colony forming ability), or stem cell function (NOD/SCID reconstituting ability). Delivery of fluorescent dextrans to stem/progenitor cells was achieved with 52% +/- 8.4% of CD34+ cells and 42% +/- 14% of CD34(+)/CD38(-) cells still fluorescent 48 hours after injection. Single-cell transfer and culture of injected cells has demonstrated long-term survival and proliferation of CD34(+) and CD34(+)/CD38(-) cells, and retention of the ability of CD34(+)/CD38(-) cells to generate progenitor cells. Delivery of DNA constructs (currently less than or equal to 19.6 kb) and fluorescently labeled proteins into CD34(+) and CD34(+)/CD38(-) cells was achieved with transient expression of green fluorescent protein observed in up to 75% of injected cells. These data indicate that glass needle-mediated delivery of macromolecules into primitive hematopoietic cells is a valuable method for studies of stem cell biology and a promising method for human blood stem cell gene therapy, (Blood 2000;95:437-444) (C) 2000 by The American Society of hematology. C1 Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Human Biol Chem & Genet, Galveston, TX 77555 USA. Gene Cell Inc, Houston, TX USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. RP Davis, BR (reprint author), Univ Texas, Med Branch, Sealy Ctr Oncol & Hematol, MRB 9-104, Galveston, TX 77555 USA. FU NIDDK NIH HHS [R21DK53923] NR 36 TC 26 Z9 26 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2000 VL 95 IS 2 BP 437 EP 444 PG 8 WC Hematology SC Hematology GA 272QG UT WOS:000084662000013 PM 10627447 ER PT J AU Donahue, RE Wersto, RP Allay, JA Agricola, BA Metzger, ME Nienhuis, AW Persons, DA Sorrentino, BP AF Donahue, RE Wersto, RP Allay, JA Agricola, BA Metzger, ME Nienhuis, AW Persons, DA Sorrentino, BP TI High levels of lymphoid expression of enhanced green fluorescent protein in nonhuman primates transplanted with cytokine-mobilized peripheral blood CD34(+) cells SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW CELLS; COLONY-STIMULATING FACTOR; HUMAN GLUCOCEREBROSIDASE GENE; IN-VIVO EXPRESSION; REPOPULATING CELLS; RETROVIRUS TRANSDUCTION; ADENOSINE-DEAMINASE; MURINE; FIBRONECTIN AB We have used a murine retrovirus vector containing an enhanced green fluorescent protein complimentary DNA (EGFP cDNA) to dynamically follow vector-expressing cells in the peripheral blood (PB) of transplanted rhesus macaques, Cytokine:mobilized CD34(+) cells were transduced with an amphotropic vector that expressed EGFP and a dihydrofolate reductase cDNA under control of the murine stem cell virus promoter. The transduction protocol used the CH-296 recombinant human fibronectin fragment and relatively high concentrations of the flt-3 ligand and stem cell factor. Following transplantation of the transduced cells, up to 55% EGFP-expressing granulocytes were obtained in the peripheral circulation during the early posttransplant period. This level of myeloid marking, however, decreased to 0.1% or lower within 2 weeks. In contrast, EGFP expression in PB lymphocytes rose from 2%-5% shortly following transplantation to 10% or greater by week 5, After 10 weeks, the level of expression in PB lymphocytes continued to remain at 3%-5% as measured by both flow cytometry and Southern blot analysis, and EGFP expression was observed in CD4(+), CD8(+), CD20(+), and CD15/56(+) lymphocyte sub-sets. EGFP expression was only transiently detected in red blood cells and platelets soon after transplantation. Such sustained levels of lymphocyte marking may be therapeutic in a number of human gene therapy applications that require targeting of the lymphoid compartment, The transient appearance of EGFP(+) myeloid cells suggests that transduction of a lineage-restricted myeloid progenitor capable of short-term engraftment was obtained with this protocol. (Blood, 2000; 95:445-452) (C) 2000 by The American Society of Hematology. C1 NHLBI, Hematol Branch, Rockville, MD 20550 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Donahue, RE (reprint author), NHLBI, Hematol Branch, 5 Res Ct, Rockville, MD 20550 USA. FU NHLBI NIH HHS [P01HL53749] NR 38 TC 40 Z9 40 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2000 VL 95 IS 2 BP 445 EP 452 PG 8 WC Hematology SC Hematology GA 272QG UT WOS:000084662000014 PM 10627448 ER PT J AU Crapnell, K Zanjani, ED Chaudhuri, A Ascensao, JL St Jeor, S Maciejewski, JP AF Crapnell, K Zanjani, ED Chaudhuri, A Ascensao, JL St Jeor, S Maciejewski, JP TI In vitro infection of megakaryocytes and their precursors by human cytomegalovirus SO BLOOD LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; BONE-MARROW TRANSPLANTATION; IMMUNOCOMPETENT ADULT; MYELOID CELLS; STROMAL CELLS; BLOOD; INHIBITION; THROMBOCYTOPENIA; REPLICATION; SUPPRESSION AB Apart from congenital human cytomegalovirus(HCMV) infection, manifest HCMV disease occurs primarily in immunocompromised patients. In allogeneic bone marrow transplantation, HCMV is frequently associated with graft failure and cytopenias involving all hematopoietic lineages, but thrombocytopenia is the most commonly reported hematologic complication. The authors hypothesized that megakaryocytes (MK) may be a specific target for HCMV, Although the susceptibility of immature hematopoietic progenitors cells to HCMV has been established, a productive viral life cycle has only been linked to myelomonocytic maturation. The authors investigated whether HCMV can also infect MK and impair their function. They demonstrated that HCMV did not affect the thrombopoietin (TPO)-driven proliferation of CD34(+) cells until MK maturation occurred. MK challenged with HCMV showed a 50% more rapid loss of viability than mock-infected cells. MK and their early precursors were clearly shown to be susceptible to HCMV in vitro, as evidenced by the presence of HCMV in magnetic column-purified CD42(+) MK and P-color fluorescent staining with antibodies directed against CD42a and HCMV pp65 antigen, These findings were confirmed by the infection of MK with a laboratory strain of HCMV containing the beta-galactosidase (beta-gal) gene. Using chromogenic beta-gal substrates, HCMV was detected during MK differentiation of infected CD34(+) cells and after infection of fully differentiated MK, Production of infectious virus was observed in cultures infected MK, suggesting that HCMV can complete its life cycle. These results demonstrate that MK are susceptible to HCMV infection and that direct infection of these cells in vivo may contribute to the thrombocytopenia observed in patients infected with HCMV. (Blood. 2000;95:487-493) (C) 2000 by The American Society of Hematology. C1 Univ Nevada, Sch Med, Dept Cellular & Mol Biol, Reno, NV 89557 USA. Univ Nevada, Sch Med, Dept Internal Med, Reno, NV 89557 USA. Univ Nevada, Sch Med, Dept Microbiol, Reno, NV 89557 USA. RP Maciejewski, JP (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C103, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL49042, HL52955, HL63470] NR 35 TC 37 Z9 46 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2000 VL 95 IS 2 BP 487 EP 493 PG 7 WC Hematology SC Hematology GA 272QG UT WOS:000084662000019 PM 10627453 ER PT J AU Brenner, DJ Curtis, RE Hall, EJ Ron, E AF Brenner, DJ Curtis, RE Hall, EJ Ron, E TI Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery SO CANCER LA English DT Article DE second malignancies; radiation; prostate carcinoma; surgery ID MULTIPLE PRIMARY CANCERS; RADIATION-THERAPY; RETROSPECTIVE COHORT; 2ND MALIGNANCIES; CERVICAL-CANCER; BREAST-CANCER; RISK; TUMORS; IRRADIATION; REGISTRIES AB BACKGROUND. In the treatment of prostate carcinoma, radiotherapy and surgery are common choices of comparable efficacy; thus a realistic comparison of the potential long term sequelae, such as the risk of second malignancy, may be of relevance to treatment choice. METHODS. Data regarding the rate of incidence from the Surveillance, Epidemiology, and End Results Program cancer registry (1973-1993) were used to compare directly second malignancy risks in 51,584 men with prostate carcinoma who received radiotherapy (3549 of wham developed second malignancies) with 70,539 men who underwent surgery without radiotherapy (5055 of whom developed second malignancies). Data were stratified by latency period, age at diagnosis, and site of the second malignancy. Directly comparing the risks in the radiotherapy group with those in the surgery group largely avoids problems associated with underreporting second malignancies. RESULTS. Radiotherapy for prostate carcinoma was associated with a small, statistically significant increase in the risk of solid tumors (6%; P = 0.02) relative to treatment with surgery. Among patients who survived for greater than or equal to 5 years, the increased relative risk reached 15%, and was 34% for patients surviving greater than or equal to 10 years. The most significant contributors to the increased risk in the irradiated group were carcinomas of the bladder, rectum, and lung, and sarcomas within the treatment field. No significant increase in rates of leukemia was noted. CONCLUSIONS. Radiotherapy for prostate carcinoma was associated with a statistically significant, although fairly small, enhancement in the risk of second solid tumors, particularly for long term survivors. The pattern of excess second malignancies among men treated with radiotherapy was consistent with radiobiologic principles in terms of site,dose, and latency. In absolute terms, the estimated risk of developing a radiation-associated second malignancy was 1 in 290 far all prostate carcinoma patients treated with radiotherapy, increasing to 1 in 70 for long term survivors (greater than or equal to 10 years). Improvements in radiotherapeutic techniques, along with diagnosis at younger ages and earlier stages, are resulting in longer survival times for patients with prostate carcinoma. Because of the long latency period for radiation-induced tumors, this may result in radiation-related second malignancy risk becoming a more significant issue. (C) 2000 American Cancer Society. C1 Columbia Univ, Ctr Radiol Res, New York, NY 10032 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Brenner, DJ (reprint author), Columbia Univ, Ctr Radiol Res, 630 W 168th St, New York, NY 10032 USA. FU NCI NIH HHS [CA-530722] NR 39 TC 313 Z9 320 U1 0 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2000 VL 88 IS 2 BP 398 EP 406 DI 10.1002/(SICI)1097-0142(20000115)88:2<398::AID-CNCR22>3.0.CO;2-V PG 9 WC Oncology SC Oncology GA 274YX UT WOS:000084793600022 PM 10640974 ER PT J AU Kugoh, H Fujiwara, M Kihara, K Fukui, I Horikawa, I Schulz, TC Oshimura, M AF Kugoh, H Fujiwara, M Kihara, K Fukui, I Horikawa, I Schulz, TC Oshimura, M TI Cellular senescence of a human bladder carcinoma cell line (JTC-32) induced by a normal chromosome 11 SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENES; NEOPLASTIC TRANSFORMATION; INDEFINITE DIVISION; MULTIPLE PATHWAYS; HETEROZYGOSITY; IDENTIFICATION; TUMORIGENICITY; IMMORTALITY; TELOMERASE; CANCER AB Human chromosome 11 is expected to carry tumor suppressor genes for a variety of human cancers, including bladder carcinoma. To examine the functional role of a putative tumor suppressor gene(s) on this chromosome in the development of bladder carcinoma, we performed microcell-mediated transfer of chromosome 11 into the bladder carcinoma cell line, JTC-32. Fifteen of 20 colonies formed by the transfer experiment showed a remarkable change in cell morphology. They flattened and ceased growing, or senesced, prior to 10 population doublings. The presence of transferred chromosome 11-derived fragments in the growth-arrested cells was confirmed by PCR-based polymorphism analyses. The remaining 5 microcell hybrid clones exhibited a parental cell-like morphology, and presumably escaped from senescence, which was accompanied by deletions and/or rearrangements of the transferred chromosome 11. On the other hand, a transferred normal chromosome 7 neither changed the cell morphology nor arrested the cell growth. These results support the hypothesis that chromosome 11 contains a gene or genes which restore the senescence program lost during the immortalization process of JTC-32 cells. (C) Elsevier Science Inc., 1999. All rights reserved. C1 Tottori Univ, Sch Life Sci, Fac Med, Dept Mol & Cell Genet, Yonago, Tottori 683, Japan. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Tottori, Japan. Japanese Red Cross Med Ctr, Dept Clin Pathol, Tokyo, Japan. Tokyo Med & Dent Univ, Sch Med, Dept Urol, Tokyo 113, Japan. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Oshimura, M (reprint author), Tottori Univ, Sch Life Sci, Fac Med, Dept Mol & Cell Genet, 86 Nishimachi, Yonago, Tottori 683, Japan. NR 35 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JAN 15 PY 2000 VL 116 IS 2 BP 158 EP 163 DI 10.1016/S0165-4608(99)00138-7 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 267JF UT WOS:000084354300011 PM 10640149 ER PT J AU Pizer, ES Thupari, J Han, WF Pinn, ML Chrest, FJ Frehywot, GL Townsend, CA Kuhajda, FP AF Pizer, ES Thupari, J Han, WF Pinn, ML Chrest, FJ Frehywot, GL Townsend, CA Kuhajda, FP TI Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenograft SO CANCER RESEARCH LA English DT Article ID EXPRESSION; CARCINOMA; APOPTOSIS; SIZE AB A biologically aggressive subset of human breast cancers and other malignancies is characterized by elevated fatty-acid synthase (FAS) enzyme expression, elevated fatty acid (FA) synthesis, and selective sensitivity to pharmacological inhibition of FAS activity by cerulenin or the novel compound C75, In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-CoA to several fold above control Levels, whereas TOFA reduced intracellular malonyl-CoA by 60%, Simultaneous exposure of breast cancer cells to TOFA and an FAS inhibitor resulted in significantly reduced cytotoxicity and apoptosis, Subcutaneous xenografts of MCF7 breast cancer cells in nude mice treated with C75 showed FA synthesis inhibition, apoptosis, and inhibition of tumor growth to less than 1/8 of control volumes, without comparable toxicity in normal tissues, The data suggest that differences in intermediary metabolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Res Resources Branch, Flow Cytometry Unit, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. RP Kuhajda, FP (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 20 TC 246 Z9 257 U1 1 U2 13 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 JAN 15 PY 2000 VL 60 IS 2 BP 213 EP 218 PG 6 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800003 PM 10667561 ER PT J AU Hagihara, N Walbridge, S Olson, AW Oldfield, EH Youle, RJ AF Hagihara, N Walbridge, S Olson, AW Oldfield, EH Youle, RJ TI Vascular protection by chloroquine during brain tumor therapy with Tf-CRM107 SO CANCER RESEARCH LA English DT Article ID DIPHTHERIA-TOXIN; LOW PH; ENTRY; GLIOMAS; BILAYERS; RECEPTOR; BARRIER; CELLS AB Tf-CRM107 is a conjugate of transferrin and a point mutant of diphtheria toxin that selectively kills cells expressing high levels of the transferrin receptor. Tf-CRM107 has been infused intratumorally into patients with malignant brain tumors, Although approximately half of the patients exhibit tumor responses, patients receiving higher doses of Tf-CRM107 may develop magnetic resonance image (MRI) evidence of toxicity indicative of small vessel thrombosis or petechial hemorrhage, Consistent with these clinical results we found that intracerebral injection of Tf-CRM107 into rats at total doses greater than or equal to 0.025 mu g causes brain damage detectable by MRI and histology, To widen the therapeutic window of Tf-CRM107, we explored ways to prevent this damage to the vasculature, We reasoned that the vasculature may be protected to a greater extent than tumor from Tf-CRM107 infused into brain parenchyma by i.v. injection of reagents with low blood-brain barrier permeability that block the toxicity of Tf-CRM107. Chloroquine, a well-characterized antimalarial drug, blocks the toxicity of diphtheria toxin and Tf-CRM107. Systemic administration of chloroquine blocked the toxicity of Tf-CRM107 infused intracerebrally in rats and changed the maximum tolerated dose of Tf-CRM107 from 0.2 to 0.3 mu g. Moreover, chloroquine treatment completely blocked the brain damage detected by MRI caused by intracerebral infusion of 0.05 mu g of Tf-CRM107. In nude mice bearing s.c. U251 gliomas, chloroquine treatment had little effect on the antitumor efficacy of Tf-CRM107. Thus, chloroquine treatment may be useful to reduce the toxicity of Tf-CRM107 for normal brain without inhibiting antitumor efficacy and increase the therapeutic window of Tf-CRM107 for brain tumor therapy. C1 NINDS, Surg Neurol Branch, Biochem Sect, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, Clin Sect, Bethesda, MD 20892 USA. NINDS, In Vivo NMR Res Ctr, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Surg Neurol Branch, Biochem Sect, Bldg 10,Room 5D-37,MSC 1414,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 44 Z9 51 U1 1 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 JAN 15 PY 2000 VL 60 IS 2 BP 230 EP 234 PG 5 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800006 PM 10667564 ER PT J AU Newbold, RR Liehr, JB AF Newbold, RR Liehr, JB TI Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens SO CANCER RESEARCH LA English DT Article ID HUMAN-BREAST-CANCER; 4-HYDROXYLATION; CARCINOGENESIS; HAMSTERS; HORMONES AB Catechol estrogens may mediate estrogen-induced carcinogenesis because 4-hydroxyestradiol induces DNA damage and renal tumors in hamsters, and this metabolite is formed in the kidney and estrogen target tissues by a specific estrogen 4-hydroxylase, We examined the carcinogenic potential of catechol estrogen in an experimental model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal exposure to diethylstilbestrol, Outbred female CD-1 mice were treated with 2- or 4-hydroxyestradiol, 17 beta-estradiol, or 17 alpha-ethinyl estradiol on days 1-5 of neonatal life (2 mu g/pup/day) and sacrificed at 12 or 18 months of age. Mice treated with 17 beta-estradiol or 17 alpha-ethinyl estradiol had a total uterine tumor incidence of 7% or 43%, respectively. 2-Hydroxyestradiol induced tumors in 12% of the mice, but 4-hydroxyestradiol was the most carcinogenic estrogen, with a 66% incidence of uterine adenocarcinoma, Both 2- and 4-hydroxylated catechols were estrogenic and increased uterine wet weights in these neonates. These data demonstrate that both 2- and 4-hydroxyestradiol are carcinogenic metabolites. The high tumor incidence induced by 4-hydroxyestradiol supports the postulated role of this metabolite in hormone-associated cancers. C1 NIEHS, Dev Endocrinol Sect, Reprod Toxicol Grp, Toxicol Lab, Res Triangle Pk, NC 27709 USA. Stehlin Fdn Canc Res, Houston, TX 77003 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol Sect, Reprod Toxicol Grp, Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA 74971] NR 27 TC 234 Z9 237 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2000 VL 60 IS 2 BP 235 EP 237 PG 3 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800007 PM 10667565 ER PT J AU Bronte, V Apolloni, E Ronca, R Zamboni, P Overwijk, WW Surman, DR Restifo, NP Zanovello, P AF Bronte, V Apolloni, E Ronca, R Zamboni, P Overwijk, WW Surman, DR Restifo, NP Zanovello, P TI Genetic vaccination with "self" tyrosinase-related protein 2 causes melanoma eradication but not vitiligo SO CANCER RESEARCH LA English DT Article ID TUMOR REJECTION ANTIGEN; DNA; IMMUNIZATION; AUTOIMMUNITY; INDUCTION; IMMUNITY AB "Self" melanocyte differentiation antigens are potential targets for specific melanoma immunotherapy. Vaccination against murine tyrosinase-related protein (TRP)-1/gp75 was shown recently to cause melanoma rejection, which was accompanied by autoimmune skin depigmentation (vitiligo), To further explore the linkage between immunotherapy and autoimmunity, we studied the response to vaccination with a related antigen, TRP-2, i.m. inoculation of plasmid DNA encoding murine trp-2 elicited antigen-specific CTLs that recognized the B16 mouse melanoma and protected the mice from challenge with tumor cells. Furthermore, mice bearing established s.c. B16 melanomas rejected the tumor upon vaccination with a recombinant vaccinia virus encoding trp-2, Depletion experiments showed that CD8(+) lymphocytes and natural killer cells were crucial for the antitumor activity of the trp-2-encoding vaccines, Mice that rejected the tumor did not develop generalized vitiligo, indicating that protective immunity can be achieved in the absence of widespread autoimmune aggression. C1 Univ Padua, Dept Oncol & Surg Sci, Oncol Sect, I-35128 Padua, Italy. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Bronte, V (reprint author), Univ Padua, Dept Oncol & Surg Sci, Oncol Sect, Via Gattamelata 64, I-35128 Padua, Italy. RI Restifo, Nicholas/A-5713-2008; Bronte, Vincenzo/K-7902-2016; OI Bronte, Vincenzo/0000-0002-3741-5141; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 25 TC 92 Z9 97 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 JAN 15 PY 2000 VL 60 IS 2 BP 253 EP 258 PG 6 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800012 PM 10667570 ER PT J AU Reddy, BS Hirose, Y Lubet, R Steele, V Kelloff, G Paulson, S Seibert, K Rao, CV AF Reddy, BS Hirose, Y Lubet, R Steele, V Kelloff, G Paulson, S Seibert, K Rao, CV TI Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis SO CANCER RESEARCH LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; NONSTEROIDAL ANTIINFLAMMATORY DRUG; COLORECTAL-CANCER; EPITHELIAL-CELLS; MURINE MODEL; EXPRESSION; ASPIRIN; PIROXICAM; SULINDAC; TUMORS AB Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as cyclooxygenases (COXs), Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, i.e., celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, i.e., continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats, We also measured the steady-state levels of celecoxib in the plasma of animals given this inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib, At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, i.e., 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence (P < 0.01 to P < 0.0001) as well as the multiplicity (P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon (P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume (P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps. C1 Amer Hlth Fdn, Div Nutr Carcinogenesis, Valhalla, NY 10595 USA. Amer Hlth Fdn, Chemoprevent Program, Valhalla, NY 10595 USA. NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. Searle Res & Dev, St Louis, MO 63137 USA. RP Reddy, BS (reprint author), Amer Hlth Fdn, Div Nutr Carcinogenesis, 1 Dana Rd, Valhalla, NY 10595 USA. RI Chinthalapally, Rao/B-3633-2010 FU NCI NIH HHS [CA-17613, N01-CN-65119] NR 34 TC 362 Z9 387 U1 5 U2 14 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 JAN 15 PY 2000 VL 60 IS 2 BP 293 EP 297 PG 5 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800021 PM 10667579 ER PT J AU Webb, CP Hose, CD Koochekpour, S Jeffers, M Oskarsson, M Sausville, E Monks, A Vande Woude, GF AF Webb, CP Hose, CD Koochekpour, S Jeffers, M Oskarsson, M Sausville, E Monks, A Vande Woude, GF TI The geldanamycins are potent inhibitors of the hepatocyte growth factor/scatter factor-Met-urokinase plasminogen activator-plasmin proteolytic network SO CANCER RESEARCH LA English DT Article ID FACTOR SCATTER FACTOR; TYROSINE KINASE RECEPTOR; PROTOONCOGENE PRODUCT; CANCER METASTASIS; SIGNALING PATHWAY; CELL-LINE; IN-VITRO; INVASION; EXPRESSION; TUMORIGENICITY AB The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), have been implicated in human tumor development and metastasis. HGF/SF induces the expression of urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), important mediators of cell invasion and metastasis. We have developed a cell-based assay to screen for inhibitors of this signaling system using the induction of endogenous uPA and uPAR and the subsequent conversion of plasminogen to plasmin as the biological end point. Assay validation was established using a neutralizing antiserum to HGF/SF and a uPA inhibitor (B428), as well as inhibitors of the MKK-MAPK1/2 pathway, shown previously to be important in the induction of uPA and uPAR, Using this assay, we found several classes of molecules that exhibited inhibition of HGF/SF-dependent plasmin activation. However, we discovered that certain members of the geldanamycin family of anisamycin antibiotics are potent inhibitors of HGF/SF-mediated plasmin activation, displaying inhibitory properties at femtomolar concentrations and nine orders of magnitude below their growth inhibitory concentrations. lit nanomolar concentrations, the geldanamycins down-regulate Met protein expression, inhibit HGF/SF-mediated cell motility and invasion, and also revert the phenotype of both autocrine HGF/SF-Met transformed cells as well as those transformed by Met proteins with activating mutations. Thus, the geldanamycins may have important therapeutic potential for the treatment of cancers in which Met activity contributes to the invasive/metastatic phenotype. C1 NCI, Adv Biosci Labs, Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Curagen Corp, Branford, CT 06405 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NCI, Div Basic Sci, Bethesda, MD 20892 USA. RP Webb, CP (reprint author), Van Andel Res Inst, Suite 400,201 Monroe Ave NW, Grand Rapids, MI 49503 USA. RI Webb, Craig/I-8123-2012 NR 54 TC 139 Z9 153 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 JAN 15 PY 2000 VL 60 IS 2 BP 342 EP 349 PG 8 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800028 PM 10667586 ER PT J AU Bishop, AJR Barlow, C Wynshaw-Boris, AJ Schiestl, RH AF Bishop, AJR Barlow, C Wynshaw-Boris, AJ Schiestl, RH TI Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice SO CANCER RESEARCH LA English DT Article ID EYED UNSTABLE MUTATION; CHROMOSOME INSTABILITY SYNDROMES; ATAXIA-TELANGIECTASIA CELLS; CYCLE CHECKPOINT PATHWAY; DOUBLE-STRAND BREAKS; MOUSE SPOT-TEST; IONIZING-RADIATION; DNA-DAMAGE; OXIDATIVE DAMAGE; IN-VITRO AB Ataxia telangiectasia (AT) patients have inactivating mutations in both copies of the ATM gene. The ATM protein that the gene encodes is involved in DNA double-strand break (DSB) recognition; in its absence, p53 response to DSBs is delayed and reduced. In addition, AT patients have a high propensity for cancer, and cells from these patients show chromosomal instability. Here, using an in vivo mouse model system with the pink-eyed unstable mutation, we demonstrate that the absence of functional Atm results in a significantly elevated frequency of intrachromosomal recombination resulting in deletion events (wild-type 17.73%, heterozygous Atm 15.72%, and mutant Atm 30.33%), No such increase was observed in mice heterozygous for Atm. These results further advocate the role of ATM in maintaining genomic integrity after the onset of endogenous damage. This system relies on the initiation of events during a relatively short time frame to produce an observable deletion product. AT patients have a lifelong exposure to endogenous damage and perhaps similarly acting external agents, Because 25% of our genome consists of repeated elements, genomic instability due to an increased level of homologous recombination between such repeats, as observed here, may contribute to carcinogenesis in AT patients. C1 Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. Natl Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Salk Inst Biol Studies, La Jolla, CA 92037 USA. Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. RP Schiestl, RH (reprint author), Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, 665 Huntington Ave, Boston, MA 02115 USA. FU NIEHS NIH HHS [KO2 ES00299, R01 ES09519]; NIGMS NIH HHS [F32GM19147] NR 56 TC 58 Z9 59 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 JAN 15 PY 2000 VL 60 IS 2 BP 395 EP 399 PG 5 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800035 PM 10667593 ER PT J AU Guo, NH Templeton, NS Al-Barazi, H Cashel, JA Sipes, JM Krutzsch, HC Roberts, DD AF Guo, NH Templeton, NS Al-Barazi, H Cashel, JA Sipes, JM Krutzsch, HC Roberts, DD TI Thrombospondin-1 promotes alpha 3 beta 1 integrin-mediated adhesion and neurite-like outgrowth and inhibits proliferation of small cell lung carcinoma cells SO CANCER RESEARCH LA English DT Article ID HUMAN-MELANOMA CELLS; ALPHA(3)BETA(1) INTEGRIN; SULFATED GLYCOLIPIDS; HEPARIN-BINDING; RETINOIC ACID; CANCER CELLS; TUMOR-GROWTH; EXPRESSION; RECEPTOR; PROTEIN AB Although human small cell lung carcinoma (SCLC) cell lines are typically anchorage-independent and do not attach on most extracellular matrix proteins, OH-1, and several other SCLC cell lines attached on substrates coated with thrombospondin-1 (TSP1). SCLC cells grew longterm as adherent cells on a TSP1-coated substrate. Adhesion of SCLC cells on TSP1 was inhibited by heparin, function-blocking antibodies recognizing alpha 3 or beta 1 integrin subunits, and by soluble alpha 3 beta 1 integrin ligands. SCLC cells extended neurite-like processes on a TSP1 substrate, which was also mediated by alpha 3 beta 1 integrin, Process formation on a TSP1 substrate was specifically stimulated by epidermal growth factor and somatostatin. Adhesion on TSP1 weakly inhibited SCLC fell proliferation, but this inhibition was strongly enhanced in the presence of epidermal growth factor. TSP1 and an alpha 3 beta 1 integrin-binding peptide from TSP1 also inhibited proliferation when added in solution. High-affinity binding of I-125-labeled TSP1 to OH-1 cells was heparin-dependent and may be mediated by sulfated glycolipids, which are the major sulfated glycoconjugates synthesized by these cells. Synthesis or secretion of TSP1 by SCLC cells could not be detected. On the basis of these results, the alpha 3 beta 1 integrin and sulfated glycolipids cooperate to mediate adhesion of SCLC cells on TSP1, Interaction with TSP1 through this integrin inhibits growth and induces neurotypic differentiation, which suggests that this response to TSP1 may be exploited to inhibit the progression of SCLC. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 68 TC 60 Z9 60 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2000 VL 60 IS 2 BP 457 EP 466 PG 10 WC Oncology SC Oncology GA 279JZ UT WOS:000085041800043 PM 10667601 ER PT J AU Ennis, DG Woodgate, R Shi, MX AF Ennis, DG Woodgate, R Shi, MX TI Selective inhibition of RecA functions by the Hc1 nucleoid condensation protein from Chlamydia trachomatis SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE DNA repair; recombination; competitive inhibition; pathogenesis; genetics ID ESCHERICHIA-COLI; DNA; RECOMBINATION; CLEAVAGE AB During the normal biphasic life cycle of Chlamydia trackomatis, the histone-like protein Hc1 promotes the condensation of nucleoids in elementary bodies, it may also displace nucleoproteins, including repair functions from chromatin. Hc1 was found to effectively inhibit the recombination and repair of the weak binding RecA430 mutant protein from Escherichia coli, but had minimal effects on the parental RecA(+) protein. Expression of Hcl was also found to inhibit the repair activities of the C. trachomatis RecA protein but not recombination. These results suggest that chlamydial RecA may have evolved mechanisms to minimize Hcl competition for recombinational activities. (C) 2000 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Univ Louisiana, Dept Biol, Lafayette, LA 70504 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. RP Ennis, DG (reprint author), Univ Louisiana, Dept Biol, POB 42451, Lafayette, LA 70504 USA. NR 10 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD JAN 15 PY 2000 VL 182 IS 2 BP 279 EP 283 DI 10.1111/j.1574-6968.2000.tb08908.x PG 5 WC Microbiology SC Microbiology GA 274LB UT WOS:000084766400014 PM 10620679 ER PT J AU Dracheva, SV Remmers, EF Chen, S Chang, L Gulko, PS Kawahito, Y Longman, RE Wang, JP Du, Y Shepard, J Ge, L Joe, B Kotake, S Salstrom, JL Furuya, T Hoffman, J Cannon, GW Griffiths, MM Wilder, RL AF Dracheva, SV Remmers, EF Chen, S Chang, L Gulko, PS Kawahito, Y Longman, RE Wang, JP Du, Y Shepard, J Ge, L Joe, B Kotake, S Salstrom, JL Furuya, T Hoffman, J Cannon, GW Griffiths, MM Wilder, RL TI An integrated genetic linkage map with 1137 markers constructed from five F2 crosses of autoimmune disease-prone and -resistant inbred rat strains SO GENOMICS LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; POLYMORPHIC DNA MARKERS; LABORATORY RAT; LOCI; CHROMOSOME-1; MOUSE AB The rat (Rattus norvegicus) is an important experimental model for many human diseases including arthritis, diabetes, and other autoimmune and chronic inflammatory diseases. The rat genetic linkage map, however, is less well developed than those of mouse and human. Integrated rat genetic linkage maps have been previously reported by Pravenec ef al. (1996, Mamm. Genome 7: 117-127) (500 markers mapped in one cross), Bihoreau et al. (1997, Genome Res. 7: 434-440) (767 markers mapped in three crosses), Wei ef al. (1998, Mamm. Genome 9: 1002-1007) (562 markers mapped in two crosses), Brown et al. (1998, Mamm. Genome 9: 521-530) (678 markers mapped in four crosses), and Nordquist ef at (1999, Rot Genome 5: 15-20) (330 markers mapped in two crosses). The densest linkage map combined with a radiation hybrid map, reported by Steen ef al. (1999, Genome Res. 9: AP1-AP8), includes 4736 markers mapped in two crosses. Here, we present an integrated linkage map with 1137 markers. We have constructed this map by genotyping F2 progeny of five crosses: F344/NHsd x LEW/NHsd (673 markers), DA/Bkl x F344/NHsd (531 markers), BN/SsN x LEW/N (714 markers), DA/Bkl x BN/SsNHsd (194 markers), and DA/Bkl x ACI/SegHsd (245 markers). These inbred rat strains vary in susceptibility/resistance to multiple autoimmune diseases and are used extensively for many types of investigation. The integrated map includes 360 loci mapped in three or more crosses. The map contains 196 new SSLP markers developed by our group, as well as many SSLP markers developed by other groups. Two hundred forty genes are incorporated in the map. This integrated map should allow comparison of rat genetic maps from different groups and thereby facilitate genetic studies of rat autoimmune and related disease models. (C) 2000 Academic Press. C1 NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Med Rheumatol, Salt Lake City, UT 84132 USA. Vet Affairs Med Ctr, Res Serv, Salt Lake City, UT 84132 USA. Columbia Univ Coll Phys & Surg, Div Autoimmune & Mol Dis, New York, NY 10032 USA. Kyoto Prefectural Univ Med, Dept Internal Med 1, Kamigyo Ku, Kyoto 602, Japan. Tokyo Womens Med Coll, Inst Rheumatol, Shinjuku Ku, Tokyo 162054, Japan. RP Wilder, RL (reprint author), NIAMSD, Inflammatory Joint Dis Sect, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N240,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. NR 46 TC 17 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JAN 15 PY 2000 VL 63 IS 2 BP 202 EP 226 DI 10.1006/geno.1999.6074 PG 25 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 286PB UT WOS:000085453400006 PM 10673333 ER PT J AU Yabuta, N Fujii, T Copeland, NG Gilbert, DJ Jenkins, NA Nishiguchi, H Endo, Y Toji, S Tanaka, H Nishimune, Y Nojima, H AF Yabuta, N Fujii, T Copeland, NG Gilbert, DJ Jenkins, NA Nishiguchi, H Endo, Y Toji, S Tanaka, H Nishimune, Y Nojima, H TI Structure, expression, and chromosome mapping of LATS2, a mammalian homologue of the Drosophila tumor suppressor gene lats/warts SO GENOMICS LA English DT Article ID MYOTONIC-DYSTROPHY KINASE; PROTEIN-KINASE; CELL-CYCLE; POLARITY; ENCODES; FAMILY; YEAST AB We have cloned and characterized LATS2, a novel mammalian homologue of the Drosophila tumor suppressor gene lats/warts, Northern blot analysis showed ubiquitous expression of mouse LATS2 (MmLATS2) mRNA, whereas expression of human LATS2 (HsLATS2) mRNA was enhanced in skeletal muscle and heart. Immunoblotting analysis of fractionated cell lysates showed HsLats2 to be a nuclear protein, We mapped the MmLATS2 gene to mouse chromosome 14 by interspecific backcross analysis. We also mapped the HsLATS2 gene (by fluorescence in situ hybridization) to the 13q11-q12 region, in which a loss of heterozygosity has been frequently observed in many primary cancers and to which the tumor suppressor genes RE and BRCA2 have also been mapped. (C) 2000 Academic Press. C1 Osaka Univ, Dept Mol Genet, Suita, Osaka 5650871, Japan. Osaka Univ, Dept Sci Lab Anim Expt, Microbial Dis Res Inst, Suita, Osaka 5650871, Japan. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. Toyobo Co Ltd, Tsuruga Inst Biotechnol, Tsuruga 9140047, Japan. Fukushima Med Coll, Dept Biochem, Fukushima 9601247, Japan. MBL Co Ltd, Ina Labs, Nagano 3960002, Japan. RP Nojima, H (reprint author), Osaka Univ, Dept Mol Genet, 3-1 Yamadaoka, Suita, Osaka 5650871, Japan. NR 23 TC 74 Z9 77 U1 0 U2 6 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 JAN 15 PY 2000 VL 63 IS 2 BP 263 EP 270 DI 10.1006/geno.1999.6065 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 286PB UT WOS:000085453400010 PM 10673337 ER PT J AU Gardner, HP Rajan, JV Ha, SI Copeland, NG Gilbert, DJ Jenkins, NA Marquis, ST Chodosh, LA AF Gardner, HP Rajan, JV Ha, SI Copeland, NG Gilbert, DJ Jenkins, NA Marquis, ST Chodosh, LA TI Cloning, characterization, and chromosomal localization of Pnck, a Ca2+/calmodulin-dependent protein kinase SO GENOMICS LA English DT Article ID POLYMERASE CHAIN-REACTION; II MUTANT MICE; TYROSINE KINASE; MOLECULAR-CLONING; CONSERVED FEATURES; STRUCTURAL BASIS; CELL DEVELOPMENT; TRANSGENIC MICE; SKELETAL-MUSCLE; CDNA CLONING AB Calcium is an important second messenger in eukaryotic cells. Many of the effects of calcium are mediated via its interaction with calmodulin and the subsequent activation of Ca2+/calmodulin-dependent (CaM) kinases. CaM kinases are involved in a wide variety of cellular processes including muscle contraction, neurotransmitter release, cell cycle control, and transcriptional regulation. While CaMKII has been implicated in learning and memory, the biological role of the other multifunctional CaM kinases, CaMKI and CaMKIV, is largely unknown. In the course of a degenerate RT-PCR protein kinase screen, we identified a novel serine/threonine kinase, Pnck. In this report, we describe the cloning, chromosomal localization, and expression of Pnck, which encodes a 38-kDa protein kinase whose catalytic domain shares 45-70% identity with members of the CaM kinase family. The gene for Pnck localizes to mouse chromosome X, in a region of conserved synteny with human chromosome Xq28 that is associated with multiple distinct mental retardation syndromes. Pnck is upregulated during intermediate and late stages of murine fetal development with highest levels of expression in developing brain, bone, and gut. Pnck is also expressed in a tissue-specific manner in adult mice with highest levels of expression detected in brain, uterus, ovary, and testis. Interestingly, Pnck expression in these tissues is restricted to particular compartments and appears to be further restricted to subsets of cells within those compartments. The chromosomal localization of Pnck, along with its tissue-specific and restricted pattern of spatial expression during development, suggests that Pnck may be involved in a variety of developmental processes including development of the central nervous system. (C) 2000 Academic Press. C1 Univ Penn, Sch Med, Dept Mol & Cellular Engn, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Frederick, MD 21702 USA. RP Univ Penn, Sch Med, Dept Mol & Cellular Engn, 612 Biomed Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM chodosh@mail.med.upenn.edu FU NCI NIH HHS [CA71513, CA78410, CA83849] NR 63 TC 20 Z9 22 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD JAN 15 PY 2000 VL 63 IS 2 BP 279 EP 288 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 286PB UT WOS:000085453400012 PM 10673339 ER PT J AU Somasundaram, R Robbins, P Moonka, D Loh, E Marincola, F Patel, A Guerry, D Herlyn, D AF Somasundaram, R Robbins, P Moonka, D Loh, E Marincola, F Patel, A Guerry, D Herlyn, D TI CD4(+), HLA class I-restricted, cytolytic T-lymphocyte clone against primary malignant melanoma cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID RECOGNITION; LINES; CTL; IMMUNOTHERAPY; SPECIFICITY; MECHANISMS; CARCINOMA; ANTIGENS AB The involvement of HLA-class I in target cell lysis by CD4(+) cytolytic T cells (CTL) has been a controversial issue. A CTL clone of CD4 phenotype was derived from the peripheral blood lymphocytes of a patient with primary melanoma. The CTL clone stably lysed the autologous primary melanoma cells for approximately 9 months in culture. Both the V alpha 2/ V beta 8 T-cell receptor and CD4 were involved in CTL cytotoxicity. Of a large panel of allogeneic primary and metastatic melanoma or colorectal carcinoma cells, autologous and allogeneic Epstein-Barr virus-transformed B cells and autologous fibroblasts, only allogeneic metastatic melanoma cells matched with the autologous tumor cells for HLA-class I (B57[17]) were lysed and induced IFN-gamma secretion by the CTL clone. Lysis of the autologous tumor cells was significantly blocked by monoclonal antibody to HLA-B17. Importantly, allogeneic, HLA-class I- and class Ii-unmatched melanoma cells were lysed by the CTL only following transfection of the cells with B57[17] cDNA. Our results provide direct evidence for the involvement of both CD4 and HLA-class I in tumor cell lysis by CD4(+) CTL. Int. J. Cancer 85:253-259, 2000. (C) 2000 Wiley-Liss, Inc. C1 Wistar Inst, Philadelphia, PA 19104 USA. NCI, Bethesda, MD 20892 USA. Hosp Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. RP Somasundaram, R (reprint author), Wistar Inst, 3601 Spruce St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA 25874-17] NR 21 TC 21 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2000 VL 85 IS 2 BP 253 EP 259 DI 10.1002/(SICI)1097-0215(20000115)85:2<253::AID-IJC17>3.0.CO;2-U PG 7 WC Oncology SC Oncology GA 271JA UT WOS:000084589400017 PM 10629086 ER PT J AU Mercero, JM Barrett, P Lam, CW Fowler, JE Ugalde, JM Pedersen, LG AF Mercero, JM Barrett, P Lam, CW Fowler, JE Ugalde, JM Pedersen, LG TI Quantum mechanical calculations on phosphate hydrolysis reactions SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE dephosphorylation; serine; threonine; reaction mechanism; ab initio ID TYROSINE-PHOSPHATASE; GAS-PHASE; HYDRATION; ANION AB Multiple biological processes are regulated by kinases and phosphatases. This study aims to provide nonenzymatic models for phosphorylation and dephosphorylation of serine, threonine, and tyrosine phosphate using ab initio guantum mechanical calculations. We reduce the problem to methyl phosphate hydrolysis to model serine/threonine, and the hydrolysis of phenyl phosphate to model the tyrosine. HF, B3LYP, and MP2 calculations with a 6-31+G(d) basis set were employed. The effect of water as a catalyst was also analyzed. As expected, the activation energy barrier is lowered. (C) 2000 John Wiley & Sons, Inc. C1 Euskal Herriko Unibertsitatea, Kim Fakultatea, Donostia 20080, Euskal Herria, Spain. NIEHS, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Mercero, JM (reprint author), Euskal Herriko Unibertsitatea, Kim Fakultatea, PK 1072, Donostia 20080, Euskal Herria, Spain. RI Mercero, Jose/E-6828-2010; Pedersen, Lee/E-3405-2013; Ugalde, Jesus/M-2771-2014 OI Mercero, Jose/0000-0003-4857-6685; Pedersen, Lee/0000-0003-1262-9861; Ugalde, Jesus/0000-0001-8980-9751 NR 21 TC 31 Z9 31 U1 0 U2 4 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 15 PY 2000 VL 21 IS 1 BP 43 EP 51 DI 10.1002/(SICI)1096-987X(20000115)21:1<43::AID-JCC5>3.3.CO;2-# PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 264LE UT WOS:000084183100005 ER PT J AU Surman, DR Dudley, ME Overwijk, WW Restifo, NP AF Surman, DR Dudley, ME Overwijk, WW Restifo, NP TI CD4(+) T cell control of CD8(+) T cell reactivity to a model tumor antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-II; SELF-ANTIGENS; ADOPTIVE TRANSFER; DENDRITIC CELLS; IMMUNOTHERAPY; LYMPHOCYTES; EXPRESSION; INDUCTION; HELP; REJECTION AB Neoantigens resulting from the inherent genomic instability of tumor cells generally do not trigger immune recognition. Similarly, transfection of tumors with model Ags often fails to elicit CD8(+) T cell responses or alter a tumor's growth rate or lethality. We report here that the adoptive transfer of activated Th1-type CD4(+) T cells specific for a model tumor Ag results in the de novo generation of CD8(+) T cells with specificity to that Ag and concomitant tumor destruction. The anti-tumor effects of the CD4(+) T cells required the presence of both MHC class I and class II on host cells, as evidenced by experiments in knockout mice, suggesting that CD4(+) T cells enhanced the ability of host APC to activate endogenous CD8(+) T cells. These results indicate that the apparent inability of tumor cells expressing highly immunogenic epitopes to activate tumor-specific CD8(+) T cells can be altered by activated CD4(+) T cells. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr, 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 27 TC 128 Z9 132 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 JAN 15 PY 2000 VL 164 IS 2 BP 562 EP 565 PG 4 WC Immunology SC Immunology GA 273LF UT WOS:000084708600004 PM 10623795 ER PT J AU Mason, LH Willette-Brown, J Mason, AT McVicar, D Ortaldo, JR AF Mason, LH Willette-Brown, J Mason, AT McVicar, D Ortaldo, JR TI Interaction of Ly-49D(+) NK cells with H-2D(d) target cells leads to Dap-12 phosphorylation and IFN-gamma secretion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; CLASS-I MOLECULES; INTERFERON-GAMMA; TYROSINE KINASE; INHIBITORY RECEPTOR; SIGNAL-TRANSDUCTION; CYTOKINE PRODUCTION; MULTIGENE FAMILY; CYTOTOXICITY; PHOSPHATASE AB Murine Ly-49D augments NK cell function upon recognition of target cells expressing H-2D(d). Ly-49D activation is mediated by the immunoreceptor tyrosine-based activation moth-containing signaling moiety Dap-12, In this report we demonstrate that Ly-49D receptor ligation can lead to the rapid and potent secretion of IFN-gamma. Cytokine secretion can be induced from Ly-49D(+) NK cells after receptor ligation,vith Ab or after interaction with target cells expressing their H-2D(d) ligand, Consistent with the dominant inhibitory function of Ly-49G, NK cells coexpressing Ly-49D and Ly-49G show a profound reduction in IFN-gamma secretion after interaction with targets expressing their common ligand, H-2D(d). Importantly, we are able to demonstrate for the first time that effector/target cell interactions using Ly-49D(+) NK cells and H-2Dd targets result in the rapid phosphorylation of Dap-12 However, Dap-12 is not phosphorylated when Ly-49D(+) NK cells coexpress the inhibitory receptor, Ly-49G, These studies are novel in describing Ly-49 activation vs inhibition, where two Ly-49 receptors recognize the same class I ligand, with the dominant inhibitory receptor down-regulating phosphorylation of Dap-12, cytokine secretion, and cytotoxicity in NK cells. C1 NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Mason, LH (reprint author), NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Bldg 560,Room 31-93, Frederick, MD 21702 USA. NR 37 TC 50 Z9 50 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 JAN 15 PY 2000 VL 164 IS 2 BP 603 EP 611 PG 9 WC Immunology SC Immunology GA 273LF UT WOS:000084708600010 PM 10623801 ER PT J AU Hemmer, B Pinilla, C Gran, B Vergelli, M Ling, N Conlon, P McFarland, HF Houghten, R Martin, R AF Hemmer, B Pinilla, C Gran, B Vergelli, M Ling, N Conlon, P McFarland, HF Houghten, R Martin, R TI Contribution of individual amino acids within MHC molecule or antigenic peptide to TCR ligand potency SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RECEPTOR; SYNTHETIC COMBINATORIAL LIBRARY; CLASS-II MOLECULES; ALPHA-BETA; CROSS-REACTIVITY; LIFE-SPAN; RECOGNITION; EPITOPES; COMPLEX; BINDING AB The TCR recognition of peptides bound to MHC class' II molecules is highly flexible in some T cells. Although progress has been made in understanding the interactions within the trimolecular complex, to what extent the individual components and their amino acid composition contribute to ligand recognition by individual T cells is not completely understood. We investigated how single amino acid residues influence Ag recognition of T cells by combining several experimental approaches. We defined TCR moths for CD4(+) T cells using peptide synthetic combinatorial libraries in the positional scanning format (PS-SCL) and single amino acid-modified peptide analogues, The similarity of the TCR moths defined by both methods and the identification of stimulatory antigenic peptides by the PS-SCL approach argue for a contribution of each amino acid residue to the overall potency of the antigenic peptide ligand, In some instances, however, moths are formed by adjacent amino acids, and their combined influence is superimposed on the overall contribution of each amino acid within the peptide epitope, In contrast to the flexibility of the TCR to interact with different peptides, recognition was very sensitive toward modifications of the MBC-restriction element, Exchanges of just one amino acid of the MHC molecule drastically reduced the number of peptides recognized. The results indicate that a specific MHC molecule not only selects certain peptides, but also is crucial for setting an affinity threshold for TCR recognition, which determines the flexibility in peptide recognition for a given TCR. C1 Univ Marburg, Dept Neurol, Clin Neuroimmunol Grp, D-35033 Marburg, Germany. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. Mixture Sci Inc, San Diego, CA 92121 USA. Univ Florence, Dipartimento Sci Neurol & Psichiat, Florence, Italy. RP Hemmer, B (reprint author), Univ Marburg, Dept Neurol, Clin Neuroimmunol Grp, Rudolf Bultmann Str 8, D-35033 Marburg, Germany. RI Gran, Bruno/A-2288-2013 OI Gran, Bruno/0000-0001-6384-2342 NR 55 TC 51 Z9 53 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2000 VL 164 IS 2 BP 861 EP 871 PG 11 WC Immunology SC Immunology GA 273LF UT WOS:000084708600042 PM 10623833 ER PT J AU Chiaramonte, MG Hesse, M Cheever, AW Wynn, TA AF Chiaramonte, MG Hesse, M Cheever, AW Wynn, TA TI CpG oligonucleotides can prophylactically immunize against Th2-mediated schistosome egg-induced pathology by an IL-12-independent mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-GAMMA PRODUCTION; NECROSIS-FACTOR-ALPHA; IMMUNOSTIMULATORY DNA-SEQUENCES; CYTOKINE GENE-EXPRESSION; MYCOBACTERIUM-BOVIS BCG; CELL STIMULATORY FACTOR; NATURAL-KILLER-CELLS; BACTERIAL-DNA; IFN-GAMMA; GRANULOMA-FORMATION AB Using a Schistosoma mansoni egg-induced granuloma model, we examined the ability of CpG oligodeoxynucleotides (ODN) to suppress Th2-type cytokine expression and to prophylactically immunize against Th2-dependent pulmonary pathology. The mechanism was examined by studying Th2 response regulation in cytokine-deficient mice. Surprisingly, our findings revealed several functions of CpG DNA that were completely IL-12 independent. Most striking was the marked suppression in Th2 cytokine expression and granulomatous inflammation observed in eeg/CpG-sensitized IL-12-deficient mice. Immune deviation was not dependent on NK or B cells. However, a role for IL-10, B7.1, and CD40 expression in Th2 response inhibition was suggested. Indeed, CpG ODN up-regulated all three elements in both wild-type and IL-12-deficient mice. The role of IL-10 was demonstrated in mice exhibiting combined deficiencies in IL-12 and IL-10, Here, a marked increase in egg-specific IL-4/IL-5-producing cells confirmed a role for both cytokines in Th2 response inhibition. Nevertheless, the frequency of Th2-producing cells was again reduced by CpG ODN, However, in marked contrast to IL-12-deficient animals, a significant increase in IFN-gamma-producing cells likely explains the reduced Th2 response in IL-10/IL-12-deficient mice. Thus, a novel IL-12-independent type 1-inducing pathway was revealed in the combined absence of IL-12 and IL-10, Together, these data demonstrate 1) that the Th1-promoting activity of CpG DNA is controlled by IL-12 and IL-10, and 2) that Th2 response inhibition by CpG ODN involves IL-12-independent changes in IL-10 and costimulatory molecule expression. These findings illustrate the utility of CpG DNA as adjuvants for vaccines designed to prevent Th2-dependent immunopathology. C1 NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, 9000 Rockville Pike,Bldg 4-126, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 61 TC 52 Z9 56 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 JAN 15 PY 2000 VL 164 IS 2 BP 973 EP 985 PG 13 WC Immunology SC Immunology GA 273LF UT WOS:000084708600056 PM 10623847 ER PT J AU Holz, A Bielekova, B Martin, R Oldstone, MBA AF Holz, A Bielekova, B Martin, R Oldstone, MBA TI Myelin-associated oligodendrocytic basic protein: Identification of an encephalitogenic epitope and association with multiple sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RECOGNITION; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; PERIPHERAL NERVOUS-SYSTEM; PROTEOLIPID PROTEIN; MOLECULAR MIMICRY; RECEPTOR REPERTOIRE; SJL MICE; EXPRESSION; PEPTIDE; IMMUNODOMINANT AB Myelin-associated oligodendrocytic basic protein (MOBP) is an abundant myelin constituent expressed exclusively by oligodendrocytes, the myelin-forming cells of the CNS,We report that MOBP causes experimental allergic encephalomyelitis and is associated with multiple sclerosis, First, we note that purified recombinant MOBP inoculated into SJL/J mice produces CNS disease, Tests of overlapping peptides spanning the murine MOBP molecule map the encephalitogenic site to-amino acids 37-60, MOBP-induced experimental allergic encephalomyelitis shows a severe clinical course and is characterized by a prominent CD4(+) T lymphocyte infiltration and a lesser presence of CD8(+) T cells and microglia/macrophages around vessels and in the white matter of the CNS, Second, PBL obtained from patients with relapsing/remitting multiple sclerosis mount a proliferative response to human MOBP, especially at amino acids 21-39, This response equals or exceeds the response to myelin basic protein and an influenza virus hemagglutinin peptide, both serving as internal controls. Thus, a novel myelin Ag, MOBP aa 37-60, plays a role in rodent autoimmune CNS disease, and its human MOBP counterpart is associated with the human demyelinating disease multiple sclerosis. C1 Scripps Res Inst, Dept Neuropharmacol, Div Virol, Viral Immunobiol Lab, La Jolla, CA 92037 USA. NINCDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Holz, A (reprint author), Scripps Res Inst, Dept Neuropharmacol, Div Virol, Viral Immunobiol Lab, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NIAID NIH HHS [AI09484]; NINDS NIH HHS [NS38719] NR 54 TC 56 Z9 57 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 JAN 15 PY 2000 VL 164 IS 2 BP 1103 EP 1109 PG 7 WC Immunology SC Immunology GA 273LF UT WOS:000084708600071 PM 10623862 ER PT J AU Bielekova, B Lincoln, A McFarland, H Martin, R AF Bielekova, B Lincoln, A McFarland, H Martin, R TI Therapeutic potential of phosphodiesterase-4 and-3 inhibitors in Th1-mediated autoimmune diseases SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; CEREBROSPINAL-FLUID CELLS; MULTIPLE-SCLEROSIS; ATOPIC-DERMATITIS; INDUCED ARTHRITIS; ELEVATING AGENTS; CHOLERA-TOXIN; IFN-GAMMA; CAMP; EXPRESSION AB Phosphodiesterase-4 (PDE4) inhibitors have the potential to modulate immune responses from the Th1 toward the Th2 phenotype and are considered candidate therapies for Th1-mediated autoimmune disorders. However, depending on the model and cell types employed, studies of atopic individuals have come to the opposite conclusion, i.e., that PDE inhibitors may be beneficial in asthma, Using in vitro immunopharmacologic techniques we analyzed the effects of PDE4 and PDE3 inhibitors on human immune cells to address these discrepancies and broaden our understanding of their mechanism of action. Our results indicate that PDE inhibitors have complex inhibitory effects within in vivo achievable concentration ranges on Th1-mediated immunity, whereas Th2-mediated responses are mostly unaffected or enhanced. The Th2 skewing of the developing immune response is explained by the effects of PDE inhibitors on several factors contributing to T cell priming: the cytokine milieu; the type of costimulatory signal, i.e., up-regulation of CD86 and down-regulation of CD80; and the Ag avidity. The combination of PDE4 and PDE3 inhibitors expresses synergistic effects and may broaden the therapeutic window. Finally, we observed a differential sensitivity to PDE inhibition in autoreactive vs foreign Ag-specific T cells and cells derived from multiple sclerosis patients vs those derived from healthy donors. This suggests that PDE inhibition,weakens the strength of the T cell stimulus and corrects the underlying disease-associated cytokine skew in T cell-mediated autoimmune disorders. These new findings broaden the understanding of the immunomodulatory actions of PDE inhibitors and underscore their promising drug profile for the treatment of autoimmune disorders. C1 NINCDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINCDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr MSC 1400, Bethesda, MD 20892 USA. NR 48 TC 78 Z9 79 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 JAN 15 PY 2000 VL 164 IS 2 BP 1117 EP 1124 PG 8 WC Immunology SC Immunology GA 273LF UT WOS:000084708600073 PM 10623864 ER PT J AU Provencio, I Rodriguez, IR Jiang, GS Hayes, WP Moreira, EF Rollag, MD AF Provencio, I Rodriguez, IR Jiang, GS Hayes, WP Moreira, EF Rollag, MD TI A novel human opsin in the inner retina SO JOURNAL OF NEUROSCIENCE LA English DT Article DE circadian; melanopsin; opsin; photoreceptor; retina; retinal ganglion cell ID EXTRA-OCULAR PHOTORECEPTION; CIRCADIAN-RHYTHMS; RETINOHYPOTHALAMIC TRACT; SUPRACHIASMATIC NUCLEUS; SPECTRAL SENSITIVITY; VISUAL PIGMENTS; BINDING PROTEIN; GANGLION-CELLS; MICE; GENE AB Here we report the identification of a novel human opsin, melanopsin, that is expressed in cells of the mammalian inner retina. The human melanopsin gene consists of 10 exons and is mapped to chromosome 10q22. This chromosomal localization and gene structure differs significantly from that of other human opsins that typically have four to seven exons. A survey of 26 anatomical sites indicates that, in humans, melanopsin is expressed only in the eye. In situ hybridization histochemistry shows that melanopsin expression is restricted to cells within the ganglion and amacrine cell layers of the primate and murine retinas. Notably, expression is not observed in retinal photoreceptor cells, the opsin-containing cells of the outer retina that initiate vision. The unique inner retinal localization of melanopsin suggests that it is not involved in image formation but rather may mediate nonvisual photoreceptive tasks, such as the regulation of circadian rhythms and the acute suppression of pineal melatonin. The anatomical distribution of melanopsin-positive retinal cells is similar to the pattern of cells known to project from the retina to the suprachiasmatic nuclei of the hypothalamus, a primary circadian pacemaker. C1 Uniformed Serv Univ Hlth Sci, Dept Anat & Cell Biol, Bethesda, MD 20814 USA. NEI, NIH, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. RP Rollag, MD (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 46 TC 552 Z9 576 U1 7 U2 64 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 JAN 15 PY 2000 VL 20 IS 2 BP 600 EP 605 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 277JC UT WOS:000084929600013 PM 10632589 ER PT J AU Mamounas, LA Altar, CA Blue, ME Kaplan, DR Tessarollo, L Lyons, WE AF Mamounas, LA Altar, CA Blue, ME Kaplan, DR Tessarollo, L Lyons, WE TI BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neurotrophin; BDNF; TrkB; serotonin; structural plasticity; sprouting; cerebral cortex; neurotoxicity; amphetamines; p-chloroamphetamine ID NERVE GROWTH-FACTOR; TRK PROTOONCOGENE PRODUCT; NEUROTROPHIC FACTOR BDNF; MESSENGER-RNA; ANTEROGRADE TRANSPORT; HIPPOCAMPAL-FORMATION; RETROGRADE TRANSPORT; SPINAL-CORD; IN-VIVO; INFUSION AB Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the adult brain and can prevent the severe loss of cortical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However, it has not been determined whether BDNF promotes the survival of 5-HT axons during PCA-insult or facilitates their regenerative sprouting after injury. We show here that BDNF fails to protect most 5-HT axons from PCA-induced degeneration. Instead, chronic BDNF infusions markedly stimulate the sprouting of both intact and PCA-lesioned 5-HT axons, leading to a hyperinnervation at the neocortical infusion site. BDNF treatment promoted the regrowth of 5-HT axons when initiated up to a month after PCA administration. The sprouted axons persisted in cortex for at least 5 weeks after terminating exogenous BDNF delivery. BDNF also encouraged the regrowth of the 5-HT plexus in the hippocampus, but only in those lamina where 5-HT axons normally ramify. In addition, intracortical BDNF infusions induced a sustained local activation of the TrkB receptor. The dose-response profiles for BDNF to stimulate 5-HT sprouting and Trk signaling were remarkably similar, suggesting a physiological link between the two events; both responses were maximal at intermediate doses of BDNF but declined at higher doses ("inverted-U-shaped" dose-response curves). Underlying the downregulation of the Trk signal with excessive BDNF was a decline in full-length TrkB protein, but not truncated TrkB protein or TrkB mRNA levels. Thus, BDNF-TrkB signaling does not protect 5-HT neurons from axonal injury, but has a fundamental role in promoting the structural plasticity of these neurons in the adult brain. C1 Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. Otsuka Amer Pharmaceut Inc, Global Neurosci Res, Rockville, MD 20850 USA. Johns Hopkins Univ, Sch Med, Kennedy Krieger Res Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. NCI, Neural Dev Grp, Adv Biosci Labs,Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Mamounas, LA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, 558 Ross Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. FU NIMH NIH HHS [R29MH85433] NR 65 TC 213 Z9 219 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 15 PY 2000 VL 20 IS 2 BP 771 EP 782 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 277JC UT WOS:000084929600030 PM 10632606 ER PT J AU Sernagor, E Eglen, SJ O'Donovan, MJ AF Sernagor, E Eglen, SJ O'Donovan, MJ TI Differential effects of acetylcholine and glutamate blockade on the spatiotemporal dynamics of retinal waves SO JOURNAL OF NEUROSCIENCE LA English DT Article DE retinal waves; spatiotemporal properties; chick embryo; glutamate; acetylcholine; visual system development; calcium imaging; retinal ganglion cells ID GANGLION-CELLS; CHICK-EMBRYOS; INTRAOCULAR INJECTION; MAMMALIAN RETINA; RABBIT RETINA; VISUAL-SYSTEM; TETRODOTOXIN; TRANSMISSION; EMERGENCE AB In the immature vertebrate retina, neighboring ganglion cells express spontaneous bursting activity (SBA), resulting in propagating waves. Previous studies suggest that the spontaneous bursting activity, asynchronous between the two eyes, controls the refinement of retinal ganglion cell projections to central visual targets. To understand how the patterns encoded within the waves contribute to the refinement of connections in the visual system, it is necessary to understand how wave propagation is regulated. We have used video-rate calcium imaging of spontaneous bursting activity in chick embryonic retinal ganglion cells to show how glutamatergic and cholinergic connections, two major excitatory synaptic drives involved in spontaneous bursting activity, contribute differentially to the spatiotemporal patterning of the waves. During partial blockade of cholinergic connections, cellular recruitment declines, leading to spatially more restricted waves. The velocity of wave propagation decreases during partial blockade of glutamatergic connections, but cellular recruitment remains substantially higher than during cholinergic blockade, thereby altering correlations in the activity of neighboring and distant ganglion cells. These findings show that cholinergic and glutamatergic connections exert different influences on the spatial and temporal properties of the waves, raising the possibility that they may play distinct roles during visual development. C1 Med Sch Newcastle Upon Tyne, Dept Child Hlth, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. Univ Edinburgh, Inst Adapt & Naural Computat, Div Informat, Edinburgh EH8 9LW, Midlothian, Scotland. NINCDS, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP Sernagor, E (reprint author), Med Sch Newcastle Upon Tyne, Dept Child Hlth, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 32 TC 31 Z9 32 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 JAN 15 PY 2000 VL 20 IS 2 BP art. no. EP RC56 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 277JC UT WOS:000084929600003 PM 10632622 ER PT J AU Hernandez, I Sokolov, BP AF Hernandez, I Sokolov, BP TI Abnormalities in 5-HT2A receptor mRNA expression in frontal cortex of chronic elderly schizophrenics with varying histories of neuroleptic treatment SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE schizophrenia; frontal cortex; 5-HT2A receptor; neuroleptic treatment ID MESSENGER-RNAS; SEROTONIN RECEPTORS; ANTIPSYCHOTIC-DRUGS; CEREBRAL-CORTEX; TEMPORAL CORTEX; DNA-SEQUENCE; RAT-BRAIN; CLOZAPINE; ASSOCIATION; HALOPERIDOL AB Alterations in the 5-HT2A receptor gene expression in the prefrontal cortex have been suggested to play a role in the pathophysiology and pharmacotherapy of schizophrenia. This study measured mRNA encoding 5-HT2A receptor in the left superior frontal gyrus from chronic elderly schizophrenics (n = 21) with varying neuroleptic-free intervals before death (72 hr to more than 5 years), and normal drug-free elderly controls (n = 14). Levels of 5-HT2A mRNA in schizophrenics correlated significantly and inversely with neuroleptic-free interval before death (r = -0.77; P < 0.0001). In schizophrenics who had been receiving neuroleptic until time of death, levels of 5-HT2A mRNA were similar to controls or greater. In schizophrenics who had been free of neuroleptic for more than six months levels of 5-HT2A mRNA were significantly lower than in controls. These results confirm previous findings of decreased expression of the 5-HT2A receptor gene in the frontal cortex of some schizophrenics and suggest that regulation of this gene may be involved in the therapeutic actions of typical neuroleptics. (C) 2000 Wiley-Liss, Inc. C1 Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Sokolov, BP (reprint author), NIDA, Mol Neurobiol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 44 TC 47 Z9 49 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JAN 15 PY 2000 VL 59 IS 2 BP 218 EP 225 DI 10.1002/(SICI)1097-4547(20000115)59:2<218::AID-JNR8>3.0.CO;2-H PG 8 WC Neurosciences SC Neurosciences & Neurology GA 272CC UT WOS:000084632100008 PM 10650880 ER PT J AU Koch, CA Skarulis, MC Patronas, NJ Sarlis, NJ AF Koch, CA Skarulis, MC Patronas, NJ Sarlis, NJ TI Thyrotropin-secreting pituitary adenoma: Follow-up over 16 years SO MEDIZINISCHE KLINIK LA German DT Article ID HORMONE; TUMORS C1 NICHD, NIH, Bethesda, MD 20892 USA. RP Koch, CA (reprint author), NICHD, NIH, Bldg 10,Rm 10N 262, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 6 TC 7 Z9 7 U1 0 U2 0 PU URBAN & VOGEL PI MUNICH PA LINDWURMSTRASSE 95, D-80337 MUNICH, GERMANY SN 0723-5003 J9 MED KLIN JI Med. Klin. PD JAN 15 PY 2000 VL 95 IS 1 BP 49 EP 50 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 277JJ UT WOS:000084930200008 PM 10668345 ER PT J AU Moser, MJ Kamath-Loeb, AS Jacob, JE Bennett, SE Oshima, J Monnat, RJ AF Moser, MJ Kamath-Loeb, AS Jacob, JE Bennett, SE Oshima, J Monnat, RJ TI WRN helicase expression in Werner syndrome cell lines SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SYNDROME GENE-PRODUCT; SYNDROME PROTEIN; DNA HELICASE; NUCLEAR-LOCALIZATION; MUTATIONS; EXONUCLEASE; SYSTEM AB Mutations in the chromosome 8p WRN gene cause Werner syndrome (WRN), a human autosomal recessive disease that mimics premature aging and is associated with genetic instability and an increased risk of cancer. All of the WRN mutations identified in WRN patients are predicted to truncate the WRN protein with loss of a C-terminal nuclear localization signal, However, many of these truncated proteins would retain WRN helicase and/or nuclease functional domains, We have used a combination of immune blot and immune precipitation assays to quantify WRN protein and its associated 3'-->5' helicase activity in genetically characterized WRN patient cell lines, None of the cell lines from patients harboring four different WRN mutations contained detectable WRN protein or immune-precipitable WRN helicase activity, Cell lines from WRN heterozygous individuals contained reduced amounts of both WRN protein and helicase activity, Quantitative immune blot analyses indicate that both lymphoblastoid cell lines and fibroblasts contain similar to 6 x 10(4) WRN molecules/cell, Our results indicate that most WRN mutations result in functionally equivalent null alleles, that WRN heterozygote effects may result from haploinsufficiency and that successful modeling of WRN pathogenesis in the mouse or in other model systems will require the use of WRN mutations that eliminate WRN protein expression. C1 Univ Washington, Dept Pathol, Seattle, WA 98195 USA. Univ Washington, Dept Genet, Seattle, WA 98195 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Monnat, RJ (reprint author), Univ Washington, Dept Pathol, Box 357705, Seattle, WA 98195 USA. NR 41 TC 62 Z9 63 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 15 PY 2000 VL 28 IS 2 BP 648 EP 654 DI 10.1093/nar/28.2.648 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278AF UT WOS:000084965200034 PM 10606667 ER PT J AU Palm, GJ Billy, E Filipowicz, W Wlodawer, A AF Palm, GJ Billy, E Filipowicz, W Wlodawer, A TI Crystal structure of RNA 3 '-terminal phosphate cyclase, a ubiquitous enzyme with unusual topology SO STRUCTURE LA English DT Article DE adenylation; cyclic phosphate; RNA cyclase; selenomethionine ID UDP-N-ACETYLGLUCOSAMINE; HELA-CELL EXTRACT; 3-DIMENSIONAL STRUCTURE; PROTEIN-STRUCTURE; ESCHERICHIA-COLI; WHEAT-GERM; LIGASE; SITE; RESOLUTION; MECHANISM AB Background: RNA cyclases are a family of RNA-modifying enzymes that are conserved in eucarya, bacteria and archaea. They catalyze the ATP-dependent conversion of the 3'-phosphate to the 2',3'-cyclic phosphodiester at the end of RNA, in a reaction involving formation of the covalent AMP-cyclase intermediate. These enzymes might be responsible for production of the cyclic phosphate RNA ends that are known to be required by many RNA ligases in both prokaryotes and eukaryotes. Results: The high-resolution structure of the Escherichia coli RNA S'-terminal phosphate cyclase was determined using multiwavelength anomalous diffraction. Two orthorhombic crystal forms of E. coli cyclase (space group P2(1)2(1)2(1) and P2(1)2(1)2) were used to solve and refine the structure to 2.1 Angstrom resolution (R factor 20.4%; R-free 27.6%). Each molecule of RNA cyclase consists of two domains. The larger domain contains three repeats of a folding unit comprising two parallel cc helices and a four-stranded beta sheet; this fold was previously identified in translation initiation factor 3 (IF3). The large domain is similar to one of the two domains of 5-enolpyruvylshikimate-3-phosphate synthase acid UDP-N-acetylglucosamine enolpyruvyl transferase. The smaller domain uses a similar secondary structure element with different topology, observed in many other proteins such as thioredoxin. Conclusions: The fold of RNA cyclase consists of known elements connected in a new and unique manner. Although the active site of this enzyme could not be unambiguously assigned, it can be mapped to a region surrounding His309, an adenylate acceptor, in which a number of amino acids are highly conserved in the enzyme from different sources. The structure of E. coli cyclase will be useful for interpretation of structural and mechanistic features of this and other related enzymes. C1 NCI, Frederick Canc Res & Dev Ctr, Program Struct Biol, Macromol Crystallog Lab, Frederick, MD 21702 USA. Friedrich Miescher Inst, CH-4002 Basel, Switzerland. RP NCI, Frederick Canc Res & Dev Ctr, Program Struct Biol, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov NR 61 TC 17 Z9 18 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JAN 15 PY 2000 VL 8 IS 1 BP 13 EP 23 DI 10.1016/S0969-2126(00)00076-9 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 276HW UT WOS:000084873000003 PM 10673421 ER PT J AU Garner, CE Burka, LT Etheridge, AE Matthews, HB AF Garner, CE Burka, LT Etheridge, AE Matthews, HB TI Catechol metabolites of polychlorinated biphenyls inhibit the catechol-O-methyltransferase-mediated metabolism of catechol estrogens SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID ESTRADIOL-INDUCED TUMORIGENESIS; OXIDATIVE STRESS; TUMOR INITIATION; DNA-DAMAGE; IN-VITRO; CATECHOLESTROGENS; CANCER; ACTIVATION; ADDUCTS; KIDNEY AB The catechol metabolites of estradiol, 2- and 4-hydroxyestradiol (2-OHE2 and 4-OHE2, respectively) are potent signaling molecules and are hypothesized to be central to estrogen-linked carcinogenesis. Methylation by catechol-O-methyltransferase (COMT) is the principal means of catechol estrogen (CE) deactivation in the liver and other tissues. The present studies were conducted to determine the effects of PCBs and catechol metabolites of PCBs on the COMT-mediated catabolism of 4-OHE2 and 2-OHE2 in vitro and in vivo. Liver homogenates of female Sprague-Dawley rats treated with Aroclor 1254 for 21 days (5 mg/kg/day) showed a 30 and 40% reduction of COMT activity toward 2-OHE2 and 4-OHE2, respectively. Incubation of [H-3]-beta-estradiol with these same liver homogenates, followed by HPLC analysis, demonstrated an elevation of CEs and a nearly complete reduction in levels of methylated catechol estrogens. In classical enzyme kinetics studies, COMT was demonstrated to have a high affinity for catechol PCBs, with K-m's approximately equivalent to those of CEs. Catechol PCBs were also potent inhibitors of CE O-methylation. These data suggest that PCBs may significantly alter the metabolism of catechol estrogens in vivo and that this effect may be mediated by catechol metabolites of PCBs. It is further speculated that methyltransferase inhibition by PCB catechols may contribute to PCB-mediated endocrine effects and liver carcinogenesis. C1 NIEHS, Lab Pharmacol & Chem, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Res Triangle Inst, Ctr Bioorgan Chem, Res Triangle Pk, NC 27709 USA. RP Garner, CE (reprint author), Dupont Co, Pharmaceut, Dept Drug Metab & Pharmacokinet, POB 30, Newark, DE 19714 USA. NR 44 TC 29 Z9 30 U1 0 U2 2 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 JAN 15 PY 2000 VL 162 IS 2 BP 115 EP 123 DI 10.1006/taap.1999.8823 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 328MY UT WOS:000087855700006 PM 10637135 ER PT J AU Garner, CE Matthews, HB Burka, LT AF Garner, CE Matthews, HB Burka, LT TI Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: A possible mechanism for carcinogenicity SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID ESTRADIOL-INDUCED TUMORIGENESIS; TUMOR INITIATION; SYRIAN-HAMSTER; CANCER-CELLS; IN-VITRO; 2-METHOXYESTRADIOL; CATECHOLESTROGENS; INDUCTION; ACTIVATION; APOPTOSIS AB Phenolphthalein (PT), used in over-the-counter laxatives, has recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. We hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT) and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. The present studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT-CAT concentration in urine reached plateau levels by 7 days of exposure. An O-methylated metabolite of PT-CAT was detected in feces. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT, In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis. C1 NIEHS, Lab Pharmacol & Chem, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Garner, CE (reprint author), Dupont Co, Pharmaceut, Dept Drug Metab & Pharmacokinet, POB 30, Newark, DE 19714 USA. NR 42 TC 9 Z9 9 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 JAN 15 PY 2000 VL 162 IS 2 BP 124 EP 131 DI 10.1006/taap.1999.8830 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 328MY UT WOS:000087855700007 PM 10637136 ER PT J AU Kofoed, KF Schoder, H Knight, RJ Buxton, DB AF Kofoed, KF Schoder, H Knight, RJ Buxton, DB TI Glucose metabolism in reperfused myocardium measured by [2-F-18] 2-fluorodeoxyglucose and PET SO CARDIOVASCULAR RESEARCH LA English DT Article DE glycolysis; reperfusion; regional blood flow; coronary disease; ischemia ID LUMPED CONSTANT; POSTISCHEMIC MYOCARDIUM; RAT-HEART; FLUORODEOXYGLUCOSE; DEHYDROGENASE; DEOXYGLUCOSE; TOMOGRAPHY; BRAIN AB Objective: [2-F-18] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences, The effects of ischemia and reperfusion on the LC in vivo are unknown, To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. Methods: FDG metabolic rate, measured with FDG and PET, was; compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion, Results: The FDG metabolic rate was decreased 20+/-4% in reperfused relative to remote myocardium, Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26+/-6% and 60+/-8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium, A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium, Estimates of the LC from the slopes of the regression lines were similar in repel-fused and remote myocardium, 1.25 and 1.44 respectively, and did nor differ significantly from the LC determined in control dogs, 1.1. Conclusions: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo. (C) 2000 Elsevier Science BN. All rights reserved. C1 Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA. Univ Copenhagen, Rigshosp, Dept Med B, Div Cardiol, DK-2100 Copenhagen, Denmark. RP Buxton, DB (reprint author), NIH, Mol Cardiol Lab, Bldg 10,Room 8N202,10 Ctr Dr MSC 1762, Bethesda, MD 20892 USA. OI Buxton, Denis/0000-0003-3077-6435 FU NHLBI NIH HHS [HL 29845] NR 29 TC 17 Z9 17 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JAN 14 PY 2000 VL 45 IS 2 BP 321 EP 329 DI 10.1016/S0008-6363(99)00278-3 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 272HL UT WOS:000084644400009 PM 10728352 ER PT J AU Zingone, A Hiraiwa, H Pan, CJ Lin, BC Chen, HW Ward, JM Chou, JY AF Zingone, A Hiraiwa, H Pan, CJ Lin, BC Chen, HW Ward, JM Chou, JY TI Correction of glycogen storage disease type 1a in a mouse model by gene therapy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECOMBINANT ADENOVIRUSES IMPROVES; GLUCOSE-6-PHOSPHATASE SYSTEM; MURINE GLUCOSE-6-PHOSPHATASE; LIVER; TRANSPLANTATION; TRANSPORT; GLUCOSE; CLONING; VECTORS; E2A AB Glycogen storage disease type 1a (GSD-1a), characterized by hypoglycemia, liver and kidney enlargement, growth retardation, hyperlipidemia, and hyperuricemia, is caused by a deficiency in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. To evaluate the feasibility of gene replacement therapy for GSD-1a, we have infused adenoviral vector containing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-/-)) mice that manifest symptoms characteristic of human GSD-1a. Whereas < 15% of G6Pase(-/-) mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase, 90% of which lived to 3 months of age. Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored to 19% of that in G6Pase(+/+) mice at 7-14 days post-infusion; the activity persisted for at least 70 days. Ad-mG6Pase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Furthermore, liver and kidney enlargement was less pronounced with near-normal levels of glycogen depositions in both organs. Our data demonstrate that a single administration of a recombinant adenoviral vector can alleviate the pathological manifestations of GSD-1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy. C1 NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Acad Sinica, Inst Biol Chem, Taipei, Taiwan. NCI, Frederick Canc Res & Dev Ctr, Vet & Tumor Pathol Sect,Off Lab Anim Sci, NIH, Frederick, MD 21702 USA. RP Chou, JY (reprint author), NICHD, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241, Bethesda, MD 20892 USA. RI Lin, Baochuan/A-8390-2009 OI Lin, Baochuan/0000-0002-9484-0785 NR 23 TC 42 Z9 43 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 JAN 14 PY 2000 VL 275 IS 2 BP 828 EP 832 DI 10.1074/jbc.275.2.828 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600018 PM 10625614 ER PT J AU Nemir, M Bhattacharyya, D Li, XM Singh, K Mukherjee, AB Mukherjee, BB AF Nemir, M Bhattacharyya, D Li, XM Singh, K Mukherjee, AB Mukherjee, BB TI Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSGENIC MICE; GENE-EXPRESSION; CELL-ADHESION; BASEMENT-MEMBRANE; GROWTH-FACTOR; IN-VITRO; C-SRC; PROTEIN; INTEGRIN; PROMOTER AB Osteopontin (OPN) is a sialic acid-rich, adhesive, extracellular matrix (ECM) protein with Arg-Gly-Asp cell-binding sequence that interacts with several integrins, including alpha(v)beta(3), Since the ECM is a key regulator of mammary gland morphogenesis, and mammary epithelial cells express OPN at elevated levels, we sought to determine whether this protein plays a role in the postnatal mammary gland development. By generating transgenic mice that express OPN antisense-RNA (AS-OPN mice) in the mammary epithelia we achieved suppression of OPN production in this organ. The pregnant AS-OPN mice displayed a lack of mammary alveolar structures, a drastic reduction in the synthesis of beta-casein, whey acidic milk protein, and lactation deficiency. In agreement with these findings, we uncovered that a mammary cell line, NMuMG, which undergoes both structural and functional differentiation on ECM-coated plates, when transfected with an antisense OPN-cDNA construct, failed to undergo such differentiation. Furthermore, the results of gel-invasion assays demonstrated that these cells manifest elevated matrix metalloproteinase (MMP) activity when OPN expression is significantly reduced. The identity of this proteinase as MMP-2 is confirmed by Western blotting, zymography, and inhibition of its activity by a specific inhibitor, TIMP-2. Taken together, our results demonstrate, for the first time, an essential role of OPN in mammary gland differentiation and that the molecular mechanism(s) of its action, at least in part, involves downregulation of MMP-2. C1 McGill Univ, Dept Biol, Montreal, PQ H3A 1B1, Canada. McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. NICHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Mukherjee, BB (reprint author), McGill Univ, Dept Biol, 1205 Doctor Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM baridm@bio1.lan.mcgill.ca NR 47 TC 69 Z9 74 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 14 PY 2000 VL 275 IS 2 BP 969 EP 976 DI 10.1074/jbc.275.2.969 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600038 PM 10625634 ER PT J AU Kimura, A Singh, D Wawrousek, EF Kikuchi, M Nakamura, M Shinohara, T AF Kimura, A Singh, D Wawrousek, EF Kikuchi, M Nakamura, M Shinohara, T TI Both PCE-1/RX and OTX/CRX interactions are necessary for photoreceptor-specific gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-BINDING SPECIFICITY; HOMEOBOX GENE; HOMEODOMAIN PROTEINS; BOX GENE; PROMOTER; RETINA; SITE; TRANSCRIPTION; DROSOPHILA; MUTATIONS AB RX, a homeodomain-containing protein essential for proper eye development (Mathers, P. H. Grinberg, A., Mahon, K. A., and Jamrich, M. (1997) Nature 387, 603-607), binds to the photoreceptor conserved element-1 (PCE-1/Ret 1) in the photoreceptor cell-specific arrestin promoter and stimulates gene expression. RX is found in many retinal cell types including photoreceptor cells. Another homeodomain-containing protein, CRX, which binds to the OTX element to stimulate promoter activity, is found exclusively in photoreceptor cells (Chen, S., Wang, Q. L., Nie, Z., Sun, H., Lennon, G., Copeland, N. G., Gillbert, D. J. Jenkins, N. A., and Zack, D. J. (1997) Neuron 19, 1017-1030; Furukawa, T., Morrow, E. M., and Cepko, C. L. (1997) Cell 91, 531-541). Binding assay and cell culture studies indicate that both PCE-1 and OTX elements and at least two different regulatory factors RX and CRX are necessary for high level, photoreceptor cell-restricted gene expression. Thus, photoreceptor specificity can be achieved by multiple promoter elements interacting with a combination of both photoreceptor-specific regulatory factors and factors present in closely related cell lineages. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Ophthalmol,Ctr Ophthalm Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Ophthalmol,Cerebrovasc & NeuroSci Res Inst, Boston, MA 02115 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Shinohara, T (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Ophthalmol,Ctr Ophthalm Res, Boston, MA 02115 USA. RI Wawrousek, Eric/A-4547-2008; OI Shinohara, Toshimichi/0000-0002-7197-9039 NR 29 TC 102 Z9 106 U1 1 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 JAN 14 PY 2000 VL 275 IS 2 BP 1152 EP 1160 DI 10.1074/jbc.275.2.1152 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600062 PM 10625658 ER PT J AU Asano, K Mizobuchi, K AF Asano, K Mizobuchi, K TI Structural analysis of late intermediate complex formed between plasmid ColIb-P9 Inc RNA and its target RNA - How does a single antisense RNA repress translation of two genes at different rates? SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REPLICATION CONTROL; LEADER PEPTIDE; RIBOSOME-BINDING; REPA SYNTHESIS; R1; PSEUDOKNOT; EXPRESSION; INHIBITION; DUPLEX; COPA AB The antisense Inc RNA encoded by the IncI alpha Colib-P9 plasmid replicon controls the translation of repZ encoding the replication initiator and its leader peptide repY at different rates with different mechanisms. The initial loop-loop base pairing between Inc RNA and the target in the repZ mRNA leader inhibits formation of a pseudoknot required for repZ translation. A subsequent base pairing at the 5' leader of Inc RNA blocks repY translation. To delineate the molecular basis for the differential control, we analyzed the intermediate complexes formed between RepZ mRNA and Inc RNA(54), a 5'-truncated Inc RNA derivative. We found that the initial base pairing at the loops transforms into a more stable intermediate complex by its propagation in both directions. The resulting extensive base pairing indicates that the inhibition of the pseudoknot formation is established at this stage. Furthermore, the region of extensive base pairing includes bases different in related plasmids showing different incompatibility. Thus, the observed extensive base pairing is important for determining the incompatibility of the low-copy-number plasmids. We discuss the evolution of replication control systems found in IncI alpha, IncB, and IncFII group plasmids. C1 Univ Tokyo, Grad Sch Sci, Dept Biochem & Biophys, Tokyo 1130033, Japan. Univ Electrocommun, Dept Appl Phys & Chem, Chofu, Tokyo 1828585, Japan. RP Asano, K (reprint author), NICHD, Lab Eukaryot Gene Regulat, NIH, Bldg 6A,Rm B1-A13, Bethesda, MD 20892 USA. NR 30 TC 27 Z9 28 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 JAN 14 PY 2000 VL 275 IS 2 BP 1269 EP 1274 DI 10.1074/jbc.275.2.1269 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600076 PM 10625672 ER PT J AU Dell'Angelica, EC Aguilar, RC Wolins, N Hazelwood, S Gahl, WA Bonifacino, JS AF Dell'Angelica, EC Aguilar, RC Wolins, N Hazelwood, S Gahl, WA Bonifacino, JS TI Molecular characterization of the protein encoded by the Hermansky-Pudlak syndrome type 1 gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AP-3 ADAPTER COMPLEX; PALE EAR EP; VESICLE FORMATION; LOCUS HETEROGENEITY; HPS GENE; CLATHRIN; ENDOCYTOSIS; MUTATION; TRANSPORT; DOMAIN AB Hermansky-Pudlak syndrome (HPS) comprises a group of genetic disorders characterized by defective lysosome-related organelles. The most common form of HPS (HPS type 1) is caused by mutations in a gene encoding a protein with no homology to any other known protein. Here we report the identification and biochemical characterization of this gene product, termed HPS1p, Endogenous HPS1p was detected in a wide variety of human cell lines and exhibited an electrophoretic mobility corresponding to a protein of similar to 80 kDa, In contrast to previous theoretical analysis predicting that HPS1p is an integral membrane protein, we found that this protein was predominantly cytosolic, with a small amount being peripherally associated with membranes, The sedimentation coefficient of the soluble form of HPS1p was similar to 6 S as inferred from ultracentrifugation on sucrose gradients. HPS1p-deficient cells derived from patients with HPS type 1 displayed normal distribution and trafficking of the lysosomal membrane proteins, CD63 and Lamp-1. This was in contrast to cells from HPS type 2 patients, having mutations in the beta 3A subunit of the AP-3 adaptor complex, which exhibited increased routing of these lysosomal proteins through the plasma membrane, Similar analyses performed on fibroblasts from 10 different mouse models of HPS revealed that only the AP-3 mutants pearl and mocha display increased trafficking of Lamp-1 through the plasma membrane. Taken together, these observations suggest that the product of the HPS1 gene is a cytosolic protein capable of associating with membranes and involved in the biogenesis and/or function of lysosome-related organelles by a mechanism distinct from that dependent on the AP-3 complex. C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NICHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Rm 101, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 40 TC 81 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 JAN 14 PY 2000 VL 275 IS 2 BP 1300 EP 1306 DI 10.1074/jbc.275.2.1300 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600081 PM 10625677 ER PT J AU Greener, T Zhao, XH Nojima, H Eisenberg, E Greene, LE AF Greener, T Zhao, XH Nojima, H Eisenberg, E Greene, LE TI Role of cyclin G-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEIN; TUMOR-SUPPRESSOR; GOLGI MEMBRANES; MOLECULAR CHAPERONE; AUXILIN; ATPASE; DNAJ; DISSOCIATION; HOMOLOGS; BINDING AB Auxilin is a brain-specific DnaJ homolog that is required for Hsc70 to dissociate clathrin from bovine brain clathrin-coated vesicles. However, Hsc70 is also involved in uncoating clathrin-coated vesicles formed at the plasma membrane of non-neuronal cells suggesting that an auxilin homolog may be required for uncoating in these cells. One candidate is cyclin G-associated kinase (GAK), a 150-kDa protein expressed ubiquitously in various tissues. GAK has a C-terminal domain with high sequence similarity to auxilin; like auxilin this C-terminal domain consists of three subdomains, an N-terminal tensin-like domain, a clathrin-binding domain, and a C-terminal J-domain, Western blot analysis shows that GAK is present in rat liver, bovine testes, and bovine brain clathrin-coated vesicles. More importantly, liver clathrin-coated vesicles, which contain GAK but not auxilin, are uncoated by Hsc70, suggesting that GAK acts as an auxilin homolog in non-neuronal cells. In support of this view, the clathrin-binding domain of GAK alone induces clathrin polymerization into baskets and the combined clathrin-binding domain and J-domain of GAK supports uncoating of AP180-clathrin baskets by Hsc70 at pH 7 and induces Hsc70 binding to clathrin baskets at pH 6, Immunolocalization studies suggest that GAK is a cytosolic protein that is concentrated in the perinuclear region; it appears to be highly associated with the trans-Golgi where the budding of clathrin-coated vesicles occurs. We propose that GAK is a required cofactor for the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Osaka Univ, Res Inst Microbial Dis, Dept Mol Genet, Suita, Osaka 5650871, Japan. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 3,B1-22, Bethesda, MD 20892 USA. NR 37 TC 102 Z9 104 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 JAN 14 PY 2000 VL 275 IS 2 BP 1365 EP 1370 DI 10.1074/jbc.275.2.1365 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 275TQ UT WOS:000084836600090 PM 10625686 ER PT J AU Hallock, YF Sowder, RC Pannell, LK Hughes, CB Johnson, DG Gulakowski, R Cardellina, JH Boyd, MR AF Hallock, YF Sowder, RC Pannell, LK Hughes, CB Johnson, DG Gulakowski, R Cardellina, JH Boyd, MR TI Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID CIRCULIN-A AB Four novel anti-HIV macrocyclic peptides containing 28-31 amino acid residues, named cycloviolins A-D, have been isolated from the hitherto unstudied tropical plant Leonia cymosa. Their primary structure, including amino acid composition and sequence, was determined by a combination of MALDI-TOF and FAB MS and by enzymatic digestion of reduced derivatives, followed by Edman degradation and mass analyses. All of the cycloviolins contain six cysteines, which are present as three intramolecular disulfide bridges. Intriguingly, cycloviolins A-D showed high degrees of sequence homology to the known cyclopsychotride A and circulins A and B from the Rubiaceae family but much less homology to the vary peptides from Violet, a member of the same family (Violaceae). C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Frederick, MD 21702 USA. Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIDDKD, Analyt Chem Lab, Bethesda, MD 20892 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Frederick, MD 21702 USA. NR 17 TC 85 Z9 91 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JAN 14 PY 2000 VL 65 IS 1 BP 124 EP 128 DI 10.1021/jo990952r PG 5 WC Chemistry, Organic SC Chemistry GA 275JD UT WOS:000084816300019 PM 10813905 ER PT J AU Bachmaier, K Krawczyk, C Kozieradzki, I Kong, YY Sasaki, T Oliveira-dos-Santos, A Mariathasan, S Bouchard, D Wakeham, A Itie, A Le, J Ohashi, PS Sarosi, I Nishina, H Lipkowitz, S Penninger, JM AF Bachmaier, K Krawczyk, C Kozieradzki, I Kong, YY Sasaki, T Oliveira-dos-Santos, A Mariathasan, S Bouchard, D Wakeham, A Itie, A Le, J Ohashi, PS Sarosi, I Nishina, H Lipkowitz, S Penninger, JM TI Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b SO NATURE LA English DT Article ID T-CELL RECEPTOR; PROTEIN; MICE; PROTOONCOGENE; TOLERANCE; ANTIGENS; KINASE; TISSUE; BINDS; VAV AB The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules(1). Changes in co-stimulatory pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the induction of clonal anergy(2). The molecular mechanisms that maintain immunotolerance in vivo and integrate co-stimulatory signals with antigen receptor signals in T and B lymphocytes are poorly understood. Members of the Cbl/Sli family of molecular adaptors function downstream from growth factor and antigen receptors(3-5). Here we show that gene-targeted mice lacking the adaptor Cbl-b develop spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage. Resting cbl-b(-/-) lymphocytes hyperproliferate upon antigen receptor stimulation, and cbl-b(-/-) T cells display specific: hyperproduction of the T-celI growth factor interleukin-2, hut not interferon-gamma or tumour necrosis factor-alpha. Mutation of Cbl-b uncouples T-cell proliferation, interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1 from the requirement for CD28 costimulation. Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity. C1 Univ Toronto, Amgen Inst, Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2C1, Canada. Univ Toronto, Amgen Inst, Ontario Canc Inst, Dept Immunol, Toronto, ON M5G 2C1, Canada. Univ Toronto, Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. Univ Toronto, Ontario Canc Inst, Dept Immunol, Toronto, ON M5G 2M9, Canada. Amgen Inc, Dept Pathol, Thousand Oaks, CA 91320 USA. NCI, Med Branch, Dept Genet, Naval Hosp, Bethesda, MD 20889 USA. RP Penninger, JM (reprint author), Univ Toronto, Amgen Inst, Ontario Canc Inst, Dept Med Biophys, Toronto, ON M5G 2C1, Canada. RI Penninger, Josef/I-6860-2013; Bachmaier, Kurt/B-6331-2014 OI Penninger, Josef/0000-0002-8194-3777; Bachmaier, Kurt/0000-0002-0299-2707 NR 23 TC 429 Z9 453 U1 1 U2 17 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 13 PY 2000 VL 403 IS 6766 BP 211 EP 216 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 275TB UT WOS:000084835300059 PM 10646608 ER PT J AU Chiang, YPJ Kole, HK Brown, K Naramura, M Fukuhara, S Hu, RJ Jang, IK Gutkind, JS Shevach, E Gu, H AF Chiang, YPJ Kole, HK Brown, K Naramura, M Fukuhara, S Hu, RJ Jang, IK Gutkind, JS Shevach, E Gu, H TI Cbl-b regulates the CD28 dependence of T-cell activation SO NATURE LA English DT Article ID RECEPTOR TRANSGENIC MICE; SIGNAL-TRANSDUCTION; C-CBL; ANTIGEN RECEPTORS; DEFICIENT MICE; VAV; PROTOONCOGENE; THYMOCYTES; RESPONSES; PRODUCT AB Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers T-cell activation, stimulation of the TCR alone may result in an anergic state or T-cell deletion, both possible mechanisms of tolerance induction(1,2), Here we show that T cells that are deficient in the adaptor molecule Cbl-b, (ref. 3) do not require CD28 engagement for interleukin-2 production, and that the Cbl-b-null mutation (Cbl-b(-/-)) fully res;tores T-cell-dependent antibody responses in CD28(-/-) mice. The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase C gamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells. In contrast, the activation of Vav, a guanine nucleotide exchange factor for Rac1/Rho/CDC42, was significantly enhanced. Our findings indicate that Cbl-b may influence the CD28 dependence of T-cell activation by selectively suppressing TCR-mediated Vav activation, Mice deficient in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis. C1 NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. NIH, Bethesda, MD 20892 USA. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gu, H (reprint author), NIAID, Immunol Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 26 TC 381 Z9 399 U1 1 U2 8 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 13 PY 2000 VL 403 IS 6766 BP 216 EP 220 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 275TB UT WOS:000084835300060 PM 10646609 ER PT J AU Reddy, DE Keck, CL Popescu, N Athwal, RS Kaur, GP AF Reddy, DE Keck, CL Popescu, N Athwal, RS Kaur, GP TI Identification of a YAC from 16q24 carrying a senescence gene for breast cancer cells SO ONCOGENE LA English DT Article DE cell senescence; breast cancer; YAC contig; YAC transfer; functional complementation ID YEAST ARTIFICIAL CHROMOSOMES; MAMMALIAN-CELLS; MOUSE CELLS; CELLULAR SENESCENCE; ALLELIC IMBALANCE; IN-SITU; CARCINOMA; FUSION; EXPRESSION; COMPLEMENTATION AB We have identified a 360 kb YAC that carries a cell senescence gene, SEN16. In our earlier studies, we localized SEN16 within a genetic interval of 3-7 cM at 16q24.3. Six overlapping YACs spanning the chromosomal region of senescence activity, were assembled in a contig. Candidate YACs, identified by the markers located in the vicinity of SEN16, were retrofitted to introduce a neo selectable marker. Retrofitted YACs were first transferred into mouse A9 cells to generate A9/YAC hybrids. YAC DNA present in A9/YAC hybrids was further transferred by microcell fusion into immortal cell lines derived from human and rat mammary tumors. YAC d792t2 restored senescence in both human and rat mammary tumor cell lines, while an unrelated YAC from chromosome 6q had no senescence activity. C1 Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Kaur, GP (reprint author), Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, 3307 N Broad St,AHP Room 201, Philadelphia, PA 19140 USA. NR 37 TC 8 Z9 8 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 13 PY 2000 VL 19 IS 2 BP 217 EP 222 DI 10.1038/sj.onc.1203264 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 275XA UT WOS:000084844400006 PM 10644999 ER PT J AU Imatani, A Callahan, R AF Imatani, A Callahan, R TI Identification of a novel NOTCH-4/INT-3 RNA species encoding an activated gene product in certain human tumor cell lines SO ONCOGENE LA English DT Article DE NOTCH-4/INT-3; activated gene product; human ID MAMMARY EPITHELIAL-CELLS; SPLIT COMPLEX GENES; TRUNCATED INT3 GENE; NOTCH-GENE; NEOPLASTIC TRANSFORMATION; DROSOPHILA NOTCH; MAMMALIAN NOTCH; HUMAN HOMOLOG; C-MYC; DIFFERENTIATION AB Ectopic expression of the intracellular domain of NOTCH-4/INT-3 leads to tumorigenesis in the mouse mammary gland. This results from a gain-of-function mutation. To evaluate gain-of-function NOTCH-4/INT-3 activity in human cancers we have surveyed human breast, lung, and colon carcinoma tissue culture cell lines for evidence of increased NOTCH-4/INT-3 RNA expression. High levels of a 1.8 Kb NOTCH-4/INT-3 RNA species are detected in normal human testis but not in other tissues where a 6.5 Kb species is prevalent. Transformed human cancer cell lines express the 1.8 Kb NOTCH-4/INT-3 RNA species. We show that this RNA species encodes a truncated form of the NOTCH-4/INT3 intracellular domain (ICD), This novel NOTCH-4/ INT-3 protein includes the CDC10 repeats and amino acid residues C-terminal to them, but is missing the CBF-1 binding region of the NOTCH-4/INT-3 ICD, This suggests that it has a different mode of action, Furthermore, we show that a transgene which expresses the 1.8 Kb NOTCH-4/INT-3 RNA species in the 'normal' human mammary epithelial cell line MCF-10A enables these cells to grow in soft agar. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Callahan, R (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B50, Bethesda, MD 20892 USA. NR 38 TC 76 Z9 77 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 13 PY 2000 VL 19 IS 2 BP 223 EP 231 DI 10.1038/sj.onc.1203295 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 275XA UT WOS:000084844400007 PM 10645000 ER PT J AU Nam, SW Clair, T Campo, CK Lee, HY Liotta, LA Stracke, ML AF Nam, SW Clair, T Campo, CK Lee, HY Liotta, LA Stracke, ML TI Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells SO ONCOGENE LA English DT Article DE autotaxin; invasion; metastasis; motility; ras ID MOTILITY-STIMULATING PROTEIN; SURFACE-ANTIGENS; EXPRESSION; CLONING; GROWTH; BRAIN; SITE AB Autotaxin (ATX), an exo-nucleotide pyrophosphatase and phosphodiesterase, was originally isolated as a potent stimulator of tumor cell motility. In order to study whether ATX expression affects motility-dependent processes such as invasion and metastasis, we stably transfected full-length ATX cDNA into two nonexpressing cell lines, parental and ras-transformed NIH3T3 (clone7) cells. The effect of ATX secretion on in vitro cell motility was variable, The ras-transformed, ATX-secreting subclones had enhanced motility to ATX as chemoattractant, but there was little difference in the motility responses of NIH3T3 cells transfected with atx, an inactive mutant gene, or empty vector, In MatrigelTM invasion assays, all subclones, which secreted enzymatically active ATX, demonstrated greater spontaneous and ATX-stimulated invasion than appropriate controls. This difference in invasiveness was not caused by differences in gelatinase production, which was constant within each group of transfectants, In vivo studies with athymic nude mice demonstrated that injection of atx-transfected NIH3T3 cells resulted in a weak tumorigenic capacity with few experimental metastases. Combination of ATX expression with ras transformation produced cells with greatly amplified tumorigenesis and metastatic potential compared to ras-transformed controls, Thus, ATX appears to augment cellular characteristics necessary for tumor aggressiveness. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Nam, SW (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33, Bethesda, MD 20892 USA. NR 23 TC 138 Z9 139 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 13 PY 2000 VL 19 IS 2 BP 241 EP 247 DI 10.1038/sj.onc.1203263 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 275XA UT WOS:000084844400009 PM 10645002 ER PT J AU Soukharev, S Berlin, W Hanover, JA Bethke, B Sauer, B AF Soukharev, S Berlin, W Hanover, JA Bethke, B Sauer, B TI Organization of the mouse ASGR1 gene encoding the major subunit of the hepatic asialoglycoprotein receptor SO GENE LA English DT Article DE endocytosis; glycoprotein; lectin; transcription ID LATE-STAGE SPERMATIDS; CDNA SEQUENCE; MICE LACKING; LIVER; EXPRESSION; CHROMOSOME-11; RECOGNITION; SURFACE AB The hepatic asialoglycoprotein receptor was the first of the mammalian lectins to be recognized and has been the subject of intense investigation for three decades. Yet, the precise biological role of this major hepatic endocytic receptor has remained elusive. We describe here the characterization of the mouse gene for the major subunit of this receptor (ASGR1) along with 3.5 kb of the upstream 5' region. The gene comprises eight coding exons, with the major transcript in liver displaying a single non-coding 5' exon. A minor hepatic transcript initiates 435 bp upstream of the major start and includes an additional 5' non-coding exon and intron. A minimal 600 bp proximal region of ASGR1 exhibits hepatic-specific promoter activity in HepG2 cells in vitro. These results provide the basis for more detailed genetic studies on the functional role of the hepatic asialoglycoprotein receptor in mammals. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Oklahoma Med Res Fdn, Dev Biol Program, Oklahoma City, OK 73104 USA. NIDDKD, Biochem & Metab Lab, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. RP Sauer, B (reprint author), Oklahoma Med Res Fdn, Dev Biol Program, 825 NE 13th St,MS 49, Oklahoma City, OK 73104 USA. NR 24 TC 5 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 11 PY 2000 VL 241 IS 2 BP 233 EP 240 DI 10.1016/S0378-1119(99)00493-X PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 277PV UT WOS:000084942700005 PM 10675034 ER PT J AU Karpati, G Dalakas, MC AF Karpati, G Dalakas, MC TI Viral hide-and-seek in sporadic ALS - A new challenge SO NEUROLOGY LA English DT Editorial Material ID INFECTIONS; VIRUS C1 McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Karpati, G (reprint author), McGill Univ, Montreal Neurol Inst, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. NR 15 TC 17 Z9 17 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 JAN 11 PY 2000 VL 54 IS 1 BP 6 EP 7 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900003 PM 10636117 ER PT J AU Choi, YC Dalakas, MC AF Choi, YC Dalakas, MC TI Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies SO NEUROLOGY LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the American-Academy-of-Neurology CY APR 17-24, 1999 CL TORONTO, CANADA SP Amer Acad Neurol DE matrix metalloproteinases 2 and 9; inflammatory myopathies; beta-amyloid precursor protein ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS LESIONS; EXTRACELLULAR-MATRIX; GELATINASE-B; ACTIVATION; PRECURSOR; DISEASES; PURIFICATION; FIBROBLASTS; CLEAVES AB Objective: To investigate the role of matrix metalloproteinases (MMPs) in the pathogenesis of inflammatory myopathies and the amyloid formation in sporadic inclusion body myositis (s-IBM). Background: MMPs comprise a family of calcium-dependent zinc endoproteinases induced by cytokines and secreted by inflammatory cells. They enhance T-cell migration or adhesion and degrade components of the extracellular matrix proteins. Some MMPs also have been implicated in the formation of beta-amyloid. Methods: We examined the expression of MMPs with single and double immunocytochemistry using antibodies against MMP-2, MMP-3, MMP-7, MMP-9, major histocompatibility complex (MHC) class I, CD8(+) cells, macrophage, and beta-amyloid precursor protein (beta-APP) on serial muscle biopsy sections from patients with s-IBM, polymyositis (PM), dermatomyositis (DM), and disease control specimens. The enzyme activity of MMPs was measured by gelatin substrate zymography. Results: Only the gelatinases, MMP-9 and MMP-2, were expressed in the muscle. In s-IBM and PM, but not the control specimens, MMP-9 and MMP-2 immunostained the non-necrotic and MHC class-I-expressing muscle fibers, and MMP-9, but not MMP-2, immunostained the autoinvasive CD8(+) cytotoxic T cells. Zymography in muscle homogenates confirmed the increased MMP-2 and MMP-9 enzymatic activity. MMP-2, but not MMP-9, immunostained the rimmed vacuoles in s-IBM and colocalized with beta-APP, suggesting a possible involvement with the amyloid deposits. Conclusions: Because collagen TV is prominent on the muscle membrane, the overexpression of matrix metalloproteinases (MMPs) 2 and 9 on the non-necrotic muscle fibers in polymyositis (PM) and sporadic inclusion body myositis (s-IBM) may facilitate lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading extracellular matrix proteins. The findings may have practical implications in considering therapeutic trials with MMP inhibitors in patients with PM and s-IBM. 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 31 TC 93 Z9 98 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 11 PY 2000 VL 54 IS 1 BP 65 EP 71 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900013 PM 10636127 ER PT J AU Lippa, CF Schmidt, ML Nee, LE Bird, T Nochlin, D Hulette, C Mori, H Lee, VMY Trojanowski, JQ AF Lippa, CF Schmidt, ML Nee, LE Bird, T Nochlin, D Hulette, C Mori, H Lee, VMY Trojanowski, JQ TI AMY plaques in familial AD - Comparison with sporadic Alzheimer's disease SO NEUROLOGY LA English DT Article DE AD; AMY; amyloid precursor protein; confocal laser scanning microscopy; familial AD; presenilin ID BETA DEPOSITION; PROTEIN; PRESENILIN-1; MUTATION; BRAINS; HETEROGENEITY; KINDREDS; PEPTIDE AB Objective: To assess AMY expression in familial AD (FAD). Background: The discovery of non beta-amyloid (A beta), plaque-like deposits composed of a 100-kd protein (AMY) in sporadic AD (SAD) brains prompted us to determine whether these plaques (AMY plaques) also occur in AD due to mutations of the presenilin-1 (PS-1), presenilin-2 (PS-2), or the amyloid precursor protein (APP) genes. Methods. We used immunohistochemistry and confocal laser scanning microscopy to probe the brains of 22 patients with FAD (13 with PS-1, 5 with PS-2, and 4 with APP mutations) and 14 patients with SAD. Results: AMY plaques were present in all SAD and FAD brains, including an FAD/PS-1 brain from an individual with preclinical disease. The morphology of AMY plaques in SAD and FAD brains was indistinguishable, but they differed from A beta deposits because AMY plaques lacked an immunoreactive core. AMY plaques sometimes colocalized with A beta(x-42) deposits, but they did not colocalize with A beta(x-40) plaque cores in either SAD or FAD brains. The percent of cortical area occupied by AMY was greater in FAD than in SAD brains (mean percent area = 9.8% and 5.9%, t = 2.487, p = 0.018). In particular, APP and PS-1 cases had more AMY deposition than PS-2 or SAD cases (12.9%, 10.5%, 6.2% in APP, PS-1, and PS-2 AD). Conclusions: AMY plaques are consistently present in familial AD due to presenilin-1 (PS-1), PS-2, and amyloid precursor protein mutations, and they can begin to accumulate before the emergence of dementia. C1 MCP Hahnemann Univ, Dept Neurol, Philadelphia, PA 19102 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. NINDS, Family Studies Unit, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Seattle, WA USA. Vet Affairs Med Ctr, Dept Neurol, Seattle, WA 98108 USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Osaka City Univ, Dept Neurosci, Aebnoku, Japan. RP Lippa, CF (reprint author), MCP Hahnemann Univ, Dept Neurol, 3300 Henry Ave, Philadelphia, PA 19102 USA. FU NIA NIH HHS [AG09215, AG10124, AG16323] NR 35 TC 9 Z9 10 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 JAN 11 PY 2000 VL 54 IS 1 BP 100 EP 104 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900019 PM 10636133 ER PT J AU Sanchez-Pernaute, R Kunig, G Alba, AD de Yebenes, JG Vontobel, P Leenders, KL AF Sanchez-Pernaute, R Kunig, G Alba, AD de Yebenes, JG Vontobel, P Leenders, KL TI Bradykinesia in early Huntington's disease SO NEUROLOGY LA English DT Article DE Huntington's disease; striatum; raclopride C11; bradykinesia; PET; D-2 receptor ID POSITRON EMISSION TOMOGRAPHY; DOPAMINE-RECEPTOR-BINDING; SUBCORTICAL DEMENTIA; C-11 RACLOPRIDE; REPEAT LENGTH; BASAL GANGLIA; HUMAN-BRAIN; PET; CHOREA; NEUROPSYCHOLOGY AB Background: Hunting-ton's disease (HD) is generally considered a hyperkinetic disorder, although hypokinetic features are part of the motor syndrome. Moreover, the striatum is considered to play a key role in initiating and executing motor programs and achieving optimal scheduling in response generation. Controversial results regarding the association between clinical features and markers of progression of the disease might be the result of inadequate restriction of clinical signs to the choreatic syndrome. Objective: To determine the relationship of neurologic motor and cognitive indices in patients with HD with intrinsic neuronal loss in the striatum, as measured using raclopride C11 and PET. Patients and Methods: A cross-sectional study was performed on 11 patients with mild HD (stages 0-2). Motor (Unified Huntington's Disease Rating Scale [UHDRS], saccadic and tapping speed) and cognitive (verbal fluency, Trail Making Test, Stroop Test, Symbol Digit Modalities Test, Conditioned Associative Learning Test, and silhouette identification and object decision of the Visual Object and Space Perception battery) scores were correlated with raclopride C11 binding. Results: Bradykinesia (a summation of five items of the UHDRS motor scale) was the best predictor for stage, that is, functional capacity, and showed a highly significant relationship with putaminous D-2 binding (r = -0.94) and with CAG expansion length x years of age (r = 0.96). The exclusion of two patients with a rigid-akinetic HD variant did not alter these coefficients. Chorea was less well correlated than bradykinesia with D-2 binding in all striatal regions. Performance on different cognitive tests, especially in timed tasks, was highly correlated with raclopride C11 binding in caudate nucleus and ventral striatum. Conclusion: Loss of D-2 binding in the striatum is highly correlated with the deficit in fast motor and cognitive processing in patients with early Huntington's Disease. Thus, impairment of rapid execution of adequate responses to environmental changes seems to be a common manifestation of striatal disorders. C1 Fdn Jimenez Diaz, Dept Neurol, E-28040 Madrid, Spain. Paul Scherrer Inst, PET Unit, Villigen, Switzerland. Acad Ziekenhuis, Dept Neurol, Groningen, Netherlands. RP Sanchez-Pernaute, R (reprint author), NINDS, Lab Mol Med & Neurosci, Bldg 36,Room 5W21,36 Convent Dr, Bethesda, MD 20892 USA. NR 49 TC 57 Z9 59 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 11 PY 2000 VL 54 IS 1 BP 119 EP 125 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900022 PM 10636136 ER PT J AU Greenberg, BD Ziemann, U Cora-Locatelli, G Harmon, A Murphy, DL Keel, JC Wassermann, EM AF Greenberg, BD Ziemann, U Cora-Locatelli, G Harmon, A Murphy, DL Keel, JC Wassermann, EM TI Altered cortical excitability in obsessive-compulsive disorder SO NEUROLOGY LA English DT Article DE obsessive-compulsive disorder; transcranial magnetic stimulation; intracortical inhibition; basal ganglia ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; GLUCOSE METABOLIC-RATE; SILENT PERIOD; BASAL GANGLIA; INHIBITION; FACILITATION; EXCITATION; CIRCUITS; DYSTONIA AB Objective: To assess cortical inhibitory and excitatory mechanisms in obsessive-compulsive disorder (OCD). Background: Transcranial magnetic stimulation (TMS) studies have found decreased neuronal inhibition and a reduced cortical silent period in the primary motor area in Tourette's syndrome, focal dystonia, and other disorders believed to involve dysfunction of subcortical structures, including the basal ganglia. Dysfunction of the basal ganglia and linked regions also has been implicated in OCD, which has significant clinical and familial overlap with tic disorders. Methods: We applied the TMS techniques previously used in Tourette's syndrome to a group of 16 OCD patients (seven unmedicated) and II age-matched healthy volunteers extensively screened for psychopathology. Measures of motor cortex excitability included resting and active motor threshold, cortical silent period duration, and intracortical inhibition and facilitation using a paired-pulse TMS technique with a subthreshold conditioning stimulus. Results: Similar to recent findings in Tourette's syndrome and focal dystonia, this study reports significantly decreased intracortical inhibition (ICI) relative to the volunteers at interstimulus intervals from 2 to 5 msec. We also found decreased active and resting motor evoked potential threshold in the OCD patients, another indication of increased cortical excitability. Neither abnormality appeared medication related. The decreases in ICI and motor threshold were greatest in OCD patients with comorbid ties, but remained significant in patients without ties. Conclusions: The data suggest abnormal cortical excitability in obsessive-compulsive disorder. These findings are congruent with the hypothesis that Tourette's syndrome and obsessive compulsive disorder (OCD) are analogous disorders with overlapping dysfunction in corticobasal circuits. Patients with tic-related OCD may have more abnormal motor cortex excitability than OCD patients without tics. C1 NIMH, Clin Sci Lab, Adult OCD Res Unit, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Greenberg, BD (reprint author), NIMH, Clin Sci Lab, Adult OCD Res Unit, NIH, 10 Ctr Dr,MSC 1264, Bethesda, MD 20892 USA. NR 35 TC 159 Z9 166 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 11 PY 2000 VL 54 IS 1 BP 142 EP 147 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900026 PM 10636140 ER PT J AU Ross, JL Roeltgen, D Feuillan, P Kushner, H Cutler, GB AF Ross, JL Roeltgen, D Feuillan, P Kushner, H Cutler, GB TI Use of estrogen in young girls with Turner syndrome - Effects on memory SO NEUROLOGY LA English DT Article DE Turner syndrome; estrogen; cholinergic systems; memory ID SURGICALLY MENOPAUSAL WOMEN; COGNITIVE FUNCTION; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; ALZHEIMERS-DISEASE; OLDER WOMEN; PERFORMANCE; ESTRADIOL; CHILDREN; SKILLS AB Background: The Turner syndrome (TS) phenotype is characterized by a specific neurocognitive profile of normal verbal skills, impaired visual-spatial and visual-perceptual abilities, and impaired nonverbal more than verbal memory. We compared verbal and nonverbal memory in estrogen- and placebo-treated girls with TS (ages 7 to 9 years) and age-matched female controls. Methods: Children received either estrogen (ethinyl estradiol, 25 ng/kg/d) or placebo for 1 to 3 years (mean, 2.1 +/- 0.9 years) in a randomized, double-blind study. Memory and language tasks administered included the Wechsler intelligence Scale for Children-Revised, Digit Span (forward and backward), the Children's Word List, the Denman Paragraph, the Peabody Picture Vocabulary Test, Boston Naming, immediate and delayed Recall of the Rey Complex Figure, Nonword Reading, Wide Range Achievement Test-Revised reading subtest, Verbal fluency, and the Token Test. Results: The estrogen-treated TS group performed better than the placebo-treated TS group for the Children's Ward List immediate and delayed recall and the Digit Span backwards test (p < 0.01 to 0.04), although the results were not significant after adjusting for multiple comparisons. The placebo-treated TS group performed less well than the controls for recall of Digit Span backward (p < 0.0001; placebo-treated, 2.8 +/- 1.3; estrogen-treated, 3.4 +/- 1.2; and controls, 4.2 +/- 1.3) and immediate and delayed recall of the Children's Word List (delayed recall, p < 0.0001; placebo-treated, 6.2 +/- 3.1; estrogen-treated, 8.0 +/- 2.9; and controls, 9.0 +/- 2.9). Performance for these measures was similar for the estrogen-treated TS group and the control group. Conclusions: Estrogen replacement therapy in young girls with Turner Syndrome is associated with improved verbal and nonverbal memory. The optimal patient age, dose, and duration of estrogen replacement require further study. C1 Thomas Jefferson Univ, Dept Pediat, Philadelphia, PA 19107 USA. Penn State Coll Med, Dept Neurol, Hershey, PA USA. Susquehanna Hlth Syst, Williamsport, PA USA. NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD USA. Med Coll Penn & Hahnemann Univ, Dept Biostat, Philadelphia, PA USA. RP Ross, JL (reprint author), Thomas Jefferson Univ, Dept Pediat, 1025 Walnut St, Philadelphia, PA 19107 USA. EM Ross4@jeflin.tju.edu FU NINDS NIH HHS [NS29857] NR 43 TC 72 Z9 74 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 11 PY 2000 VL 54 IS 1 BP 164 EP 170 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900029 PM 10636143 ER PT J AU Gaillard, WD Hertz-Pannier, L Mott, SH Barnett, AS LeBihan, D Theodore, WH AF Gaillard, WD Hertz-Pannier, L Mott, SH Barnett, AS LeBihan, D Theodore, WH TI Functional anatomy of cognitive development - fMRI of verbal fluency in children and adults SO NEUROLOGY LA English DT Article DE functional MRI; language; verbal fluency; children; dominance ID CEREBRAL BLOOD-FLOW; HUMAN-BRAIN; LANGUAGE DOMINANCE; PREFRONTAL CORTEX; FRONTAL-CORTEX; MRI; ACTIVATION; LOCALIZATION; ADOLESCENTS; STIMULATION AB Objective: To identify age-dependent activation patterns of verbal fluency with functional MRT (fMRI), Background: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. Methods: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Sigma MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. Results: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca's area) and left, middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. Conclusions. In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity. C1 Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. RP Gaillard, WD (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NINDS NIH HHS [KO8 NSO 1663-02] NR 43 TC 255 Z9 260 U1 5 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 11 PY 2000 VL 54 IS 1 BP 180 EP 185 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 273VE UT WOS:000084727900031 PM 10636145 ER PT J AU Efiok, BJS Safer, B AF Efiok, BJS Safer, B TI Transcriptional regulation of E2F-1 and eIF-2 genes by alpha-Pal: a potential mechanism for coordinated regulation of protein synthesis, growth, and the cell cycle SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE alpha-Pal; E2F-1; apoptosis; cell-cycle ID EUKARYOTIC INITIATION FACTOR-2-ALPHA; S-PHASE ENTRY; DNA-BINDING; SACCHAROMYCES-CEREVISIAE; RESTRICTION POINT; CDK INHIBITORS; EXPRESSION; APOPTOSIS; INDUCTION; PROLIFERATION AB alpha-Pal regulates the basal transcription of the alpha and beta subunits of eukaryotic initiation factor two (eIF-2), a rate-limiting enzyme for the initiation of protein biosynthesis. We recently showed that its global function may be to modulate the expression of key metabolic genes in response to cellular proliferation. In this paper, we examined a potential molecular mechanism by which alpha-Pal may achieve this function. When overexpressed, alpha-Pal upregulated protein synthesis and growth, but downregulated the cell cycle. The mechanism for the increased protein synthesis and growth appeared to be a transcriptional upregulation of the eIF-2 alpha and eIF-2 beta genes. The mechanism for the cell cycle downregulation appeared to be a transcriptional downregulation of E2F-1, a transcription factor that regulates genes required for cell cycle progression beyond the G1/S interphase. Specifically, an apparently modified species of alpha-Pal bound to the eIF-2 promoters and induced transcriptional upregulation, whereas, an apparently unmodified species of the alpha-Pal bound to the E2F-1 promoter and induced transcriptional downregulation, By this mechanism, alpha-Pal may participate in coordinating the regulation of global protein synthesis, growth and the cell cycle; a regulation that is essential to cellular differentiation. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NHLBI, Lab Mol Hematol, Sect Prot & RNA Biosynth, NIH, Bethesda, MD 20892 USA. RP Efiok, BJS (reprint author), NHLBI, Lab Mol Hematol, Sect Prot & RNA Biosynth, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 53 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD JAN 10 PY 2000 VL 1495 IS 1 BP 51 EP 68 DI 10.1016/S0167-4889(99)00138-X PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 276QV UT WOS:000084889600007 PM 10634932 ER PT J AU Villegas, R Villegas, GM Longart, M Hernandez, M Maqueira, B Buonanno, A Garcia, R Castillo, C AF Villegas, R Villegas, GM Longart, M Hernandez, M Maqueira, B Buonanno, A Garcia, R Castillo, C TI Neuregulin found in cultured-sciatic nerve conditioned medium causes neuronal differentiation of PC12 cells SO BRAIN RESEARCH LA English DT Article DE neuregulin; sciatic nerve; conditioned medium; Schwann cell; PC12 cell; neuronal differentiation ID NEURITE-PROMOTING FACTORS; FIBROBLAST GROWTH-FACTORS; SPINAL-CORD NEURONS; PERIPHERAL-NERVE; NEUROTROPHIC FACTOR; SCHWANN-CELLS; EXTRACELLULAR-MATRIX; SECRETE NEUREGULINS; GLIAL-CELLS; REGENERATION AB The present work deals with the search and identification of the molecule or combination of molecules, present in a medium conditioned by cultured rat-sciatic nerves (CM), able to cause neuronal differentiation of PC12 cells. The molecular mass range of the active fraction, as well as the thermostability and heparin affinity of the active component found in previous work, all characteristics shared with neuregulin (NRG) family members, led us to search for a NRG protein in the CM. Nerves were previously cultured for 8 days and the CM collected every 24 h, the following 3 days. The CM was concentrated (30,000 NMWL) and fractionated by quaternary ammonium chromatography and Cibacron blue affinity chromatography. The most active fraction B1.2 was further characterized by heparin affinity chromatography, size exclusion HPLC, Western blotting and immunoprecipitation. Results reveal abundance of MIG mRNA in the cultured nerves, presence of a 54 kDa NRG protein in the CM that increases along fractionation, and progressive diminution of fraction B1.2 differentiation activity on PC12 cells by gradual removal of the NRG protein by immuprecipitation. The abundance of Schwann cells and the lack of axons in the cultured nerves suggest Schwann cells as the main NRG source, to which fibroblasts and perineurial cells might contribute. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 Inst Estudios Avanzados IDEA, Ctr Biociencias, Caracas 1015A, Venezuela. NIH, Mol Neurobiol Unit, LDN, Bethesda, MD 20892 USA. RP Villegas, R (reprint author), Inst Estudios Avanzados IDEA, Ctr Biociencias, Apartado 17606, Caracas 1015A, Venezuela. NR 67 TC 27 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 10 PY 2000 VL 852 IS 2 BP 305 EP 318 DI 10.1016/S0006-8993(99)02109-5 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 276QP UT WOS:000084889100009 PM 10678757 ER PT J AU Qiu, CY Sora, I Ren, K Uhl, G Dubner, R AF Qiu, CY Sora, I Ren, K Uhl, G Dubner, R TI Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor-deficient mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE inflammation; mu-opioid receptor; knockout mice ID MORPHINE-INDUCED ANALGESIA; TRIGEMINAL NUCLEUS SLICES; DORSAL HORN NEURONS; SUBSTANCE-P; BETA-ENDORPHIN; SPINAL-CORD; RESPONSES; RELEASE; LACKING; HYPERALGESIA AB Inflammatory hyperalgesia was induced in wild-type, heterozygous and mu-opioid receptor knockout mice after an intraplantar injection of complete Freund's adjuvant, mu-Opioid receptor knockout mice exhibited faster recovery from hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice. Naloxone restored hyperalgesia in all genotypes. Naltrindole (delta-opioid receptor-selective antagonist) partially restored the hyperalgesia only in mu-opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (kappa-opioid receptor-selective antagonist) had no effect. The (mu-opioid receptor-selective agonist, [D-Ala(2),MePhe(4),Gly-ol(5)]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in mu-opioid receptor knockout mice while U69,593 {(+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide, kappa-opioid receptor-selective) produced similar effects in all mice. The delta-opioid receptor-selective agonists, [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and deltorphin ([D-Ala(2)]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P<0.05). The findings suggest that mu-opioid receptors may be involved in the persistence of inflammatory hyperalgesia and that a delta-opioid receptor-mediated compensatory mechanism in the absence of the mu-opioid receptor is activated by persistent hyperalgesia, (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Maryland, Sch Dent, Dept Oral & Craniofacial Biol Sci, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. Johns Hopkins Univ, Sch Med, NIDA, IRP, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol & Neurosci, Baltimore, MD 21224 USA. RP Univ Maryland, Sch Dent, Dept Oral & Craniofacial Biol Sci, Room 5E-08,666 W Baltimore St, Baltimore, MD 21201 USA. EM rnd001@dental.umaryland.edu FU NIDA NIH HHS [DA10275]; NIDCR NIH HHS [DE11964] NR 36 TC 45 Z9 46 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 10 PY 2000 VL 387 IS 2 BP 163 EP 169 DI 10.1016/S0014-2999(99)00813-4 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 277BW UT WOS:000084913700006 PM 10650156 ER PT J AU Gasior, M Ungard, JT Witkin, JM AF Gasior, M Ungard, JT Witkin, JM TI Lethal seizures predicted after aminophylline therapy in cocaine abusers SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE seizure; lethality; sensitization AB Mice with a history of chronic (10 days), but not acute, treatment with a non-convulsant dose of cocaine showed increased sensitivity (P < 0.001) to the toxic effects of aminophylline (seizures, lethality) relative to controls even days after the cessation of cocaine treatment. The present finding suggests that individuals with a history of cocaine use may be at increased risk for convulsive and lethal complications associated with the therapeutic use of aminophylline. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDA, Drug Dev Grp, Behav Neurosci Res Branch, NIH, Baltimore, MD 21224 USA. RP Gasior, M (reprint author), NIDA, Drug Dev Grp, Behav Neurosci Res Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 10 PY 2000 VL 387 IS 2 BP R15 EP R16 DI 10.1016/S0014-2999(99)00801-8 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 277BW UT WOS:000084913700018 PM 10650168 ER PT J AU Espey, MG Namboodiri, MAA AF Espey, MG Namboodiri, MAA TI Selective metabolism of kynurenine in the spleen in the absence of indoleamine 2,3-dioxygenase induction SO IMMUNOLOGY LETTERS LA English DT Article DE quinolinic acid; kynurenine; follicle; spleen ID MARGINAL-ZONE MACROPHAGES; RAT-LIVER CELLS; INTERFERON-GAMMA; QUINOLINIC ACID; BACTERIAL LIPOPOLYSACCHARIDE; TRYPTOPHAN DEGRADATION; TOXOPLASMA-GONDII; HUMAN-FIBROBLASTS; IMMUNE-SYSTEM; MOUSE LUNG AB The kynurenine pathway of L-tryptophan degradation is differentially regulated dependent on the level of immune system activation. During inflammation and disease, activity of the hepatocellular enzyme tryptophan 2,3-dioxygenase (TDO) decreases and a second enzyme, indoleamine 2,3-dioxygenase (IDO), is induced in extrahepatic sites. Substantial formation of a metabolise downstream of this step, quinolinic acid (Quin), subsequently occurs only in select regions of the lymphoid tissues, such as spleen, in a temporally restricted manlier. The goal of this study was to determine the localization of Quin in unstimulated mice under conditions where rate-limiting control of the pathway by both TDO and IDO was by-passed. Supplementation of drinking water with L-kynurenine, a pathway intermediate that lies between tryptophan and Quin, resulted in a dose-dependent increase in Quin immunoreactivity in the follicles and discontinuous regions of the marginal zones of the spleen, Strongly immunoreactive cells in the periarteriole lymphoid sheaths adopted a highly reactive morphology despite the lack of immunostimulation and IDO induction. In contrast, a patchy to diffuse pallor of staining was observed in the liver parenchyma with 1 and 10 mM L-kynurenine ingestion, respectively. These data show that selective tryptophan metabolism can occur in discrete subcompartments of the lymphoid tissues beyond the level of IDO. In vivo manipulation of Quin synthesis in the absence of IDO induction may serve as a model for studying regulation and function of the kynurenine pathway activation in the immune system. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. Georgetown Univ, Dept Biol, Washington, DC 20007 USA. RP Espey, MG (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. NR 42 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD JAN 10 PY 2000 VL 71 IS 1 BP 67 EP 72 DI 10.1016/S0165-2478(99)00179-0 PG 6 WC Immunology SC Immunology GA 287RP UT WOS:000085520000011 PM 10709788 ER PT J AU Nadon, NL AF Nadon, NL TI Aberrant dendrite growth in central nervous system white matter induced by a mutant proteolipid protein transgene SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE myelin; oligodendrocyte; transgenic mice; DM20 ID MYELIN-DEFICIENT RAT; OLIGODENDROCYTE DEVELOPMENT; SCHWANN-CELLS; MESSENGER-RNA; JIMPY MOUSE; GENE; EXPRESSION; DM-20; DM20; ABSENCE AB Transgenic mice were produced that carry a construct encoding a mutant form of the DM20 isoform of myelin proteolipid protein. The transgene is under the direction of the human Plp gene promoter, which has previously been shown to direct tissue-specific expression of transgenes. Two lines of mice were generated with this construct, both of which express the transgene at extremely low levels. Central nervous system myelination proceeds normally in the transgenic mice. However, in aged transgenic mice, areas of dendrite processes synapsed with axonal termini were observed within the white matter of the spinal cord. This phenotype was accompanied by focal areas of astrocytic hypertrophy and an increase in apoptotic cell death in white matter but not gray matter. One interpretation of these findings is that expression of the mutant DM20 alters signaling between oligodendrocytes and neurons, producing abnormal neurite outgrowth. J. Comp. Neurol. 416:262-268, 2000. (C) 2000 Wiley-Liss, Inc. C1 Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. RP Nadon, NL (reprint author), NIA, Biol Aging Program, 7201 Wisconsin Ave,GW 2C231, Bethesda, MD 20892 USA. FU NINDS NIH HHS [NS31800] NR 38 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 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 10 PY 2000 VL 416 IS 2 BP 262 EP 268 DI 10.1002/(SICI)1096-9861(20000110)416:2<262::AID-CNE10>3.0.CO;2-C PG 7 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 262AF UT WOS:000084043000010 PM 10581470 ER PT J AU Lane, MA Tilmont, EM De Angelis, H Handy, A Ingram, DK Kemnitz, JW Roth, GS AF Lane, MA Tilmont, EM De Angelis, H Handy, A Ingram, DK Kemnitz, JW Roth, GS TI Short-term calorie restriction improves disease-related markers in older male rhesus monkeys (Macaca mulatta) SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE aging; diabetes; glucoregulation; lipids ID AGE-RELATED-CHANGES; DIETARY RESTRICTION; INSULIN SENSITIVITY; FOOD RESTRICTION; WEIGHT-LOSS; GLUCOSE; METABOLISM; HDL2; RATS AB Calorie restriction (CR) is widely known for its effects on life span, physiological aging and age-related disease in laboratory rats and mice. Emerging data from CR studies in rhesus monkeys suggest that this nutritional intervention paradigm may also have beneficial effects in long-lived mammals. Studies from our laboratory and others have suggested that young- or adult-onset CR might have beneficial effects on cardiovascular disease and diabetes. For example, long-term CR reduced body fat and serum triglycerides, and increased a subfraction of HDL cholesterol associated with decreased cardiovascular disease risk. These studies suggested that long-term CR begun in young or adult animals might have important effects on markers relevant to age-related disease. Few studies have examined the effects of CR initiated in older animals (rodents or monkeys), and the temporal nature of some potentially beneficial effects of CR is unknown. The present study examined several markers related to diabetes and cardiovascular disease in thirteen older adult (> 18 year) non-obese (body fat <22%), male rhesus monkeys during a short-term CR paradigm. Specifically, we collected these data at baseline (ad libitum feeding), 10, 20, and 30% CR, and at 6 and 12 months on 30% CR. Fasting and peak insulin were significantly reduced as were the acute and second-phase insulin responses. CR also marginally reduced triglycerides (50% reduction), but had no effect on total serum cholesterol or blood pressure. Interestingly, the observed glucoregulatory changes emerged prior to any evidence of a change in body composition suggesting that certain effects of CR may not be wholly dependent on changes in body composition in older monkeys. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Intramural Res Program, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. ROW Sci, Gaithersburg, MD USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. RP Lane, MA (reprint author), NIA, Intramural Res Program, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 26 TC 58 Z9 60 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing. Dev. PD JAN 10 PY 2000 VL 112 IS 3 BP 185 EP 196 DI 10.1016/S0047-6374(99)00087-1 PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 276MA UT WOS:000084880500002 PM 10687924 ER PT J AU Gary, DS Sooy, K Chan, SL Christakos, S Mattson, MP AF Gary, DS Sooy, K Chan, SL Christakos, S Mattson, MP TI Concentration- and cell type-specific effects of calbindin D28k on vulnerability of hippocampal neurons to seizure-induced injury SO MOLECULAR BRAIN RESEARCH LA English DT Article DE calcium; epilepsy; excitotoxicity; kainic acid; microtubule associated protein; spectrin ID TEMPORAL-LOBE EPILEPSY; ADULT-RAT BRAIN; NEUROTROPHIC FACTORS; ALZHEIMERS-DISEASE; STATUS EPILEPTICUS; QUINOLINIC ACID; CALPAIN-I; CALCIUM; ISCHEMIA; D-28K AB The calcium-binding protein calbindin D28k (CB) is expressed in limited subpopulations of neurons in the brain. In the hippocampus, CB is expressed in all dentate granule cells and a subpopulation of CA1 pyramidal neurons, but is absent from CA3 neurons. This pattern of CB expression is inversely correlated with neuronal vulnerability to seizure-induced damage suggesting the possibility that expression of CB confers resistance to excitotoxicity. While data from cell culture studies support an excitoprotective role for calbindin, it is not known whether CB is a key determinant of neuronal vulnerability in vivo. We therefore examined the pattern of damage to hippocampal neurons following intrahippocampal injection of the seizure-inducing excitotoxin kainate in CB homozygous (CB -/-) and CB heterozygous (CB +/-) knockout mice in comparison with wild-type mice (CB +/+). Whereas the extent of damage to CA1 neurons was similar in CB -/- and CB +/+ mice, damage to CA1 neurons was significantly reduced in CB +/- mice. Dentate granule neurons were not damaged following kainate-induced seizures in CB +/+, CB +/- or CB -/- mice. These findings suggest that CB can modify vulnerability of hippocampal CA1 neurons to seizure-induced injury, and that either CB is not a critical determinant of resistance of dentate granule neurons, or compensatory changes occur and lack of CB is not the only difference between CB -/- and CB +/+ mice. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Anat & Neurobiol, Lexington, KY 40536 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Mol Biol, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, Grad Sch Biomed Sci, Newark, NJ 07103 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Univ Kentucky, Sanders Brown Ctr Aging, 211 Sanders Brown Bldg,800 S Limestone St, Lexington, KY 40536 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 43 TC 26 Z9 26 U1 0 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 JAN 10 PY 2000 VL 75 IS 1 BP 89 EP 95 DI 10.1016/S0169-328X(99)00299-5 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 276HH UT WOS:000084871600010 ER PT J AU Nemukhin, AV Grigorenko, BL Skasyrskaya, EY Topol, IA Burt, SK AF Nemukhin, AV Grigorenko, BL Skasyrskaya, EY Topol, IA Burt, SK TI A new hybrid approach for modeling reactions in molecular clusters: Application for the hydrogen bonded systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DYNAMICS; SIMULATIONS; DISSOCIATION; FLUORIDE; ENERGY; PROTON; FIELD; HF AB A hybrid quantum mechanical diatomics-in-molecules (QM/DIM) method is formulated that aims to describe chemical reactions in an environment within the framework of a discrete (or cluster) approach. Starting from the conventional DIM formalism, first-order intermolecular perturbation theory is applied to calculate interactions between reacting particles and environmental molecules, and to introduce ab initio QM energies for the central system. In this approach no boundary problems appear when combining two parts of the entire system. The pairwise contributions to the interaction energy come from the true potential curves of the fragments. A proper treatment of excited electronic states is also provided in this approach. As a first application, we compute potential curves for the dissociation reaction of a single hydrogen fluoride molecule surrounded by a selected number of solvent HF molecules. (C) 2000 American Institute of Physics. [S0021-9606(00)30302-6]. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. NCI, Adv Biomed Comp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Nemukhin, AV (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RI Nemukhin, Alexander/P-9662-2015 NR 35 TC 8 Z9 8 U1 0 U2 1 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JAN 8 PY 2000 VL 112 IS 2 BP 513 EP 521 DI 10.1063/1.480542 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 269ZB UT WOS:000084507000003 ER PT J AU Valdez, H Smith, KY Landay, A Connick, E Kuritzkes, DR Kessler, H Fox, L Spritzler, J Roe, J Lederman, MB Lederman, HM Evans, TG Heath-Chiozzi, M Lederman, MM AF Valdez, H Smith, KY Landay, A Connick, E Kuritzkes, DR Kessler, H Fox, L Spritzler, J Roe, J Lederman, MB Lederman, HM Evans, TG Heath-Chiozzi, M Lederman, MM CA ACTG 375 Team TI Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen SO AIDS LA English DT Article; Proceedings Paper CT 6th Conference on Retroviruses and Opportunistic Infections CY JAN 31-FEB 04, 1999 CL CHICAGO, ILLINOIS DE antibodies; antiretroviral therapy; delayed-type hypersensitivity responses; keyhole limpet hemocyanin; hepatitis A; immune activation; immunization; lymphocyte proliferative responses; pathogenesis; protease inhibitors; tetanus toxoid ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL ACTIVATION; ACTIVE ANTIRETROVIRAL THERAPY; TUMOR NECROSIS FACTOR; ANTIBODY-RESPONSE; HOMOSEXUAL MEN; INFECTED PATIENTS; TYPE-1 INFECTION; CONTROLLED TRIAL; CD28 EXPRESSION AB Objectives: To ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. Design and setting: Open-label study carried out at three university-affiliate AIDS Clinical Trials Units in the United States. Subjects and methods: Thirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toroid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. Results: The LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after, immunization. Eighty-three percent of patients experienced at least a four-fold rise in,KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naive CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens. C1 Univ Hosp Cleveland, Div Infect Dis, AIDS Clin Trials Unit, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. Rush Med Coll, Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. VA Med Ctr, Denver, CO USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. AIDS Clin Trials Grp, Operat Ctr, Rockville, MD USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Univ Rochester, Infect Dis Unit, Rochester, NY USA. Abbott Labs, Abbott Pk, IL 60064 USA. RP Valdez, H (reprint author), Univ Hosp Cleveland, Div Infect Dis, AIDS Clin Trials Unit, Foley Bldg Room 301B,2061 Cornell Rd, Cleveland, OH 44106 USA. FU NIAID NIH HHS [AI-32790, AI-32770, AI-25879] NR 57 TC 106 Z9 107 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 JAN 7 PY 2000 VL 14 IS 1 BP 11 EP 21 DI 10.1097/00002030-200001070-00002 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 276WQ UT WOS:000084901700002 PM 10714563 ER PT J AU Park, JS Boyer, S Mitchell, K Gilfor, D Birrer, M Darlington, G El Deiry, W Firestone, GL Munger, K Band, V Fisher, PB Dent, P AF Park, JS Boyer, S Mitchell, K Gilfor, D Birrer, M Darlington, G El Deiry, W Firestone, GL Munger, K Band, V Fisher, PB Dent, P TI Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21Cip-1/WAF1/MDA6 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOGEN-ACTIVATED PROTEIN; CYCLIN-DEPENDENT KINASES; ADULT-RAT HEPATOCYTES; CELL-PROLIFERATION; P53 GENE; P53-INDEPENDENT INDUCTION; P21(WAF1/CIP1) EXPRESSION; HUMAN KERATINOCYTES; LIVER-REGENERATION; PRIMARY CULTURES AB The impact of human papilloma virus (HPV16) E7 proteins and retinoblastoma (RB) antisense oligonucleotides upon mitogen-activated protein kinase (MAPK)-mediated inhibition of DNA synthesis via p21(Cip-1/WAF1/MDA6) (p21) was determined in primary hepatocytes. Prolonged activation of the MAPK pathway in p21(+/+) or p21(-/-) hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Either transfection with RE antisense oligonucleotides, expression of wild type E7, or RE binding mutant E7 (C24S) proteins increased p21 levels and reduced DNA synthesis in p21(+/+) hepatocytes. RE antisense oligonucleotides and E7 proteins increased apoptosis in p21(+/+), but not p21(-/-), hepatocytes. Expression of wild type E7 increased DNA synthesis above control levels in p21(-/-) cells, which was additive with prolonged MAPK activation. In contrast, expression of mutant E7 did not alter DNA synthesis above control levels in p21(-/-) cells and was supra-additive with prolonged MAPK activation. Antisense ablation of RE in p21(-/-) hepatocytes had a weak stimulatory effect upon DNA synthesis itself but enhanced the capacity of mutant E7 protein to stimulate DNA synthesis to the same level observed using wild type E7. The ability of prolonged MAPK activation to stimulate DNA synthesis in the presence of mutant E7 and antisense RE was additive. Collectively, the present data demonstrate that loss of RE function together with loss of pal function plays an important role in the E7- and MAPK-dependent modulation of apoptosis and DNA synthesis in primary hepatocytes. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Urol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Pathol, New York, NY 10032 USA. Tufts Univ, Sch Med, New England Med Ctr, Dept Radiat Oncol, Boston, MA 02111 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77071 USA. NCI, Med Branch, NIH, Bethesda, MD 20181 USA. Univ Penn, Sch Med, Ctr Canc, Dept Med,Howard Hughes Med Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Inst Human Gene Therapy, Philadelphia, PA 19104 USA. RP Dent, P (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. OI Munger, Karl/0000-0003-3288-9935 FU NCI NIH HHS [R01CA35675, R01CA74468]; NIDDK NIH HHS [R01DK52825] NR 64 TC 24 Z9 26 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 JAN 7 PY 2000 VL 275 IS 1 BP 18 EP 28 DI 10.1074/jbc.275.1.18 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295DN UT WOS:000085951600004 PM 10617580 ER PT J AU Leonardi, A Ellinger-Ziegelbauer, H Franzoso, G Brown, K Siebenlist, U AF Leonardi, A Ellinger-Ziegelbauer, H Franzoso, G Brown, K Siebenlist, U TI Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TNF RECEPTOR-1; TERMINAL KINASE; JNK/SAPK ACTIVATION; SIGNAL TRANSDUCER; CELL-DEATH; FAMILY; ALPHA; TRAF2; BETA AB Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an intracellular protein involved in signal transduction from TNF receptor I and II and related receptors. TRAF2 is required for TNF-induced activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and TRAF2 can also mediate activation of NF-kappa B. Here we have identified the actin-binding protein Filamin (actin-binding protein-280) as a TRAF2-interacting protein. Filamin binds to the Ring zinc finger domain of TRAF2, Overexpressed Filamin inhibits TRAF2-induced activation of JNI/SAPK and of NF-kappa B. Furthermore, ectopically expressed Filamin inhibits NF-kappa B activation induced via TNF, interleukin-1, Toll receptors, and TRAF6 but not activation induced via overexpression of NIK, a downstream effector in these pathways. Importantly, TNF fails to activate SAPK or NF-kappa B in a human melanoma cell line deficient in Filamin. Reintroduction of Filamin into these cells restores the TNF response. The data imply a role for Filamin in inflammatory signal transduction pathways. C1 NIAID, Immune Activat Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIAID, Immune Activat Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11B16, Bethesda, MD 20892 USA. OI LEONARDI, Antonio/0000-0001-8636-9623 NR 70 TC 91 Z9 95 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 JAN 7 PY 2000 VL 275 IS 1 BP 271 EP 278 DI 10.1074/jbc.275.1.271 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295DN UT WOS:000085951600039 PM 10617615 ER PT J AU Perera, LP AF Perera, LP TI The TATA motif specifies the differential activation of minimal promoters by varicella zoster virus immediate-early regulatory protein IE62 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR TFIIB; BINDING-PROTEIN; DNA COMPLEX; HUMAN CYTOMEGALOVIRUS; ZTA TRANSACTIVATOR; GENE-EXPRESSION; DOMAIN; ELEMENTS; YEAST; TBP AB The immediate-early IE62 protein of varicella tester virus is an acidic transcriptional activator capable of up-regulating many viral and cellular promoters with varying efficiencies. We demonstrate that, in the context of a minimal promoter, a TATA element is both sufficient and essential for IE62-mediated transcriptional activation. Differential levels of activation by IE62 in this context were conferred by a panel of naturally occurring sequence variations within the TATA motif itself. TATA motif-specific, differential induction was not obtained when the IE62 acidic activation domain was targeted as a GALE fusion protein to the same panel. The prototype acidic transactivator, VP16 of herpes simplex virus, failed to discriminate between these different TATA motifs when they were placed into an appropriate responsive promoter context. Nonetheless, a chimeric IE62 polypeptide substituted with the VP16 activation domain retained the ability to differentially modulate minimal promoters with various TATA motifs. Taken together with its binding to TATA box-binding protein (TBP) and transcription factor IIB in vitro, we suggest that IE62 has the unusual ability to achieve differential levels of transcriptional activation through different TATA motifs, which may be accomplished either directly or indirectly by recognizing conformational variations in DNA-bound TBP, TBP-transcription factor IIA/B, or TBP-TATA-associated factor complexes. C1 NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Perera, LP (reprint author), NCI, Metab Branch, Div Clin Sci, NIH, Bldg 10,Rm 4B40,MSC 1374, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI 00687] NR 68 TC 28 Z9 28 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 JAN 7 PY 2000 VL 275 IS 1 BP 487 EP 496 DI 10.1074/jbc.275.1.487 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295DN UT WOS:000085951600067 PM 10617643 ER PT J AU Freifeld, AG Steinberg, SM Pizzo, PA AF Freifeld, AG Steinberg, SM Pizzo, PA TI Oral antibiotics for febrile patients with neutropenia due to cancer chemotherapy - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID COLONY-STIMULATING FACTOR; REDUCTION C1 Univ Nebraska, Med Ctr, Omaha, NE 68198 USA. NCI, Bethesda, MD 20892 USA. Childrens Hosp, Boston, MA 02115 USA. RP Freifeld, AG (reprint author), Univ Nebraska, Med Ctr, 600 S 42nd St, Omaha, NE 68198 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 6 PY 2000 VL 342 IS 1 BP 56 EP 57 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 271CE UT WOS:000084575600015 ER PT J AU Chang, J Lee, C Hahm, KB Yi, Y Choi, SG Kim, SJ AF Chang, J Lee, C Hahm, KB Yi, Y Choi, SG Kim, SJ TI Over-expression of ERT(ESX/ESE-1/ELF3), an ets-related transcription factor, induces endogenous TGF-beta type II receptor expression and restores the TGF-beta signaling pathway in Hs578t human breast cancer cells SO ONCOGENE LA English DT Article DE transcription factor; cancer; TGF-beta; tumorigenicity ID GROWTH-FACTOR-BETA; MICROSATELLITE INSTABILITY; DOMAIN PROTEIN; GENE; FAMILY; INHIBITION; MEMBER; COLON; CDNA AB The epithelium-specific transcription factor, ERT/ESX/ ESE-1/ELF3, binds to the TGF-beta RII promoter in a sequence specific manner and regulates its expression, In this study, we investigated whether ERT could regulate endogenous TGF-beta RII expression in Hs578t breast cancer cells. Analyses of the Hs578t parental cell line revealed ion RII mRNA expression and resistance to the growth inhibitory effects of TGF-beta. Infection of this cell Line with a retroviral construct expressing ERT induced higher levels of endogenous RII mRNA expression and protein expression relative to cells infected with chloramphenicol acetyltransferase (CATneo) as a control. Relative to control cells, the ERTneo-expressing Hs578t cells show approximately a 50% reduction in cell growth in the presence of exogenous TGF-beta 1, as well as a fourfold higher induction of activation in transient transfection assays using the 3TP-luciferase reporter construct. When transplanted into athymic mice, ERT-expressing Hs578t cells showed decreased and delayed tumorigenicity compared with control cells. This data strongly suggests that ERT plays an important role as a transcriptional activator of TGF-P RII expression, and that deregulated ERT expression may play a critical role in rendering Hs578t human breast cancer cells insensitive to TGF-beta's growth inhibitory effects. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NR 25 TC 39 Z9 42 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 6 PY 2000 VL 19 IS 1 BP 151 EP 154 DI 10.1038/sj.onc.1203252 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 275WZ UT WOS:000084844300017 PM 10644990 ER PT J AU Lodmell, DL Ray, NB Ulrich, JT Ewalt, LC AF Lodmell, DL Ray, NB Ulrich, JT Ewalt, LC TI DNA vaccination of mice against rabies virus: effects of the route of vaccination and the adjuvant monophosphoryl lipid A (MPL (R)) SO VACCINE LA English DT Article DE DNA rabies vaccine; monophosphoryl lipid A (MPL (R)) ID PROTECTIVE IMMUNITY; T-CELLS; ANTIBODY; GLYCOPROTEIN; RESPONSES; RESISTANCE; INFECTION; VACCINES AB Adjuvants are known to strongly enhance immune responses generated by traditional vaccines, but less is known about the effects of adjuvants on vaccination with DNA. In this study, we investigated the use of the immunostimulant monophosphoryl lipid A (MPL (R)) as an adjuvant, and analyzed three routes of DNA vaccination to determine if this adjuvant could enhance anti-rabies virus neutralizing antibody responses. Compared with antibody titers elicited with DNA only, antibody titers were enhanced after initial intradermal (i.d.) and gene gun immunizations with the combination of DNA and MPL (R). Antibody was not detected after primary intramuscular (i.m.) immunization unless MPL (R) was included with the DNA. Surprisingly, antibody titers of MPL (R)-treated mice decreased after i.d. or i.m. booster vaccinations, but increased after gene gun booster vaccinations. In contrast to these varied responses, booster immunizations without MPL (R) via the three different routes consistently increased antibody titers. All mice with detectable levels of neutralizing antibody at the time of challenge survived virus infection. There was no difference in the survival rate between groups of mice that received similar vaccinations with MPL (R)/DNA or DNA only. The data suggest that MPL (R) can enhance the neutralizing antibody response when used with the initial injection of DNA. Suppression of neutralizing antibody responses after i.d. or i.m, boaster vaccinations that included MPL (R) suggests that the number of vaccinations, and the route of vaccination, should be carefully considered when MPL (R) is used with DNA vaccines. Published by Elsevier Science Ltd. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RIBI Immunochem Res Inc, Hamilton, MT 59840 USA. RP Lodmell, DL (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. NR 35 TC 57 Z9 60 U1 0 U2 6 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 JAN 6 PY 2000 VL 18 IS 11-12 BP 1059 EP 1066 DI 10.1016/S0264-410X(99)00352-7 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 271NH UT WOS:000084600000005 PM 10590326 ER PT J AU Schiffman, M Herrero, R Hildesheim, A Sherman, ME Bratti, M Wacholder, S Alfaro, M Hutchinson, M Morales, J Greenberg, MD Lorincz, AT AF Schiffman, M Herrero, R Hildesheim, A Sherman, ME Bratti, M Wacholder, S Alfaro, M Hutchinson, M Morales, J Greenberg, MD Lorincz, AT TI HPV DNA testing in cervical cancer screening - Results from women in a high-risk province of Costa Rica SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN PAPILLOMAVIRUS INFECTION; ATYPICAL SQUAMOUS CELLS; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; TYPE-16; TRIAGE AB Context Human papillomaviruses (HPVs) are known to cause most cervical cancer worldwide, but the utility of HPV DNA testing in cervical cancer prevention has not been determined. Objective To provide comprehensive data on the screening performance of HPV testing for the most common carcinogenic types, at different levels of analytic sensitivity. Design Laboratory analysis conducted during 1993-1995, using 3 cytologic techniques and cervicography, followed by colposcopic examination of women with any abnormal cervical finding, to detect all high-grade intraepithelial lesions and cancer (reference standard of clinically significant disease). The HPV testing was performed subsequently with masking regarding clinical findings. Setting Guanacaste Province, Costa Rica, a region with a high age-adjusted incidence of cervical cancer. Participants Of 11742 randomly selected women, 8554 nonpregnant, sexually active women without hysterectomies underwent initial HPV DNA testing using the original Hybrid Capture Tube test; a stratified subsample of 1119 specimens was retested using the more analytically sensitive second generation assay, the Hybrid Capture II test. Main Outcome Measures Receiver operating characteristic analysis of detection of cervical high-grade intraepithelial lesions and cancer by HPV DNA testing based on different cut points of positivity. Results An analytic sensitivity of 1.0 pg/mL using the second generation assay would have permitted detection of 88.4% of 138 high-grade lesions and cancers (all 12 cancers were HPV-positive), with colposcopic referral of 12.3% of women. Papanicolaou testing using atypical squamous cells of undetermined significance as a cut point for referral resulted in 77.7% sensitivity and 94.2% specificity, with 6.9% referred. Specificity of the second generation assay for positivity for high-grade lesions and cancer was 89.0%, with 33.8% of remaining HPV DNA-positive subjects having low-grade or equivocal microscopically evident lesions. The higher detection threshold of 10 pg/mL used with the original assay had a sensitivity of 74.8% and a specificity of 93.4%, Lower levels of detection with the second generation assay (<1 pg/mL) proved clinically nonspecific without gains in diagnostic sensitivity, Conclusions In this study population, a cut point of 1.0 pg/mL using the second generation assay permitted sensitive detection of cervical high-grade lesions and cancer, yielding an apparently optimal trade-off between high sensitivity and reasonable specificity for this test. The test will perform best in settings in which sensitive detection of high-grade lesions and cancer is paramount. Because HPV prevalence varies by population, HPV testing positive predictive value for detection of high-grade lesions and cancer will vary accordingly, with implications for utility relative to other cervical cancer screening methods. C1 NCI, Interdisciplinary Studies Sect, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Int Agcy Res Canc, F-69372 Lyon, France. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Costa Rican Social Secur Adm, San Jose, Costa Rica. Brown Univ, Women & Infants Hosp, Providence, RI USA. Omnia, Blue Bell, PA USA. Digene Corp, Silver Spring, MD USA. RP Schiffman, M (reprint author), NCI, Interdisciplinary Studies Sect, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Room 7066,6120 Execut Blvd, Rockville, MD 20852 USA. NR 31 TC 372 Z9 397 U1 0 U2 7 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 JAN 5 PY 2000 VL 283 IS 1 BP 87 EP 93 DI 10.1001/jama.283.1.87 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 270AZ UT WOS:000084514400030 PM 10632285 ER PT J AU Lee, TH Cleeman, JI Grundy, SM Gillett, C Pasternak, RC Seidman, J Sennett, C AF Lee, TH Cleeman, JI Grundy, SM Gillett, C Pasternak, RC Seidman, J Sennett, C TI Clinical coals and performance measures for cholesterol management in secondary prevention of coronary heart disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SERUM-CHOLESTEROL; LOWERING THERAPY; EVENTS; RISK; PRAVASTATIN; REDUCTION; PROGRAM; TRIAL; DEATH AB Guidelines from the National Cholesterol Education Program (NCEP) recommend reduction of low-density lipoprotein cholesterol (LDL-C) to 100 mg/dL (2.59 mmol/l)or less in patients with established coronary heart disease (CHD), However, the National Committee for Quality Assurance (NCQA) is implementing a new performance measure as part of the Health Plan Employer and Data Information Set (HEDIS) that appears to endorse a different target. The new HEDIS measure will require managed care organizations seeking NCQA accreditation to measure and report the percentage of patients who have had major CHD events who achieve LDL-C levels less than 130 mg/dL (3.36 mmol/L) between 60 and 365 days after discharge. These different LDL-C thresholds emphasize the difference between a clinical goal for the management of individual patients (less than or equal to 100 mg/dL) and a performance measure used to evaluate the care of a population of patients (<130 mg/dL), This article discusses the rationale for each threshold and explains the use of 2 different thresholds for these 2 purposes. Both the NCQA and NCEP expect that the new HEDIS measure will encourage managed care organizations to develop systems that improve secondary prevention of CHD. C1 Partners Community HealthCare Inc, Boston, MA 02199 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Grp Hlth Cooperat Puget Sound, Clin Planning & Improvement, Seattle, WA 98121 USA. Natl Comm Qual Assurance, Washington, DC USA. RP Lee, TH (reprint author), Partners Community HealthCare Inc, Prudential Tower,Suite 1150,800 Boylston St, Boston, MA 02199 USA. NR 16 TC 35 Z9 36 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 5 PY 2000 VL 283 IS 1 BP 94 EP 98 DI 10.1001/jama.283.1.94 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 270AZ UT WOS:000084514400031 PM 10632286 ER PT J AU Shoemaker, RH AF Shoemaker, RH TI Genetic and epigenetic factors in anticancer drug resistance SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MULTIDRUG-RESISTANCE; CELL LINES; CANCER; CARCINOMA; MARKER C1 NCI, Frederick Canc Res & Dev Ctr, Screening Technol Branch, Frederick, MD 21702 USA. RP Shoemaker, RH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Screening Technol Branch, Bldg 431A, Frederick, MD 21702 USA. NR 18 TC 16 Z9 17 U1 0 U2 2 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 JAN 5 PY 2000 VL 92 IS 1 BP 4 EP 5 DI 10.1093/jnci/92.1.4 PG 2 WC Oncology SC Oncology GA 271AB UT WOS:000084568300001 PM 10620620 ER PT J AU Radmacher, MD Simon, R AF Radmacher, MD Simon, R TI Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL-ADJUVANT-BREAST; CANCER; TRIAL; THERAPY; MODEL AB Background: Several randomized clinical trials have tested the hypothesis that tamoxifen is effective in preventing breast cancer. The largest such trial, the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (BCPT), reported a 49% reduction in risk of invasive breast cancer for the tamoxifen group. However, it is unclear whether the effect of tamoxifen in this trial was mainly due to prevention of newly forming tumors or to treatment of occult disease. Methods: We used various tumor growth models (i.e., exponential and Gompertzian [growth limited by tumor size]) and a computer simulation to approximate the percentage of detected tumors that were initiated after study entry. Maximum likelihood techniques were then used to estimate separately the efficacy of tamoxifen in treating occult disease and in preventing the formation and growth of new tumors, Results: Under the assumptions of most of the growth models, the trial was sufficiently long for substantial numbers of new tumors to form, grow, and be detected during the trial. With the Gompertzian model and all available incidence data from the BCPT, it was estimated that 60% (95% confidence interval [CI] = 40%-80%) fewer new tumors were detected in the tamoxifen group than in the placebo group. Likewise, 35% (95% CI = 6%-63%) fewer occult tumors were detected in the tamoxifen group. With this model, the estimated incidence rate of invasive breast cancer among women in the placebo group of the BCPT was 7.7 (95% CI = 6.6-8.9) per 1000 women per year. Similar results were obtained with three exponential tumor growth models. Conclusions: These results support the concept that tamoxifen reduced cancer incidence in the BCPT through both treatment of occult disease and prevention of new tumor formation and growth. However, data from prevention trials may never be sufficient to completely distinguish prevention of new tumor formation from treatment of occult disease. C1 NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Radmacher, MD (reprint author), NIH, 7550 Wisconsin Ave,MS 9015, Bethesda, MD 20892 USA. NR 17 TC 42 Z9 42 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 JAN 5 PY 2000 VL 92 IS 1 BP 48 EP 53 DI 10.1093/jnci/92.1.48 PG 6 WC Oncology SC Oncology GA 271AB UT WOS:000084568300012 PM 10620633 ER PT J AU Legler, JM Ries, LAG Smith, MA Warren, JL Heineman, EF Kaplan, RS Linet, MS AF Legler, JM Ries, LAG Smith, MA Warren, JL Heineman, EF Kaplan, RS Linet, MS TI Brain and other central nervous system cancers: Recent trends in incidence and mortality - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Control & Populat Sci, Canc Surveillance Res Program, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Div Canc Etiol, Bethesda, MD 20892 USA. RP Legler, JM (reprint author), NIH, Execut Plaza N,Suite 313, Bethesda, MD 20892 USA. NR 2 TC 4 Z9 4 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 JAN 5 PY 2000 VL 92 IS 1 BP 77 EP 78 PG 2 WC Oncology SC Oncology GA 271AB UT WOS:000084568300018 ER PT J AU Peterson, DS Wellems, TE AF Peterson, DS Wellems, TE TI EBL-1, a putative erythrocyte binding protein of Plasmodium falciparum, maps within a favored linkage group in two genetic crosses SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Plasmodium falciparum; gene; erythrocytes ID MALARIA PARASITES; RECEPTOR; FAMILY; ANTIGEN; MICRONEMES; MEROZOITES; EXPRESSION; RESISTANCE; KNOWLESI; INVASION AB The Duffy binding-like (DBL) superfamily of Plasmodium falciparum encompasses genes which encode ligands for host cell receptors. This superfamily includes two distinct groups of genes, the var genes which encode antigenically variant cytoadherence proteins (PfEMP1), and the eba-175 gene which encodes a glycophorin A binding protein involved in erythrocyte invasion. Here we describe another DBL superfamily member related to eba-175, the ebl-1 gene. Like the eba-175 gene; ebl-1 is a single copy gene encoding DBL domains that have sequences and an overall arrangement distinct from om genes, The inheritance of ebl-1 was found to be strongly favored in two genetic crosses in which one parental clone lacked a chromosome segment carrying the gene. A proliferation phenotype has been previously linked to the same chromosome segment in the first genetic cross. These results suggest that ebl-1 and eba-175 are related members of a multigene family involved in the invasion of erythrocytes by P. falciparum. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Georgia, Coll Vet Med, Dept Med Microbiol & Parasitol, Athens, GA 30602 USA. NIAAA, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Peterson, DS (reprint author), Univ Georgia, Coll Vet Med, Dept Med Microbiol & Parasitol, Athens, GA 30602 USA. NR 35 TC 46 Z9 48 U1 0 U2 0 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 JAN 5 PY 2000 VL 105 IS 1 BP 105 EP 113 DI 10.1016/S0166-6851(99)00173-5 PG 9 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 264EV UT WOS:000084168400010 PM 10613703 ER PT J AU Ott, DE Coren, LV Johnson, DG Kane, BP Sowder, RC Kim, YD Fisher, RJ Zhou, XZ Lu, KP Henderson, LE AF Ott, DE Coren, LV Johnson, DG Kane, BP Sowder, RC Kim, YD Fisher, RJ Zhou, XZ Lu, KP Henderson, LE TI Actin-binding cellular proteins inside human immunodeficiency virus type 1 SO VIROLOGY LA English DT Article ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; CYCLOPHILIN-A; HIV-1 VIRIONS; MN STRAIN; CELLS; CYTOSKELETON; MICROFILAMENTS; DICTYOSTELIUM; LOCALIZATION; ASSOCIATION AB Host proteins are incorporated both on and inside human immunodeficiency virus type 1 (HIV-1) virions. To identify cellular proteins inside HIV-1, virion preparations were treated by a protease-digestion technique that removes external host proteins, allowing for the study of the proteins inside the virus. Treated HIV-1 preparations were analyzed by immunoblot, high-pressure liquid chromatography, and protein sequence analyses. These analyses identified several cellular proteins inside HIV-1: elongation factor 1 alpha, glyceraldehyde-3-phosphate dehydrogenase, HS-1, phosphatidylethanolamine-binding protein, Pin1, Lck, Nm23-H1, and the C-terminal tail of CD43. Several of these proteins were found as fragments of their full-sized proteins that appear to be generated by our protease treatment of the virions, the HIV-1 protease, or a cellular protease. Recent advances in cell biology and biochemistry have identified some of these proteins as actin-binding proteins. These results support the hypothesis that actin filaments are incorporated into the virion and may provide additional clues for the understanding of the interaction between viral and cellular proteins during assembly and budding. (C) 2000 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC, AIDS Vaccine Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Prot Chem Lab, Frederick, MD 21702 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med,Dept Med, Div Hematol & Oncol,Canc Biol Program, Boston, MA 02215 USA. RP Ott, DE (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC, AIDS Vaccine Program, Frederick, MD 21702 USA. RI Fisher, Robert/B-1431-2009 FU NCI NIH HHS [N01-CO-56000]; NIGMS NIH HHS [R01GM58556] NR 58 TC 93 Z9 95 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 JAN 5 PY 2000 VL 266 IS 1 BP 42 EP 51 DI 10.1006/viro.1999.0075 PG 10 WC Virology SC Virology GA 282RX UT WOS:000085233300006 PM 10612659 ER PT J AU Okin, PM Devereux, RB Howard, BV Fabsitz, RR Lee, ET Welty, TK AF Okin, PM Devereux, RB Howard, BV Fabsitz, RR Lee, ET Welty, TK TI Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians - The strong heart study SO CIRCULATION LA English DT Article DE electrocardiography; risk factors; QT interval; QT dispersion ID LONG-QT; VENTRICULAR REPOLARIZATION; LEAD SELECTION; CARDIAC DEATH; DISEASE; PROLONGATION; POPULATION; ALGORITHMS AB Background-Both a prolonged QT interval and increased QT interval dispersion (QTD) have been proposed as surface ECG markers of vulnerability to ventricular arrhythmias and potential predictors of mortality. Methods and Results-The predictive values of QT prolongation and QTD were assessed in 1839 participants in the Strong Heart Study, a prospective study of cardiovascular disease in American Indians. ECGs were acquired at 250 Hz; QT intervals were measured by computer in all 12 leads and corrected for heart rate (QTc) by use of Bazett's formula. QTD was calculated as the difference between the maximum and minimum QTc. After a mean follow-up of 3.7+/-0.9 years, there were 188 deaths from all causes, including 55 cardiovascular deaths. In univariate Cox analyses, prolonged QTc and increased QTD were significant predictors of all-cause mortality (chi(2)=53.0, P<0.0001; chi(2)=11.3, P=0.0008) and cardiovascular mortality (chi(2)=14.7, P=0.0001; chi(2)=26.5, P<0.0001). In multivariate Cox regression analyses control ling for risk factors, QTc remained a strong predictor of all-cause mortality (chi(2)=16.5, P<0.0001) and a weaker predictor of cardiovascular mortality (chi(2)=5.8, P=0.016); QTD remained a significant predictor of cardiovascular mortality only (chi(2)=12.5, P=0.0004). Conclusions-These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization. C1 Cornell Univ, Med Ctr, Dept Med, Div Cardiol, New York, NY 10021 USA. Medlantic Res Inst, Washington, DC USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Sch Publ Hlth, Oklahoma City, OK USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. RP Okin, PM (reprint author), Cornell Univ, Med Ctr, Dept Med, Div Cardiol, 525 E 68th St, New York, NY 10021 USA. EM pokin@mail.med.cornell.edu FU NHLBI NIH HHS [U01-HL-41642, U01-HL-41654, U01-HL-41652] NR 34 TC 227 Z9 235 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 4 PY 2000 VL 101 IS 1 BP 61 EP 66 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 272RF UT WOS:000084664200014 PM 10618305 ER PT J AU Birghan, C Mundt, E Gorbalenya, AE AF Birghan, C Mundt, E Gorbalenya, AE TI A non-canonical Lon proteinase lacking the ATPase domain employs the Ser-Lys catalytic dyad to exercise broad control over the life cycle of a double-stranded RNA virus SO EMBO JOURNAL LA English DT Article DE autoproteolysis; birnavirus; capsid biogenesis; La (Lon) protein; serine-lysine protease ID BURSAL DISEASE VIRUS; PANCREATIC NECROSIS VIRUS; DEPENDENT PROTEASE-LA; GENOME SEGMENT-A; ESCHERICHIA-COLI; ACTIVE-SITE; MULTIPLE ALIGNMENT; SEQUENCE-ANALYSIS; CRYSTAL-STRUCTURE; LEADER PEPTIDASE AB We have identified a region related to the protease domain of bacterial and organelle ATP-dependent Lon proteases in virus protein 4 (VP4) of infectious bursal disease virus strain P2 (IBDVP2), a two-segmented double-stranded RNA virus, Unlike canonical Lens, IBDVP2 VP4 possesses a proteinase activity though it lacks an ATPase domain. Ser652 and Lvs692 of IBDVP2 VP4 are conserved across the Lon/VP4 family and are essential for catalysis, Lys692 has the properties of a general base, increasing the nucleophilicity of Ser652; a similar catalytic dyad may function in the other Lens, VP4 can cleave in trails and is responsible for the interdomain proteolytic autoprocessing of the QVP2-VP4-VP3 polyprotein encoded by RNA segment A. VP2, which is later derived from pVP2, and VP3 are major capsid proteins of birnaviruses, Results of the characterization of a range of the IBDVP2 VP4 mutants in cell cultures implicate VP4 in trails-activation of the synthesis of VP1, putative RNA-dependent RNA polymerase encoded by RNA segment B, and in cleavage rate-dependent control of process(es) crucial for the generation of the infectious virus progeny. C1 NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. Fed Res Ctr Virus Dis Anim, Inst Mol Biol, Friedrich Loeffler Inst, D-174988 Insel Riems, Germany. RP Gorbalenya, AE (reprint author), NCI, Frederick Canc Res & Dev Ctr, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 FU NCI NIH HHS [N01-CO-56000] NR 77 TC 125 Z9 130 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 4 PY 2000 VL 19 IS 1 BP 114 EP 123 DI 10.1093/emboj/19.1.114 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 272UA UT WOS:000084668300013 PM 10619850 ER PT J AU Sutrave, P Leferovich, JM Kelly, AM Hughes, SH AF Sutrave, P Leferovich, JM Kelly, AM Hughes, SH TI The induction of skeletal muscle hypertrophy by a ski transgene is promoter-dependent SO GENE LA English DT Article DE c-ski; muscle phenotype; tissue-specific expression; transgenic mice ID C-SKI; ONCOGENE; MICE; EXPRESSION; DIFFERENTIATION; OVEREXPRESSION; PROTOONCOGENE; SEQUENCE; DEFECTS; VECTORS AB The chicken c-ski gene expresses at least three alternatively spliced messages. Transgenic mice expressing proteins from cDNA corresponding to two of these messages (FB27 and FB29) under the control of a murine sarcoma virus (MSV) long terminal repeat (LTR) express the transgene in skeletal muscle and develop a muscular phenotype. Both a biologically active form of c-ski and the MSV LTR are required for the development of the muscular phenotype. The normal c-ski gene linked to two other tissue-specific promoters failed to induce muscle growth in transgenic mice, as did an inactive mutant of c-ski expressed under the control of the MSV LTR. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. RP Hughes, SH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NR 32 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 4 PY 2000 VL 241 IS 1 BP 107 EP 116 DI 10.1016/S0378-1119(99)00461-8 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 278CX UT WOS:000084971300013 PM 10607904 ER PT J AU Wolford, JK Bogardus, C Ossowski, V Prochazka, M AF Wolford, JK Bogardus, C Ossowski, V Prochazka, M TI Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians SO GENE LA English DT Article DE association; candidate gene; chromosome 1q; linkage; single nucleotide polymorphism; type 2 diabetes mellitus ID EXPRESSION; PHOSPHOPROTEIN; SEQUENCE; PEA-15 AB The PEA15 gene encoding a protein kinase C substrate is widely expressed, and its overexpression may contribute to impairment of glucose uptake. PEA15 is located within a region on human 1q linked with type 2 diabetes in both Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within this locus to disease susceptibility in the Pimas, we have investigated its genomic sequences. The PEA15 locus is composed of four exons spanning approximately 10.2 kb of genomic DNA, flanked upstream by an potentially expressed Alu element, downstream by the H326 gene, and is located within 250 kb of KCNJ9. We also sequenced over 2 kb of the promoter region and identified various motifs analogous to known transcription factor binding sites. By analysis of 22 Pimas, including 13 diabetic subjects, we detected four single nucleotide polymorphisms (SNPs) in the non-coding regions of PEA15, including three frequent variants that were in allelic disequilibrium, and one variant found only in a single Pima. The three SNPs were not associated with type 2 diabetes mellitus in 50 affected and 50 control Pimas (p = 0.12-0.17), and we conclude that mutations in this gene probably do not contribute significantly to disease susceptibility in this Native American tribe, However, knowledge of the genomic structure of PEA15 provides the basis for similar systematic examinations of this candidate locus in relation to type 2 diabetes and other metabolic disorders in other populations. Published by Elsevier Science B.V. C1 NIDDKD, NIH, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), NIDDKD, NIH, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, 4212 N 16Th St, Phoenix, AZ 85016 USA. NR 20 TC 19 Z9 20 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 JAN 4 PY 2000 VL 241 IS 1 BP 143 EP 148 DI 10.1016/S0378-1119(99)00455-2 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 278CX UT WOS:000084971300017 PM 10607908 ER PT J AU Belnap, DM McDermott, BM Filman, DJ Cheng, NQ Trus, BL Zuccola, HJ Racaniello, VR Hogle, JM Steven, AC AF Belnap, DM McDermott, BM Filman, DJ Cheng, NQ Trus, BL Zuccola, HJ Racaniello, VR Hogle, JM Steven, AC TI Three-dimensional structure of poliovirus receptor bound to poliovirus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AMINO-ACID-RESIDUES; BIOLOGICAL MACROMOLECULES; CONFORMATIONAL ALTERATION; 3-DIMENSIONAL STRUCTURE; MOLECULAR-CLONING; CAPSID RESIDUES; CELL RECEPTORS; VIRUS BINDING; PROTEIN; SURFACE AB Poliovirus initiates infection by binding to its cellular receptor (Pvr). We have studied this interaction by using cryoelectron microscopy to determine the structure, at 21-Angstrom resolution, of poliovirus complexed with a soluble form of its receptor (sPvr). This density map aided construction of a homology-based model of sPvr and, in conjunction with the known crystal structure of the virus, allowed delineation of the binding site. The virion does not change significantly in structure on binding sPvr in short incubations at 4 degrees C. We infer that the binding configuration visualized represents the initial interaction that is followed by structural changes in the virion as infection proceeds. sPvr is segmented into three well-defined Ig-like domains. The two domains closest to the virion (domains 1 and 2) are aligned and rigidly connected, whereas domain 3 diverges at an angle of approximate to 60 degrees. Two nodules of density on domain 2 are identified as glycosylation sites. Domain 1 penetrates the "canyon" that surrounds the 5-fold protrusion on the capsid surface, and its binding site involves all three major capsid proteins. The inferred pattern of virus-sPvr interactions accounts for most mutations that affect the binding of Pvr to poliovirus. C1 NIAMSD, Struct Biol Lab, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Microbiol, New York, NY 10032 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bldg 6,Room B2-34,MSC 2717, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI20017, AI20566, R01 AI020566, R21 AI020566, R37 AI020566] NR 40 TC 165 Z9 168 U1 0 U2 12 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 JAN 4 PY 2000 VL 97 IS 1 BP 73 EP 78 DI 10.1073/pnas.97.1.73 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500016 PM 10618373 ER PT J AU Contursi, C Wang, IM Gabriele, L Gadina, M O'Shea, J Morse, HC Ozato, K AF Contursi, C Wang, IM Gabriele, L Gadina, M O'Shea, J Morse, HC Ozato, K TI IFN consensus sequence binding protein potentiates STAT1-dependent activation of IFN gamma-responsive promoters in macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID REGULATORY FACTOR FAMILY; AFFINITY FC RECEPTOR; MUTANT-CELL LINE; INTERFERON-GAMMA; SIGNAL-TRANSDUCTION; PERITONEAL-MACROPHAGES; TRANSCRIPTION FACTOR; TARGETED DISRUPTION; ICSBP GENE; IN-VIVO AB IFN gamma, once called the macrophage-activating factor, stimulates many genes in macrophages, ultimately leading to the elicitation of innate immunity. IFN gamma's functions depend on the activation of STAT1, which stimulates transcription of IFN gamma-inducible genes through the GAS element. The IFN consensus sequence binding protein (icsb gamma or IFN regulatory factor 8), encoding a transcription factor of the IFN regulatory factor family, is one of such IFN gamma-inducible genes in macrophages. We found that macrophages from ICSBP-/- mice were defective in inducing some IFN gamma-responsive genes, even though they were capable of activating STAT1 in response to IFN gamma. Accordingly, IFN gamma activation of luciferase reporters fused to the GAS element was severely impaired in ICSBP-/- macrophages, but transfection of ICSBP resulted in marked stimulation of these reporters. Consistent with its role in activating IFN gamma-responsive promoters, ICSBP stimulated reporter activity in a GAS-specific manner, even in the absence of IFN gamma treatment, and in STAT1 negative cells. Indicative of a mechanism for this stimulation, DMA affinity binding assays revealed that endogenous ICSBP was recruited to a multiprotein complex that bound to GAS. These results suggest that ICSBP, when induced by IFN gamma through STAT1, in turn generates a second wave of transcription from GAS-containing promoters, thereby contributing to the elicitation of IFN gamma's unique activities in immune cells. C1 NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, Bethesda, MD 20892 USA. NIAMD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 NR 39 TC 51 Z9 51 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 JAN 4 PY 2000 VL 97 IS 1 BP 91 EP 96 DI 10.1073/pnas.97.1.91 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500019 PM 10618376 ER PT J AU Muller, S Stanyon, R Finelli, P Archidiacono, N Wienberg, J AF Muller, S Stanyon, R Finelli, P Archidiacono, N Wienberg, J TI Molecular cytogenetic dissection of human chromosomes 3 and 21 evolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IN-SITU HYBRIDIZATION; INSITU SUPPRESSION HYBRIDIZATION; ZOO-FISH ANALYSIS; GENOMIC REORGANIZATION; MONKEY CHROMOSOMES; DNA LIBRARIES; HOMOLOGY; PROBES; REARRANGEMENTS; TRANSLOCATIONS AB Chromosome painting in placental mammalians illustrates that genome evolution is marked by chromosomal synteny conservation and that the association of chromosomes 3 and 21 may be the largest widely conserved syntenic block known for mammals, We studied intrachromosomal rearrangements of the syntenic block 3/21 by using probes derived from chromosomal subregions with a resolution of up to 10-15 Mbp, We demonstrate that the rearrangements visualized by chromosome painting, mostly translocations, are only a fraction of the actual chromosomal changes that have occurred during evolution. The ancestral segment order for both primates and carnivores is still found in some species in both orders. From the ancestral primate/carnivore condition an inversion is needed to derive the pig homolog, and a fission of chromosome 21 and a pericentric inversion is needed to derive the Bornean orangutan condition. Two overlapping inversions in the chromosome 3 homolog then would lead to the chromosome form found in humans and African apes, This reconstruction of the origin of human chromosome 3 contrasts with the generally accepted scenario derived from chromosome banding in which it was proposed that only one pericentric inversion was needed. From the ancestral form for Old World primates (now found in the Bornean orangutan) a pericentric inversion and centromere shift leads to the chromosome ancestral for all Old World monkeys. Intrachromosomal rearrangements, as shown here, make up a set of potentially plentiful and informative markers that can be used for phylogenetic reconstruction and a more refined comparative mapping of the genome. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. Univ Munich, Inst Anthropol & Human Genet, D-80333 Munich, Germany. Univ Bari, Inst Genet, I-70126 Bari, Italy. RP Wienberg, J (reprint author), NCI, Lab Genom Divers, Bldg 560,Room 11-75, Frederick, MD 21702 USA. RI archidiacono, nicoletta/B-8471-2011; Finelli, Palma/A-3578-2016; OI Finelli, Palma/0000-0001-8464-6906; archidiacono, nicoletta/0000-0002-1439-9521; Stanyon, Roscoe/0000-0002-7229-1092 NR 41 TC 61 Z9 61 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2000 VL 97 IS 1 BP 206 EP 211 DI 10.1073/pnas.97.1.206 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500039 PM 10618396 ER PT J AU Shou, YP Martelli, ML Gabrea, A Qi, Y Brents, LA Roschke, A Dewald, G Kirsch, IR Bergsagel, PL Kuehl, WM AF Shou, YP Martelli, ML Gabrea, A Qi, Y Brents, LA Roschke, A Dewald, G Kirsch, IR Bergsagel, PL Kuehl, WM TI Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PLASMA-CELL LEUKEMIA; CHROMOSOMAL TRANSLOCATIONS; INCREASED EXPRESSION; LINES; GENE; AMPLIFICATION; PROTOONCOGENE; ACTIVATION; REGIONS; REVEAL AB Translocations involving c-myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c-myc or L-myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These abnormalities include unusual and complex translocations and insertions that often juxtapose myc with an IgH or IgL locus. For two advanced primary MM tumors, some tumor cells contain a karyotypic abnormality of the c-myc locus, whereas other tumor cells do not, indicating that this karyotypic abnormality of c-myc occurs as a late event. All informative MM cell lines show monoallelic expression of c-myc. For Burkitt's lymphoma and mouse plasmacytoma tumors, balanced translocation that juxtaposes c-myc with one of the Ig loci is an early, invariant event that is mediated by B cell-specific DNA modification mechanisms. By contrast, for MM, dysregulation of c-myc apparently is caused principally by complex genomic rearrangements that occur during late stages of MM progression and do not involve B cell-specific DNA modification mechanisms. C1 USN Hosp, Natl Canc Inst, Dept Genet, Med Branch, Bethesda, MD 20889 USA. Mayo Clin, Cytogenet Lab, Rochester, MN 55905 USA. Cornell Univ, New York Presbyterian Hosp, Weill Med Coll, Dept Med,Div Hematol Oncol, New York, NY 10021 USA. RP Kuehl, WM (reprint author), USN Hosp, Natl Canc Inst, Dept Genet, Med Branch, Bldg 8,Room 5101, Bethesda, MD 20889 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 FU NCI NIH HHS [CA74265] NR 43 TC 193 Z9 197 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2000 VL 97 IS 1 BP 228 EP 233 DI 10.1073/pnas.97.1.228 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500043 PM 10618400 ER PT J AU Herrera, PL Harlan, DM Vassalli, P AF Herrera, PL Harlan, DM Vassalli, P TI A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: Possible role of membrane TNF SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-NECROSIS-FACTOR; PANCREATIC BETA-CELLS; TRANSGENIC MICE; FACTOR-ALPHA; DEFICIENT MICE; HASHIMOTOS-THYROIDITIS; LYMPHOTOXIN-ALPHA; GRAVES-DISEASE; KILLER-CELLS; NOD MICE AB Double transgenic mice [rat insulin promoter (RIP)-tumor necrosis factor (TNF) and RIP-CD80] whose pancreatic beta cells release TNF and bear CD80 all develop an acute early (6 wk) and lethal diabetes mediated by CD8 T cells. The first ultrastructural changes observed in beta cells, so far unreported, are focal lesions of endoplasmic reticulum swelling at the points of contact with islet-infiltrating lymphoblasts, followed by cytoplasmic, but not nuclear, apoptosis, Such double transgenic mice were made defective in either the perforin, Fas, or TNF pathways. Remarkably, diabetes was found to be totally independent of perforin and Fas. Mice lacking TNF receptor (TNFR) II had no or late diabetes, but only a minority had severe insulitis, Mice lacking the TNF-lymphotoxin (LT alpha) locus (whose sole source of TNF are the beta cells) all had insulitis comparable to that of nondefective mice, but no diabetes or a retarded and milder form, with lesions suggesting different mechanisms of injury. Because both TNFR II and TNF-LT alpha mutations have complex effects on the immune system, these data do not formally incriminate membrane TNF as the major T cell mediator of this acute autoimmune diabetes; nevertheless, in the absence of involvement of the perforin or Fas cytotoxic pathways, membrane TNF appears to be the likeliest candidate. C1 Univ Geneva, Sch Med, Dept Morphol, CH-1211 Geneva 4, Switzerland. Univ Geneva, Sch Med, Dept Pathol, CH-1211 Geneva, Switzerland. USN, NIDDK, Navy Transplantat & Autoimmun Branch, Med Res Ctr, Bethesda, MD 20889 USA. RP Herrera, PL (reprint author), Univ Geneva, Sch Med, Dept Morphol, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. NR 49 TC 41 Z9 41 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 JAN 4 PY 2000 VL 97 IS 1 BP 279 EP 284 DI 10.1073/pnas.97.1.279 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500052 PM 10618409 ER PT J AU Arichi, T Saito, T Major, ME Belyakov, IM Shirai, M Engelhard, VH Feinstone, SM Berzofsky, JA AF Arichi, T Saito, T Major, ME Belyakov, IM Shirai, M Engelhard, VH Feinstone, SM Berzofsky, JA TI Prophylactic DNA vaccine for hepatitis C virus (HCV) infection: HCV-specific cytotoxic T lymphocyte induction and protection from HCV-recombinant vaccinia infection in an HLA-A2.1 transgenic mouse model (Retracted Article. See vol 98, pg 5943, 2001) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article; Retracted Publication ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; PLASMID DNA; CELL MEMORY; B-VIRUS; STRUCTURAL PROTEINS; CTL RESPONSES; CORE PROTEIN; IN-VIVO; MICE AB DNA vaccines express antigens intracellularly and effectively induce cellular immune responses. Because only chimpanzees can be used to model human hepatitis C virus (HCV) infections, we developed a small-animal model using HLA-A2.1-transgenic mice to test induction of HLA-A2.1-restricted cytotoxic T lymphocytes (CTLs) and protection against recombinant vaccinia expressing HCV-core, A plasmid encoding the HCV-core antigen induced CD8(+) CTLs specific for three conserved endogenously expressed core peptides presented by human HLA-A2.1, When challenged, DNA-immunized mice showed a substantial (5-12 log(10)) reduction in vaccinia virus titer compared with mock-immunized controls. This protection, lasting at least 14 mo, was shown to be mediated by CD8+ cells. Thus, a DNA vaccine expressing HCV-core is a potential candidate for a prophylactic vaccine for HLA-A2.1(+) humans. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Viruses, Div Viral Prod, Bethesda, MD 20892 USA. Yamaguchi Univ, Sch Med, Dept Microbiol, Ube, Yamaguchi 755, Japan. Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12,MSC 1578, Bethesda, MD 20892 USA. EM berzofsk@helix.nih.gov NR 58 TC 25 Z9 26 U1 3 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2000 VL 97 IS 1 BP 297 EP 302 DI 10.1073/pnas.97.1.297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500055 PM 10618412 ER PT J AU Wong, ML Kling, MA Munson, PJ Listwak, S Licinio, J Prolo, P Karp, B McCutcheon, IE Geracioti, TD DeBellis, MD Rice, KC Goldstein, DS Veldhuis, JD Chrousos, GP Oldfield, EH McCann, SM Gold, PW AF Wong, ML Kling, MA Munson, PJ Listwak, S Licinio, J Prolo, P Karp, B McCutcheon, IE Geracioti, TD DeBellis, MD Rice, KC Goldstein, DS Veldhuis, JD Chrousos, GP Oldfield, EH McCann, SM Gold, PW TI Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: Relation to hypercortisolism and corticotropin-releasing hormone SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CEREBROSPINAL-FLUID; CUSHINGS-DISEASE; RAT; NOREPINEPHRINE; CORTICOSTERONE; SECRETION; RESPONSES; LESIONS; STRESS AB Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features. C1 NIH, NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. NIH, Analyt Biostat Sect, Struct Biol Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. NIH, Med Chem Lab, NIDDK, Bethesda, MD 20892 USA. NIH, Clin Neurosci Branch, Bethesda, MD 20892 USA. NIH, Surg Neurol Branch, NINDS, Bethesda, MD 20892 USA. NIH, Dev Endocrinol Branch, NICHHD, Bethesda, MD 20892 USA. Baltimore Vet Affairs Med Ctr, Dept Psychiat, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Cincinnati, Med Ctr, Dept Psychiat, Cincinnati, OH 45267 USA. Univ Pittsburgh, Med Ctr, Dept Child & Adolescent Psychiat, Pittsburgh, PA 15213 USA. Univ Virginia, Hlth Sci Ctr, Dept Internal Med, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Natl Sci Fdn Ctr Biol Timing, Charlottesville, VA 22908 USA. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Gold, PW (reprint author), NIH, NIMH, Clin Neuroendocrinol Branch, Bldg 10-2D46,10 Ctr Dr,MSC 1284, Bethesda, MD 20892 USA. RI Kling, Mitchel/F-4152-2010; Wong, Ma-Li/D-7903-2011; Licinio, Julio/L-4244-2013 OI Kling, Mitchel/0000-0002-2232-1409; Licinio, Julio/0000-0001-6905-5884 FU NCRR NIH HHS [M01 RR000847, MO1 RR-00847]; NIMH NIH HHS [MH 51853] NR 50 TC 332 Z9 339 U1 3 U2 17 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 JAN 4 PY 2000 VL 97 IS 1 BP 325 EP 330 DI 10.1073/pnas.97.1.325 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500060 PM 10618417 ER PT J AU Murakami, T Freed, EO AF Murakami, T Freed, EO TI The long cytoplasmic tail of gp41 is required in a cell type-dependent manner for HIV-1 envelope glycoprotein incorporation into virions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENDOPLASMIC-RETICULUM; TRANSMEMBRANE PROTEIN; PLASMA-MEMBRANE; INFECTED-CELLS; MATRIX PROTEIN; HOST-RANGE; MDCK CELLS; DOMAIN; INFECTIVITY AB Lentiviruses, including HIV-1, have transmembrane envelope (Env) glycoproteins with cytoplasmic tails that are quite long compared with those of other retroviruses. However, mainly because of the lack of biochemical studies performed in cell types that are targets for HIV-1 infection, no clear consensus exists regarding the function of the long lentiviral Env cytoplasmic tail in virus replication. In this report, we characterize the biological and biochemical properties of an HIV-1 mutant lacking the gp41 cytoplasmic tail. We find that the gp41 cytoplasmic tail is necessary for the efficient establishment of a productive, spreading infection in the majority of T cell lines tested, peripheral blood mononuclear cells, and monocyte-derived macrophages. Biochemical studies using a high-level, transient HIV-1 expression system based on pseudotyping with the vesicular stomatitis virus glycoprotein demonstrate that in HeLa and MT-4 cells, mutant Env incorporation into virions is reduced only 3-fold relative to wild type. In contrast, gp120 levels in virions produced from a number of other T cell lines and primary macrophages are reduced more than 10-fold by the gp41 truncation. The Env incorporation defect imposed by the cytoplasmic tail truncation is not the result of increased shedding of gp120 from virions or reduced cell-surface Env expression. These results demonstrate that in the majority of T cell lines, and in primary cell types that serve as natural targets for HIV-1 infection in vivo, the gp41 cytoplasmic tail is essential for efficient Env incorporation into virions. C1 NIH, NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NIH, NIAID, Mol Microbiol Lab, Bldg 4,Room 307, Bethesda, MD 20892 USA. NR 47 TC 149 Z9 150 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 JAN 4 PY 2000 VL 97 IS 1 BP 343 EP 348 DI 10.1073/pnas.97.1.343 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500063 PM 10618420 ER PT J AU Schiffmann, R Murray, GJ Treco, D Daniel, P Sellos-Moura, M Myers, M Quirk, JM Zirzow, GC Borowski, M Loveday, K Anderson, T Gillespie, F Oliver, KL Jeffries, NO Doo, E Liang, TJ Kreps, C Gunter, K Frei, K Crutchfield, K Selden, RF Brady, RO AF Schiffmann, R Murray, GJ Treco, D Daniel, P Sellos-Moura, M Myers, M Quirk, JM Zirzow, GC Borowski, M Loveday, K Anderson, T Gillespie, F Oliver, KL Jeffries, NO Doo, E Liang, TJ Kreps, C Gunter, K Frei, K Crutchfield, K Selden, RF Brady, RO TI Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENZYME REPLACEMENT THERAPY; INVOLVEMENT; PROTEINS AB Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb(3); also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified alpha-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered alpha-gal A, (ii) to assess the pharmacokinetics of i.v.-administered alpha-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb(3), alpha-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr, After the single dose of alpha-gal A, nine of the 10 patients had significantly reduced Gb(3) levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of alpha-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb(3) burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder. C1 NIH, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. NIH, Biometry Branch, NINDS, Bethesda, MD 20892 USA. NIH, Liver Dis Sect, NIDDK, Bethesda, MD 20892 USA. Transkaryot Therapies Inc, Cambridge, MA 02139 USA. RP Schiffmann, R (reprint author), NIH, Dev & Metab Neurol Branch, Bldg 10,Room 3D03,10 Ctr Dr,MSC 1260, Bethesda, MD 20892 USA. NR 28 TC 248 Z9 257 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 JAN 4 PY 2000 VL 97 IS 1 BP 365 EP 370 DI 10.1073/pnas.97.1.365 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500067 PM 10618424 ER PT J AU Sacks, DL Modi, G Rowton, E Spath, G Epstein, L Turco, SJ Beverley, SM AF Sacks, DL Modi, G Rowton, E Spath, G Epstein, L Turco, SJ Beverley, SM TI The role of phosphoglycans in Leishmania-sand fly interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PHLEBOTOMUS-PAPATASI DIPTERA; SURFACE LIPOPHOSPHOGLYCAN; GLYCOSYLATED PHOSPHATIDYLINOSITOLS; DONOVANI LIPOPHOSPHOGLYCAN; DEVELOPMENTAL STAGES; MAJOR PROMASTIGOTES; VIRULENCE GENES; PSYCHODIDAE; EXPRESSION; GLYCOCONJUGATE AB Leishmania promastigotes synthesize an abundance of phosphoglycans, either attached to the cell surface through phosphatidylinositol anchors (lipophosphoglycan, LPG) or secreted as protein-containing glycoconjugates. These phosphoglycans are thought to promote the survival of the parasite within both its vertebrate and invertebrate hosts. The relative contributions of different phosphoglycan-containing molecules in Leishmania-sand fly interactions were tested by using mutants specifically deficient in either total phosphoglycans or LPG alone. Leishmania donovani promastigotes deficient in both LPC and protein-linked phosphoglycans because of loss of LPG2 (encoding the Co(gi GDP-Man transporter) failed to survive the hydrolytic environment within the early blood-fed midgut, In contrast, L. donovani and Leishmania major mutants deficient solely in LPC expression because of loss of LPG 1 (involved in biosynthesis of the core oligosaccharide LPG domain) had only a slight reduction in the survival and growth of promastigotes within the early blood-fed midgut. The ability of the LPG1-deficient promastigotes to persist in the midgut after blood meal excretion was completely lost, and this defect was correlated with their inability to bind to midgut epithelial cells in vitro. For both mutants, when phosphoglycan expression was restored to wild-type levels by reintroduction of LPG1 or LPG2 (as appropriate), then the wild-type phenotype was also restored. We conclude, first, that LPG is not essential for survival in the early blood-fed midgut but. along with other secreted phosphoglycan-containing glycoconjugates, can protect promastigotes from the digestive enzymes in the gut and, second, that LPG is required to mediate midgut attachment and to maintain infection in the fly during excretion of the digested blood meal. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. Univ Kentucky, Med Ctr, Dept Biochem, Lexington, KY 40536 USA. Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RI Rowton, Edgar/A-1975-2011; Rowton, Edgar/A-4474-2012; Spaeth, Gerald/B-1393-2014; OI Rowton, Edgar/0000-0002-1979-1485; Beverley, Stephen/0000-0001-5319-0811 FU NIAID NIH HHS [R01 AI031078, AI31078] NR 43 TC 125 Z9 131 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 4 PY 2000 VL 97 IS 1 BP 406 EP 411 DI 10.1073/pnas.97.1.406 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 271ZA UT WOS:000084624500074 PM 10618431 ER PT J AU Lands, WEM AF Lands, WEM TI Stories about acyl chains SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review ID UNSATURATED FATTY-ACIDS; PROSTAGLANDIN-H SYNTHASE; ANTI-INFLAMMATORY DRUGS; SHEEP VESICULAR GLAND; ASCITES TUMOR-CELLS; ESCHERICHIA-COLI; RAT-LIVER; SACCHAROMYCES-CEREVISIAE; SELECTIVE INCORPORATION; LIPID PEROXIDES C1 NIAAA, NIH, Bethesda, MD USA. RP Lands, WEM (reprint author), NIAAA, NIH, Bethesda, MD USA. NR 139 TC 86 Z9 88 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD JAN 3 PY 2000 VL 1483 IS 1 BP 1 EP 14 DI 10.1016/S1388-1981(99)00177-8 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 272EG UT WOS:000084637100001 PM 10601692 ER PT J AU Maeda, DY Williams, W Bowen, WD Coop, A AF Maeda, DY Williams, W Bowen, WD Coop, A TI A sigma-1 receptor selective analogue of BD1008. A potential substitute for (+)-opioids in sigma receptor binding assays SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID LIGANDS AB A simple, achiral monoamine sigma-1 (sigma(1)) receptor selective ligand (sigma(2)K/sigma(i) K-i > 2000) is described, which could replace the chiral (+)-pentazocine or dextrallorphan as a sigma(1) masking agent in sigma(2) binding assays. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Coop, A (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 N Pine St, Baltimore, MD 21201 USA. NR 8 TC 19 Z9 20 U1 0 U2 2 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 JAN 3 PY 2000 VL 10 IS 1 BP 17 EP 18 DI 10.1016/S0960-894X(99)00590-9 PG 2 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 271AD UT WOS:000084568500005 PM 10636233 ER PT J AU Toth, A Medgyes, A Bajza I Liptak, A Batta, G Kontrohr, T Peterffy, K Pozsgay V AF Toth, A Medgyes, A Bajza, I Liptak, A Batta, G Kontrohr, T Peterffy, K Pozsgay, V TI Synthesis of the repeating unit of the O-specific polysaccharide of Shigella sonnei and quantitation of its serologic activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID PROMOTED REACTIONS; VACCINES; ACID AB The chemical synthesis of the zwitterionic disaccharide 2 is described that corresponds to the repeating unit of the O-specific polysaccharide (1) of the Gram-negative human pathogen Shigella sonnei. Passive hemolysis inhibition tests using a hyperimmune rabbit serum raised against S. sonnei showed that the serologic activity of the disaccharide 2 is nearly 2- to 3-fold higher than those of its component monosaccharides. NMR data of 2 are in support of the proposed structure of the O-specific polysaccharide. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 Hungarian Acad Sci, Res Grp Carbohydrates, H-4010 Debrecen, Hungary. Univ Debrecen, Inst Biochem, H-4010 Debrecen, Hungary. Hungarian Acad Sci, Antibiot Res Grp, H-4010 Debrecen, Hungary. Univ Med Sch, Inst Microbiol, Pecs, Hungary. NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Liptak, A (reprint author), Hungarian Acad Sci, Res Grp Carbohydrates, H-4010 Debrecen, Hungary. EM liptaka@tigris.klte.hu RI Batta, Gyula/H-4567-2011 OI Batta, Gyula/0000-0002-0442-1828 NR 14 TC 12 Z9 12 U1 0 U2 2 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 JAN 3 PY 2000 VL 10 IS 1 BP 19 EP 21 DI 10.1016/S0960-894X(99)00585-5 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 271AD UT WOS:000084568500006 PM 10636234 ER PT J AU Webb, TR Melman, N Lvovskiy, D Ji, XD Jacobson, KA AF Webb, TR Melman, N Lvovskiy, D Ji, XD Jacobson, KA TI The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID DERIVATIVES; LIGANDS; POTENT; INHIBITORS AB Pharmacophore queries from previously known potent selective A(3) antagonists were generated by Chem-X. These queries were used to search a pharmacophore database of diverse compounds (CNS-Set(TM)). In vitro assays of 186 'hits' yielded over 30 active compounds, for four adenosine receptor subtypes. This search strategy may also be applicable to the discovery of new ligands via receptor homology data. (C) 1999 Elsevier Science Ltd. All rights reserved. C1 ChemBridge Corp, San Diego, CA 92127 USA. NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Webb, TR (reprint author), ChemBridge Corp, 16981 Via Tazon,Suite G, San Diego, CA 92127 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 24 TC 24 Z9 24 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 JAN 3 PY 2000 VL 10 IS 1 BP 31 EP 34 DI 10.1016/S0960-894X(99)00583-1 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 271AD UT WOS:000084568500009 PM 10636237 ER PT J AU Yefimov, S Yergey, AL Chrambach, A AF Yefimov, S Yergey, AL Chrambach, A TI Transfer of SDS-proteins from gel electrophoretic zones into mass spectrometry, using electroelution of the band into buffer without sectioning of the gel SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE mass spectrometry; real-time scanning; fluorescent proteins; electroeluates; HPGE apparatus ID HPGE-1000 APPARATUS; RESOLUTION; SYSTEM; FIELD; SENSITIVITY; RECOVERY AB Five SDS-proteins, ranging in molecular weight from 14 to 66 kDa, were detected without covalent fluorescent labeling by the automated gel electrophoresis apparatus with intermittent fluorescence scanning (HPGE apparatus, LabIntelligence) during electrophoresis in barbiturate buffer in the presence of Cascade Blue. The SDS-proteins were electroeluted from the gel into 220 mu l of buffer by a modification of the procedure of Gombocz and Cortez [1]. The electroeluate was freed of SDS, ultrafiltered and subjected to MALDI-TOF mass spectrometry. The masses of the five native proteins were found to be maintained after electrophoresis and electroelution in the presence of the potential contaminants SDS, barbituric acid and Cascade Blue. The procedure of protein transfer from SDS-PAGE into mass spectrometry, without excision of bands, gel maceration and protein recovery by diffusion, therefore is shown to be suitable for the identification by mass of intact proteins derived from gel electrophoretic bands. (C) 2000 Elsevier Science BN. All rights reserved. C1 NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NICHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Room 9D50, Bethesda, MD 20892 USA. NR 21 TC 12 Z9 13 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD JAN 3 PY 2000 VL 42 IS 1-2 BP 65 EP 78 DI 10.1016/S0165-022X(99)00048-2 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 271KK UT WOS:000084592600006 PM 10647815 ER PT J AU Arudchandran, R Brown, MJ Peirce, MJ Song, JS Zhang, JA Siraganian, RP Blank, U Rivera, J AF Arudchandran, R Brown, MJ Peirce, MJ Song, JS Zhang, JA Siraganian, RP Blank, U Rivera, J TI The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of C-jun NH2-terminal kinase 1 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE Vav; Fc epsilon receptor I; mast cell; glycosphingolipid-enriched microdomains; plasma membrane ID PROTEIN-TYROSINE KINASE; AFFINITY IGE RECEPTOR; T-CELL RECEPTOR; FC-EPSILON-RI; PROTOONCOGENE PRODUCT; IMMUNOGLOBULIN-E; MAST-CELLS; SIGNAL-TRANSDUCTION; GAMMA-CHAIN; PATHWAY AB Vav is a hematopoietic cell-specific guanine nucleotide exchange factor (GEF) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav redistributes to the plasma membrane in response to Fc epsilon receptor I (Fc epsilon RI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The Fc epsilon RI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs). The scaffold protein, linker for activation of T cells (LAT), and Rad (a target of Vav activity) were constitutively present in GEMs. Expression of an SH2 domain-containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-containing leukocyte protein of 76 kD), and LAT. However, assembly of the multiprotein complex containing these proteins was inhibited. In addition, Fc epsilon RI-dependent activation of c-Jun NH2-terminal kinase 1 (JNK1) was also inhibited. Thus, Vav localization to the: plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1. C1 NIAMSD, Sect Chem Immunol, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Immunol Lab, NIH, Bethesda, MD 20892 USA. Inst Pasteur, F-75724 Paris, France. RP Rivera, J (reprint author), NIAMSD, Sect Chem Immunol, NIH, Bldg 10,Rm 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. NR 65 TC 67 Z9 67 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 3 PY 2000 VL 191 IS 1 BP 47 EP 59 DI 10.1084/jem.191.1.47 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 273MT UT WOS:000084712000006 PM 10620604 ER PT J AU Deb-Rinker, P O'Reilly, RL Torrey, EF Singh, SM AF Deb-Rinker, P O'Reilly, RL Torrey, EF Singh, SM TI Retroviral-related sequences obtained by RDA from discordant MZ twins are heavily methylated and placentally-expressed SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 Univ Western Ontario, Dept Zool, Mol Genet Unit, London, ON N6A 5B7, Canada. Univ Western Ontario, Inst Psychiat, Div Med Genet, London, ON N6A 5B7, Canada. NIMH, Neurosci Ctr St Elizabeths, Stanley Fdn Res Programs, Washington, DC 20032 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI BP 23 EP 24 DI 10.1016/S0920-9964(00)90355-4 PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600041 ER PT J AU Goldberg, TE Dodge, M Egan, MF Aloia, M Weinberger, DR AF Goldberg, TE Dodge, M Egan, MF Aloia, M Weinberger, DR TI Neuroleptic medication, priming, and thought disorder: Evidence for an effect on associative networks SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, IRP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A34 BP 53 EP 54 DI 10.1016/S0920-9964(00)90419-5 PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600105 ER PT J AU Nicholson, R Lenane, M Singaracharlu, S Bedwell, J Giedd, JN Hamburger, SD Thaker, GK Malaspina, D Fernandez, T Wudarsky, M Hommer, DW Rapoport, JL AF Nicholson, R Lenane, M Singaracharlu, S Bedwell, J Giedd, JN Hamburger, SD Thaker, GK Malaspina, D Fernandez, T Wudarsky, M Hommer, DW Rapoport, JL TI Premorbid speech and language impairments in childhood-onset schizophrenia: Association with risk factors SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/J-9644-2015; Fernandez, Thomas/D-4295-2009 OI Giedd, Jay/0000-0003-2002-8978; Fernandez, Thomas/0000-0003-0830-022X NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A35 BP 54 EP 54 DI 10.1016/S0920-9964(00)90420-1 PG 1 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600106 ER PT J AU Callicott, JH Egan, MF Mattay, VS Bertolino, A Bone, A Weinberger, DR AF Callicott, JH Egan, MF Mattay, VS Bertolino, A Bone, A Weinberger, DR TI Prefrontal cortex inefficiency: Potential intermediate phenotype in schizophrenics and their siblings SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A129 BP 89 EP 89 DI 10.1016/S0920-9964(00)90511-5 PG 1 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600197 ER PT J AU Egan, MF Goldberg, TE Gscheidle, T Bigelow, L Weinberger, DR AF Egan, MF Goldberg, TE Gscheidle, T Bigelow, L Weinberger, DR TI Heritability estimates for independent domains of cognitive dysfunction in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A131 BP 89 EP 90 DI 10.1016/S0920-9964(00)90513-9 PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600199 ER PT J AU Malhotra, AK Goldman, D AF Malhotra, AK Goldman, D TI Reverse pharmacogenetics: Molecular genetics in the prediction of rapid relapse following antipsychotic drug discontinuation SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 Hillside Hosp, Glen Oaks, NY 11004 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A154 BP 97 EP 98 DI 10.1016/S0920-9964(00)90536-X PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600222 ER PT J AU Winterer, G Raedler, T Weinberger, DR Coppola, R AF Winterer, G Raedler, T Weinberger, DR Coppola, R TI Reduced phase-locking in the frontotemporal circuit during an auditory oddball paradigm in patients with schizophrenia and unaffected siblings SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA A281 BP 149 EP 150 DI 10.1016/S0920-9964(00)90663-7 PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600349 ER PT J AU O'Sullivan, BT Cervantes, R Young, J Woodham, B Barrett, N Smith, G Michie, P Karayanidis, F Cho, SD Horwitz, B AF O'Sullivan, BT Cervantes, R Young, J Woodham, B Barrett, N Smith, G Michie, P Karayanidis, F Cho, SD Horwitz, B TI Pet imaging of vulnerable cognitive processes in schizophrenia: Can early compensatory changes be used as a biological marker for early psychosis? SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 Cent Sydney Area Hlth, Dept Psychiat, Sydney, NSW, Australia. Cent Sydney Area Hlth, Dept Physiol, Sydney, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA B13 BP 181 EP 181 DI 10.1016/S0920-9964(00)90739-4 PG 1 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600425 ER PT J AU Bertolino, A Callicott, JH Elman, I Mattay, VS Weidenhammer, KM Breier, A Frank, JA Pickar, D Weinberger, DR AF Bertolino, A Callicott, JH Elman, I Mattay, VS Weidenhammer, KM Breier, A Frank, JA Pickar, D Weinberger, DR TI The effects of treatment with antipsychotics on N-acetylaspartate measures in patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA B121 BP 219 EP 219 DI 10.1016/S0920-9964(00)90847-8 PG 1 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600533 ER PT J AU Vawter, MP Usen, N Thatcher, L Zhang, P Vander Putten, DM Conant, C Herman, MM Hyde, TM Freed, WJ AF Vawter, MP Usen, N Thatcher, L Zhang, P Vander Putten, DM Conant, C Herman, MM Hyde, TM Freed, WJ TI Identification of cytosolic human N-CAM. An isoform of N-CAM which is increased in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIDA, IRP, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA B203 BP 249 EP 250 DI 10.1016/S0920-9964(00)90928-9 PG 2 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600614 ER PT J AU Elvevag, B Weinberger, DR Goldberg, TE AF Elvevag, B Weinberger, DR Goldberg, TE TI Short-term memory for serial order in schizophrenia: An output problem? SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 3 PY 2000 VL 41 IS 1 SI SI MA B287 BP 281 EP 281 DI 10.1016/S0920-9964(00)91012-0 PG 1 WC Psychiatry SC Psychiatry GA 279PP UT WOS:000085054600692 ER PT B AU Long, LR Thoma, GR AF Long, LR Thoma, GR GP IEEE IEEE TI Use of shape models to search digitized spine x-rays SO 13TH IEEE SYMPOSIUM ON COMPUTER-BASED MEDICAL SYSTEMS (CBMS 2000), PROCEEDINGS LA English DT Proceedings Paper CT 13th IEEE Symposium on Computer-Based Medical Systems (CBMS 2000) CY JUN 22-24, 2000 CL UNIV TEXAS, MD ANDERSON CANC CTR, HOUSTON, TX SP IEEE, Comp Soc, IEEE, Reg 6, IEEE, Houston Sect HO UNIV TEXAS, MD ANDERSON CANC CTR ID VERTEBRAL MORPHOMETRY; IMAGES AB We are building a biomedical information resource consisting of digitized x-ray images and associated textual data from national health surveys. This resource, the Web-based Medical Information Retrieval System, or WebMIRS, is currently in beta test. In a future WebMIRS system, we plan to have not only text and raw image data, but quantitative anatomical feature information derived from the images and capability to retrieve images based on image characteristics, either alone or in conjunction with text descriptions associated with the images. Our archive consists of data collected in the second and third National Health and Nutrition Examination Surveys (NHANES), conducted by the National Center for Health Statistics. For the NHANES II survey, the records contain information for approximately 20,000 participants. Each record contains about two thousand data points, including demographic information, answers to health questionnaires, anthropometric information, and the results of a physician's examination. In addition, approximately 10,000 cervical spine and 7,000 lumbar spine x-rays were collected. WebMIRS makes the text and images retrievable. Only raw images are returned; no quantitative or descriptive information about the images is stored in the database. We are conducting research into the problem of automatically or semi-automatically segmenting spine vertebrae in these images and determining vertebral boundaries with enough accuracy to be useful in classifying the vertebrae into categories of interest to researchers in osteoarthritis. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Long, LR (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 8 TC 20 Z9 20 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA BN 0-7695-0484-1 PY 2000 BP 255 EP 260 DI 10.1109/CBMS.2000.856908 PG 6 WC Computer Science, Interdisciplinary Applications; Medicine, General & Internal SC Computer Science; General & Internal Medicine GA BQ75Q UT WOS:000089403800039 ER PT S AU Hattery, D Loew, M Chernomordik, V Gandjbakhche, A AF Hattery, D Loew, M Chernomordik, V Gandjbakhche, A BE Sanfeliu, A Villanueva, JJ Vanrell, M Alquezar, R Crowley, J Shirai, Y TI Optical signatures of small, deeply embedded, tumor-like inclusions in tissue-like turbid media based on a random-walk theory of photon migration SO 15TH INTERNATIONAL CONFERENCE ON PATTERN RECOGNITION, VOL 4, PROCEEDINGS: APPLICATIONS, ROBOTICS SYSTEMS AND ARCHITECTURES SE INTERNATIONAL CONFERENCE ON PATTERN RECOGNITION LA English DT Proceedings Paper CT 15th International Conference on Pattern Recognition (ICPR-2000) CY SEP 03-07, 2000 CL BARCELONA, SPAIN SP Int Assoc Pattern Recognit, Assoc Pattern Recognit & Image Anal, Ctr Visio Comp, Univ Autonoma Barcelona, Univ Politecn Catalunya, Comissionat Universitats Recerca, Generalitat Catalunya Dept Presidencia, Minist Ciencia Tecnol, Fdn Catalana Recerca, HP Invent AB Optical methods for detecting tumors in tissue are desirable in part because optical photons are non-ionizing. The highly scattering nature of tissue makes traditional, and even time-gated, optical imaging impractical for sites deeper than a few millimeters. Scattering in tissue causes dispersion in the path lengths of traversing photons which blurs images. With a theoretical description of path length dispersion, however, the perturbation caused by a localized anomaly may be identified from time-resolved intensity data. Random walk theory has used to show a quantitative, closed-form relationship between the perturbation and the inclusion size and scattering properties relative to the background. Using Monte carlo data, we show a method for analyzing the sensitivity of the relationship to signatures of small, deeply embedded, abnormally scattering inclusions. C1 NIH, Bethesda, MD 20892 USA. RP Hattery, D (reprint author), NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 1051-4651 BN 0-7695-0751-4 J9 INT C PATT RECOG PY 2000 BP 348 EP 351 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BR56Q UT WOS:000166815200078 ER PT B AU Malmedal, K Sen, PK AF Malmedal, K Sen, PK GP IEEE IEEE TI Arcing fault current and the criteria for setting ground fault relays in solidly-grounded low voltage systems SO 2000 IEEE INDUSTRIAL & COMMERCIAL POWER SYSTEMS TECHNICAL CONFERENCE, CONFERENCE RECORD LA English DT Proceedings Paper CT Annual Meeting of the IEEE Industrial and Commercial Power Systems Technical Conference CY MAY 07-11, 2000 CL CLEARWATER BEACH, FL SP IEEE, Ind Applicat Soc, Ind Power Syst Dept, IEEE, Florida W Coast Sect DE low voltage protection; safety practices; arcing ground faults AB In the 1960's numerous damages were documented on 480V, 3-phase, 4-wire power systems due to arcing ground faults. To alleviate this problem, the National Electrical Code (NEC) now requires ground fault protection in law voltage switchgear with continuous current ratings above 1,000A and operating at more than 150V phase-to-ground on solidly-grounded systems. However, bun down damage and personal injury continues to occur. This paper provides a simplified technique to accurately estimate this arcing fault current, and discusses its effects on the settings of relays and interrupting devices utilized in low voltage systems. It suggests that the criteria for setting the ground fault sensing devices should be changed to accommodate the maximum allowable exposure of personnel to are flashes that may occur in the system. This is a much stricter guideline than that currently required by the NEC. C1 NEI, Elect Power Engn, Arvada, CO 80001 USA. RP NEI, Elect Power Engn, Arvada, CO 80001 USA. EM kmalmedal@neiengineering.com; psen@carbon.cudenver.edu NR 13 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-5843-0 PY 2000 BP 185 EP 191 DI 10.1109/ICPS.2000.854370 PG 7 WC Engineering, Electrical & Electronic SC Engineering GA BQ63R UT WOS:000089019400021 ER PT S AU Cannata, JM Ritter, TA Chen, WH Shung, KK AF Cannata, JM Ritter, TA Chen, WH Shung, KK BE Schneider, SC Levy, M McAvoy, BR TI Design of focused single element (50-100 MHz) transducers using lithium niobate SO 2000 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 SE ULTRASONICS SYMPOSIUM LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 22-25, 2000 CL SAN JUAN, PR SP IEEE Ultrason, Ferroelect, & Frequency Control Soc ID FREQUENCY AB This paper discusses two fabrication procedures used to build LiNbO3 single element ultrasonic transducers with center frequencies in the 50 -100 MHz range. Transducers of varying dimensions were built according to an f-number range of 2.5-3.0. A quarter wavelength silver epoxy matching layer (Z(a) = 7.3 MRayls), and a silver epoxy backing (Z(a) = 5.9 MRayls), were used in all designs. The desired focal depths were achieved by either casting an acoustic lens on the transducer face or press-focusing the piezoelectric into a spherical curvature. The lens material EPO-TEK 301 (Z(a) = 3.1 MRayls) was modeled as a second matching layer. Parylene (Z(a) = 2.6 MRayls) was used as the second matching layer in the press-focused transducer design. For designs that required electrical impedance matching, a low impedance transmission line coaxial cable was used. All transducers were tested in a pulse-echo insertion loss arrangement, whereby the center frequency, bandwidth, insertion loss, and focal depth were measured. Numerous transducers were fabricated with center frequencies in the 50 to 100 MHz range. The measured -6dB bandwidths and two-way insertion loss values ranged from 50% to 70% and 12.5dB to 23.0dB, respectively. Both fabrication procedures proved successful in producing very sensitive, high frequency single element ultrasonic imaging transducers. The press-focused devices displayed significantly lower insertion loss levels than lensed devices. The Parylene matching layer provided a better acoustic match to the load medium water (Z(a) = 1.5 MRayls) and a reduced attenuation compared to the lens, which may account for the discrepancy insertion in loss levels. Finally, transmission line tuning demonstrated a 3dB reduction in insertion loss and a 6% increase in device bandwidth. C1 Penn State Univ Bioengn, Resource Ctr Med Ultrason Transducer Engn, NIH, University Pk, PA 16802 USA. RP Cannata, JM (reprint author), Penn State Univ Bioengn, Resource Ctr Med Ultrason Transducer Engn, NIH, 205 Hallowell Bldg, University Pk, PA 16802 USA. NR 7 TC 7 Z9 7 U1 1 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 0-7803-6365-5 J9 ULTRASON PY 2000 BP 1129 EP 1133 PG 3 WC Acoustics; Engineering, Industrial; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BT07X UT WOS:000171881300246 ER PT S AU Wen, H Bennett, E AF Wen, H Bennett, E BE Schneider, SC Levy, M McAvoy, BR TI The feasibility of Hall effect imaging in humans SO 2000 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 SE ULTRASONICS SYMPOSIUM LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 22-25, 2000 CL SAN JUAN, PR SP IEEE Ultrason, Ferroelect, & Frequency Control Soc ID TOMOGRAPHY AB Hall effect imaging is a new technique for mapping the electrical properties of a sample non-invasively. Its principle has been demonstrated with two and three-dimensional imaging of phantoms and biological samples. This paper addresses the potential of this technique for diagnostic imaging of the human body, based on experimental data and theoretical models of this technique developed over the past few years. The analysis is applicable to complex biological samples in general. The arguments are given at the basic physics level, so that the conclusion is independent of current technology status. These arguments are corroborated with imaging experiments of an aorta sample. The conclusion is that Hall effect imaging is not suited for quantifying the electrical constants in complex biological systems. Although this technique is able to produce detailed images that qualitatively reflect the electrical heterogeneity of a tissue sample, quantitative measurements of electrical constants are not practical for complex biological systems. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Rm B1D-523,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 0-7803-6365-5 J9 ULTRASON PY 2000 BP 1619 EP 1622 PG 4 WC Acoustics; Engineering, Industrial; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BT07X UT WOS:000171881300356 ER PT S AU Pham, DL AF Pham, DL GP IEEE IEEE TI Edge-adaptive clustering for unsupervised image segmentation SO 2000 INTERNATIONAL CONFERENCE ON IMAGE PROCESSING, VOL I, PROCEEDINGS SE IEEE International Conference on Image Processing (ICIP) LA English DT Proceedings Paper CT IEEE International Conference on Image Processing (ICIP 2000) CY SEP 10-13, 2000 CL VANCOUVER, CANADA SP IEEE, Signal Processing Soc AB When used for image segmentation, most standard clustering algorithms can shift image boundaries due to intensity fluctuations within an image. In this paper, a novel approach to clustering is proposed for performing unsupervised image segmentation based upon a,generalization of the standard K-means clustering algorithm. By incorporating a new term into the objective function of the K-means algorithm, boundaries between regions in the resulting segmentation are forced to occur at the same locations as edges in the observed image. A straightforward iterative algorithm is derived for minimizing this edge-adaptive K-means objective function. The result is an efficient segmentation algorithm that reconstructs boundaries in the image more accurately than standard methods. C1 NIA, Gerontol Res Ctr, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. RP Pham, DL (reprint author), NIA, Gerontol Res Ctr, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 0-7803-6298-5 J9 IEEE IMAGE PROC PY 2000 BP 816 EP 819 PG 4 WC Computer Science, Artificial Intelligence; 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 BR78F UT WOS:000167496300206 ER PT S AU Freidlin, RZ Ohazama, CJ Arai, AE McGarry, DP Panza, JA Trus, BL AF Freidlin, RZ Ohazama, CJ Arai, AE McGarry, DP Panza, JA Trus, BL BE Oliver, WR TI NIHmagic: 3D visualization, registration and segmentation tool SO 28TH AIPR WORKSHOP: 3D VISUALIZATION FOR DATA EXPLORATION AND DECISION MAKING SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT 28th AIPR Workshop CY OCT 13-15, 1999 CL WASHINGTON, D.C. SP SPIE, AIPR DE 3D visualization; volume rendering; texture mapping; interactive segmentation ID VOLUME AB Interactive visualization of multi-dimensional biological images has revolutionized diagnostic and therapy planning. Extracting complementary anatomical and functional information from different imaging modalities provides a synergistic analysis capability for quantitative and qualitative evaluation of the objects under examination. We have been developing NIHmagic, a visualization tool for research and clinical use, on the SGI OnyxII Infinite Reality platform. Images are reconstructed into a three-dimensional volume by volume rendering, a display technique that employs three-dimensional texture mapping to provide a translucent appearance to the object. A stack of slices is rendered into a volume by an opacity mapping function, where the opacity is determined by the intensity of the voxel and its distance from the viewer. NIHmagic incorporates three-dimensional visualization of time-sequenced images, manual registration of two-dimensional slices, segmentation of anatomical structures, and colored-coded re-mapping of intensities. Visualization of MRI, PET, CT, Ultrasound, and 3D reconstructed electron microscopy images has been accomplished using NIHmagic. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Freidlin, RZ (reprint author), NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 21 TC 1 Z9 1 U1 0 U2 1 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 0-8194-3517-1 J9 P SOC PHOTO-OPT INS PY 2000 VL 3905 BP 194 EP 201 DI 10.1117/12.384874 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Optics SC Computer Science; Optics GA BQ31L UT WOS:000087913500021 ER PT B AU Rindflesch, TC Rajan, JV Hunter, L AF Rindflesch, TC Rajan, JV Hunter, L GP acl TI Extracting molecular binding relationships from biomedical text SO 6TH APPLIED NATURAL LANGUAGE PROCESSING CONFERENCE/1ST MEETING OF THE NORTH AMERICAN CHAPTER OF THE ASSOCIATION FOR COMPUTATIONAL LINGUISTICS, PROCEEDINGS OF THE CONFERENCE AND PROCEEDINGS OF THE ANLP-NAACL 2000 STUDENT RESEARCH WORKSHOP LA English DT Proceedings Paper CT 6th Applied Natural Language Processing Conference/1st Meeting of the North American Chapter of the Association-for-Computational-Linguistics/ANLP-NAACL 2000 Student Research Workshop CY APR 29-MAY 04, 2000 CL Seattle, WA SP Assoc Computat Linguist, N Amer Chapter AB ARBITER is a Prolog program that extracts assertions about macromolecular binding relationships from biomedical text. We describe the domain knowledge and the under-specified linguistic analyses that support the identification of these predications. After discussing a formal evaluation of ARBITER, we report on its application to 491,000 MEDLINE(R) abstracts, during which almost 25,000 binding relationships suitable for entry into a database of macromolecular function were extracted. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Rindflesch, TC (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 27 TC 2 Z9 2 U1 0 U2 0 PU ASSOCIATION COMPUTATIONAL LINGUISTICS PI SOMERSET PA PO BOX 6090, SOMERSET, NJ 08875 USA BN 1-55860-704-8 PY 2000 BP 188 EP 195 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Linguistics SC Computer Science; Linguistics GA BAP09 UT WOS:000223099500026 ER PT J AU Han, ZJ Rhee, S Liu, KL Miles, HT Davies, DR AF Han, ZJ Rhee, S Liu, KL Miles, HT Davies, DR TI Crystallization and preliminary crystallographic study of triple-helical DNA SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article AB Single crystals of d(CTCCT(S)CCGCGCG).d(CGCGCGGAG) have been grown by the vapor-diffusion method using 2-methyl-2,4-pentanediol as a precipitant. The crystals are tetragonal, space group P4(2), with unit-cell parameters a = b = 53.8, c = 43.1 Angstrom, and diffract to 1.8 Angstrom resolution at a synchrotron X-ray beamline. In the crystal, the asymmetric unit contains one copy of the construct. The two halves of the structure are related by non-crystallographic twofold symmetry. These observations are consistent with the conclusion that the sequences of the 12-mer and 9-mer oligonucleotides form a duplex DNA at one end and a tripler DNA at the other end. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Han, ZJ (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 12 TC 4 Z9 5 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2000 VL 56 BP 104 EP 105 DI 10.1107/S0907444999012895 PN 1 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 280HD UT WOS:000085095500025 PM 10666643 ER PT J AU Segal, M Murphy, D AF Segal, M Murphy, D TI Estradiol induces formation of dendritic spines in hippocampal neurons: functional correlates SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT Meeting on Nature and Nurture in Epilepsy and Psychiatry - Implications for New Treatment Strategies CY 2000 CL OSLO, NORWAY ID DENSITY C1 Weizmann Inst Sci, IL-76100 Rehovot, Israel. NINDS, NIH, Bethesda, MD 20892 USA. RP Segal, M (reprint author), Weizmann Inst Sci, IL-76100 Rehovot, Israel. NR 6 TC 0 Z9 0 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PY 2000 VL 102 SU 175 BP 8 EP 8 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 390WR UT WOS:000166322500003 ER PT J AU Post, RM Leverich, GS Weiss, SRB Speer, AM Obrocea, G Denicoff, KD AF Post, RM Leverich, GS Weiss, SRB Speer, AM Obrocea, G Denicoff, KD TI Cellular mechanisms in the cyclic affective disorders SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT Meeting on Nature and Nurture in Epilepsy and Psychiatry - Implications for New Treatment Strategies CY 2000 CL OSLO, NORWAY ID TERM LITHIUM TREATMENT; STRESS; MODEL; RATS; EXCITOTOXICITY; EXPRESSION; BCL-2 C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, Bldg 10,Room 35239,10 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 0 Z9 0 U1 1 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PY 2000 VL 102 SU 175 BP 15 EP 17 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 390WR UT WOS:000166322500009 ER PT J AU Lahiri, DK Farlow, MR Hintz, N Utsuki, T Greig, NH AF Lahiri, DK Farlow, MR Hintz, N Utsuki, T Greig, NH TI Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer's disease SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 6th International Stockholm Springfield Symposium on Advances in Alzheimer Therapy CY APR 05-08, 2000 CL STOCKHOLM, SWEDEN DE Alzheimer's disease; beta-amyloid precursor protein; beta-peptide; anticholinesterase; cholinergic; cholinomimetics; butyrylcholinesterase; neuroblastoma cells ID COGNITIVE IMPAIRMENT; SENILE DEMENTIA; CELL-LINES; TACRINE; SECRETION; PHYSOSTIGMINE; PHENSERINE; FOREBRAIN; INCREASE; RELEASE AB The extracellular deposition of amyloid beta-peptide (A beta) in the form of cerebrovascular amyloid and extracellular plaques is one of the major neuropathological manifestations of Alzheimer's disease (AD). A beta is generated proteolytically from the large beta-amyloid precursor protein (APP). APP is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma. CSF and cultured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current approved AD drugs, such as aricept and tacrine, are based on the use of cholinesterase inhibitors (ChEIs) and have been reported to improve memory deficits and cognitive decline in some patients with AD. To compare the effects of ChEIs on APP processing, we have tested a series of ChEIs such as tacrine, physostigmine, metrifonate, phenserine and cymserine in cultured human neuroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of AS by a sensitive sandwich ELISA. Based on these results, ChEIs can be divided into three groups: the first group of ChEIs had no effect on sAPP secretion, the second decreased the sAPP secretion only, and third group affected the secretion of sAPP and A beta. The difference in the action of metrifonate, physostigmine. phenserine and tacrine on APP processing is independent of their selectivity for the cholinesterase enzymes. This possibly is due to the different targets that are used by ChEIs. Studying the effects of ChEIs on different targets is useful to maximize the benefit of ChEIs for the treatment of AD subjects. C1 Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Lahiri, DK (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Room PR-313,791 Union Dr, Indianapolis, IN 46202 USA. NR 41 TC 12 Z9 12 U1 2 U2 2 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PY 2000 VL 102 SU 176 BP 60 EP 67 DI 10.1034/j.1600-0404.2000.00309.x PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 403WJ UT WOS:000167065200010 ER PT J AU Greig, NH De Micheli, E Holloway, HW Yu, QS Utsuki, T Perry, TA Brossi, A Ingram, DK Deutsch, J Lahiri, DK Soncrant, TT AF Greig, NH De Micheli, E Holloway, HW Yu, QS Utsuki, T Perry, TA Brossi, A Ingram, DK Deutsch, J Lahiri, DK Soncrant, TT TI The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 6th International Stockholm Springfield Symposium on Advances in Alzheimer Therapy CY APR 05-08, 2000 CL STOCKHOLM, SWEDEN DE Alzheimer's disease; anticholinesterases; acelylcholine; cholinomimetics; acetylcholinesterase; butyrylcholinesterase; in vivo microdialysis ID 14-UNIT T-MAZE; INDUCED LEARNING IMPAIRMENT; AMYLOID PRECURSOR PROTEIN; EXTRACELLULAR ACETYLCHOLINE; SENILE DEMENTIA; CHOLINESTERASE INHIBITION; INVIVO MICRODIALYSIS; CHOLINERGIC SYSTEM; NUCLEUS BASALIS; CEREBRAL-CORTEX AB Phenserine. a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a > 50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (,70%;,) and long-lasting inhibition of AChE was achieved (half-life > 8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-lift, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. C1 NIA, Neurosci Lab, Intramural Res Program, Gerontol Res Ctr, Baltimore, MD 21224 USA. Hebrew Univ Jerusalem, Dept Pharmaceut Chem, Jerusalem, Israel. Indiana Univ, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Cure Inc, Silver Spring, MD USA. RP Greig, NH (reprint author), LNS, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 56 TC 8 Z9 8 U1 1 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PY 2000 VL 102 SU 176 BP 74 EP 84 DI 10.1034/j.1600-0404.2000.00311.x PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 403WJ UT WOS:000167065200012 ER PT J AU LaPoint, SF Powers, JM Woodruff, JM MacCollin, M Jacoby, LB Vortmeyer, AO Zhuang, ZP Fong, CT Ifthikharuddin, SF Teot, L Coniglio, JU Sullivan, RP AF LaPoint, SF Powers, JM Woodruff, JM MacCollin, M Jacoby, LB Vortmeyer, AO Zhuang, ZP Fong, CT Ifthikharuddin, SF Teot, L Coniglio, JU Sullivan, RP TI Schwann cell-onion bulb tumor of the trigeminal nerve: hyperplasia, dysplasia or neoplasia? SO ACTA NEUROPATHOLOGICA LA English DT Article DE nerve; neurocutaneous; onion bulb; Schwann; trigeminal ID LOCALIZED HYPERTROPHIC MONONEUROPATHY; MULTIPLE-SCLEROSIS; NEUROPATHY; PERINEURIOMA; CHARCOT; MARIE; TOOTH AB Onion bulbs are concentric lamellar structures formed by Schwann or perineurial cells, which may be seen in several generalized or localized diseases of the peripheral nerve. There is debate regarding the pathogenesis of localized tumefactions displaying these microscopic structures. We report the fifth case, to our knowledge, of a Schwann cell-onion bulb tumor, which arose in the trigeminal nerve of a child with an unclassifiable, probably distinct, neurocutaneous syndrome; we also provide evidence for a neoplastic or hamartomatous origin. Molecular studies failed to establish an abnormality in the NF1, NF2, PMP22, or Connexin 32 genes. Similar and previously reported cases are discussed, as well as other onion bulb-forming entities. C1 Univ Rochester, Med Ctr, Dept Pathol, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Div Otolaryngol, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Radiol, Rochester, NY 14642 USA. Massachusetts Gen Hosp E, Mol Neurogenet Unit, Charlestown, MA USA. Massachusetts Gen Hosp E, Ctr Neurosci, Charlestown, MA USA. Mem Hosp, Dept Pathol, New York, NY USA. NIH, Pathol Lab, Mol Diagnost Unit, Bethesda, MD 20892 USA. RP Powers, JM (reprint author), Univ Rochester, Med Ctr, Dept Pathol, Box 626,601 Elmwood Ave, Rochester, NY 14642 USA. NR 27 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JAN PY 2000 VL 99 IS 1 BP 67 EP 72 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 267AZ UT WOS:000084333600011 PM 10651030 ER PT J AU Karamychev, VN Reed, MW Neumann, RD Panyutin, IG AF Karamychev, VN Reed, MW Neumann, RD Panyutin, IG TI Distribution of DNA strand breaks produced by iodine-123 and indium-111 in synthetic oligodeoxynucleotides SO ACTA ONCOLOGICA LA English DT Article; Proceedings Paper CT 4th International Symposium on Biophysical Aspects of Auger Processes CY JUL 15-16, 1999 CL LUND UNIV, LUND, SWEDEN HO LUND UNIV ID I-125 LABELED OLIGONUCLEOTIDES; DECAY; TRIPLEX; DAMAGE; CELLS AB Antigene radiotherapy, a procedure based on delivery of short-range Auger-electron-emitting radioisotopes to target genes via sequence-specific tripler-forming oligonucleotides, has been successfully demonstrated in vitro using the well-studied radionuclide I-125. To proceed with in vivo trials, Auger electron emitters with shorter half-lives than I-125 are required. Here we report a study of the efficiency and distribution of sequence-specific DNA strand breaks produced by decay of I-123 and In-111. I-123 and In-111 were introduced into triplex- and duplex-forming oligodeoxyribonucleotides (ODNs) through carbohydrate linkers of various lengths. Labeling with radioiodine was performed through tributylstannylbenzamide intermediates while In-111 was attached via DTPA. The Auger-emitter-labeled ODNs were hybridized to a single-stranded DNA target, to form duplexes. After decay accumulation, the target DNA samples were assayed for strand breaks using a sequencing gel-electrophoresis technique. For the first time, we observed footprints of DNA strand breaks produced by I-123 and In-111. Most of the breaks were located within 10 nucleotides from the decay site. The yield of strand breaks per decay varies; decay of In-111 breaks DNA almost 10 times more effectively than decay of I-123. Both I-123 and In-111 are less effective in breaking DNA strands than I-125, which reflects the higher total energy of the Auger decay process of I-125. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20854 USA. Epoch Pharmaceut, Redmond, WA USA. RP Panyutin, IG (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, 10 Ctr Dr,Room 1C401, Bethesda, MD 20854 USA. NR 17 TC 14 Z9 15 U1 1 U2 2 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2000 VL 39 IS 6 BP 687 EP 692 PG 6 WC Oncology SC Oncology GA 377WT UT WOS:000165549800006 PM 11130005 ER PT J AU Nikjoo, H Panyutin, IG Terrissol, M Vrigneaud, JM Laughton, CA AF Nikjoo, H Panyutin, IG Terrissol, M Vrigneaud, JM Laughton, CA TI Distribution of strand breaks produced by Auger electrons in decay of I-125 in triplex DNA SO ACTA ONCOLOGICA LA English DT Article; Proceedings Paper CT 4th International Symposium on Biophysical Aspects of Auger Processes CY JUL 15-16, 1999 CL LUND UNIV, LUND, SWEDEN HO LUND UNIV ID INDIRECT MECHANISMS CONTRIBUTE; CELLS IN-VITRO; INCORPORATED I-125; AQUEOUS-SOLUTION; DAMAGE; HELIX; I125 AB In this study we investigate the possibility of using Auger electrons as a probing agent for the study of structures of nucleic acids. To this end, we present the distribution of breaks produced in strands of a DNA duplex and a tripler-forming oligonucleotide (TFO) carrying Auger emitting radionuclide I-125. The method of calculation includes use of a molecular model of plasmid DNA duplex with bound TFO carrying a labelled I-125 at position C5 of a single deoxycytosine residue, a source of Auger spectra, Monte Carlo electron track structure and the ensuing chemistry codes, to simulate the distribution of breaks produced in both strands of a plasmid DNA. Frequencies of fragment length distributions were obtained for the TFO, the purine and the pyrimidine strands. The frequency of breaks in the purine strand showed good correlation with the published experimental results, while that for the pyrimidine strand is lower by a factor of 3. It is concluded that the true structure of tripler DNA map not be purely of B-form. C1 MRC, Radiat & Genome Stabil Unit, Harwell OX11 0RD, Oxon, England. NIH, Dept Nucl Med, Bethesda, MD USA. Univ Toulouse 3, CPAT, F-31062 Toulouse, France. Univ Nottingham, Sch Pharmaceut Sci, Nottingham NG7 2RD, England. RP Nikjoo, H (reprint author), MRC, Radiat & Genome Stabil Unit, Harwell OX11 0RD, Oxon, England. RI Laughton, Charles/E-5667-2010 OI Laughton, Charles/0000-0003-4090-3960 NR 30 TC 6 Z9 6 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2000 VL 39 IS 6 BP 707 EP 712 PG 6 WC Oncology SC Oncology GA 377WT UT WOS:000165549800009 PM 11130008 ER PT J AU Schnermann, J Traynor, T Pohl, H Thomas, DW Coffman, TM Briggs, JP AF Schnermann, J Traynor, T Pohl, H Thomas, DW Coffman, TM Briggs, JP TI Vasoconstrictor responses in thromboxane receptor knockout mice: tubuloglomerular feedback and ureteral obstruction SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 4th International Symposium on Vasodilators in the Development of Hyperttension - NO and Dopamine CY JUN 04-07, 1999 CL UPPSALA, SWEDEN SP Acta Physiologica Scandinavica, Scandinavian Physiol Soc, AstraZeneca, Astra Merck, Bristol Myers Squibb, Merk Sharp & Dome, Swedish Med Res Council DE knockout mice; micropuncture; thromboxane; tubuloglomerular feedback; ureteral obstruction; vasoconstriction ID RAT-KIDNEY; PRESSURE; NEPHRON; EXPRESSION; INHIBITION; SYNTHASE; FLOW; A(2) AB The role of thromboxane (TP) in the vasoconstriction induced by tubuloglomerular feedback or 18-h ureteral obstruction was studied in wild type mice (TP +/+), and in heterozygous (TP +/-) and homozygous TP receptor knockout mice (TPR -/-). TGF function was assessed from the response of stop flow pressure (P-SF) to a maximum increase in loop of Henle flow rate (0-30 nL min(-1)). P-SF fell by 6.4 +/- 0.4 mmHg in wild-type mice, by 6.1 +/- 0.6 mmHg in TP +/-, and by 7.9 +/- 0.7 mmHg in TP -/- mice. In the presence of the TP receptor agonist U46,619 (10(-5) M) the P-SF reduction increased to 10.4 +/- 0.8 mmHg in TP +/+, and to 10.6 +/- 2.8 mmHg in TP +/-, but was unchanged at 7.7 +/- 0.7 mmHg in TP -/-. Mean arterial blood pressures were comparable between groups (103 +/- 3 mmHg in TP +/+, 113 +/- 4.6 in TP +/- and 113 +/- 2.4 mmHg in TP -/- mice). Intratubular pressure following unilateral ureteral obstruction was significantly higher in TP -/- than in TP +/+ mice both in the early phase (0-3 h) and late phase (18 h) of obstruction. These results indicate that chronic TP receptor deficiency does not significantly alter maximum TGF responses in mice, and that it is accompanied by exaggerated vasodilatation during short-term unilateral ureteral obstruction and attenuated vasoconstriction during longer lasting obstruction. We conclude that thromboxane is primarily a regulator of renal vascular tone under pathophysiological conditions. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. Duke Univ, Dept Med, Durham, NC USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Room 4D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [DK39255, DK37448, DK40042] NR 29 TC 14 Z9 14 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD JAN PY 2000 VL 168 IS 1 BP 201 EP 207 PG 7 WC Physiology SC Physiology GA 290CZ UT WOS:000085659800029 PM 10691801 ER PT S AU Barker, N Morin, PJ Clevers, H AF Barker, N Morin, PJ Clevers, H BE VandeWoude, GF Klein, G TI The yin-yang of TCF/beta-catenin signaling SO ADVANCES IN CANCER RESEARCH, VOL 77 SE Advances in Cancer Research LA English DT Review ID GLYCOGEN-SYNTHASE KINASE-3; TRANSCRIPTION FACTOR LEF-1; TUMOR-SUPPRESSOR PROTEIN; TCR-ALPHA ENHANCER; C-ELEGANS EMBRYOS; BETA-CATENIN; HMG-BOX; XENOPUS EMBRYOS; FUNCTIONAL INTERACTION; NUCLEAR-LOCALIZATION C1 Univ Hosp, Dept Immunol, NL-85500 GA Utrecht, Netherlands. NIA, Baltimore, MD 21224 USA. RP Univ Hosp, Dept Immunol, NL-85500 GA Utrecht, Netherlands. RI Barker, Nick/A-5535-2011 NR 90 TC 216 Z9 224 U1 2 U2 12 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 0-12-006677-7 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2000 VL 77 BP 1 EP 24 PG 24 WC Oncology SC Oncology GA BP33A UT WOS:000084726500001 PM 10549354 ER PT J AU Leonard, EJ Danilkovitch, A AF Leonard, EJ Danilkovitch, A TI Macrophage stimulating protein SO ADVANCES IN CANCER RESEARCH, VOL 77 SE ADVANCES IN CANCER RESEARCH LA English DT Review ID HEPATOCYTE GROWTH-FACTOR; FOCAL ADHESION KINASE; FACTOR SCATTER FACTOR; RECEPTOR TYROSINE KINASE; NUCLEOTIDE EXCHANGE FACTOR; STEM-CELL FACTOR; SIGNAL-TRANSDUCTION; PHOSPHATIDYLINOSITOL 3-KINASE; C-MET; EXTRACELLULAR DOMAIN C1 NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Leonard, EJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. NR 142 TC 28 Z9 28 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X J9 ADV CANCER RES JI Adv.Cancer Res. PY 2000 VL 77 BP 139 EP 167 PG 29 WC Oncology SC Oncology GA BP33A UT WOS:000084726500004 PM 10549357 ER PT S AU Kelloff, GJ AF Kelloff, GJ BE VandeWoude, GF Klein, G TI Perspectives on cancer chemoprevention research and drug development SO ADVANCES IN CANCER RESEARCH, VOL 78 SE Advances in Cancer Research LA English DT Review ID NITRIC-OXIDE SYNTHASE; PROSTAGLANDIN ENDOPEROXIDE SYNTHASE; HUMAN PROSTATE-CANCER; NONSTEROIDAL ANTIINFLAMMATORY DRUG; EPIDERMAL GROWTH-FACTOR; 9-CIS RETINOIC ACID; HUMAN BREAST-CANCER; CERVICAL INTRAEPITHELIAL NEOPLASIA; NUTRITION INTERVENTION TRIALS; 12-LIPOXYGENASE MESSENGER-RNA C1 NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. RP Kelloff, GJ (reprint author), NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. NR 370 TC 197 Z9 201 U1 1 U2 4 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 0-12-006678-5 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2000 VL 78 BP 199 EP 334 PG 136 WC Oncology SC Oncology GA BP55A UT WOS:000085482300005 PM 10547671 ER PT B AU Quyyumi, AA AF Quyyumi, AA BE Osterhues, HH Hombach, V Moss, AJ TI Circadian variation in myocardial ischemia and infarction SO ADVANCES IN NONINVASIVE ELECTROCARDIOGRAPHIC MONITORING TECHNIQUES SE DEVELOPMENTS IN CARDIOVASCULAR MEDICINE LA English DT Proceedings Paper CT 8th International Congress on Holter and Noninvasive Electrocardiology CY MAY 22-23, 1998 CL ULM, GERMANY SP Int Soc Holter & Noninvasive Electrocardiol ID CORONARY-ARTERY DISEASE; NITRIC-OXIDE ACTIVITY; HEART-RATE; DAILY LIFE; L-ARGININE; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR-DISEASE; AMBULATORY ISCHEMIA; MORNING INCREASE; ANGINA-PECTORIS C1 NIH, Cardiol Branch, Bethesda, MD 20892 USA. RP Quyyumi, AA (reprint author), NIH, Cardiol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 55 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-6214-4 J9 DEV CARDIOVASC MED PY 2000 VL 229 BP 247 EP 261 PG 15 WC Cardiac & Cardiovascular Systems; Medical Laboratory Technology SC Cardiovascular System & Cardiology; Medical Laboratory Technology GA BP88V UT WOS:000086496500023 ER PT S AU Chen, YD Kamat, V Dougherty, ER Bittner, ML Meltzer, PS Trent, JM AF Chen, YD Kamat, V Dougherty, ER Bittner, ML Meltzer, PS Trent, JM BE Limbach, PA Owicki, JC Raghavachari, R Tan, W TI Expression ratio statistics and its applications to microarray data analysis SO ADVANCES IN NUCLEIC ACID AND PROTEIN ANALYSES, MANIPULATION, AND SEQUENCING SE PROGRESS IN BIOMEDICAL OPTICS LA English DT Proceedings Paper CT Conference on Advances in Nucleic Acid and Protein Analyses, Manipulation, and Sequencing CY JAN 26-27, 2000 CL SAN JOSE, CA SP SPIE, Int Biomed Opt Soc AB Microarray technology makes it possible to monitor expression levels of thousands of genes simultaneously during single or multiple experiments. Routinely, in order to analyze gene expressions level quantitatively, two fluorescent-labeled RNAs are hybridized to an array of cDNA probes on a glass slide. Ratios of gene expression levels arising from two co-hybridized samples are obtained through image segmentation and signal detection methods. During the past three years, we have developed a gene expression analysis system in which ratio statistics have been applied to expression analysis, and a ratio confidence interval, has been established to identify ratio outliers. By using local background subtraction and weak target elimination, we have been able to assume that the fluorescent background level does not interfere with ratio measurement; however, experience suggests that ratios derived from either weak targets or in regions of high local background possess greater variation than those from strong targets. This paper proposes a new interaction model between fluorescent background and hybridization signals in which ratio statistics are numerically evaluated and a self-adjusting confidence interval is employed. The self-adjusting confidence interval, which automatically adapts under different signal-to-background ratios, provides a better criterion to further interrogate weak expression levels. C1 NIH, Canc Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Chen, YD (reprint author), NIH, Canc Genet Branch, Natl Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 5 Z9 5 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 1017-2661 BN 0-8194-3542-2 J9 PROG BIOM O PY 2000 VL 1 BP 142 EP 149 PG 8 WC Engineering, Biomedical; Optics SC Engineering; Optics GA BP95C UT WOS:000086711300018 ER PT J AU Ponting, CP Schultz, J Copley, RR Andrade, MA Bork, P AF Ponting, CP Schultz, J Copley, RR Andrade, MA Bork, P TI Evolution of domain families SO ADVANCES IN PROTEIN CHEMISTRY, VOL 54 SE ADVANCES IN PROTEIN CHEMISTRY LA English DT Review ID RNA-BINDING DOMAIN; HORIZONTAL GENE-TRANSFER; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; CAENORHABDITIS-ELEGANS; DNA-BINDING; PROTEIN SEQUENCES; ESCHERICHIA-COLI; GENOME SEQUENCE; LIGAND-BINDING C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. EMBL, D-20894 Heidelberg, Germany. RP Ponting, CP (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RI Andrade, Miguel/B-6565-2008; Schultz, Joerg/B-9346-2008; Bork, Peer/F-1813-2013 OI Andrade, Miguel/0000-0001-6650-1711; Bork, Peer/0000-0002-2627-833X NR 236 TC 55 Z9 58 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-3233 J9 ADV PROTEIN CHEM JI Adv.Protein Chem. PY 2000 VL 54 BP 185 EP 244 DI 10.1016/S0065-3233(00)54007-8 PG 68 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ26S UT WOS:000087752000008 PM 10829229 ER PT J AU Koonin, EV Wolf, YI Aravind, L AF Koonin, EV Wolf, YI Aravind, L TI Protein fold recognition using sequence profiles and its application in structural genomics SO ADVANCES IN PROTEIN CHEMISTRY, VOL 54 SE ADVANCES IN PROTEIN CHEMISTRY LA English DT Review ID MYCOPLASMA-GENITALIUM PROTEINS; HIDDEN MARKOV-MODELS; ESCHERICHIA-COLI DNA; RNA-BINDING DOMAIN; OF-THE-ART; CRYSTAL-STRUCTURE; STRUCTURE PREDICTION; CATALYTIC DOMAIN; HISTIDINE KINASE; GENE-TRANSFER 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 105 TC 58 Z9 60 U1 0 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-3233 J9 ADV PROTEIN CHEM JI Adv.Protein Chem. PY 2000 VL 54 BP 245 EP 275 DI 10.1016/S0065-3233(00)54008-X PG 35 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ26S UT WOS:000087752000009 PM 10829230 ER PT S AU Martin, R Bielekova, B Gran, B McFarland, HF AF Martin, R Bielekova, B Gran, B McFarland, HF BE Riederer, P Calne, DB Horowski, R Mizuno, Y Olanow, CW Poewe, W Youdim, MBH TI Lessons from studies of antigen-specific T cell responses in Multiple Sclerosis SO ADVANCES IN RESEARCH ON NEURODEGENERATION, VOL 8 SE ADVANCES IN RESEARCH ON NEURODEGENERATION LA English DT Proceedings Paper CT 8th International Winter Conference on Neurodegeneration (IWCN) CY FEB 09-13, 2000 CL TEGERNSEE, GERMANY SP Merz & Co GmbH & Co, SmithKline Beecham Pharma GmbH, Boehringer Ingelheim Pharma KG, Schering AG ID MYELIN BASIC-PROTEIN; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; FACTOR-ALPHA PRODUCTION; SJL-J-MICE; OLIGODENDROCYTE GLYCOPROTEIN; PROTEOLIPID PROTEIN; ENCEPHALITOGENIC EPITOPE; B-CELL AB Multiple Sclerosis (MS) is considered a T cell-mediated autoimmune disease of central nervous system myelin. Based on elegant experiments in an animal model of MS, experimental allergic encephalomyelitis (EAE), a number of myelin proteins and peptides derived from these can induce inflammatory demyelinating lesions. Recent studies with transgenic mice expressing human HLA-DR molecules and a myelin basic protein (MBP)-specific T cell receptor as well as data from a phase II clinical trial with an altered peptide ligand based on MBP peptide (83-99) provide convincing evidence that the pathogenetic concepts which largely stem from the above EAE studies are valid in MS, too. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr MSC1400, Bethesda, MD 20892 USA. OI Gran, Bruno/0000-0001-6384-2342 NR 103 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, A-1201 VIENNA, AUSTRIA SN 1068-719X BN 3-211-83538-5 J9 ADV RES NEURODEGENER PY 2000 VL 8 BP 361 EP 373 PG 13 WC Neurosciences SC Neurosciences & Neurology GA BR80G UT WOS:000167600700026 ER PT J AU Carr, A Yarchoan, R AF Carr, A Yarchoan, R TI Clinical treatment SO AIDS LA English DT Editorial Material C1 St Vincents Hosp, HIV Immunol & Infect Dis Clin Serv Unit, Darlinghurst, NSW 2010, Australia. NIH, Bethesda, MD 20892 USA. RP Carr, A (reprint author), St Vincents Hosp, HIV Immunol & Infect Dis Clin Serv Unit, Cahill Bldg Level 17,Victoria St, Darlinghurst, NSW 2010, Australia. NR 0 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 PY 2000 VL 14 SU 3 BP S187 EP S188 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 371RN UT WOS:000165192100019 PM 11086861 ER PT J AU Falloon, J AF Falloon, J TI Salvage antiretroviral therapy SO AIDS LA English DT Article DE HIV; AIDS; antiretroviral; therapy; drugs; salvage ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE INHIBITOR THERAPY; TYPE-1 REVERSE-TRANSCRIPTASE; HIV-INFECTED PATIENTS; SAQUINAVIR-CONTAINING REGIMEN; VIROLOGICAL TREATMENT FAILURE; DRUG-RESISTANCE MUTATIONS; LONG-TERM RESPONSE; HIV-1-INFECTED INDIVIDUALS; PHENOTYPIC RESISTANCE C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Falloon, J (reprint author), NIAID, Immunoregulat Lab, NIH, Room 11C103,Bldg 10,10 Ctr Dr,MSC 1880, Bethesda, MD 20892 USA. NR 99 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PY 2000 VL 14 SU 3 BP S209 EP S217 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 371RN UT WOS:000165192100022 PM 11086864 ER PT J AU Puri, A Riley, JL Kim, D Ritchey, DW Hug, P Jernigan, K Rose, P Blumenthal, R Carroll, RG AF Puri, A Riley, JL Kim, D Ritchey, DW Hug, P Jernigan, K Rose, P Blumenthal, R Carroll, RG TI Influenza virus upregulates CXCR4 expression in CD4(+) cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID T-CELLS; CD28 COSTIMULATION; HIV-1 ENTRY; DISEASE PROGRESSION; EPITHELIAL-CELLS; FUSION COFACTOR; TROPIC HIV-1; INFECTION; HEMAGGLUTININ; RECEPTOR AB We examined the effect of prior influenza virus infection on the susceptibility of CD4(+) cells to HIV-1 infection. Influenza virus infection of HeLa-CD4 cells resulted in a marked increase in susceptibility to infection by CXCR4-dependent but not CCR5-dependent HIV isolates. Influenza virus infection resulted in an increase in the steady state level of CXCR4 transcripts and an increase in cell surface CXCR4 expression. Our observations suggest that infectious agents such as influenza may contribute to HIV disease progression by modulating coreceptor availability. C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. Henry M Jackson Fdn Advancement Mil Med, US Mil HIV Res Program, Bethesda, MD 20889 USA. RP Puri, A (reprint author), NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 33 TC 6 Z9 6 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN 1 PY 2000 VL 16 IS 1 BP 19 EP 25 DI 10.1089/088922200309566 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 309QQ UT WOS:000086781100004 PM 10628813 ER PT J AU Brooks, PJ Lipsky, RH AF Brooks, PJ Lipsky, RH TI Future directions in alcoholism research - Genomics and gene transfer SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE gene expression; protein synthesis; genome; virus; mRNA; hippocampus; ventral tegmental area; animal model ID NERVOUS-SYSTEM; DIFFERENTIAL DISPLAY; EXPRESSION; BRAIN; VECTORS; CNS AB Alcohol affects the process by which genes direct the synthesis of proteins (i.e., expression). Therefore, patterns of gene expression in the presence of alcohol can help scientists identify the specific molecular sites of alcohol's actions within the brain. New technologies can detect and quantify changes in the expression of thousands of genes simultaneously by scanning microscopic gene arrays applied to glass or silicon chips an inch or so square. However, genes whose activity is altered in the presence of alcohol may either be contributing to alcoholism development or may be reacting to alcohol's presence. This question can be researched by observing the effects of manipulating the level of specific gene products. One way to accomplish this end is by means of viruses that have been engineered to express a specific gene in infected cells. This technique has been applied successfully in studying addictive behaviors. It is suggested that patterns of gene expression may become a diagnostic fool, with different disease states being characterized by distinct expression profiles. C1 NIAAA, Neurogenet Lab, Bethesda, MD USA. RP Brooks, PJ (reprint author), NIAAA, Neurogenet Lab, Bethesda, MD USA. OI Lipsky, Robert/0000-0001-7753-1473 NR 22 TC 2 Z9 2 U1 0 U2 0 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 0090-838X J9 ALCOHOL RES HEALTH JI Alochol Res. Health PY 2000 VL 24 IS 3 BP 189 EP 192 PG 4 WC Substance Abuse SC Substance Abuse GA 398MH UT WOS:000166759900007 PM 11199290 ER PT J AU Dawson, DA AF Dawson, DA TI Alcohol consumption, alcohol dependence, and all-cause mortality SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE mortality; consumption; dependence; alcoholism ID MIDDLE-AGED MEN; CARDIOVASCULAR-DISEASE; HEART-DISEASE; COMORBIDITY; POPULATION; DISORDERS; DRINKING; BEER; DEPRESSION; PREVALENCE AB Background: This study examined the effects of alcohol consumption and DSM-IV alcohol dependence on the risk of mortality. Methods: Data from the 1988 National Health Interview Survey Alcohol Supplement were matched to the National Death Index for the years 1988 to 1995 (baseline n = 37,682 U.S. adults age greater than or equal to 25 linked to 3,586 deaths). All mortality analyses were based on proportional hazards models that adjusted for age, sex, race/ethnicity, marital status, education, income, labor force status, body mass index; smoking status, and poor health indicators at baseline. Results: When dependence was not considered and all past-year abstainers were used as the reference group, both light and moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of 0.76 (0.68-0.84) and 0.84 (0.74-0.96). Heavy drinkers had about the same risk of dying as did past-year abstainers, and very heavy drinkers had an increased risk that was not significant (OR = 1.17, CI = 0.93-1.47). When lifetime abstainers were used as the reference category, the protective effect of moderate drinking fell short of significance, and there were nearly significant increased risks among former drinkers and very heavy drinkers. When dependence was considered, light and moderate drinkers without dependence had a reduced mortality risk regardless of reference group, and there was no significant effect among heavy or very heavy drinkers without dependence. Among dependent drinkers, there was no protective effect of light or moderate drinking, and very heavy drinkers had a significantly increased risk (OR = 1.56 relative to past-year abstainers and 1.65 relative to lifetime abstainers). Conclusions: Because alcohol dependence nullifies the protective effect of light and moderate drinking, it is important to understand its role as an independent risk factor for mortality. Differences between dependent and nondependent drinkers who drank comparable amounts suggest that this risk may result from longer and heavier drinking histories before baseline, more severe health problems at baseline, more heavy episodic drinking, and, possibly, differences in beverage preference. C1 NIAAA, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Div Biometry & Epidemiol, NIH, Willco Bldg,Suite 514,6000 Execut Blvd,MSC 7003, Bethesda, MD 20892 USA. NR 53 TC 96 Z9 96 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2000 VL 24 IS 1 BP 72 EP 81 DI 10.1097/00000374-200001000-00012 PG 10 WC Substance Abuse SC Substance Abuse GA 276WT UT WOS:000084901900012 PM 10656196 ER PT J AU Metcalfe, DD AF Metcalfe, DD TI Differential diagnosis of the patient with unexplained flushing/anaphylaxis SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID BLOOD MONONUCLEAR-CELLS; C-KIT; MASTOCYTOSIS; DISORDERS; MUTATION AB In unusual cases of flushing and anaphylaxis, and after the elimination of the more obvious causes of anaphylaxis or those that may be evaluated by readily available techniques, if is possible to confront a limited and difficult differential diagnosis, which includes idiopathic flushing anaphylaxis, and neoplastic syndromes associated with mastocytosis and carcinoid tumor. Interestingly, there are rather few features that distinguish one of these possibilities from another However, the presence of allergic signs and symptoms tend to favor the diagnosis of recurrent idiopathic anaphylaxis; and right-sided valvular heart disease, the presence of excessive 5-HIAA in the urine, and a response to somatostatin favor the diagnosis of carcinoid syndrome. The distinguishing features of mastocytosis include the presence of characteristic skin lesions and diagnostic histopathologic findings on bone marrow biopsy. Counts of absolute mast cell numbers in the skin are less helpful. Following such guidelines, it is often possible to focus on the most likely diagnosis, be it idiopathic anaphylaxis, benign cutaneous flushing, mastocytosis, or carcinoid tumor. C1 NIAID, NIH, LAD, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, NIH, LAD, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 11 TC 23 Z9 23 U1 0 U2 1 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JAN-FEB PY 2000 VL 21 IS 1 BP 21 EP 24 DI 10.2500/108854100778249006 PG 4 WC Allergy SC Allergy GA 291JB UT WOS:000085729900004 PM 10748948 ER PT J AU Cohen, SG AF Cohen, SG TI From immunity to autoimmune disease, a historic trail Part I SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article C1 NIAID, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JAN-FEB PY 2000 VL 21 IS 1 BP 63 EP 68 DI 10.2500/108854100778249024 PG 6 WC Allergy SC Allergy GA 291JB UT WOS:000085729900011 PM 10748954 ER PT S AU Mattson, MP AF Mattson, MP BE Khachaturian, ZS Mesulam, MM TI Existing data suggest that Alzheimer's disease is preventable SO ALZEHEIMER'S DISEASE: A COMPENDIUM OF CURRENT THEORIES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Towards a Comprehensive Theory for Alzheimers Diaease CY APR 30-MAY 02, 1999 CL ORLANDO, FLORIDA SP Bayer, EISAI, Hoechst Marion Roussel, Pfizer, Roche DE amyloid; apoptosis; calorie restriction; diet; glucose; neurotrophic factor ID PROTECTS HIPPOCAMPAL-NEURONS; DIETARY RESTRICTION; PARKINSONS-DISEASE; BRAIN-DAMAGE; MICE; DEGENERATION; MECHANISM; STRESS AB The ultimate goal of Alzheimer's disease (AD) research is to prevent the onset of the neurodegenerative process and thereby allow successful aging without cognitive decline. Herein I argue that a simple and effective preventative approach for AD may be in hand. AD is a disorder associated with the aging process and is, accordingly, characterized by cellular and molecular changes that occur in age-related diseases in other organ systems. Such changes include increased levels of oxidative stress, perturbed energy metabolism, and accumulation of insoluble (oxidatively modified) proteins (prominent among which are amyloid P-peptide and tau). The risk of several other prominent age-related disorders, including cardiovascular disease, cancer, and diabetes, is known to be influenced by the level of food intake-high food intake increases risk, and low food intake reduces risk. An overwhelming body of data from studies of rodents and monkeys has documented the profound beneficial effects of dietary restriction (DR) in extending life span and reducing the incidence of age-related diseases. Reduced levels of cellular oxidative stress and enhancement of energy homeostasis contribute to the beneficial effects of DR. Recent findings suggest that DR may enhance resistance of neurons in the brain to metabolic, excitotoxic, and oxidative insults relevant to the pathogenesis of AD and other neuro degenerative disorders. While further studies will be required to establish the extent to which DR will reduce the incidence of AD, it would seem prudent (based on existing data) to recommend DR as widely applicable preventative approach for age-related disorders including neurodegenerative disorders. C1 NIA, Lab Neurosci 4F01, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci 4F01, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 22 TC 22 Z9 26 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-297-5 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2000 VL 924 BP 153 EP 159 PG 7 WC Multidisciplinary Sciences; Clinical Neurology SC Science & Technology - Other Topics; Neurosciences & Neurology GA BT10Q UT WOS:000171966500022 PM 11193791 ER PT J AU Cahill, M Wichman, A AF Cahill, M Wichman, A TI Research involving persons with cognitive impairments: Results of a survey of Alzheimer disease research centers in the United States SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; clinical research; cognitively impaired; decisionally impaired ID PROPOSED GUIDELINES; CLINICAL RESEARCH; ETHICAL ISSUES; LEGAL ISSUES; DEMENTIA; CONSENT AB Research involving persons with cognitive impairments presents ethical and practical challenges, including how to obtain valid informed consent. We asked the directors of the 29 U.S. research centers funded by the National Institute on Aging as "Alzheimer Disease Centers" to provide us with policies or guidelines used in their centers or associated institutions with regard to research involving cognitively impaired subjects. Twenty-four of the 29 centers (83%) responded. Five institutions (21%) had authored their own institutional policies, seven (29%) used guidelines issued by the Department of Health and Human Service's Office for Protection from Research Risks, and 12 (50%) had no policy or guidelines. The five institutional policies addressed a variety of issues, including obtaining consent from cognitively impaired subjects or their authorized representatives, subjects' assent to research participation, and guidance concerning determination of subjects' intellectual capacity. A well-written policy on the protection of cognitively impaired research subjects is one way a research institution demonstrates that it gives serious attention to the rights and welfare of these vulnerable persons. We recommend that all institutions conducting such research author written policies articulating appropriate safeguards for these vulnerable subjects. To promote the protection of cognitively impaired subjects, federal agencies and other funding groups may want to consider requiring written institutional policies as one condition of receiving funds to conduct such research. C1 NIH, Off Human Subjects Res, Bethesda, MD 20892 USA. RP Wichman, A (reprint author), NIH, Off Human Subjects Res, Bldg 10,Room 1C116, Bethesda, MD 20892 USA. NR 22 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JAN-MAR PY 2000 VL 14 IS 1 BP 20 EP 27 DI 10.1097/00002093-200001000-00003 PG 8 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 290KJ UT WOS:000085675200003 PM 10718201 ER PT J AU Berkman, LF Carney, R Blumenthal, J Czakowski, S Hosking, J Jaffe, A Babyak, M Carels, R Coleman, E Curtis, S Davis, L Fath, K Forman, L Hassett, A Hegde, SB Herman, SH Hinderliter, A Khatri, P Krishnan, KR Levenberg, S Mark, D Marz, P Matthews, J McCarthy, R Mieszkalski, K Miller, G Norten, J O'Connor, C Puma, J Rutt, L Sessions, W Siegler, I Wadley, V Watkins, L Waugh, R Williams, R Zakhary, BG Powell, LH Calvin, JE Clark, DC Creech, S Eaton, C Elliott, JW Hernandez, P Kassem, L Luten, A deLeon, CM Munoz-Dunbar, R Pfenninger, P Pitula, CR Sampson, NL Szeplakay, S Vale, D Zajecka, J DeBusk, RF Christopherson, D Forseth, LF Froelicher, ES Kaiser, H Madan, S Marnell, M Martin, K Miller, NH Parker, K Raymond, P Rao, S Strachowski, D Taylor, CB Thoresen, CE Raczynski, JM Adams, BL Bandy, M Barton, J Bittner, V Caddell, D Cole, M Cornell, CE Doce, JJ Fort, A Gilliland, J Gardner, T Kingle, D Jordan, SD Markovitz, J Mason, DA Pierce, T Shuster, J Taylor, H Thompson, S Winders, SE Schneiderman, N Dixon, D Gellman, M Gutt, M Ironson, G Jimenez, H Kilbourn, K Lamas, G Lopez-Jimenez, F Manrique-Reichard, ME McCalla, JR Mellman, T Myerburg, R Penedo, F Robinson, EV Saab, P Sequeira, R Teixeiro, P Whitelock, J Mitchell, P Betrus, P Bridges, E Buzaitis, A Chen, W Concannon, V Cowan, MJ Cunningham, SL DeRook, F Erickson, C Hanrahan, P Hardin, P Kimball, B Kirkness, C Budzynski, HNK Kosins, D Kunz, D Ruskind, M Sholl, S Stewart, F Sturm, K Veith, RC Wilkinson, C Woods, SL Carney, RM Beller, L Bence, K Benoist, T Brewer, L Cohen, JD Eisenberg, PR Finn, J Freedland, KE Hofius, A Hoffman, P Kanakis, D Koprowsky, J Lynch, T Meyer, J Misuraco, A Rich, MW Ristvedt, S Sitton, D Skala, J Swanner, B Weiss, ES Weiss, B Burg, MM Abrams, D Clark, PP Ginter, S Gonsor, KR Krumholz, H McGloin, J Mukherjee, S Stewart, T Farber, S Hartley, LH Kochevar, R Metalides, T Sherwood, J Stoll, A Stone, P Bland, E Hersh, J Cowan, MJ Jaffe, AS Keefe, F Light, K Martin, L Ooro, A Schaefer, JH Sheps, D Tripp, A Youngblood, ME Hill, R Hunsberger, S Jennings, CA Kaufmann, P Knox, S Norman, J Reid, J Voorhees, CC Dank, N Johnston, C Sokol, L Chaitman, BR Cameron, P Cannon, S Gussak, I Miller, M Stocke, K Strickland, J Jaffe, AS AF Berkman, LF Carney, R Blumenthal, J Czakowski, S Hosking, J Jaffe, A Babyak, M Carels, R Coleman, E Curtis, S Davis, L Fath, K Forman, L Hassett, A Hegde, SB Herman, SH Hinderliter, A Khatri, P Krishnan, KR Levenberg, S Mark, D Marz, P Matthews, J McCarthy, R Mieszkalski, K Miller, G Norten, J O'Connor, C Puma, J Rutt, L Sessions, W Siegler, I Wadley, V Watkins, L Waugh, R Williams, R Zakhary, BG Powell, LH Calvin, JE Clark, DC Creech, S Eaton, C Elliott, JW Hernandez, P Kassem, L Luten, A deLeon, CM Munoz-Dunbar, R Pfenninger, P Pitula, CR Sampson, NL Szeplakay, S Vale, D Zajecka, J DeBusk, RF Christopherson, D Forseth, LF Froelicher, ES Kaiser, H Madan, S Marnell, M Martin, K Miller, NH Parker, K Raymond, P Rao, S Strachowski, D Taylor, CB Thoresen, CE Raczynski, JM Adams, BL Bandy, M Barton, J Bittner, V Caddell, D Cole, M Cornell, CE Doce, JJ Fort, A Gilliland, J Gardner, T Kingle, D Jordan, SD Markovitz, J Mason, DA Pierce, T Shuster, J Taylor, H Thompson, S Winders, SE Schneiderman, N Dixon, D Gellman, M Gutt, M Ironson, G Jimenez, H Kilbourn, K Lamas, G Lopez-Jimenez, F Manrique-Reichard, ME McCalla, JR Mellman, T Myerburg, R Penedo, F Robinson, EV Saab, P Sequeira, R Teixeiro, P Whitelock, J Mitchell, P Betrus, P Bridges, E Buzaitis, A Chen, W Concannon, V Cowan, MJ Cunningham, SL DeRook, F Erickson, C Hanrahan, P Hardin, P Kimball, B Kirkness, C Budzynski, HNK Kosins, D Kunz, D Ruskind, M Sholl, S Stewart, F Sturm, K Veith, RC Wilkinson, C Woods, SL Carney, RM Beller, L Bence, K Benoist, T Brewer, L Cohen, JD Eisenberg, PR Finn, J Freedland, KE Hofius, A Hoffman, P Kanakis, D Koprowsky, J Lynch, T Meyer, J Misuraco, A Rich, MW Ristvedt, S Sitton, D Skala, J Swanner, B Weiss, ES Weiss, B Burg, MM Abrams, D Clark, PP Ginter, S Gonsor, KR Krumholz, H McGloin, J Mukherjee, S Stewart, T Farber, S Hartley, LH Kochevar, R Metalides, T Sherwood, J Stoll, A Stone, P Bland, E Hersh, J Cowan, MJ Jaffe, AS Keefe, F Light, K Martin, L Ooro, A Schaefer, JH Sheps, D Tripp, A Youngblood, ME Hill, R Hunsberger, S Jennings, CA Kaufmann, P Knox, S Norman, J Reid, J Voorhees, CC Dank, N Johnston, C Sokol, L Chaitman, BR Cameron, P Cannon, S Gussak, I Miller, M Stocke, K Strickland, J Jaffe, AS CA ENRICHD Investigators TI Enhancing recovery in coronary heart disease patients (ENRICHD): Study design and methods SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; STRESS-MONITORING-PROGRAM; ARTERY DISEASE; SOCIAL SUPPORT; PREVENTION PROJECT; CONTROLLED TRIAL; A BEHAVIOR; FOLLOW-UP; DEPRESSION; MORTALITY AB Psychosocial factors, particularly depression and tack of social support, are important predictors of morbidity and mortality in patients with coronary heart disease, This article describes the design and methods of the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) study, a multicenter, randomized clinical trial involving 3000 patients enrolled after acute myocardial infarction. ENRICHD aims to investigate the effects of a psychosocial intervention that targets depression and/or low social support on survival and reinfarction among adult men and women who are at high risk for recurrent cardiac events because of psychosocial factors (depressive or social isolation). Design features include the use of an individually tailored yet standardized intervention, rigorous clinical trial methods, and enrollment of a large number of women and minorities. C1 Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. Duke Univ, Durham, NC 27706 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Stanford Univ, Palo Alto, CA 94304 USA. Univ Alabama, Birmingham, AL USA. Univ Miami, Coral Gables, FL USA. Univ Washington, Seattle, WA 98195 USA. Washington Univ, St Louis, MO USA. Yale Univ, New Haven, CT USA. Harvard Univ, Boston, MA 02115 USA. Univ N Carolina, Coordinating Ctr, Chapel Hill, NC USA. NHLBI, Project Off, Bethesda, MD 20892 USA. Beck Inst Cognit Therapy & Res, Ctr Therapist Training & Qual Control, Bala Cynwyd, PA USA. St Louis Univ, Electrocardiogram Reading Ctr, St Louis, MO USA. RP Hosking, J (reprint author), Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, CB 8030,137 E Franklin St,Suite 203, Chapel Hill, NC 27514 USA. NR 41 TC 10 Z9 11 U1 1 U2 10 PU MOSBY-YEAR BOOK 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 JAN PY 2000 VL 139 IS 1 BP 1 EP 9 PN 1 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 272BU UT WOS:000084631300001 ER PT J AU Antman, E Feinstein, S Gersh, B Gibler, B Haigney, M Hochman, J Opie, L Rogers, W Woods, K McKinlay, S Hagner, S Domanski, M Rosenberg, Y Cooper, H Norman, J Mills, P AF Antman, E Feinstein, S Gersh, B Gibler, B Haigney, M Hochman, J Opie, L Rogers, W Woods, K McKinlay, S Hagner, S Domanski, M Rosenberg, Y Cooper, H Norman, J Mills, P CA MAGIC Steering Comm TI Rationale and design of the Magnesium in Coronaries (MAGIC) study: A clinical trial to reevaluate the efficacy of early administration of magnesium in acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID INTRAVENOUS-MAGNESIUM; THROMBOLYTIC THERAPY; RANDOMIZED TRIALS; REPERFUSION; SULFATE; SIZE AB Background Mortality rate from ST-elevation myocardial infarction remains high in elderly patients and in patients who are not eligible for reperfusion therapy, intravenous magnesium is a promising adjunctive treatment that may reduce reperfusion injury. Several earlier trials demonstrated a mortality rate reduction with magnesium treatment, but one large trial found no benefit. Study Design Magnesium in Coronaries (MAGIC) is a large, simple trial designed to maximize the potential treat ment effect of magnesium. 10,400 high-risk patients with ST-elevation myocardial infarction will be randomly assigned to early treatment with intravenous magnesium sulfate or matching placebo. The primary end point is death at 30 days. Information on the need for treatment of shock and sustained ventricular arrhythmias will be collected to investigate the mechanisms by which magnesium might exert a beneficial effect. Implications If magnesium proves beneficial, its use will provide a simple, cost-effective means to improve survival in this large patient population. C1 New England Res Inst, Clin Trial Ctr Magnesium Coronaries, Watertown, MA 02472 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. Mayo Clin, Rochester, MN USA. Univ Cincinnati Hosp, Cincinnati, OH USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. St Lukes Roosevelt Hosp, New York, NY 10025 USA. Cape Heart Ctr, Cape Town, South Africa. Univ Alabama Birmingham, Birmingham, AL USA. Leicester Royal Infirm, Leicester, Leics, England. NHLBI, Bethesda, MD 20892 USA. RP McKinlay, S (reprint author), New England Res Inst, Clin Trial Ctr Magnesium Coronaries, 9 Galen St, Watertown, MA 02472 USA. EM Sonjam@neri.org NR 23 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2000 VL 139 IS 1 BP 10 EP 14 PN 1 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 272BU UT WOS:000084631300002 ER PT J AU Denkins, YM Woods, J Whitty, JE Hannigan, JH Martier, SS Sokol, RJ Salem, N AF Denkins, YM Woods, J Whitty, JE Hannigan, JH Martier, SS Sokol, RJ Salem, N TI Effects of gestational alcohol exposure on the fatty acid composition of umbilical cord serum in humans SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT International Conference on Highly Unsaturated Fatty Acids in Nutrition and Disease Prevention CY NOV 04-06, 1996 CL BARCELONA, SPAIN SP F Hoffmann LaRoche Ltd, Int Soc Study Fatty Acids & Lipids, Inst Natl Rech, Japanese Soc Nutrit & Food Sci DE docosahexaenoic acid; DHA; poly-unsaturated fatty acids; PUFAs; lipids; ethanol; alcohol in pregnancy; gestational alcohol exposure; neonate; fetus; umbilical cord serum ID DOCOSAHEXAENOIC ACID; BLOOD-PRESSURE; PREGNANCY; WOMEN; BRAIN; HYPERTENSION; ERYTHROCYTES; DRINKING; INCREASE; INFANTS AB This study examined the effects of maternal periconceptional alcohol intake on polyunsaturated fatty acid (PUFA) concentrations in human neonates. The area percentage of each fatty acid in cord blood serum from 12 infants born to control women (who consumed <2 mt absolute ethanol/d) was compared with that of 9 infants born to women whose periconceptional alcohol intake averaged greater than or equal to 30 mt absolute ethanol/d. Periconceptional alcohol use was associated with a 30% increase in the proportion of docosahexaenoic acid (22:6n-3) in cord blood (3.0% of total lipid in control infants compared with 3.9% in alcohol-exposed infants; P < 0.01). The rise in the proportion of 22:6n-3 was responsible for increases in the ratio of n-3 to n-6 fatty acids and the ratio of long-chain n-3 to n-6 fatty acids (P < 0.055). Examination of the lipid-class fatty acid profile indicated that serum lipid alterations were localized to the cholesterol esters; 22:6n-3 in the cholesterol esters of alcohol-exposed infants increased 54% (P < 0.011) and arachidonic acid increased 55% (P < 0.005). The relative fatty acyl composition of maternal serum showed a significant increase in 18:0 fatty acids in the alcohol-exposed group (25%, P < 0.005) but there were no changes in the other fatty acids. The increase in the proportion of 22:6n-3 was unexpected but is consistent with the hypothesis that this essential lipid may be conserved selectively. These results imply that the lifelong neurobehavioral and sensory dysfunction in fetal alcohol syndrome and other alcohol-related neurodevelopmental disorders may be due in part to PUFA dysregulation. C1 NIAAA, LMBB, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Salem, N (reprint author), NIAAA, LMBB, Div Intramural Clin & Biol Res, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. FU NIAAA NIH HHS [P50-AA07606] NR 46 TC 25 Z9 26 U1 0 U2 1 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 JAN PY 2000 VL 71 IS 1 SU S BP 300S EP 306S PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 271VM UT WOS:000084614800021 PM 10617986 ER PT J AU Hibbeln, JR Umhau, JC George, DT Shoaf, SE Linnoila, M Salem, N AF Hibbeln, JR Umhau, JC George, DT Shoaf, SE Linnoila, M Salem, N TI Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT International Conference on Highly Unsaturated Fatty Acids in Nutrition and Disease Prevention CY NOV 04-06, 1996 CL BARCELONA, SPAIN SP F Hoffmann LaRoche Ltd, Int Soc Study Fatty Acids & Lipids, Inst Natl Rech, Japanese Soc Nutrit & Food Sci ID DOCOSAHEXAENOIC ACID; 5-HYDROXYINDOLEACETIC ACID; DIETARY-CHOLESTEROL; HEALTHY-VOLUNTEERS; HABITUALLY VIOLENT; HOMOVANILLIC-ACID; ALCOHOL INTAKE; HUMAN CSF; SEROTONIN; BRAIN AB Low concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent com parison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence. C1 NIAAA, LMBB, Rockville, MD 20852 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. RP Salem, N (reprint author), NIAAA, LMBB, Pk 5,Room 158,12420 Parklawn Dr, Rockville, MD 20852 USA. NR 72 TC 25 Z9 25 U1 2 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2000 VL 71 IS 1 SU S BP 331S EP 338S PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 271VM UT WOS:000084614800027 PM 10617992 ER PT J AU Fiel, MI Schiano, TD Guido, M Thung, SN Lindsay, KL Davis, GL Lewis, JH Seeff, LB Bodenheimer, HC AF Fiel, MI Schiano, TD Guido, M Thung, SN Lindsay, KL Davis, GL Lewis, JH Seeff, LB Bodenheimer, HC TI Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE hemosiderosis; viral hepatitis; hepatitis C virus, interferon ID RECOMBINANT INTERFERON-ALFA; COMBINATION THERAPY; CONTROLLED TRIAL; INFECTION AB Increased levels of hepatic iron may impair the response of patients with chronic hepatitis C to treatment with interferon-alfa, but combination therapy with ribavirin has demonstrated efficacy in the treatment of hepatitis C. When used alone or with inferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic anemia. We compared the extent and cellular localization of iron deposition in liver tissue from biopsy specimens obtained before and after 36 weeks of therapy with ribavirin or placebo for 59 patients with chronic hepatitis C. Paired slides were available for review from 26 ribavirin and 27 placebo recipients. Ii on deposition was assessed using coded slides stained with Perls Prussian blue and was semiquantitated in hepatocytes, Kupffer cells, and areas of fibrosis. The overall iron score fell by 0.96 in the placebo group and increased 1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes; the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group. The amount of iron staining in Kupffer cells declined in the placebo group and increased slightly in the ribavirin group. Iron changes in areas of fibrosis were minor and did not differ between groups. Increased total hepatic iron deposition occurred during a 9-month course of ribavirin. Ribavirin-associated hemolysis deposits iron preferentially in hepatocytes. This increased deposition of hepatic iron does not seem to affect the biochemical or histologic response to ribavirin therapy but may have implications for hepatocyte susceptibility to future injury. C1 CUNY, Mt Sinai Med Ctr, Dept Med, Div Liver Dis, New York, NY 10029 USA. CUNY, Mt Sinai Med Ctr, Lillian & Henry M Stratton Hans Popper Dept Patho, New York, NY 10029 USA. Univ So Calif, Dept Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ Florida, Dept Med, Sect Hepatobiliary Dis, Gainesville, FL USA. Georgetown Univ, Med Ctr, Dept Med, Div Gastroenterol,Div Liver Dis, Washington, DC 20007 USA. NIH, Bethesda, MD 20892 USA. RP Bodenheimer, HC (reprint author), CUNY, Mt Sinai Med Ctr, Dept Med, Div Liver Dis, 1 Gustave Levy Pl, New York, NY 10029 USA. NR 30 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC CLIN PATHOLOGISTS PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JAN PY 2000 VL 113 IS 1 BP 35 EP 39 PG 5 WC Pathology SC Pathology GA 269CB UT WOS:000084457200005 PM 10631856 ER PT J AU Sgambati, MT Stolle, C Choyke, PL Walther, MM Zbar, B Linehan, WM Glenn, GM AF Sgambati, MT Stolle, C Choyke, PL Walther, MM Zbar, B Linehan, WM Glenn, GM TI Mosaicism in von Hippel-Lindau disease: Lessons from kindreds with germline mutations identified in offspring with mosaic parents SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENE; LINE MOSAICISM; PHENOTYPE; FEATURES; LOCUS AB von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Genet Diagnost Lab, Philadelphia, PA 19104 USA. NCI, Immunobiol Lab, Div Basic Sci, Frederick, MD 21701 USA. RP Glenn, GM (reprint author), 6120 Execut Blvd,EPS 7108,MSC 7236, Bethesda, MD 20892 USA. NR 28 TC 80 Z9 82 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2000 VL 66 IS 1 BP 84 EP 91 DI 10.1086/302726 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 279FK UT WOS:000085033600009 PM 10631138 ER PT J AU Feldman, G Li, M Martin, S Urbanek, M Urtizberea, JA Fardeau, M LeMerrer, M Connor, JM Triffitt, J Smith, R Muenke, M Kaplan, FS Shore, EM AF Feldman, G Li, M Martin, S Urbanek, M Urtizberea, JA Fardeau, M LeMerrer, M Connor, JM Triffitt, J Smith, R Muenke, M Kaplan, FS Shore, EM TI Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27-31 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BONE MORPHOGENETIC PROTEINS; OSTEOBLAST DIFFERENTIATION; CLEIDOCRANIAL DYSPLASIA; REGULATORS; CBFA1; GENE; INTERLEUKIN-15; TRANSCRIPTION; LOCALIZATION AB Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein-signaling pathway. C1 Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Assoc Francaise Contre Myopathies, Inst Myol, Paris, France. Hop Necker Enfants Malad, INSERM, U393, Paris, France. Univ Glasgow, Sch Med, Inst Med Genet, Yorkhill Hosp, Glasgow, Lanark, Scotland. Univ Oxford, Nuffield Orthopaed Ctr, Nuffield Dept Orthopaed Surg, Bone Res Lab, Oxford OX1 2JD, England. Natl Human Genet Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. RP Shore, EM (reprint author), Univ Penn, Dept Orthopaed, 424 Stemmler Hall,36th & Hamilton Walk, Philadelphia, PA 19104 USA. RI Shore, Eileen/D-2593-2009 FU NIAMS NIH HHS [2R01-AR41916-04, R01 AR041916] NR 46 TC 59 Z9 63 U1 2 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2000 VL 66 IS 1 BP 128 EP 135 DI 10.1086/302724 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 279FK UT WOS:000085033600014 PM 10631143 ER PT J AU Umbach, DH Weinberg, CR AF Umbach, DH Weinberg, CR TI The use of case-parent triads to study joint meets of genotype and exposure SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LINKAGE DISEQUILIBRIUM; GENES; ASSOCIATION; DISEASE; TESTS AB Most noninfectious disease is caused by low-penetrance alleles interacting with other genes and environmental factors. Consider the simple setting where a diallelic autosomal candidate gene and a binary exposure together affect disease susceptibility. Suppose that one has genotyped affected probands and their parents and has determined each proband's exposure status. One proposed method for assessment of etiologic interaction of genotype and exposure, an extension of the transmission/disequilibrium test, tests for differences in transmission of the variant allele from heterozygous parents to exposed versus unexposed probands. We show that this test is not generally valid. An alternative approach compares the conditional genotype distribution of unexposed cases, given parental genotypes, versus that of exposed cases. This approach provides maximum-likelihood estimators for genetic relative-risk parameters and genotype-exposure-interaction parameters, as well as a likelihood-ratio test (LRT) of the no-interaction null hypothesis. We show how to apply this approach, using log-linear models. When a genotype-exposure association arises solely through incomplete mixing of subpopulations that differ in both exposure prevalence and allele frequency, the LRT remains valid. The LRT becomes invalid, however, if offspring genotypes do not follow Mendelian proportions in each parental mating type-for example, because of genotypic differences in survival-or if a genotype-exposure association reflects an influence of genotype on propensity for exposure-for example, through behavioral mechanisms. Because the needed assumptions likely hold in many situations, the likelihood-based approach should be broadly applicable for diseases in which probands commonly have living parents. C1 NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Umbach, DH (reprint author), NIEHS, Biostat Branch, NIH, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 97 Z9 101 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2000 VL 66 IS 1 BP 251 EP 261 DI 10.1086/302707 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 279FK UT WOS:000085033600026 PM 10631155 ER PT J AU Dharmaraj, S Li, YY Robitaille, JM Silva, E Zhu, DP Mitchell, TN Maltby, LP Baffoe-Bonnie, AB Maumenee, IH AF Dharmaraj, S Li, YY Robitaille, JM Silva, E Zhu, DP Mitchell, TN Maltby, LP Baffoe-Bonnie, AB Maumenee, IH TI A novel locus for Leber congenital amaurosis maps to chromosome 6q SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID CAROLINA MACULAR DYSTROPHY; RECESSIVE RETINITIS-PIGMENTOSA; DISEASE GENE ABCR; CHORIORETINAL ATROPHY PBCRA; CONE-ROD DYSTROPHY; STARGARDT-DISEASE; FUNDUS-FLAVIMACULATUS; LINKAGE ANALYSIS; MUTATIONS; MCDR1 C1 Johns Hopkins Med Inst, Wilmer Eye Inst, Johns Hopkins Ctr Hereditary Eye Dis, Baltimore, MD 21287 USA. Dalhousie Univ, IWK Grace Hlth Ctr, Halifax, NS, Canada. N Carolina Dept Hlth & Human Serv, Wilmington, NC USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Natl Human Genome Res Inst, Div Stat Genet, NIH, Bethesda, MD USA. RP Dharmaraj, S (reprint author), Johns Hopkins Med Inst, Wilmer Eye Inst, Johns Hopkins Ctr Hereditary Eye Dis, Maumenee Bldg,Suite 517,600 N Wolfe St, Baltimore, MD 21287 USA. NR 53 TC 56 Z9 56 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2000 VL 66 IS 1 BP 319 EP 326 DI 10.1086/302719 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 279FK UT WOS:000085033600032 PM 10631161 ER PT J AU Wolz, M Cutler, J Roccella, EJ Rohde, F Thom, T Burt, V AF Wolz, M Cutler, J Roccella, EJ Rohde, F Thom, T Burt, V TI Statement from the National High Blood Pressure Education Program: Prevalence of hypertension SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article C1 NHLBI, Natl High Blood Pressure Educ Program, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Atlanta, GA USA. RP Roccella, EJ (reprint author), NHLBI, Natl High Blood Pressure Educ Program, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 57 Z9 61 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JAN PY 2000 VL 13 IS 1 BP 103 EP 104 DI 10.1016/S0895-7061(99)00241-1 PN 1 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 281LD UT WOS:000085160800017 PM 10678279 ER PT J AU Wolfe, RA Ashby, VB Daugirdas, JT Agodoa, LYC Jones, CA Port, FK AF Wolfe, RA Ashby, VB Daugirdas, JT Agodoa, LYC Jones, CA Port, FK TI Body size, dose of hemodialysis, and mortality SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE body mass index (BMI); urea reduction ratio (URR); hemodialysis dose; nutritional status; equilibrated Kt/V (eKt/V); total body water (TBW) ID DIALYSIS; PREDICTORS AB This study investigates the role of body size on the mortality risk associated with dialysis dose in chronic hemodialysis patients, A national US random sample from the US Renal Data System was used for this observational longitudinal study of 2-year mortality. Prevalent hemodialysis patients treated between 1990 and 1995 were included (n = 9,165), A Cox proportional hazards model, adjusting for patient characteristics, was used to calculate the relative risk (RR) for mortality. Both dialysis dose (equilibrated Kt/V [eKt/V]) and body size (body weight, body volume, and body mass index) were independently and significantly (P < 0.01 for each measure) inversely related to mortality when adjusted for age and diabetes. Mortality was less among larger patients and those receiving greater eKt/V. The overall association of mortality risk with eKt/V was negative and significant in all patient subgroups defined by body size and by race-sex categories in the range 0.6 < eKt/V < 1.6. The association was negative in the restricted range 0.9 < eKt/V < 1.6 (although not generally significant) for all body-size subgroups and for three of four race-by-sex subgroups, excepting black men (RR = 1.003/0.1 eKt/V; P > 0.95), These findings suggest that dose of dialysis and several measures of body size are important and independent correlates of mortality, These results suggest that patient management protocols should attempt to ensure both good patient nutrition and adequate dose of dialysis, in addition to managing coexisting medical conditions. (C) 2000 by the National Kidney Foundation, Inc. C1 Univ Michigan, US Renal Data Syst Coordinating Ctr, Ann Arbor, MI 48103 USA. Univ Chicago, Westside Vet Adm Hosp, Chicago, IL 60637 USA. NIDDKD, Bethesda, MD 20892 USA. RP Wolfe, RA (reprint author), Univ Michigan, US Renal Data Syst Coordinating Ctr, 315 W Huron,Ste 240, Ann Arbor, MI 48103 USA. NR 17 TC 162 Z9 163 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 JAN PY 2000 VL 35 IS 1 BP 80 EP 88 DI 10.1016/S0272-6386(00)70305-2 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 271BJ UT WOS:000084572400014 PM 10620548 ER PT J AU Maisonneuve, P Agodoa, L Gellert, R Stewart, JH Buccianti, G Lowenfels, AB Wolfe, RA Jones, E Disney, APS Briggs, D McCredie, M Boyle, P AF Maisonneuve, P Agodoa, L Gellert, R Stewart, JH Buccianti, G Lowenfels, AB Wolfe, RA Jones, E Disney, APS Briggs, D McCredie, M Boyle, P TI Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: Results from an international comparative study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE renal dialysis; end-stage renal disease (ESRD); kidney diseases; classification; cross-cultural comparison AB This report notes the differences in the classification of the primary renal disease (PRD) used in different renal dialysis and transplant registries worldwide. The heterogeneity of coding systems complicates the comparative analysis of end-stage renal disease from different regions. Using data collected over two decades in the United States, Europe, and Australia/New Zealand, we present a method for reorganization of the classes of PRD that allows a straightforward comparison of retrospective data from these registries. (C) 2000 by the National Kidney Foundation, Inc. C1 European Inst Oncol, Div Epidemiol & Biostat, I-20141 Milan, Italy. Hosp E Bassini San Gerardo, Dept Nephrol & Dialysis, Monza, Italy. NIDDK, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. New York Med Coll, Valhalla, NY 10595 USA. Univ Michigan, US Renal Data Syst Coordinat Ctr, Ann Arbor, MI 48109 USA. Dept Internal Med & Nephrol, Warsaw, Poland. Univ Otago, Dept Med, Dunedin, New Zealand. European Renal Assoc, European Dialysis & Transplant Assoc Registry, London, England. Australia & New Zealand Dialysis & Transplant Reg, Adelaide, SA, Australia. Univ Otago, Dept Prevent & Social Med, Dunedin, New Zealand. NSW Canc Council, Canc Epidemiol Res Unit, Sydney, NSW, Australia. RP Maisonneuve, P (reprint author), European Inst Oncol, Div Epidemiol & Biostat, Via Ripamonti 435, I-20141 Milan, Italy. RI Gellert, Ryszard/F-4604-2010; Boyle, Peter/A-4380-2014; OI Boyle, Peter/0000-0001-6251-0610; Maisonneuve, Patrick/0000-0002-5309-4704 NR 5 TC 154 Z9 170 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 JAN PY 2000 VL 35 IS 1 BP 157 EP 165 DI 10.1016/S0272-6386(00)70316-7 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 271BJ UT WOS:000084572400026 PM 10620560 ER PT J AU Levy, LM AF Levy, LM TI Toward an understanding of syringomyelia: MR imaging of CSF flow and neuraxis motion SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Editorial Material C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Levy, LM (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 12 Z9 13 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JAN PY 2000 VL 21 IS 1 BP 45 EP 46 PG 2 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 279QD UT WOS:000085055900012 PM 10669223 ER PT J AU Crumlish, CM Bracken, J Hand, MM Keenan, K Ruggiero, H Simmons, D AF Crumlish, CM Bracken, J Hand, MM Keenan, K Ruggiero, H Simmons, D TI When time is muscle SO AMERICAN JOURNAL OF NURSING LA English DT Article C1 Amer Nurses Assoc, Washington, DC 20024 USA. Villanova Univ, Coll Nursing, Villanova, PA 19085 USA. Cook Cty Hosp, Nursing Educ Program, Evergreen Pk, IL 60642 USA. NHLBI, Natl Heart Attack Alert Program, NIH, Bethesda, MD 20892 USA. NHAAPCC, Amer Assoc Crit Care Nurses, Arlington, MA 02174 USA. Univ Virginia, Nephrol Outpatient Clin, Charlottesville, VA 22903 USA. RP Crumlish, CM (reprint author), Amer Nurses Assoc, Washington, DC 20024 USA. NR 4 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD JAN PY 2000 VL 100 IS 1 BP 26 EP + DI 10.2307/3521796 PG 6 WC Nursing SC Nursing GA 291PP UT WOS:000085745500019 PM 10705836 ER PT J AU Athayde, N Romero, R Maymon, E Gomez, R Pacora, P Yoon, BH Edwin, SS AF Athayde, N Romero, R Maymon, E Gomez, R Pacora, P Yoon, BH Edwin, SS TI Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and microbial invasion of the amniotic cavity SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 18th Annaul Meeting of the Society-for-Perinatal-Obstetricians CY FEB 02-07, 1998 CL MIAMI, FLORIDA SP Soc Preinatal Obstretricians DE interleukin 16; intra-amniotic infection; labor; premature rupture of membranes; preterm labor ID LYMPHOCYTE CHEMOATTRACTANT FACTOR; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; PRETERM PARTURITION; HUMAN LYMPHOKINES; FLUID; TERM; MIGRATION; IDENTIFICATION; ASSOCIATION AB OBJECTIVE: Interleukin 16 is a proinflammatory cytokine that promotes the recruitment of nonclonotypic T cells and eosinophils to sites of inflammation and induces resistance to activation-induced apoptosis. This peptide has no homology with members of the chemokine family and is produced by epithelial cells. No information is available about the expression of this cytokine during human pregnancy. This study was conducted to determine whether interleukin 16 is present in amniotic fluid and to examine the effects of labor and intrauterine infection on the concentrations of this cytokine. STUDY DESIGN: A cross-sectional study was constructed with 230 women in the following groups: (1) midtrimester (n = 25); (2) term not in labor (n = 25), term in labor (n = 25), and term premature rupture of membranes not in labor (n = 40); (3) preterm labor and intact membranes with (n = 21) and without (n = 42) intra-ammiotic infection; and (4) preterm premature rupture of membranes in the presence (n = 29) and absence (n = 23) of microbial invasion of the amniotic cavity. Interleukin 16 concentration was measured with sensitive and specific immunoassays validated for amniotic fluid. Data were analyzed with nonparametric statistics. RESULTS: (1) Interleukin 16 was detected in 87.8% (202/230) of amniotic fluid samples. (2) Amniotic fluid interleukin 16 concentrations were significantly higher in women in the midtrimester than in those at term not in labor (median, 321.5 pg/mL; range, 146.9-1185.8 pg/mL; vs median, 85.9 pg/mL; range, <25-409.8 pg/mL; P <.001). (3) Labor at term was not associated with a significant increase in the median amniotic fluid interleukin 16 concentration. (4) Patients with preterm labor who delivered preterm had a significantly higher median amniotic fluid interleukin 16 concentration than those with preterm labor who delivered at term (median, 328.1 pg/mL; range, 38.9-4660 pg/mL; vs median, 119.8 pg/mL; range, <25-558.5 pg/mL; P <.05). (5) Microbial invasion of the amniotic cavity was associated with a significant increase in median amniotic fluid interleukin 16 concentration in patients with preterm labor and intact membranes (microbial invasion of the amniotic cavity: median, 839 pg/mL; range, <25-8620 pg/mL; vs no microbial invasion of the amniotic cavity: median, 119.8 pg/mL; range, <25-558.5 pg/mL; P <.001) and in patients with preterm premature rupture of the membranes (microbial invasion of the amniotic cavity: median, 1005.8 pg/mL; range, <25-4590 pg/mL; vs no microbial invasion of the amniotic cavity: median, 204.9 pg/mL; range, 42.6-2347 pg/mL; P<.05). (6) Spontaneous rupture of the membranes at term but not preterm was associated with a significant decrease in amniotic fluid concentrations of interleukin 16 (term premature rupture of the membranes: median, <25 pg/mL; range, <25-231.2 pg/mL; vs term intact membranes: median, 85.9 pg/mL; range, <25-409.8 pg/mL; P<.05). CONCLUSIONS: Amniotic fluid interleukin-16 concentrations decreased with advancing gestational age. Women with preterm labor that led to preterm delivery and women with microbial invasion of the amniotic cavity had higher interleukin 16 amniotic fluid concentrations than those with preterm labor who delivered at term or those with sterile amniotic fluid. Microbial invasion of the amniotic cavity but not spontaneous labor at term or rupture of membranes was associated with increased concentrations of interleukin 16 in amniotic fluid. C1 Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, NICHHD,Perinatol Res Branch, Detroit, MI 48201 USA. Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, NICHHD,Perinatol Res Branch, 4707 St Antoine Blvd, Detroit, MI 48201 USA. RI Yoon, Bo Hyun/H-6344-2011 NR 25 TC 62 Z9 67 U1 0 U2 2 PU MOSBY-YEAR BOOK 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 JAN PY 2000 VL 182 IS 1 BP 135 EP 141 DI 10.1016/S0002-9378(00)70502-3 PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 278JR UT WOS:000084987100021 PM 10649168 ER PT J AU Roilides, E Kyriakides, G Kadiltsoglou, I Farmaki, E Venzon, D Katsaveli, A Kremenopoulos, G AF Roilides, E Kyriakides, G Kadiltsoglou, I Farmaki, E Venzon, D Katsaveli, A Kremenopoulos, G TI Septicemia due to multiresistant Klebsiella pneumoniae in a neonatal unit: A case-control study SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE septicemia; Klebsiella pneumoniae; neonates; risk factors ID INTENSIVE-CARE UNIT; OUTBREAK AB An unusually high incidence of septicemia due to multiresistant Klebsiella pneumoniae occurred in the Aristotle University Neonatology Department. Forty neonates suffered from 42 episodes of septicemia. Mortality was 43% ranging from 32% in neonates with birth weight (BW) greater than or equal to 1500 g to 55% with < 1500 g. No differences were found between 17 neonates who died and 23 survivors. All isolates were resistant to aminoglycosides, third-generation cephalosporins, and aztreonam, but susceptible to imipenem and ciprofloxacin. The neonates with septicemia due to K. pneumoniae were matched 1:1 with neonates without septicemia (31 pairs) or with neonates with septicemia due to other organisms (8 pairs) according to BW and time of admission. Factors associated with septicemia were mechanical ventilation (p = 0.004) and ongoing parenteral nutrition (p = 0.027). In a multivariate model, nutrition exhibited no independent association after adjusting for ventilation. No differences were detected between the patients with Klebsiella septicemia and those with septicemia due to other organisms. Enhanced Infection Control measures and a temporary change of antibiotic policy reduced this serious complication. Three small outbreaks of multiresistant K. pneumoniae previously reported in neonates are reviewed. C1 Aristotelian Univ Salonika, Dept Pediat 3, GR-54006 Salonika, Greece. Aristotelian Univ Salonika, Dept Neonatol, GR-54006 Salonika, Greece. Hippokratio Gen Hosp, Dept Microbiol, Salonika, Greece. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Roilides, E (reprint author), Hippokration Hosp, Dept Pediat 3, Konstaninoupoleos 49, GR-54642 Salonika, Greece. RI Venzon, David/B-3078-2008 NR 6 TC 7 Z9 9 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PY 2000 VL 17 IS 1 BP 35 EP 39 DI 10.1055/s-2000-7290 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 334CH UT WOS:000088167200006 PM 10928602 ER PT J AU Meis, PJ Goldenberg, RL Mercer, BM Iams, JD Moawad, AH Miodovnik, M Menard, MK Caritis, SN Thurnau, GR Dombrowski, MP Das, A Roberts, JM McNellis, D AF Meis, PJ Goldenberg, RL Mercer, BM Iams, JD Moawad, AH Miodovnik, M Menard, MK Caritis, SN Thurnau, GR Dombrowski, MP Das, A Roberts, JM McNellis, D TI Preterm prediction study: Is socioeconomic status a risk factor for bacterial vaginosis in black or in white women? SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE bacterial vaginosis; pregnancy; socioeconomic status; race ID LOW-BIRTH-WEIGHT; CHLAMYDIA-TRACHOMATIS; PREGNANCY; ASSOCIATION; INFECTIONS; DELIVERY AB Bacterial vaginosis (BV), an important risk factor for preterm birth, is a more common infection in Black compared with White pregnant women. Because Black women in the United States are more likely to have lower measures-of socioeconomic status (SES), this study examined the hypothesis that BV is associated with low SES. The project evaluated data from the Preterm Prediction Study of 2929 women prospectively followed during their pregnancies. The women, who were screened for BV at 24 and 28 weeks of gestation, underwent a structured interview to evaluate demographic factors, SES, home and work environment, drug or alcohol use, and prior medical history. Black women in the study had many measures of lower SES compared with the White women, and reported less use of tobacco, alcohol and drugs; In neither the Black nor White women was an association found between BV and measures of SES (with the sole exception of "absence of a home telephone"). Most measures of SES do not explain the difference in rates of BV in Black and in White pregnant women. C1 NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. RP Meis, PJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI caritis, steve/0000-0002-2169-0712 FU NICHD NIH HHS [HD21410, HD21414, HD27860] NR 14 TC 18 Z9 18 U1 0 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PY 2000 VL 17 IS 1 BP 41 EP 45 DI 10.1055/s-2000-7292 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 334CH UT WOS:000088167200007 PM 10928603 ER PT J AU Kolman, CJ Tuross, N AF Kolman, CJ Tuross, N TI Ancient DNA analysis of human populations SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE aDNA; mitochondrial DNA; PCR contamination; New World ID HUMAN MITOCHONDRIAL-DNA; NEW-WORLD; NUCLEAR-DNA; AMPLIFICATION; PCR; SEQUENCE; MTDNA; DIVERSITY; ORIGIN; EXTRACTION AB The use of ancient DNA (aDNA) in the reconstruction of population origins and evolution is becoming increasingly common. The resultant increase in number of samples and polymorphic sites assayed and the number of studies published may give the impression that all technological hurdles associated with aDNA technology have been overcome. However, analysis of aDNA is still plagued by two issues that emerged at the advent of aDNA technology, namely the inability to amplify a significant number of samples and the contamination of samples with modern DNA. Herein, we analyze five well-preserved skeletal specimens from the western United States dating from 800-1600 A.D. These specimens yielded DNA samples with levels of contamination ranging from 0-100%, as determined by the presence or absence of New World-specific mitochondrial markers. All samples were analyzed by a variety of protocols intended to assay genetic variability and detect contamination, including amplification of variously sized DNA targets, direct DNA sequence analysis of amplification products and sequence analysis of cloned amplification products, analysis of restriction fragment length polymorphisms, quantitation of target DNA, amino acid racemization, and amino acid quantitation. Only the determination of DNA sequence from a cloned amplification product clearly revealed the presence of both ancient DNA and contaminating DNA in the same extract. Our results demonstrate that the analysis of aDNA is still an excruciatingly slow and meticulous process. All experiments, including stringent quality and contamination controls, must be performed in an environment as free as possible of potential sources of contaminating DNA, including modern DNA extracts. Careful selection of polymorphic markers capable of discriminating between ancient DNA and probable DNA contaminants is critical. Research strategies must be designed with a goal of identifying all DNA contaminants in order to differentiate convincingly between contamination and endogenous DNA. (C) 2000 Wiley-Liss, Inc. C1 Smithsonian Ctr Mat Res & Educ, Suitland, MD 20746 USA. RP Kolman, CJ (reprint author), NIAAA, NIH, LNG, 12420 Parklawn Dr,Pk Bldg,Room 451, Rockville, MD 20852 USA. NR 44 TC 109 Z9 112 U1 0 U2 13 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD JAN PY 2000 VL 111 IS 1 BP 5 EP 23 PG 19 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 273NK UT WOS:000084713600002 PM 10618586 ER PT J AU Jaquish, CE Coady, S Rabsitz, RR Larson, MG Cupples, LA Myers, RH Levy, D AF Jaquish, CE Coady, S Rabsitz, RR Larson, MG Cupples, LA Myers, RH Levy, D TI Aging and the genetics of adiposity: Insights from 50 years of the Framingham Heart Study. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 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 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2000 SU 30 BP 188 EP 188 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 286RJ UT WOS:000085458900271 ER PT J AU Kolman, CJ Sambuughin, N Goldfarb, L AF Kolman, CJ Sambuughin, N Goldfarb, L TI The Mongolian diaspora? SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Univ Florida, Dept Anthropol, Gainesville, FL 32611 USA. NIAAA, Bethesda, MD 20892 USA. NINDS, NIH, Clin Neurogenet Unit, Bethesda, MD 20892 USA. NR 0 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 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2000 SU 30 BP 199 EP 199 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 286RJ UT WOS:000085458900300 ER PT J AU Lorenz, JG Wang, YL Romero, FC Kittles, RA Goldman, D Long, JC AF Lorenz, JG Wang, YL Romero, FC Kittles, RA Goldman, D Long, JC TI Sequence diversity among haplogroup A mtDNA control region lineages in an Alaskan Na-Dene population. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. Howard Univ, Ctr Canc, Washington, DC 20059 USA. NR 0 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 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2000 SU 30 BP 213 EP 213 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 286RJ UT WOS:000085458900338 ER PT J AU Rilling, J Kilts, C Williams, S Beran, M Giroux, M Hoffman, JM Rapoport, S Savage-Rumbaugh, S Rumbaugh, D AF Rilling, J Kilts, C Williams, S Beran, M Giroux, M Hoffman, JM Rapoport, S Savage-Rumbaugh, S Rumbaugh, D TI A comparative PET study of linguistic processing in humans and language-competent chimpanzees. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Georgia State Univ, Language Res Ctr, Atlanta, GA 30303 USA. NIA, Dept Psychiat, Bethesda, MD 20892 USA. Emory Univ, Dept Radiol, Atlanta, GA 30322 USA. NR 0 TC 1 Z9 1 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2000 SU 30 BP 263 EP 263 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 286RJ UT WOS:000085458900478 ER PT J AU Liu, J Ginis, T Spatz, M Hallenbeck, JM AF Liu, J Ginis, T Spatz, M Hallenbeck, JM TI Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-alpha and ceramide SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE ischemia; hypoxia; tolerance; neurons; tumor necrosis factor-alpha ID TUMOR-NECROSIS-FACTOR; BETA-PEPTIDE TOXICITY; PROGRAMMED CELL-DEATH; HIPPOCAMPAL-NEURONS; INDUCED APOPTOSIS; SPHINGOMYELIN PATHWAY; CEREBRAL-ISCHEMIA; TOLERANCE; STROKE; INDUCTION AB Brief "preconditioning" ischemia induces ischemic tolerance (IT) and protects the animal brain from subsequent otherwise lethal ischemia. Identification of the signaling steps most proximal to the development of the IT will allow induction of the resistance to ischemia shortly after the onset of stroke. Animal studies demonstrate a key role of tumor necrosis factor-alpha (TNF-alpha) in induction of IT. The sphingolipid ceramide is known as a second messenger in many of the multiple effects of TNF-alpha. We hypothesized that ceramide could mediate IT. We demonstrate that preconditioning of rat cortical neurons with mild hypoxia protects them from hypoxia and O-2-glucose deprivation injury 24 h later (50% protection). TNF-alpha pretreatment could be substituted for hypoxic preconditioning (HP). HP was attenuated by TNF-alpha neutralizing antibody. HP and TNF-alpha pretreatment cause a two- to threefold increase of intracellular ceramide levels, which coincides with the state of tolerance. Fumonisin B-1, an inhibitor of ceramide synthase, attenuated ceramide upregulation and HP. C-2 ceramide added to the cultures right before the hypoxic insult mimicked the effect of HP. Ceramide did not induce apoptosis. These results suggest that HP is mediated via ceramide synthesis triggered by TNF-alpha. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Ginis, T (reprint author), NINDS, Stroke Branch, NIH, Bldg 36,Rm 4A03, Bethesda, MD 20892 USA. NR 45 TC 119 Z9 122 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2000 VL 278 IS 1 BP C144 EP C153 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 274UN UT WOS:000084783600019 PM 10644522 ER PT J AU Ito, T Hou, W Katsuno, T Igarashi, H Pradhan, TK Mantey, SA Coy, DH Jensen, RT AF Ito, T Hou, W Katsuno, T Igarashi, H Pradhan, TK Mantey, SA Coy, DH Jensen, RT TI Rat and guinea pig pancreatic acini possess both VIP1 and VIP2 receptors, which mediate enzyme secretion SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE vasoactive intestinal peptides; adenosine 3 ',5 '-cyclic monophosphate; pancreatic secretion; vasoactive intestinal peptide receptors ID VASOACTIVE-INTESTINAL-PEPTIDE; CYCLASE-ACTIVATING POLYPEPTIDE; FUNCTIONAL-CHARACTERIZATION; IN-VITRO; CLONING; EXPRESSION; CELLS; RO-25-1553; AGONIST; FRAGMENTS AB Pancreatic acini from most species possess vasoactive intestinal peptide (VIP) receptors. Recently, two subtypes of VIP receptors, VIP1-R and VIP2-R, were cloned. Which subtype exists on pancreatic acini or mediates secretion is unclear. To address this, we examined pancreatic acini from both rat and guinea pig. VIP1-R and VIP2-R mRNA were identified in dispersed acini from both species by Northern blot analysis and in rat by Southern blot analysis. With the use of the VIP2-R-selective ligand Ro-25-1553 in both species, inhibition of binding of I-125-labeled VIP to acini showed a biphasic pattern with a high-affinity component (10%) and a second representing 90%. The VIP1-R-selective ligand, [Lys(15) ,Arg(16),LeU(27)]VIP-(1- 7)-GRF-(8-27), gave a monophasic pattern. Binding of Ro-25-1553 was better fit by a two-site model. In both rat and guinea pig acini, the dose-response curve of Re-25-1553 for stimulation of enzyme secretion was biphasic, with a high-affinity component of 10-15% of the maximal secretion and a low-affinity component accounting for 85-90%. At low concentrations (10 nM) of Ro-25-1553 and [Lys(15),Arg(16),Leu(27)]VIP-(1-7)-GRF(8-27), which only occupy VIP receptors, a 4-fold and a 56-fold increase in cAMP occurred, respectively. These results show that both VIP1-R and VIP2-R subtypes exist on pancreatic acini of rat and guinea pig, their activation stimulates enzyme secretion by a cAMP-mediated mechanism, and the effects of VIP are mediated 90% by activation of VIP1-R and 10% by VIP2-R. Because VIP has a high affinity for both VIP-R subtypes, its effect on pancreatic acini is mediated by two receptor subtypes, which will need to be considered in future studies of the action of VIP in the pancreas. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Tulane Univ, Sch Med, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. NR 38 TC 19 Z9 19 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JAN PY 2000 VL 278 IS 1 BP G64 EP G74 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 275LF UT WOS:000084821100010 PM 10644563 ER PT J AU Bonner, JC Rice, AB Moomaw, CR Morgan, DL AF Bonner, JC Rice, AB Moomaw, CR Morgan, DL TI Airway fibrosis in rats induced by vanadium pentoxide SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE asthma; myofibroblasts; smooth muscle cell; collagen; metals ID OIL FLY-ASH; GROWTH-FACTOR; SUBEPITHELIAL FIBROSIS; GRANULATION-TISSUE; BRONCHIAL-ASTHMA; LUNG; MYOFIBROBLASTS; EXPOSURE; EXPRESSION; HYPERREACTIVITY AB Vanadium pentoxide (V2O5) is a cause of occupational asthma and bronchitis. We previously reported that intratracheal instillation of rats with V2O5 causes fibrosis of the lung parenchyma (J. C. Bonner, P. M. Lindroos, A. B. Rice, C. R. Moomaw, and D. L. Morgan. Am. J. Physiol. Lung Cell. Mol. Physiol. 274: L72-L80, 1998). In this report, we show that intratracheal instillation of V2O5 induces airway remodeling similar to that observed in individuals with asthma. These changes include airway smooth muscle cell thickening, mucous cell metaplasia, and airway fibrosis. The transient appearance of peribronchiolar myofibroblasts, which were desmin and vimentin positive, coincided with a twofold increase in the thickness of the airway smooth muscle layer at day 6 after instillation and preceded the development of airway fibrosis by day 15. The number of nuclear profiles within the smooth muscle layer also increased twofold after V2O5 instillation, suggesting that hyperplasia accounted for thickening of the smooth muscle layer. The majority of cells incorporating bromodeoxyuridine at day 3 were located in the connective tissue surrounding the airway smooth muscle wall that was positive for vimentin and desmin. These data suggest that myofibroblasts are the principal proliferating cell type that contributes to the progression of airway fibrosis after V2O5 injury. C1 NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Toxicol 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 35 TC 45 Z9 47 U1 0 U2 4 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 JAN PY 2000 VL 278 IS 1 BP L209 EP L216 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 275UF UT WOS:000084838000027 PM 10645909 ER PT J AU Kishore, BK Ginns, SM Krane, CM Nielsen, S Knepper, MA AF Kishore, BK Ginns, SM Krane, CM Nielsen, S Knepper, MA TI Cellular localization of P2Y(2) purinoceptor in rat renal inner medulla and lung SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; water transport; Clara cells; goblet cells; type II pneumocytes ID TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; EXTRACELLULAR ATP; ADENOSINE-TRIPHOSPHATE; COLLECTING DUCT; WATER CHANNEL; RECEPTOR; CELLS; EXPRESSION; TRANSPORT AB Physiological and pharmacological studies have demonstrated that extracellular ATP, acting through P2Y(2) purinoceptor, modulates water permeability of renal medullary collecting duct cells anti the secretion of ions, mucin, and surfactant phospholipids by respiratory epithelia. Here we provide direct molecular evidence for the expression of P2Y(2) purinoceptor in these cells. RT-PCR confirmed P2Y(2) purinoceptor mRNA expression in rat lung and kidney and demonstrated expression in renal collecting ducts. Northern analysis showed that both luni: and kidney express one 3.6-kb P2Y(2) purinoceptor mRNA transcript. Immunoblots using peptide-derived polyclonal antibody to P2Y(2) purinoceptor showed that inner medullary collecting ducts (IMCD) express two distinct and specific products (47 and 105 kDa) and account for the majority of the receptor expression in inner medulla, whereas the 105-kDa form is predominant in lung. Immunoperoxidase labeling on cryosections showed localization of receptor protein in the apical and basolateral domains of IMCD principal cells and in the secretory cells (Clara cells and goblet cells) of the terminal respiratory bronchioles. C1 Univ Cincinnati, Sch Med,Med Ctr, Div Nephrol & Hypertens, Dept Internal Med, Cincinnati, OH 45267 USA. Univ Cincinnati, Sch Med,Med Ctr, Div Nephrol & Hypertens, Dept Mol Genet, Cincinnati, OH 45267 USA. NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus, Denmark. RP Kishore, BK (reprint author), Univ Cincinnati, Sch Med,Med Ctr, Div Nephrol & Hypertens, Dept Internal Med, 231 Bethesda Ave,ML 0585, Cincinnati, OH 45267 USA. EM BK.Kishore@uc.edu FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 33 TC 72 Z9 72 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2000 VL 278 IS 1 BP F43 EP F51 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 275KV UT WOS:000084820100004 PM 10644654 ER PT J AU Wade, JB Lee, AJ Liu, J Ecelbarger, CA Mitchell, C Bradford, AD Terris, J Kim, GH Knepper, MA AF Wade, JB Lee, AJ Liu, J Ecelbarger, CA Mitchell, C Bradford, AD Terris, J Kim, GH Knepper, MA TI UT-A2: a 55-kDa urea transporter in thin descending limb whose abundance is regulated by vasopressin SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE loop of Henle; urinary concentrating mechanism; urea channel; aquaporin-1 ID RAT-KIDNEY; CONCENTRATING PROCESS; BRATTLEBORO RATS; MESSENGER-RNA; EXPRESSION; NEPHRON; CLONING; HISTOTOPOGRAPHY; LOCALIZATION; RECEPTOR AB The renal urea transporter gene (UT-A) produces different transcripts in the inner medullary collecting ducts (UT-A1) and thin descending limbs of Henle's loop (UT-A2), coding for distinct proteins. Peptide-directed rabbit polyclonal antibodies were used to identify the UT-A2 protein in renal medulla of mouse and rat. In the inner stripe of outer medulla, an antibody directed to the COOH terminus of UT-A recognized a membrane protein of 55 kDa. The abundance of this 55-kDa protein was strongly increased in response to chronic infusion of the vasopressin analog 1-deamino-[8-D-arginine]vasopressin (DDAVP) in Brattleboro rats, consistent with previous evidence that UT-A2 mRNA abundance is markedly increased. Immunofluorescence labeling with the COOH-terminal antibody in Brattleboro rats revealed labeling in the lower portion of descending limbs from short-looped nephrons (in the aquaporin-1-negative portion of this segment). This UT-A labeling was increased in response to DDAVP. Increased labeling was also seen in descending limbs of long-looped nephrons in the base of the inner medulla. These results indicate that UT-A2 is expressed as a 55-kDa protein in portions of the thin descending limbs of Henle's loop and that the abundance of this protein is strongly upregulated by vasopressin. C1 Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. Uniformed Serv Univ Hlth Sci, Dept Physiol, Bethesda, MD 20814 USA. NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Wade, JB (reprint author), Univ Maryland, Sch Med, Dept Physiol, 655 W Baltimore St, Baltimore, MD 21201 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282-KE]; NIDDK NIH HHS [DK-32839] NR 35 TC 121 Z9 123 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2000 VL 278 IS 1 BP F52 EP F62 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 275KV UT WOS:000084820100005 PM 10644655 ER PT J AU Lipkus, IM Rimer, BK Halabi, S Strigo, TS AF Lipkus, IM Rimer, BK Halabi, S Strigo, TS TI Can tailored interventions increase mammography use among HMO women? SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE mammography screening; telephone counseling; tailored print communications; barriers ID RANDOMIZED CONTROLLED TRIAL; SCREENING MAMMOGRAPHY; PROMOTE MAMMOGRAPHY; BREAST-CANCER; REMINDERS; PATIENT; STAGE; METAANALYSIS; SETTINGS; BEHAVIOR AB Background: Telephone counseling and tailored print communications have emerged as promising methods for promoting mammography screening. However, there has been little research testing, within the same randomized field trial, of the efficacy of these two methods compared to a high-quality usual care system for enhancing screening. This study addressed the question: Compared to usual care, is tailored telephone counseling more effective than tailored print materials for promoting mammography screening! Design: Three-year randomized field trial. Participants: One thousand ninety-nine women aged 50 and older recruited from a health maintenance organization in North Carolina. Intervention: Women were randomized to 1 of 3 groups: (1) usual care, (2) tailored print communications, and (3) tailored telephone counseling. Main Outcome: Adherence to mammography screening based on self-reports obtained during 1995, 1996, and 1997. Results: Compared to usual care alone, telephone counseling promoted a significantly higher proportion of women having mammograms on schedule (71% vs 61%) than did tailored print (67% vs 61%) but only after the first year of intervention (during 1996). Furthermore, compared to usual care, telephone counseling was more effective than tailored print materials at promoting being on schedule with screening during 1996 and 1997 among women who were off-schedule during the previous year. Conclusions: The effects of the intervention were most pronounced after the first intervention. Compared to usual care, telephone counseling seemed particularly effective at promoting change among nonadherent women, the group for whom the intervention was developed. These results suggest that telephone counseling rather than tailored print, might be the preferred first-line intervention for getting nonadherent women on schedule for mammography screening. Many questions would have to be answered about why the tailored print intervention was not more powerful. Nevertheless, it is clear that additional interventions will be needed to maintain women's adherence to mammography. C1 Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Canc Prevent Detect & Control Res Program, Durham, NC 27710 USA. NCI, Dic Canc Control & Populat Sci, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Community & Family Med, Div Biometry, Durham, NC 27710 USA. RP Lipkus, IM (reprint author), Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Canc Prevent Detect & Control Res Program, Box 2949, Durham, NC 27710 USA. FU NCI NIH HHS [1R01CA63782-05] NR 41 TC 89 Z9 91 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2000 VL 18 IS 1 BP 1 EP 10 DI 10.1016/S0749-3797(99)00106-3 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 275TJ UT WOS:000084836000001 PM 10808977 ER PT J AU Truman, BI Smith-Akin, K Hinman, AR Gebbie, KM Brownson, R Novick, LF Lawrence, RS Pappaioanou, M Fielding, J Evans, CA Guerra, FA Vogel-Taylor, M Mahan, CS Fullilove, M Zaza, S AF Truman, BI Smith-Akin, K Hinman, AR Gebbie, KM Brownson, R Novick, LF Lawrence, RS Pappaioanou, M Fielding, J Evans, CA Guerra, FA Vogel-Taylor, M Mahan, CS Fullilove, M Zaza, S CA Task Force Community Preventive S TI Developing the Guide to Community Preventive Services - Overview and rationale SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE community health services; decision making; evidence-based medicine; population-based interventions; practice guidelines; preventive health services; public health practice; task force ID TASK-FORCE AB When the Guide to Community Preventive Services Systematic Reviews and Evidence-Based Recommendations (the Guide) is published in 2001, it will represent a significant national effort in encouraging evidence-based public health practice in defined populations (e.g., communities or members of specific managed care plans). The Guide will make recommendations regarding public health interventions to reduce illness, disability, premature death, and environmental hazards that impair community health and quality of life. The Guide is being developed under the guidance of the Task Force on Community Preventive Services (the Task Force)-a 15-member, nonfederal, independent panel of experts. Subject matter experts, methodologists, and scientific staff are supporting the Task Force in using explicit rules to conduct systematic literature reviews of evidence of effectiveness, economic efficiency, and feasibility on which to base recommendations for community action. Contributors to the Guide are building on the experience of others to confront methodologic challenges unique to the assessment of complex multicomponent intervention studies with nonexperimental or nonrandomized designs and diverse measures of outcome and effectiveness. Persons who plan, fund, and implement population-based services and policies to improve health at the stare and local levels are invited to scrutinize the work in progress and Co communicate with contributors. When the Guide is complete, readers are encouraged to consider critically the value and relevance of its contents, the implementation of interventions the Task Force recommends, the abandonment of interventions the Task Force does not recommend, and die need for rigorous evaluation of the benefits and harms of promising interventions of unknown effectiveness. Medical Subject Headings (MeSH): community health services, decision making, evidence-based medicine, population-based interventions, practice guidelines, preventive health services, public health practice, task force. (C) 2000 American Journal of Preventive Medicene. C1 Ctr Dis Control & Prevent, Div Prevent Res & Analyt Methods, Epidemiol Program Off, Atlanta, GA 30341 USA. Ctr Dis Control & Prevent, Off Sci & Hlth Commun, Epidemiol Program Off, Atlanta, GA USA. Columbia Univ, Sch Nursing, New York, NY USA. NIH, Bethesda, MD 20892 USA. RP Truman, BI (reprint author), Ctr Dis Control & Prevent, Div Prevent Res & Analyt Methods, Epidemiol Program Off, MS-K73,4770 Buford Highway, Atlanta, GA 30341 USA. NR 28 TC 104 Z9 106 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2000 VL 18 IS 1 SU S BP 18 EP 26 DI 10.1016/S0749-3797(99)00124-5 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 276TC UT WOS:000084892600008 PM 10806976 ER PT J AU Hinman, AR Briss, PA Carande-Kulis, VG Bernier, RR Ndiaye, SM Rodewald, LE Shefer, AM Strikas, RA Williams, SM Yusuf, HR Atkins, D Chin, J Evans, CA Gyorkos, TW Isham, GJ Lett, SM Matulionis, RM Novick, LF Saari, TN Schaffner, W Scrimshaw, SC Amr, S Gendler, JE Gugelman, RJ Teagle, SE Khetsuriani, N Kimsey, CD Williams, SG Smith-Akin, CK AF Hinman, AR Briss, PA Carande-Kulis, VG Bernier, RR Ndiaye, SM Rodewald, LE Shefer, AM Strikas, RA Williams, SM Yusuf, HR Atkins, D Chin, J Evans, CA Gyorkos, TW Isham, GJ Lett, SM Matulionis, RM Novick, LF Saari, TN Schaffner, W Scrimshaw, SC Amr, S Gendler, JE Gugelman, RJ Teagle, SE Khetsuriani, N Kimsey, CD Williams, SG Smith-Akin, CK CA Task Force Community Preventive S TI Recommendations regarding interventions to improve vaccination coverage in children, adolescents, and adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article DE vaccine-preventable diseases; vaccination coverage; community health services; decision-making; evidence-based medicine; systematic reviews; population-based interventions; practice guidelines; preventive health services; public health practice; task force C1 Ctr Dis Control & Prevent, Community Prevent Serv Guide Dev Activ, Epidemiol Program Off, Atlanta, GA 30341 USA. Task Force Child Survival & Dev, Atlanta, GA USA. Ctr Dis Control & Prevent, Natl Immunizat Program, Atlanta, GA USA. US Dept HHS, Agcy Hlth Care Policy & Res, Rockville, MD 20852 USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. NIH, Bethesda, MD 20892 USA. Montreal Gen Hosp, Montreal, PQ H3G 1A4, Canada. McGill Univ, Montreal, PQ, Canada. HealthPartners, Bloomington, MN USA. Massachusetts Dept Publ Hlth, Boston, MA USA. Assoc State Territorial Directors Hlth Promot & P, Washington, DC USA. Onondaga Cty Hlth Dept, Syracuse, NY USA. Univ Wisconsin, Madison, WI USA. Vanderbilt Univ, Nashville, TN USA. Univ Illinois, Chicago, IL USA. Johns Hopkins Sch Hyg & Publ Hlth, Baltimore, MD USA. Dept Hlth & Social Serv, Wilmington, DE USA. Gugelman Melville & Associates, Chapel Hill, NC USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Briss, PA (reprint author), Ctr Dis Control & Prevent, Community Prevent Serv Guide Dev Activ, Epidemiol Program Off, MS K73,4770 Buford Highway, Atlanta, GA 30341 USA. NR 2 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2000 VL 18 IS 1 SU S BP 92 EP 96 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 276TC UT WOS:000084892600013 ER PT J AU Bertolino, A Esposito, G Callicott, JH Mattay, VS Van Horn, JD Frank, JA Berman, KF Weinberger, DR AF Bertolino, A Esposito, G Callicott, JH Mattay, VS Van Horn, JD Frank, JA Berman, KF Weinberger, DR TI Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; CARD SORTING TEST; NEUROLEPTIC-NAIVE PATIENTS; CEREBRAL BLOOD-FLOW; COGNITIVE DYSMETRIA; BRAIN ACTIVITY; CORTEX; PERFORMANCE; DYSFUNCTION; TASK AB Objective: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. Method: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic (H-1-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [O-15]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with H-1-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). Results: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships. Conclusions: These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Off Director, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Rm 4S235,MSC 1379,10 Ctr Dr, Bethesda, MD 20892 USA. RI Callicott, Joseph/C-9102-2009; Bertolino, Alessandro/O-6352-2016 OI Callicott, Joseph/0000-0003-1298-3334; Bertolino, Alessandro/0000-0002-1251-1380 NR 62 TC 113 Z9 114 U1 1 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 JAN PY 2000 VL 157 IS 1 BP 26 EP 33 PG 8 WC Psychiatry SC Psychiatry GA 270WJ UT WOS:000084559900005 PM 10618009 ER PT J AU Han, L Wang, KQ Du, ZY Cheng, YR Simons, JS Rosenthal, NE AF Han, L Wang, KQ Du, ZY Cheng, YR Simons, JS Rosenthal, NE TI Seasonal variations in mood and behavior among Chinese medical students SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID AFFECTIVE-DISORDER; PREVALENCE; DEPRESSION AB Objective: The goal of this study was to estimate the frequency of seasonal variations in mood and behavior among Chinese medical students. Method: A total of 1,358 medical students were surveyed with Chinese versions of the Seasonal Pattern Assessment Questionnaire and the Beck Depression Inventory in Jining, China. Results: The mean global seasonality score was 8.3 (SD=3.6) out of a possible 24; 81.7% (N=1,110) of the subjects reported some trouble adapting to changing seasons. Summer difficulties were more common than winter difficulties by a ratio of 3:2; estimated rates of summer seasonal affective disorder and subsyndromal seasonal affective disorder were 4.4% and 8.0%, respectively, compared with corresponding winter rates of 2.4% and 5.7%, Conclusions: These results suggest that seasonal variations in mood and behavior are common in China. The predominance of summer difficulties stands in contrast to that in most Western studies and is consistent with the only other published study performed in Asia. C1 NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. Jining Med Coll, Psychiat Hosp, Jining, Peoples R China. RP Han, L (reprint author), NIMH, Clin Psychobiol Branch, Bldg 10-3S-231,10 Ctr Dr, Bethesda, MD 20892 USA. NR 11 TC 23 Z9 26 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 JAN PY 2000 VL 157 IS 1 BP 133 EP 135 PG 3 WC Psychiatry SC Psychiatry GA 270WJ UT WOS:000084559900025 PM 10618029 ER PT J AU Grant, BF AF Grant, BF TI Estimates of US children exposed to alcohol abuse and dependence in the family SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PSYCHOPATHOLOGY; DEPRESSIVES; PREVALENCE; DRINKING; MEN AB Objectives. This Study sought to provide direct estimates of Eht: number of US children younger than Is years who are exposed to alcohol abuse or alcohol dependence in the family. Methods. Data were derived from the National Longitudinal Alcohol Epidemiologic Survey Results: Approximately 1 in 4 children younger than 18 years in the United States is exposed Lo alcohol abuse or alcohol dependence in the family. Conclusions. There is it need for approaches that integrate systems of sec-vices to enhance the lives of these children. C1 NIAAA, Div Biometry & Epidemiol, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Div Biometry & Epidemiol, Suite 514,MSC 7003, Bethesda, MD 20892 USA. NR 25 TC 90 Z9 92 U1 2 U2 5 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 JAN PY 2000 VL 90 IS 1 BP 112 EP 115 DI 10.2105/AJPH.90.1.112 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 268LY UT WOS:000084418900017 PM 10630147 ER PT J AU Umbach, DM AF Umbach, DM TI Unit conversion as a source of misclassification in US birthweight data SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID BIRTH-WEIGHT DISTRIBUTIONS; MORTALITY AB Objectives. This study explains why frequency polygons for US birthweights in 100-g weight classes appear spiky compared with their European counterparts. Methods. A probability model is used to describe how unit conversion can induce misclassification. Birthweights from the United States and Norway are used to illustrate that misclassification operates in grouped US data. Results. Spikiness represents misclassification that arises when measured birthweights are rounded to the nearer ounce, converted to grams, and then grouped into weight classes. Misclassification is ameliorated, not eliminated with 200-g weight classes. Conclusions. Possible biases from misclassification should be carefully evaluated when fitting statistical models to grouped US birthweights. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Umbach, DM (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. NR 7 TC 2 Z9 2 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 JAN PY 2000 VL 90 IS 1 BP 127 EP 129 DI 10.2105/AJPH.90.1.127 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 268LY UT WOS:000084418900022 PM 10630152 ER PT J AU Travis, WD Matsui, K Moss, J Ferrans, VJ AF Travis, WD Matsui, K Moss, J Ferrans, VJ TI Idiopathic nonspecific interstitial pneumonia: Prognostic significance of cellular and fibrosing patterns - Survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE idiopathic interstitial pneumonia; usual interstitial pneumonia; nonspecific interstitial pneumonia; idiopathic pulmonary fibrosis; cellular interstitial pneumonia; cellular, fibrosing, desquamative interstitial pneumonia; bronchiolitis obliterans organizing pneumonia acute interstitial pneumonia; diffuse alveolar damage; interstitial fibrosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH-RESOLUTION CT; PULMONARY FIBROSIS; PNEUMOCYSTIS-CARINII; HISTOLOGIC-FINDINGS; CLINICAL RELEVANCE; LUNG-DISEASE; BRONCHIOLITIS; ALVEOLITIS; FEATURES AB Nonspecific interstitial pneumonia (NSIP) has been proposed as a histologic subtype of idiopathic interstitial pneumonia with lung biopsy findings that are inconsistent with those of other idiopathic interstitial pneumonias. NSIP has a broad spectrum of histologic findings and a variable prognosis. The aim of this study was to determine whether it would be preferable to subdivide NSIP into cellular and fibrosing patterns. The authors classified lung biopsies from 101 patients with idiopathic interstitial lung disease as having histologic patterns of desquamative interstitial pneumonia (DIP), usual interstitial pneumonia (UIP), or cellular or fibrosing NSIP. Survival analysis was performed using the Kaplan-Meier method. Due to histologic, clinical, and survival similarities, the patients with idiopathic NSIP with lung biopsies that showed fibrosing as well as fibrosing and cellular patterns were combined into a single group of NSIP, fibrosing pattern. Of the 101 patients, 16 patients (9 women, 7 men) had idiopathic DIP; 56 patients (17 women, 39 men) had idiopathic UIP; 22 patients (7 women, 15 men) had idiopathic NSIP, fibrosing pattern; and 7 patients (2 women, 5 men) had idiopathic NSIP, cellular pattern. The patients had a mean age of 42, 51, 50, and 39 years respectively. Patients with idiopathic NSIP, cellular pattern had a better 5- and 10-year survival than those with idiopathic NSIP, fibrosing pattern (100% vs 90% and 100% vs 35% respectively, p = 0.027). Survival of patients with idiopathic UIP was worse than that of ;patients with idiopathic NSIP, fibrosing pattern (p = 0.014). The difference, however, was more evident at 5 years (43% vs 90%) than at 10 years (15% vs 35%). The 5- and 10-year survival of patients with idiopathic NSIP, cellular pattern and DIP was 100%, which was significantly better than that of patients with idiopathic UIP (p < 0.0001). Based on these data, NSIP should be separated into cellular and fibrosing patterns, because these histologic patterns are associated with different clinical characteristics and prognoses. C1 Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. NHLBI, Pathol Sect, Bethesda, MD 20892 USA. NHLBI, Pulm & Crit Care Med Branch, Bethesda, MD 20892 USA. RP Travis, WD (reprint author), Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Bldg 54,Room M003B,6825 NW 16th St, Washington, DC 20306 USA. NR 32 TC 313 Z9 337 U1 0 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 JAN PY 2000 VL 24 IS 1 BP 19 EP 33 DI 10.1097/00000478-200001000-00003 PG 15 WC Pathology; Surgery SC Pathology; Surgery GA 272GZ UT WOS:000084643300003 PM 10632484 ER PT J AU Kumar, S Fend, F Quintanilla-Martinez, L Kingma, DW Sorbara, L Raffeld, M Banks, PM Jaffe, ES AF Kumar, S Fend, F Quintanilla-Martinez, L Kingma, DW Sorbara, L Raffeld, M Banks, PM Jaffe, ES TI Epstein-Barr virus-positive primary gastrointestinal Hodgkin's disease - Association with inflammatory bowel disease and immunosuppression SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 88th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-26, 1999 CL SAN FRANCISCO, CALIFORNIA SP US & Canadian Acad Pathol DE Hodgkin's disease; primary gastrointestinal; Crohn's disease; inflammatory bowel disease; Epstein-Barr virus; immunosuppression; B-cell genotype; laser capture microdissection ID REED-STERNBERG CELLS; LASER CAPTURE MICRODISSECTION; LYMPHOPROLIFERATIVE DISORDERS; RENAL-TRANSPLANTATION; MALIGNANT-LYMPHOMA; CROHNS-DISEASE; COMPLICATION; COLITIS; TRACT AB Inflammatory bowel disease (IBD) is associated with an increased risk of lymphoma, which is usually extraintestinal but sometimes may involve the diseased bowel itself. Most lymphomas described in this setting are of non-Hodgkin's type, but rare cases of Hodgkin's disease (HD) have been reported. We describe the clinicopathologic and molecular features of four patients with primary gastrointestinal HD. Three patients had preexistent Crohn's disease (CD), for which two of them had received immunosuppressive therapy. The fourth patient had a longstanding history of diverticulitis and myasthenia gravis and was receiving immunosuppressive therapy for the latter. Multifocal involvement of the bowel by HD was noted in all four cases. Disease was staged as IVA in one patient, IIIB in one patient, and IE in one patient, and the fourth patient died in the postoperative period before further workup. Two patients received chemotherapy, one of whom was dead at 9 months, whereas the other has no evidence of disease at 25 months' follow-up. The patient with 1E disease did not receive any therapy because only a few microscopic foci of disease were present and is also without any evidence of disease at 17 months. The Reed-Sternberg (RS) cells in all four cases expressed CD30, CD15, EBER-1, and LMP-I; two of four were focally CD20-positive. VJ-polymerase chain reaction for immunoglobulin heavy chain (IgH) rearrangement showed a polyclonal pattern in all four cases. Tn two cases, laser capture microdissection was used to isolate individual RS and Hodgkin's cells, which contained rearranged immunoglobulin genes, confirming a B-cell genotype. Whereas one case showed a dominant clonal band present in all isolates, cells from the patient with stage IE disease clearly showed a polyclonal population of RS cells. Our findings indicate that HD arising in the setting of UBD or chronic inflammation is the result of an Epstein-Barr virus-driven lymphoproliferation, analogous to that found in other immunodeficient states. Disordered immunoregulation inherent to CD and immunosuppressive therapy for the latter may contribute to its development. The finding of polyclonal RS cells in a patient with early stage disease and apparent cure by surgical resection versus monoclonal RS cells in the patient with disseminated disease suggests that HD in the setting of immunodeficiency also may show molecular progression; in a manner similar to that occurring in conventional B-cell lymphoproliferative disorders arising in the same setting. C1 NCI, NIH, Hematopathol Sect, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RP Kumar, S (reprint author), NCI, NIH, Hematopathol Sect, Bldg 10,Room 2N202,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. NR 37 TC 70 Z9 73 U1 0 U2 0 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 JAN PY 2000 VL 24 IS 1 BP 66 EP 73 DI 10.1097/00000478-200001000-00008 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 272GZ UT WOS:000084643300008 PM 10632489 ER PT J AU Tess, BH Levin, A Brubaker, G Shao, J Drummond, JE Alter, HJ O'Brien, TR AF Tess, BH Levin, A Brubaker, G Shao, J Drummond, JE Alter, HJ O'Brien, TR TI Seroprevalence of hepatitis C virus in the general population of northwest Tanzania SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID NON-B-HEPATITIS; BLOOD-DONORS; CONFIRMATORY ASSAYS; LIVER-DISEASE; ANTI-HCV; NON-A; PREVALENCE; ANTIBODIES; INFECTION; AFRICA AB Sera from 516 participants enrolled in a population-based cross-sectional study in northwest Tanzania were tested for antibodies to hepatitis C virus (HCV). The mean age of study subjects was 29 years (range = 16-49 years); 43% were men. 6% reported a history of blood transfusion, and 4% were infected with human immunodeficiency virus-1 (HIV-1). Although 53 of 516 sera (10.3%, 95% confidence interval [CI] = 7.8-13.2%) were repeatedly reactive by a third-generation enzyme immunoassay (EIA-3), only 6 of the 53 were positive when tested with a third-generation recombinant immunoblot assay (confirmed HCV seroprevalence = 1.2%, 95% CI = 0.4-2.5%). The positive predictive value of the HCV EIA-3 in this population was 18.8% (95% CI = 7.0-36.4%). False positivity was not correlated with EIA-3 optical density values, age, sex, infection with HIV-1, or a history of blood transfusion, but it was marginally associated with increased serum IgG levels. We conclude that the prevalence of HCV is low in this region and that the HCV EIA-3 has a higher false-positivity rate in this population than has been reported among U.S. blood donors. C1 NCI, Viral Epidemiol Branch, NIH, Rockville, MD 20852 USA. St Bartholomews Hosp, Sch Med, Dept Virol, Res Triangle Inst Unit, London EC1M 6AH, England. Shirati Hosp, Shirati, Tanzania. Kilimanjaro Med Ctr, Moshi, Tanzania. Sci Applicat Int Corp, Frederick, MD 21702 USA. NIH, Dept Transfus Med, Bethesda, MD USA. RP Tess, BH (reprint author), NCI, Viral Epidemiol Branch, NIH, 6120 Execut Blvd,EPS-8003,MSC 7248, Rockville, MD 20852 USA. FU NCI NIH HHS [NCI-CP-EB-85603-57] NR 20 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JAN PY 2000 VL 62 IS 1 BP 138 EP 141 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 298NF UT WOS:000086145500026 PM 10761739 ER PT J AU Rogawski, MA AF Rogawski, MA TI Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents - toward an understanding of their favorable tolerability SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 6th International Congress on Amino Acids CY AUG 03-07, 1999 CL BONN, GERMANY SP Merck KGaA, Knoll AG Allgemeine Pharmakol & ZNS Forsch, Gruenthal GmbH, Merck Sharpe & Dohme Res Labs, Novartis Pharma AG DE amino acids; NMDA-receptors antagonists ID METHYL-D-ASPARTATE; ANALOGS DIZOCILPINE MK-801; REMACEMIDE HYDROCHLORIDE; ANTICONVULSANT ACTIVITY; ADAMANTANE DERIVATIVES; CLINICAL-EXPERIENCE; VOLTAGE-DEPENDENCY; IN-VITRO; FELBAMATE; ACID AB Studies in experimental models have suggested that NMDA receptor antagonists may have utility in the treatment of a wide variety of neurological and psychiatric disorders. However, clinical trials have not been encouraging largely because the antagonists evaluated to date have exhibited unacceptable neurobehavioral side effects. In animals, therapeutic doses of some low-affinity channel blocking (uncompetitive) NMDA receptor antagonists are associated with less gross neurological impairment and behavioral toxicity than other types of NMDA receptor antagonists. Favorable clinical experiences with several such agents has bolstered confidence in the neurotherapeutic potential of low affinity NMDA antagonists. This article reviews current research attempting to explain the improved tolerability of such antagonists. While no single mechanism appears to account for the reduced toxicity of such agents, kinetic properties, particularly rapid blocking rate, seem to be of key importance. Other factors include partial trapping, reduced agonist-independent (closed channel) block, subunit selectivity (particularly for receptors that do not contain the NR2A subunit), combined block at allosteric (voltage-independent) sites, and synergistic therapeutic effects produced by additional actions at receptor targets apart from NMDA receptors (e.g., weak positive allosteric modulation of GABA, receptors or state-dependent Na+ channel block). C1 NINDS, Neuronal Excitabil Sect, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Neuronal Excitabil Sect, Epilepsy Res Branch, NIH, Bldg 10,Room 5N-250,10 Ctr Dr MSC 1408, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 70 TC 74 Z9 78 U1 0 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PY 2000 VL 19 IS 1 BP 133 EP 149 DI 10.1007/s007260070042 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 356LV UT WOS:000089445500016 PM 11026482 ER PT J AU Ito, Y AF Ito, Y TI Centrifugal precipitation chromatography: Principle, apparatus, and optimization of key parameters for protein fractionation by ammonium sulfate precipitation SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE centrifugal precipitation chromatography; ammonium sulfate; protein fractionation; recombinant ketosteroid isomerase; monoclonal antibody; affinity separation AB A novel chromatographic system introduced here internally generates a concentration gradient of ammonium sulfate (AS) through a long separation channel under a centrifugal force field. Protein samples are exposed to a gradually increasing AS concentration and precipitated along the channel. Then, chromatographic elution is initiated by gradually decreasing the AS concentration in the gradient which causes the proteins to repeat dissolution and precipitation through the channel. Consequently, they are eluted out in the order of their solubility in the AS solution. The separation column consists of a pair of disks equipped with mutually mirror-imaged spiral grooves. A dialysis membrane is sandwiched between the disks to form two identical channels partitioned by the membrane. The disk assembly is mounted on the sealless continuous-how centrifuge, When a concentrated AS solution is eluted through one channel and water through the other channel in an opposite direction, an exponential AS gradient is formed through the water channel. A series of basic experiments was performed to study the rates of AS transfer and osmosis through the membrane, and the operational parameters including elution time, revolution speed, inclination of gradient, and sample size were optimized using stable protein samples. Preliminary applications were successful in purification of monoclonal antibody from cell culture supernatant and an affinity separation of recombinant ketosteroid isomerase from a crude Escherichia coli lysate, (C) 2000 Academic Press. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP NHLBI, Biophys Chem Lab, NIH, Bldg 10,Room 7N322, Bethesda, MD 20892 USA. NR 9 TC 28 Z9 28 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD JAN 1 PY 2000 VL 277 IS 1 BP 143 EP 153 DI 10.1006/abio.1999.4365 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 282RG UT WOS:000085231800017 PM 10610699 ER PT J AU Giaretti, W Macciocu, B Geido, E Hermsen, MAJA Postma, C Baak, JPA Williams, RA Meijer, GA AF Giaretti, W Macciocu, B Geido, E Hermsen, MAJA Postma, C Baak, JPA Williams, RA Meijer, GA TI Intratumor heterogeneity of k-ras and p53 mutations among human colorectal adenomas containing early cancer SO ANALYTICAL CELLULAR PATHOLOGY LA English DT Article DE oncogenes; tumor suppressor genes; colorectal tumor progression; molecular biology ID ABERRANT CRYPT FOCI; DNA FLOW-CYTOMETRY; GENETIC ALTERATIONS; K-RAS2 MUTATIONS; CYCLIN D1; ADENOCARCINOMAS; PROLIFERATION; ANEUPLOIDY; ACTIVATION; APOPTOSIS AB The molecular pathways and the timing of genetic events during human colorectal carcinogenesis are still not fully understood. We have addressed the intratumor heterogeneity of the mutational status of the k-ras oncogene and of the p53 on-cosuppressor gene during the adenoma-carcinoma sequence by investigating 26 human colorectal adenomas containing early cancer. An intratumor comparative analysis was obtained among the adenomatous and carcinomatous component pairs. Additionally, we have analyzed 17 adenomas having cancer in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k-ras mutations (28 and 47%) but different for p53 mutations (52 and 7%, p-value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k-ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p-value < 0.01). In addition, the mutations of p53 for the adenomatous components of the adenomas containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k-ras status during the human colorectal adenoma-carcinoma sequence suggests that the role of k-ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heterogeneity of p53 mutations indicates that the type of the p53 mutations may also be relevant for selection and expansion of new sub-clones leading to tumor progression. C1 Natl Canc Inst, IST, Lab Biophys & Cytometry, I-16132 Genoa, Italy. Free Univ Amsterdam Hosp, Dept Pathol, Amsterdam, Netherlands. St Vincents Hosp, Dept Pathol, Melbourne, Vic, Australia. RP Giaretti, W (reprint author), Natl Canc Inst, IST, Lab Biophys & Cytometry, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. NR 40 TC 20 Z9 20 U1 0 U2 8 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0921-8912 J9 ANAL CELL PATHOL JI Anal. Cell. Pathol. PY 2000 VL 21 IS 2 BP 49 EP 57 PG 9 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA 424YZ UT WOS:000168262700001 PM 11310641 ER PT J AU Best, CJM Gillespie, JW Englert, CR Swalwell, JI Pfeifer, J Krizman, DB Petricoin, EF Liotta, LA Emmert-Buck, MR AF Best, CJM Gillespie, JW Englert, CR Swalwell, JI Pfeifer, J Krizman, DB Petricoin, EF Liotta, LA Emmert-Buck, MR TI New approaches to molecular profiling of tissue samples SO ANALYTICAL CELLULAR PATHOLOGY LA English DT Review ID LASER CAPTURE MICRODISSECTION; PROSTATIC INTRAEPITHELIAL NEOPLASIA; POLYMERASE CHAIN-REACTION; GENE-EXPRESSION; DNA CHIPS; CANCER; CELLS; POPULATIONS; PROTEOMICS; GENOMICS C1 NCI, NIH, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD USA. NCI, Ctr Adv Technol, Canc Genome Anat Project, Gaithersburg, MD USA. US FDA, Ctr Biol & Res, Div Cytokine Biol, Bethesda, MD USA. RP Emmert-Buck, MR (reprint author), NCI, NIH, Pathol Lab, Pathogenet Unit, Bldg 10,Room 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 38 TC 13 Z9 13 U1 0 U2 1 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0921-8912 J9 ANAL CELL PATHOL JI Anal. Cell. Pathol. PY 2000 VL 20 IS 1 BP 1 EP 6 PG 6 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA 338GB UT WOS:000088409200001 PM 11007432 ER PT J AU Bryant, LH Yordanov, AT Linnoila, JJ Brechbiel, MW Frank, JA AF Bryant, LH Yordanov, AT Linnoila, JJ Brechbiel, MW Frank, JA TI First noncovalently bound Calix[4]arene-Gd-III-albumin complex SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE calixarenes; lanthanides; NMR spectroscopy; noncovalent interactions ID MOLECULAR RECEPTORS; CONTRAST AGENTS; METAL-COMPLEXES; WATER; GADOLINIUM(III); CALIX<4>ARENES; CALIXARENES; CHEMISTRY; RESONANCE; IONS C1 NIH, Lab Diagnost Radiol Res CC, Bethesda, MD 20892 USA. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bryant, LH (reprint author), NIH, Lab Diagnost Radiol Res CC, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. NR 23 TC 20 Z9 20 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PY 2000 VL 39 IS 9 BP 1641 EP + PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 312HT UT WOS:000086938400021 ER PT J AU Villafania, A Anwar, K Amar, S Chie, L Way, D Chung, DL Adler, V Ronai, Z Brandt-Rauf, PW Yamaizumii, Z Kung, HF Pincus, MR AF Villafania, A Anwar, K Amar, S Chie, L Way, D Chung, DL Adler, V Ronai, Z Brandt-Rauf, PW Yamaizumii, Z Kung, HF Pincus, MR TI Glutathione-S-transferase as a selective inhibitor of oncogenic ras-p21-induced mitogenic signaling through blockade of activation of jun by jun-N-terminal kinase SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Article DE glutathione-S-transferase; jun kinase; jun; ras-p21; oocyte maturation; protein kinase C ID PROTEIN-KINASE; MONOCLONAL-ANTIBODIES; OOCYTE MATURATION; RAS-P21 PROTEIN; RAS GENES; P21(RAS); INSULIN AB We have identified the intracellular detoxification enzyme, glutathione-S-transferase (GST), as a potent inhibitor of the activation of jun by its kinase, jun-N-terminal kinase (JNK), in vitro. All three major isozymes (alpha, mu, and pi) bind to JNK-jun complexes and inhibit activation of jun by JNK. We now find that GST inhibits JNK-induced oocyte maturation in vivo and strongly inhibits oocyte maturation induced by oncogenic ras-p21 protein, but not by insulin-activated normal cellular p21 protein. These results correlate with the finding that oncogenic, but not insulin-activated normal, p21 induces high levels of activated JNK. GST also strongly blocks induction of oocyte maturation by protein kinase C (PKC) which is a critical downstream target of oncogenic but not normal ras-p21. Thus, we have established a new function for GST as a potent physiological inhibitor of the ras-JNK-jun pathway. C1 VA Med Ctr, Dept Pathol & Lab Med, Brooklyn, NY 11209 USA. Long Isl Univ, Dept Chem, Brooklyn, NY USA. Long Isl Univ, Dept Biol, Brooklyn, NY USA. Mt Sinai Med Ctr, Ruttenberg Canc Ctr, New York, NY 10029 USA. Columbia Univ, Coll Phys & Surg, Div Environm Sci, New York, NY USA. Natl Canc Inst, Tokyo, Japan. NCI, Lab Biochem Physiol, Frederick, MD 21701 USA. SUNY Hlth Sci Ctr, Dept Pathol, Brooklyn, NY 11203 USA. RP Pincus, MR (reprint author), VA Med Ctr, Dept Pathol & Lab Med, 800 Poly Pl, Brooklyn, NY 11209 USA. OI RONAI, ZEEV/0000-0002-3859-0400 FU NCI NIH HHS [CA 69243, CA 42500] NR 23 TC 29 Z9 31 U1 0 U2 0 PU INST CLINICAL SCIENCE INC PI PHILADELPHIA PA 1833 DELANCEY PLACE, PHILADELPHIA, PA 19103 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD JAN PY 2000 VL 30 IS 1 BP 57 EP 64 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 279EW UT WOS:000085032300007 PM 10678584 ER PT J AU Batey, DM Kaufmann, PG Raczynski, JM Hollis, JF Murphy, JK Rosner, B Corrigan, SA Rappaport, NB Danielson, EM Lasser, NL Kuhn, CM AF Batey, DM Kaufmann, PG Raczynski, JM Hollis, JF Murphy, JK Rosner, B Corrigan, SA Rappaport, NB Danielson, EM Lasser, NL Kuhn, CM CA Phase I Trials Hypertens Prevent C TI Stress management intervention for primary prevention of hypertension: Detailed results from phase I of trials of hypertension prevention (TOHP-I) SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE hypertension; blood pressure; clinical trial; prevention; nonpharmacologic; stress; lifestyle ID BORDERLINE HYPERTENSION; BEHAVIORAL TREATMENT; HASSLES AB PURPOSE: Stress Management Intervention (SMI) was one of seven nonpharmacologic approaches evaluated in Phase I Trials of Hypertension Prevention (TOHP-I) for efficacy in lowering diastolic blood pressure (BP) in healthy men and women aged 30 to 54 years with diastolic BP 80-89 mm Hg. METHODS: A total of 242 and 320 participants were randomized to SMI or an assessment only" SMI Control, respectively, at four clinical centers. The SMI consisted of 37 contact hours in 21 group and two individual meetings over 18 months and included: training in four relaxation methods, techniques to reduce stress reactions, cognitive approaches, communication skills, time management, and anger management within a general problem-solving format. Standardized protocols detailed methods and timing for collecting BP, psychosocial measures, and urinary samples from both SMI and SMI Control participants. RESULTS: In intention-to-treat analyses, although significant baseline to termination BP reductions were observed in both groups, net differences between the SMI and SMI Control groups' BP changes (mean (95% CI)) were not significant: -0.82 (-1.86, 0.22) for diastolic BP, and -0.41 (-1.96, 1.01) for systolic BP. Extensive adherence sub-group analyses found one effect: a significant 1.36 mm Hg (p = 0.01) reduction in diastolic BP relative to SMI Controls at the end of the trial for SMI participants who completed 61% or more of intervention sessions. CONCLUSIONS: While the TOHP-I SMI was acceptable to participants as evident from high levels of session completion, the absence of demonstrated BP lowering efficacy in intention-to-treat analyses suggests that the TOHP-I SMI is an unlikely candidate for primary prevention of hypertension in a general population sample similar to study participants. The isolated finding of significant diastolic BP lowering in SMI participants with higher adherence provides very weak evidence of SMI BP lowering efficacy and may be a chance finding. Whether similar or other stress management interventions can produce significant BP lowering in populations selected for higher levels of BP, stress, or intervention adherence remains to be demonstrated. Ann Epidemiol 2000;10:45-58. Published by Elsevier Science Inc. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Prevent Cardiol Program, Newark, NJ 07103 USA. NHLBI, Behav Med Res Grp, Bethesda, MD 20892 USA. Univ Alabama, Div Prevent Med, Behav Med Unit, Birmingham, AL USA. Univ Alabama, UAB Ctr Hlth Promot, Birmingham, AL USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Mississippi, Sch Med, Dept Med, Jackson, MS 39216 USA. Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. Duke Univ, Med Ctr, Dept Pharmacol, Durham, NC 27710 USA. RP Batey, DM (reprint author), Exxon Co USA, US Med & Occupat Hlth Dept EB 3171D, 800 Bell, Houston, TX 77002 USA. FU NHLBI NIH HHS [HL367853, HL37854]; PHS HHS [H637852] NR 38 TC 15 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JAN PY 2000 VL 10 IS 1 BP 45 EP 58 DI 10.1016/S1047-2797(99)00041-1 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 274TZ UT WOS:000084782300006 PM 10658688 ER PT J AU Anderson, RN Rosenberg, HM Sorlie, PD Thom, TJ Manolio, T Burke, GL AF Anderson, RN Rosenberg, HM Sorlie, PD Thom, TJ Manolio, T Burke, GL TI The new population standard for age adjusting death rates SO ANNALS OF EPIDEMIOLOGY LA English DT Letter C1 NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Publ Hlth, Winston Salem, NC 27109 USA. Natl Ctr Hlth Stat, Div Vital Stat, Hyattsville, MD 20782 USA. RP Anderson, RN (reprint author), Natl Ctr Hlth Stat, Div Vital Stat, Hyattsville, MD 20782 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JAN PY 2000 VL 10 IS 1 BP 68 EP 68 DI 10.1016/S1047-2797(99)00054-X PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 274TZ UT WOS:000084782300008 PM 10658690 ER PT J AU Tawil, R McDermott, MP Brown, R Shapiro, BC Ptacek, LJ McManis, PG Dalakas, MC Spector, SA Mendell, JR Hahn, AF Griggs, RC AF Tawil, R McDermott, MP Brown, R Shapiro, BC Ptacek, LJ McManis, PG Dalakas, MC Spector, SA Mendell, JR Hahn, AF Griggs, RC CA Working Grp Period Paralysis TI Randomized trials of dichlorphenamide in the periodic paralyses SO ANNALS OF NEUROLOGY LA English DT Article ID WEAKNESS AB Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double-blind, placebo-controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double-blind, placebo-controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium-sensitive periodic paralysis (PSPP). In each trial, two 8-week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and Il of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects, We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP. C1 Univ Rochester, Rochester, NY 14642 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT USA. Mayo Clin, Rochester, MN USA. NINDS, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Western Ontario, London, ON, Canada. RP Tawil, R (reprint author), Univ Rochester, POB 673,601 Elmwood Ave, Rochester, NY 14642 USA. FU NCRR NIH HHS [M01-RR00044, M01-RR00585, M01-RR00034] NR 16 TC 77 Z9 80 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2000 VL 47 IS 1 BP 46 EP 53 DI 10.1002/1531-8249(200001)47:1<46::AID-ANA9>3.0.CO;2-H PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 272ED UT WOS:000084636800008 PM 10632100 ER PT J AU Pratley, RE Salbe, AD Ravussin, E Caviness, JN AF Pratley, RE Salbe, AD Ravussin, E Caviness, JN TI Higher sedentary energy expenditure in patients with Huntington's disease SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSGENIC MICE; NEUROPEPTIDE-Y; GENE-PRODUCT; INDIVIDUALS; PROGRESSION; DEFECT; REPEAT; LENGTH AB Weight loss is common among patients with Huntington's disease (HD), although the mechanisms contributing to this phenomenon are not known. We measured 24-hour sedentary energy expenditure (24-hour EE) and sleeping metabolic rate (SMR) in a human respiratory chamber in 17 patients with mild to moderate HD and 17 control subjects matched for age, sex, and body mass index. Total energy expenditure was measured during 7 days in free-living conditions, using the doubly labeled water technique, Body weight, fat mass, and fat-free mass (measured by dual-energy x-ray absorptiometry) were similar in patients with HD and control subjects. Twenty-four-hour EE was 14% higher in HD patients than controls in absolute terms (2,038 +/- 98 vs 1,784 +/- 68 kca1/24 hours) and after adjustment for age, sex, fat mass, and fat-free mass (1,998 +/- 45 vs 1,824 +/- 45 kcal/24 hours). In contrast, SMR and total energy expenditure were similar in patients and controls both in absolute terms (1,314 +/- 38 vs 1,316 +/- 42 and 2,402 +/- 102 vs 2,373 +/- 98 kcal/24 hours, respectively) and after adjustment. Spontaneous physical activity measured by radar in the chamber and the ratio of 24-hour EE to SMR were significantly higher in HD patients than controls (11.4 +/- 1.4 vs 6.1 +/- 0.6% and 1.54 +/- 0.05 vs 1.36 +/- 0.03, respectively). In the group as a whole, 24-hour EE/SMR correlated with spontaneous physical activity. Among HD patients, both 24-hour EE/SMR and spontaneous physical activity correlated with the severity of chorea, but SMR and total energy expenditure did not. There were no differences in reported energy intake during 7 days in patients with HD compared with controls. The results of this study indicate that sedentary energy expenditure is higher in patients with I-ID than in controls in proportion to the severity of the movement disorder. Total free-living energy expenditure is not higher, however, because patients with HD appear to engage in less voluntary physical activity. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Mayo Clin Scottsdale, Dept Neurol, Scottsdale, AZ USA. RP Pratley, RE (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. NR 31 TC 76 Z9 76 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2000 VL 47 IS 1 BP 64 EP 70 DI 10.1002/1531-8249(200001)47:1<64::AID-ANA11>3.0.CO;2-S PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 272ED UT WOS:000084636800010 PM 10632102 ER PT J AU Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J AF Harris, NL Jaffe, ES Diebold, J Flandrin, G Muller-Hermelink, HK Vardiman, J TI Lymphoma classification - from controversy to consensus: The REAL and WHO Classification of lymphoid neoplasms SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference on Malignant Lymphoma CY JUN 02-05, 1999 CL LUGANO, SWITZERLAND DE classification; lymphoma; pathology AB Background: Controversy in lymphoma classification dates back to the first attempts to formulate such classifications. Over the years, much of this controversy arose from the assumption that there had to be a single guiding principle - a 'gold standard - for classification, and from the existence of multiple different classifications. Design: The International Lymphoma Study Group (I.L.S.G.) developed a consensus list of lymphoid neoplasms, which was published in 1994 as the 'Revised European-American Classification of Lymphoid Neoplasms' (R.E.A.L.). The classification is based on the principle that a classification is a list of 'real' disease entities, which are defined by a combination of morphology, immunophenotype. genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. In some tumors morphology is paramount, in others it is immunophenotype, a specific genetic abnormality, or clinical features. An international study of 1300 patients, supported by the San Salvatore Foundation, was conducted to determine whether the R.E.A.L. Classification could be used by expert pathologists and had clinical relevance. Since 1995, the European Association of Pathologists (EAHP) and the Society for Hematopathology (SH) have been developing a new World Health Organization (WHO) Classification of hematologic malignancies, using an updated R.E.A.L. Classification for lymphomas and applying the principles of the R.E.A.L. Classification to myeloid and histiocytic neoplasms. A Clinical Advisory Committee (CAC) was formed to ensure that the WHO Classification will be useful to clinicians. Results: The International Lymphoma Study showed that the R.E.A.L. Classification could be used by pathologists, with inter-observer reproducibility better than for other classifications (> 85%), Immunophenotyping was helpful in some diagnoses, but not required for many others. New entities not specifically recognized in the Working Formulation accounted for 27% of the cases. Diseases that would have been lumped together as 'low grade' or 'intermediate/high grade' in the Working Formulation showed marked differences in survival, confirming that they need to be treated as distinct entities, Clinical features such as the international Prognostic Index were also important in determining patient outcome. The WHO Clinical Advisory Committee concluded that clinical groupings of lymphoid neoplasms was neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma. with the addition of grade within the turner type, if applicable, and clinical prognostic factors such as the international Prognostic Index (IPI). Conclusions: The experience of developing the WHO Classification has produced a neu; and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Labs, Boston, MA 02114 USA. Natl Canc Inst, Dept Pathol, Bethesda, MD USA. Hotel Dieu, Dept Pathol, Paris, France. Hop Necker Enfants Malad, Dept Pathol, Paris, France. Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. Univ Chicago, Pritzker Sch Med, Dept Pathol, Chicago, IL 60637 USA. RP Harris, NL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pathol Labs, Warren 2,Fruit St, Boston, MA 02114 USA. NR 18 TC 187 Z9 205 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 1 BP 3 EP 10 DI 10.1023/A:1008383406103 PG 8 WC Oncology SC Oncology GA 293YL UT WOS:000085882800002 PM 10707771 ER PT J AU Brawley, OW AF Brawley, OW TI Prostate cancer screening: The US approach. SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 4 MA 24IN BP 9 EP 9 PG 1 WC Oncology SC Oncology GA 357LV UT WOS:000089503900026 ER PT J AU Assersohn, LC Gangi, L Powles, TJ Simon, R Zhao, YD Powell, J Dowsett, M Staudt, L Edison, TL AF Assersohn, LC Gangi, L Powles, TJ Simon, R Zhao, YD Powell, J Dowsett, M Staudt, L Edison, TL TI Gene expression profiles from fine needle aspirations (FNAs) of breast cancers complementary DNA (cDNA) microarrays. SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 NCI, Microarray Facil, Bethesda, MD 20892 USA. Royal Marsden Hosp, Breast Unit, Surrey, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 4 MA 370 BP 11 EP 12 PG 2 WC Oncology SC Oncology GA 357LV UT WOS:000089503900039 ER PT J AU Brangi, M Litman, T Hudson, E Fetsch, P Abati, A Ross, DD Miyake, K Reasu, JH Catalano, G Bates, SE AF Brangi, M Litman, T Hudson, E Fetsch, P Abati, A Ross, DD Miyake, K Reasu, JH Catalano, G Bates, SE TI The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 Univ Naples, I-80138 Naples, Italy. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 2 MA B4 BP 13 EP 13 PG 1 WC Oncology SC Oncology GA 357LF UT WOS:000089502600051 ER PT J AU Jaffe, ES Sander, CA Flaig, MJ AF Jaffe, ES Sander, CA Flaig, MJ TI Cutaneous lymphomas: A proposal for a unified approach to classification using the REAL/WHO Classification SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference on Malignant Lymphoma CY JUN 02-05, 1999 CL LUGANO, SWITZERLAND DE cutaneous lymphoma; lymphoma; REAL Classification; skin ID B-CELL LYMPHOMA; EUROPEAN-AMERICAN CLASSIFICATION; MARGINAL ZONE LYMPHOMA; DISEASE; TRANSLOCATION; IMMUNOCYTOMA; NEOPLASMS; NASAL AB Background. The classification of cutaneous lymphomas has been controversial. The EORTC has proposed that conventional classification schemes are not suitable for cutaneous lymphomas, and that a unique classification system is required. Design. The authors review the suitability of the R.E.A.L. Classification for cutaneous lymphomas, and compare it with the newly proposed EORTC system. The principles of the R.E.A.L. Classification have been adopted by the WHO committees for the classification of hematopoietic and lymphoid neoplasms. Each disease is defined as a distinct entity based on an integration of morphology. immunophenotypic and genetic features, clinical presentation and course, and normal cellular counterpart. Tf either primary or secondary involvement of the skin is a constant factor, this aspect is considered integral to disease definition. Results. Organ-specific classification schemes may impede the recognition of common features of diseases involving multiple anatomic sites. For example, cutaneous marginal zone B-cell lymphomas (formerly designated cutaneous immunocytomas) mirror the features of MALT lymphomas in other anatomic sites. While the EORTC Classification for cutaneous lymphomas attempts to emphasize certain aspects of these neoplasms of importance to dermatologists, the use of multiple classification systems is a step backward, and may lead to confusion among hematologists/oncologists, and dermatologists. Nevertheless, cutaneous lymphomas often have a more indolent natural history than nodal lymphomas, and may require different therapeutic approaches. Clinical features are an important prognostic Factor and should be utilized in guiding therapy. For cutaneous lymphomas the presence or absence of systemic spread is particularly important. Additionally, the site of origin is often important in the definition of disease entities. Conclusions. Organ-specific classification schemes, such as the EORTC Classification For cutaneous lymphomas, are not required, and indeed may impede the recognition of common features of diseases involving multiple anatomic sites. A common classification system, such as the R.E.A.L./WHO Classification, should be utilized for all lymphomas, regardless of the site of origin. C1 NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. Univ Munich, Dept Dermatol, D-8000 Munich, Germany. RP Jaffe, ES (reprint author), Bldg 10-2N202,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. NR 28 TC 21 Z9 22 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 1 BP 17 EP 21 DI 10.1023/A:1008336732086 PG 5 WC Oncology SC Oncology GA 293YL UT WOS:000085882800004 PM 10707773 ER PT J AU Tallarico, D Colloca, LM Veri, A De Donatis, T Coletta, D Bonginelli, P Venditti, F Tomao, S La cava, V Di Sera, M AF Tallarico, D Colloca, LM Veri, A De Donatis, T Coletta, D Bonginelli, P Venditti, F Tomao, S La cava, V Di Sera, M TI Protective effect of trimetazidine (TRZ) in chemotherapy with anthracyclines SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 Univ La Sapienza, Dept Med, I-00185 Rome, Italy. Univ Rome La Sapienza, Dip Med Sper Pat, Rome, Italy. Natl Canc Inst, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 2 MA C41 BP 28 EP 28 PG 1 WC Oncology SC Oncology GA 357LF UT WOS:000089502600110 ER PT J AU Iori, F Veri, A De Nunzio, C Mama, A Vahedi, M Bonginelli, P Romiti, A Feroci, D Lacava, V Di Seri, M AF Iori, F Veri, A De Nunzio, C Mama, A Vahedi, M Bonginelli, P Romiti, A Feroci, D Lacava, V Di Seri, M TI Utility of maintenance intravesical immunotherapy in preventing recurrence and progression of superficial bladder cancer SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 Univ Rome La Sapienza, Dept Urol, Rome, Italy. Univ Rome La Sapienza, Dept Expt Med & Pathol, Rome, Italy. Univ Rome La Sapienza, Dept Surg, Rome, Italy. Natl Canc Inst, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 2 MA D12 BP 32 EP 32 PG 1 WC Oncology SC Oncology GA 357LF UT WOS:000089502600125 ER PT J AU Tomasello, R ChilleRizzotti, P Portale, T Priolo, C AF Tomasello, R ChilleRizzotti, P Portale, T Priolo, C TI Histocompatibility antigens and human cutaneous malignant melanoma SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 Univ Messina, I-98100 Messina, Italy. Natl Canc Inst, Satellite Unit, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 2 MA G22 BP 62 EP 62 PG 1 WC Oncology SC Oncology GA 357LF UT WOS:000089502600238 ER PT J AU Rossi, M Venditti, F Romiti, A Bezzi, M Pierleoni, M Spalletta, B Petrella, PP Manna, A Gueeriro, G Di Seri, M AF Rossi, M Venditti, F Romiti, A Bezzi, M Pierleoni, M Spalletta, B Petrella, PP Manna, A Gueeriro, G Di Seri, M TI Percutaneous radiofrequency thermal ablation of hepatocellular carcinoma (HCC) and hepatic metastases (METS) associated with chemotherapy SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 Univ Rome La Sapienza, Dept Radiol, Rome, Italy. Univ Rome La Sapienza, Dept Med & Pathol, Rome, Italy. Univ Rome La Sapienza, Dept Surg, Rome, Italy. Natl Canc Inst, Genoa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 2 MA H54 BP 74 EP 74 PG 1 WC Oncology SC Oncology GA 357LF UT WOS:000089502600287 ER PT J AU Naresh, KN Johnson, J Srinivas, V Soman, CS Saikia, T Advani, SH Badwe, RA Dinshaw, KA Muckaden, M Magrath, I Bhatia, K AF Naresh, KN Johnson, J Srinivas, V Soman, CS Saikia, T Advani, SH Badwe, RA Dinshaw, KA Muckaden, M Magrath, I Bhatia, K TI Epstein-Barr virus association in classical Hodgkin's disease provides survival advantage to patients and correlates with higher expression of proliferation markers in Reed-Sternberg cells SO ANNALS OF ONCOLOGY LA English DT Article DE Epstein-Barr virus; Hodgkin's disease; proliferation; Reed-Sternberg cell ID EBV; LYMPHOMAS; GENOMES; SUBTYPE; ADULT; PCNA; DNA AB Background: Most Epstein-Barr virus (EBV) associated lymphoproliferative disorders have high proliferation indices. However, classical Hodgkin's disease (cHD) is heterogeneous, with respect to proliferation index of the Reed-Sternberg cell (RS cell), and EBV association. Hence, we investigated whether cHD with and without EBV-association differ with respect to the proliferation index of the RS cells. Further we investigated whether this would have a bearing on patients survival. Patients and methods: We investigated 110 cases of cHD for: a) EBV association by immunohistochemical demonstration of EBV-latent membrane protein-1 and EBV encoded nuclear RNA 1 by mRNA in situhybridisation; b) Proliferating cell nuclear antigen (PCNA) expression in the RS cells. Results: EBV association was noted in 86 of 110 cases (78%). Higher PCNA expression (P = 0.004) and younger age (P = 0.001) correlated independently with EBV association. The 10 year relapse free survival (RFS) of EBV+ and EBV- patients were 60% and 44%, respectively (P = 0.03). The 10 year overall survival (OS) of EBV+ and EBV- patients were 85% and 64%, respectively (P = 0.03). EBV association maintained its significant impact on RFS and OS within Cox proportional hazard model. Conclusions: Our study suggests that EBV is likely to confer a higher PCNA expression and also contribute towards maintaining the RS cells of cHD in cell cycle. Hence, RS cells in EBV associated cHD would be more responsive to chemotherapy and radiotherapy associated DNA damage. Thus, EBV-association provides survival advantage to cHD patients treated with standard chemotherapy and radiotherapy protocols. C1 Tata Mem Hosp, Dept Pathol, Mumbai, India. Tata Mem Hosp, Dept Radiat Oncol, Mumbai, India. Tata Mem Hosp, Dept Med Oncol, Mumbai, India. Tata Mem Hosp, Dept Clin Res Secretariat, Mumbai, India. NCI, Lymphoma Biol Sect, Bethesda, MD 20892 USA. RP Naresh, KN (reprint author), Tata Mem Hosp, Dept Pathol, Mumbai, India. NR 36 TC 52 Z9 52 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2000 VL 11 IS 1 BP 91 EP 96 DI 10.1023/A:1008337100424 PG 6 WC Oncology SC Oncology GA 281ZK UT WOS:000085191200020 PM 10690394 ER PT J AU Waldmann, TA AF Waldmann, TA TI T-cell receptors for cytokines: Targets for immunotherapy of leukemia/lymphoma SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference on Malignant Lymphoma CY JUN 02-05, 1999 CL LUGANO, SWITZERLAND DE adult T-cell leukemia; anti-Tac mAb; cytokine; HTLV-1; interleukin-2; interleukin-15 ID HUMANIZED ANTI-TAC; INTERLEUKIN-2 IL-2 RECEPTOR; CARDIAC ALLOGRAFT SURVIVAL; MONOCLONAL-ANTIBODY; BETA-CHAIN; LEUKEMIA-LYMPHOMA; CANCER-THERAPY; GROWTH-FACTOR; GAMMA-CHAIN; HTLV-I AB Background: Cytokine receptors are exceptionally valuable targets for immunotherapy. For example, the high affinity IL-2 receptor is expressed by abnormal T cells in patients with certain lymphoid malignancies or autoimmune disorders and in individuals rejecting allografts whereas it is not expressed by normal resting cells. Design: To exploit this difference in receptor expression in normal resting cells and leukemic cells we have introduced different forms of IL-2 receptor directed therapy including an unmodified murine antibody to the alpha subunit of the IL-2 receptor (anti-Tac). humanized anti-Tac as well as this antibody armed with truncated Pseudomonas exotoxin or alpha- and beta-emitting radionuclides (e.g., At-211 and Y-90). In particular, unmodified murine anti-Tac was used in the therapy of HTLV-I-associated adult T-cell leukemia (ATL). Results: Six of nineteen patients treated with this antibody underwent a partial (four) or complete (two) remission. In a subsequent clinical trial involving anti-Tac armed with Y-90 over 50% of the patients with ATL treated underwent a partial or complete remission. Conclusions: New agents under development include humanized antibodies directed toward shared cytokine receptors such as IL-2/15R beta used by both IL-2 and IL-15 as well as to a shared signal transduction element Jak3 utilized by the T-cell stimulatory cytokines IL-2, IL-4, IL-7, IL-9 and IL-15. Thus our emerging understanding of cytokine receptors and their signaling pathways taken in conjunction with the ability to produce humanized antibodies armed with radionuclides or toxins are providing novel perspectives for the treatment of leukemia and lymphoma. C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, NIH, Bldg 10,Room 4N115,10 Ctr Dr,MSC 1374, Bethesda, MD 20892 USA. NR 54 TC 24 Z9 24 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 1 BP 101 EP 106 DI 10.1023/A:1008324701986 PG 6 WC Oncology SC Oncology GA 293YL UT WOS:000085882800020 PM 10707789 ER PT J AU Chesi, M Kuehl, WM Bergsagel, PL AF Chesi, M Kuehl, WM Bergsagel, PL TI Recurrent immunoglubulin gene translocations identify distinct molecular subtypes of myeloma SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT International Conference on Malignant Lymphoma CY JUN 02-05, 1999 CL LUGANO, SWITZERLAND DE chromosomal translocations; cyclin D1; FGFR3; MMSET; multiple myeloma ID GROWTH-FACTOR RECEPTOR-3; MULTIPLE-MYELOMA; DYSREGULATION; MUTATIONS; MAF AB Background: Chromosome translocations involving the immunoglobulin heavy chain gene (IgH) on 14q32 are a seminal event in the pathogenesis of many B-cell malignancies. Since myeloma is a post-germinal center tumor of mature, isotype switched plasma cells, we hypothesized that 14q32 translocations would usually involve IgH switch regions. Materials and methods: We analyzed a panel of 21 human myeloma cell lines using a Southern blot assay to detect illegitimate rearrangements involving the switch regions. We then cloned the breakpoints. developed probes for FISH analysis, and characterized the oncogenes dysregulated by the translocations. Results: Only half of the cell lines demonstrated a 14q32 abnormality by conventional karyotypic analysis, but we were able to identify translocations involving IgH switch regions in 15 of 21 lines, including all of the lines in which a 14q32 translocations was not identified by conventional karyotypic analysis. Six cell lines have an Ig translocation involving 11q13 with overexpression of cyclin D1. Six cell lines have an Ig translocation involving 16q23 with overexpression of c-maf. Five lines have an Ig translocations involving 4p16 with overexpression of FGFR3 and a novel gene, MMSET. The 4p16 breakpoints occur within the 5' introns of MMSET, and are associated with IgH-MMSET hybrid mRNA transcripts. The remaining five cell lints have translocations involving other loci, including: 6p25 (MUM1), 8q24 (c-myc), and 21q22 (?AML1). Conclusions: Recurrent Ig translocations identify at least three distinct molecular subtypes of myeloma. Our long-term goal is to determine if there are phenotypic, prognostic and therapeutic differences associated with these molecular subtypes. C1 Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Hematol Oncol, New York, NY 10021 USA. NCI, Bethesda, MD 20892 USA. RP Bergsagel, PL (reprint author), Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Div Hematol, Oncol Room C-609,525 E 68th St, New York, NY 10021 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 NR 16 TC 43 Z9 46 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2000 VL 11 SU 1 BP 131 EP 135 DI 10.1023/A:1008300325610 PG 5 WC Oncology SC Oncology GA 293YL UT WOS:000085882800026 PM 10707795 ER PT J AU Alfaro, CL Nicolson, R Lenane, M Rapoport, JL AF Alfaro, CL Nicolson, R Lenane, M Rapoport, JL TI Carbamazepine and/or fluvoxamine drug interaction with risperidone in a patient on multiple psychotropic medications SO ANNALS OF PHARMACOTHERAPY LA English DT Letter C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, Child Psychiat Branch, Bethesda, MD USA. RP Alfaro, CL (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,Room 1N257, Bethesda, MD 20892 USA. RI Nicolson, Robert/E-4797-2011 NR 5 TC 2 Z9 3 U1 0 U2 0 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JAN PY 2000 VL 34 IS 1 BP 122 EP 123 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 275TU UT WOS:000084836900019 PM 10669197 ER PT J AU Kunkel, TA Bebenek, R AF Kunkel, TA Bebenek, R TI DNA replication fidelity SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE base substitutions; frameshifts; DNA polymerase; nucleotide selectivity; proofreading ID TYPE-1 REVERSE-TRANSCRIPTASE; I KLENOW FRAGMENT; POLYMERASE-III HOLOENZYME; STATE KINETIC-ANALYSIS; CELL NUCLEAR ANTIGEN; INDUCED FRAMESHIFT MUTAGENESIS; AMINO-ACID SUBSTITUTIONS; ERROR-PRONE REPLICATION; THYMINE-THYMINE DIMER; DOUBLE-STRANDED DNA AB DNA replication fidelity is a key determinant of genome stability and is central to the evolution of species and to the origins of human diseases. Here we review our current understanding of replication fidelity, with emphasis on structural and biochemical studies of DNA polymerases that provide new insights into the importance of hydrogen bonding, base pair geometry, and substrate-induced conformational changes to fidelity. These studies also reveal polymerase interactions with the DNA minor groove at and upstream of the active site that influence nucleotide selectivity, the efficiency of exonucleolytic proofreading, and the rate of forming errors via strand misalignments. We highlight common features that are relevant to the fidelity of any DNA synthesis reaction, and consider why fidelity varies depending on the enzymes, the error, and the local sequence environment. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 216 TC 624 Z9 633 U1 16 U2 78 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4154 J9 ANNU REV BIOCHEM JI Annu. Rev. Biochem. PY 2000 VL 69 BP 497 EP 529 DI 10.1146/annurev.biochem.69.1.497 PG 33 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 361QZ UT WOS:000089735700017 PM 10966467 ER PT J AU Pham, DL Xu, CY Prince, JL AF Pham, DL Xu, CY Prince, JL TI Current methods in medical image segmentation SO ANNUAL REVIEW OF BIOMEDICAL ENGINEERING LA English DT Review DE medical imaging; image processing; classification; deformable models; magnetic resonance imaging ID MAGNETIC-RESONANCE IMAGES; TUMOR VOLUME DETERMINATION; MARKOV RANDOM-FIELD; BRAIN MR-IMAGES; TISSUE CLASSIFICATION; ACTIVE CONTOURS; NEURAL-NETWORK; NEUROANATOMICAL SEGMENTATION; INTENSITY INHOMOGENEITIES; STATISTICAL APPROACH AB Image segmentation plays a crucial role in many medical-imaging applications, by automating or facilitating the delineation of anatomical structures and other regions of interest. We present a critical appraisal of the current status of semi-automated and automated methods for the segmentation of anatomical medical images. Terminology and important issues in image segmentation are first presented. Current segmentation approaches are then reviewed with an emphasis on the advantages and disadvantages of these methods for medical imaging applications. We conclude with a discussion on the future of image segmentation methods in biomedical research. C1 Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. RP Pham, DL (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. RI Prince, Jerry/A-3281-2010 OI Prince, Jerry/0000-0002-6553-0876 NR 96 TC 783 Z9 807 U1 24 U2 129 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1523-9829 J9 ANNU REV BIOMED ENG JI Annu. Rev. Biomed. Eng. PY 2000 VL 2 BP 315 EP + DI 10.1146/annurev.bioeng.2.1.315 PG 24 WC Engineering, Biomedical SC Engineering GA 364HR UT WOS:000089887400012 PM 11701515 ER PT J AU Basser, PJ Roth, BJ AF Basser, PJ Roth, BJ TI New currents in electrical stimulation of excitable tissues SO ANNUAL REVIEW OF BIOMEDICAL ENGINEERING LA English DT Review DE electric; magnetic; stimulation; bidomain; excitable; nerve; heart; brain ID PERIPHERAL-NERVE STIMULATION; CARDIAC TISSUE; MAGNETIC STIMULATION; CABLE EQUATION; BIDOMAIN MODEL; ACTIVATING FUNCTION; VIRTUAL ELECTRODES; VOLUME CONDUCTOR; MYELINATED NERVE; COLLISION BLOCK AB Electric fields can stimulate excitable tissue by a number of mechanisms. A uniform long, straight peripheral axon is activated by the gradient of the electric field that is oriented parallel to the fiber axis. Cortical neurons in the brain are excited when the electric field, which is applied along the axon-dendrite axis, reaches a particular threshold value. Cardiac tissue is thought to be depolarized in a uniform electric field by the curved trajectories of its fiber tracts. The bidomain model provides a coherent conceptual framework for analyzing and understanding these apparently disparate phenomena. Concepts such as the activating function and virtual anode and cathode, as well as anode and cathode break and make stimulation, are presented to help explain these excitation events in a unified manner. This modeling approach can also be used to describe the response of excitable tissues to electric fields that arise from charge redistribution (electrical stimulation) and from time-varying magnetic fields (magnetic stimulation) in a self-consistent manner. It has also proved useful to predict the behavior of excitable tissues, to test hypotheses about possible excitation mechanisms, to design novel electrophysiological experiments, and to interpret their findings. C1 NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. Oakland Univ, Dept Phys, Rochester, MI 48309 USA. RP Basser, PJ (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RI Roth, Bradley/A-4920-2008; Basser, Peter/H-5477-2011 FU NHLBI NIH HHS [R01-HL57207] NR 85 TC 68 Z9 69 U1 3 U2 10 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1523-9829 J9 ANNU REV BIOMED ENG JI Annu. Rev. Biomed. Eng. PY 2000 VL 2 BP 377 EP 397 DI 10.1146/annurev.bioeng.2.1.377 PG 21 WC Engineering, Biomedical SC Engineering GA 364HR UT WOS:000089887400014 PM 11701517 ER PT J AU Hurley, JH Misra, S AF Hurley, JH Misra, S TI Signaling and subcellular targeting by membrane-binding domains SO ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE LA English DT Review DE C1 domain; C2 domain; FYVE domain; PH domain; subcellular localization ID PLECKSTRIN-HOMOLOGY-DOMAIN; PROTEIN-KINASE-C; CYTOSOLIC PHOSPHOLIPASE A(2); BRUTONS TYROSINE KINASE; PHORBOL ESTER BINDING; CYSTEINE-RICH DOMAIN; HIGH-AFFINITY BINDING; CRYSTAL-STRUCTURE; PH DOMAIN; PLASMA-MEMBRANE AB Protein kinase C homology-1 and -2, FYVE, and pleckstrin homology domains are ubiquitous in eukaryotic signal transduction and membrane-trafficking proteins. These domains regulate subcellular localization and protein function by binding to lipid ligands embedded in cell membranes. Structural and biochemical analysis of these domains has shown that their molecular mechanisms of membrane binding depend on a combination of specific and nonspecific interactions with membrane lipids. In vivo studies of green fluorescent protein fusions have highlighted the key roles of these domains in regulating protein localization to plasma and internal membranes in cells. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Misra, Saurav/0000-0002-1385-8554 NR 150 TC 202 Z9 202 U1 2 U2 9 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1056-8700 J9 ANNU REV BIOPH BIOM JI Annu. Rev. Biophys. Biomolec. Struct. PY 2000 VL 29 BP 49 EP 79 DI 10.1146/annurev.biophys.29.1.49 PG 33 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 339RU UT WOS:000088492300003 PM 10940243 ER PT J AU Dyda, F Klein, DC Hickman, AB AF Dyda, F Klein, DC Hickman, AB TI GCN5-related N-acetyltransferases: A structural overview SO ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE LA English DT Review DE melatonin; histone acetylation; GNAT; aminoglycoside; acetyl coenzyme A ID GCN5 TRANSCRIPTIONAL COACTIVATOR; COENZYME-A BINDING; CRYSTAL-STRUCTURE; CATALYTIC MECHANISM; HISTONE ACETYLATION; SACCHAROMYCES-CEREVISIAE; ANGSTROM RESOLUTION; ESCHERICHIA-COLI; IN-VIVO; PROTEIN AB Hundreds of acetyltransferases exist. All use a common acetyl donor-acetyl coenzyme A-and each exhibits remarkable specificity for acetyl accepters, which include small molecules and proteins. Analysis of the primary sequences of these enzymes indicates that they can be sorted into several superfamilies. This review covers the three-dimensional structures of members of one of these superfamilies, now referred to in the literature as the GCN5-related N-acetyltransferases (GNAT), reflecting the importance of one functional category, the histone acetyltransferases. Despite the diversity of substrate specificities, members of the GNAT superfamily demonstrate remarkable similarity in protein topology and mode of acetyl coenzyme A binding, likely reflecting a conserved catalytic mechanism. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 43 TC 252 Z9 263 U1 5 U2 26 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1056-8700 J9 ANNU REV BIOPH BIOM JI Annu. Rev. Biophys. Biomolec. Struct. PY 2000 VL 29 BP 81 EP 103 DI 10.1146/annurev.biophys.29.1.81 PG 27 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 339RU UT WOS:000088492300004 PM 10940244 ER PT J AU Eaton, WA Munoz, V Hagen, SJ Jas, GS Lapidus, LJ Henry, ER Hofrichter, J AF Eaton, WA Munoz, V Hagen, SJ Jas, GS Lapidus, LJ Henry, ER Hofrichter, J TI Fast kinetics and mechanisms in protein folding SO ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE LA English DT Review DE laser-triggering; temperature-jump; fast mixing; secondary structure; kinetic models ID MOLECULAR-DYNAMICS SIMULATIONS; MONOMERIC LAMBDA-REPRESSOR; SINGLE-DOMAIN PROTEINS; MICROSECOND TIME-SCALE; BETA-HAIRPIN FORMATION; UNFOLDED CYTOCHROME-C; SHORT LINEAR PEPTIDE; ELECTRON-TRANSFER; FAST EVENTS; ENERGY LANDSCAPE AB This review describes how kinetic experiments using techniques with dramatically improved time resolution have contributed to understanding mechanisms in protein folding. Optical triggering with nanosecond laser pulses has made it possible to study the fastest-folding proteins as well as fundamental processes in folding for the first time. These include formation of alpha-helices, beta-sheets, and contacts between residues distant in sequence, as well as overall collapse of the polypeptide chain. Improvements in the time resolution of mixing experiments and the use of dynamic nuclear magnetic resonance methods have also allowed kinetic studies of proteins that fold too fast (greater than or similar to 10(3) s(-1)) to be observed by conventional methods. Simple statistical mechanical models have been extremely useful in interpreting the experimental results. One of the surprises is that models originally developed for explaining the fast kinetics of secondary structure formation in isolated peptides are also successful in calculating folding rates of single domain proteins from their native three-dimensional structure. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Henry, Eric/J-3414-2013; Hagen, Stephen/E-9737-2015 OI Henry, Eric/0000-0002-5648-8696; Hagen, Stephen/0000-0002-3373-5033 NR 128 TC 379 Z9 383 U1 4 U2 62 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1056-8700 J9 ANNU REV BIOPH BIOM JI Annu. Rev. Biophys. Biomolec. Struct. PY 2000 VL 29 BP 327 EP 359 DI 10.1146/annurev.biophys.29.1.327 PG 33 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 339RU UT WOS:000088492300012 PM 10940252 ER PT J AU Hinshaw, JE AF Hinshaw, JE TI Dynamin and its role in membrane fission SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE receptor-mediated endocytosis; synaptic vesicle recycling; GTPase; shibire; human guanylate-binding protein 1 ID CLATHRIN-MEDIATED ENDOCYTOSIS; PLECKSTRIN HOMOLOGY DOMAIN; SYNAPTIC VESICLE ENDOCYTOSIS; PROTEIN-KINASE-C; TEMPERATURE-SENSITIVE MUTANT; TRANS-GOLGI NETWORK; DEPENDENT CONFORMATIONAL CHANGE; MITOCHONDRIAL OUTER-MEMBRANE; ADRENAL CHROMAFFIN CELLS; AMPHIPHYSIN SH3 DOMAIN AB Dynamin, a 100-kDa GTPase, is an essential component of vesicle formation in receptor-mediated endocytosis, synaptic vesicle recycling, caveolae internalization, and possibly vesicle trafficking in and out of the Golgi. In addition to the GTPase domain, dynamin also contains a pleckstrin homology domain (PH) implicated in membrane binding, a GTPase effector domain (GED) shown to be essential for self-assembly and stimulated GTPase activity, and a C-terminal proline-rich domain (PRD), which contains several SH3-binding sites. Dynamin partners bind to the PRD and may either stimulate dynamin's GTPase activity or target dynamin to the plasma membrane. Purified dynamin readily self-assembles into rings or spirals. This striking structural property supports the hypothesis that dynamin wraps around the necks of budding vesicles where it plays a key role in membrane fission. The focus of this review is on the relationship between the GTPase and self-assembly properties of dynamin and its cellular function. C1 NIH, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. RP Hinshaw, JE (reprint author), NIH, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. NR 228 TC 490 Z9 503 U1 4 U2 34 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1081-0706 J9 ANNU REV CELL DEV BI JI Annu. Rev. Cell Dev. Biol. PY 2000 VL 16 BP 483 EP + DI 10.1146/annurev.cellbio.16.1.483 PG 38 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 385NH UT WOS:000166010200019 PM 11031245 ER PT J AU Lippincott-Schwartz, J Roberts, TH Hirschberg, K AF Lippincott-Schwartz, J Roberts, TH Hirschberg, K TI Secretory protein trafficking and organelle dynamics in living cells SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE green fluorescent protein; protein trafficking; endoplasmic reticulum; Golgi complex ID GREEN FLUORESCENT PROTEIN; VESICULAR STOMATITIS-VIRUS; GOLGI INTERMEDIATE COMPARTMENT; TRANSPORT VESICLE FORMATION; DUAL-COLOR VISUALIZATION; COAGULATION-FACTOR-VIII; COPI-COATED VESICLES; ENDOPLASMIC-RETICULUM; BREFELDIN-A; CIS-GOLGI AB Green fluorescent protein chimerae acting as reporters for protein localization and trafficking within the secretory membrane system of living cells have been used in a wide variety of applications, including time-lapse imaging, double-labeling, energy transfer, quantitation, and photobleaching experiments. Results from this work are clarifying the steps involved in the formation, translocation, and fusion of transport intermediates; the organization and biogenesis of organelles; and the mechanisms of protein retention, sorting, and recycling in the secretory pathway. In so doing, they are broadening our thinking about the temporal and spatial relationships among secretory organelles and the membrane trafficking pathways that operate between them. C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RI Ward, Theresa/E-9650-2013 OI Ward, Theresa/0000-0002-9881-8649 NR 140 TC 277 Z9 287 U1 3 U2 28 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1081-0706 J9 ANNU REV CELL DEV BI JI Annu. Rev. Cell Dev. Biol. PY 2000 VL 16 BP 557 EP 589 DI 10.1146/annurev.cellbio.16.1.557 PG 33 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 385NH UT WOS:000166010200021 PM 11031247 ER PT J AU O'Brien, SJ Nelson, GW Winkler, CA Smith, MW AF O'Brien, SJ Nelson, GW Winkler, CA Smith, MW TI Polygenic and multifactorial disease gene association in man: Lessons from AIDS SO ANNUAL REVIEW OF GENETICS LA English DT Review DE AIDS; SNP; restriction gene; complex traits ID HUMAN-IMMUNODEFICIENCY-VIRUS; SINGLE-NUCLEOTIDE POLYMORPHISMS; CHEMOKINE RECEPTOR GENE; INHIBITS CYTOKINE PRODUCTION; MACROPHAGE-TROPIC HIV-1; CELL-DERIVED FACTOR-1; HUMAN-GENOME-PROJECT; LINKAGE DISEQUILIBRIUM; TYPE-1 INFECTION; MAPPING GENES AB In an age when the majority of monogenic human disease genes have been identified, a particular challenge for the coming generation of human geneticists will be resolving complex polygenic and multifactorial diseases. The tools of molecular and population genetic association have much potential as well as peril in uncovering small cryptic genetic effects in disease. We have used a candidate gene approach to identify eight distinct human loci with alleles that in different ways influence the outcome of exposure to HIV-1, the AIDS virus. The successes in these gene hunts have validated the approach and illustrate the strengths and limitations of association analysis in an actual case history. The integration of genetic associations, well-described clinical cohorts, extensive basic research on AIDS pathogenesis, and functional interpretation of gene connections to disease offers a formula for detecting such genes in complex human genetic phenotypes. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. RI Smith, Michael/B-5341-2012 NR 126 TC 61 Z9 65 U1 0 U2 2 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4197 J9 ANNU REV GENET JI Annu. Rev. Genet. PY 2000 VL 34 BP 563 EP 591 DI 10.1146/annurev.genet.34.1.563 PG 31 WC Genetics & Heredity SC Genetics & Heredity GA 390MG UT WOS:000166299400020 PM 11092839 ER PT J AU Koonin, EV AF Koonin, EV TI How many genes can make a cell: The minimal-gene-set concept SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS LA English DT Review DE comparative genomics; orthologs; nonorthologous gene displacement; genome evolution; transposon mutagenesis ID MYCOPLASMA-GENITALIUM; BACTERIAL GENOMES; PROTEIN FAMILIES; IDENTIFICATION; SEQUENCES; ARCHAEAL; LIFE AB Several theoretical and experimental studies have endeavored to derive the minimal set of genes that are necessary and sufficient to sustain a functioning cell under ideal conditions, that is, in the presence of unlimited amounts of all essential nutrients and in the absence of any adverse factors, including competition. A comparison of the first two completed bacterial genomes, those of the parasites Haemophilus influenzae and Mycoplasma genitalium, produced a version of the minimal gene set consisting of similar to 250 genes. Very similar estimates were obtained by analyzing viable gene knockouts in Bacillus subtilis, M. genitalium, and Mycoplasma pneumoniae. With the accumulation and comparison of multiple complete genome sequences, it became clear that only similar to 80 genes of the 250 in the original minimal gene set are represented by orthologs in all life forms. For similar to 15% of the genes from the minimal gene set, viable knockouts were obtained in M. genitalium; unexpectedly, these included even some of the universal genes. Thus, some of the genes that were included in the first version of the minimal gene set, based on a limited genome comparison, could be, in fact, dispensable. The majority of these genes, however, are likely to encode essential functions but, in the course of evolution, are subject to nonorthologous gene displacement, that is, recruitment of unrelated or distantly related proteins for the same function. Further theoretical and experimental studies within the framework of the minimal-gene-set concept and the ultimate construction of a minimal genome are expected to advance our understanding of the basic principles of cell functioning by systematically detecting nonorthologous gene displacement and deciphering the roles of essential but functionally uncharacterized genes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 34 TC 152 Z9 172 U1 3 U2 29 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1527-8204 J9 ANNU REV GENOM HUM G JI Annu. Rev. Genomics Hum. Genet. PY 2000 VL 1 BP 99 EP 116 DI 10.1146/annurev.genom.1.1.99 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 381NG UT WOS:000165768900006 PM 11701626 ER PT J AU Ashwell, JD Lu, FWM Vacchio, MS AF Ashwell, JD Lu, FWM Vacchio, MS TI Glucocorticoids in T cell development and function SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE thymocyte selection; T cell activation; immunosuppression; apoptosis ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; FAS-LIGAND EXPRESSION; INTERLEUKIN-5 GENE-EXPRESSION; ACTIVATION-INDUCED APOPTOSIS; STEROID-HORMONE RECEPTORS; INHIBITS MULTIPLE FORMS; PITUITARY-ADRENAL AXIS; SIDE-CHAIN CLEAVAGE; POSITIVE SELECTION AB Glucocorticoids are small lipophilic compounds that mediate their many biological effects by binding an intracellular receptor (GR) that, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription. Perhaps the most recognized biologic effect of glucocorticoids on peripheral T cells is immunosuppression, which is due to inhibition of expression of a wide variety of activation-induced gene products. Glucocorticoids have also been implicated in Th lineage development (favoring the generation of Th2 cells) and, by virtue of their downregulation of fasL expression, the inhibition of activation-induced T cell apoptosis. Glucocorticoids are also potent inducers of apoptosis, and even glucocorticoid concentrations achieved during a stress response can cause the death of CD4(+)CD8(+) thymocytes. Perhaps surprisingly, thymic epithelial cells produce glucocorticoids, and based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive acid negative selection. It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. EM jda@Box-j.nih.gov NR 217 TC 503 Z9 517 U1 4 U2 13 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 EI 1545-3278 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2000 VL 18 BP 309 EP 345 DI 10.1146/annurev.immunol.18.1.309 PG 37 WC Immunology SC Immunology GA 317PX UT WOS:000087236500012 PM 10837061 ER PT J AU Shevach, EM AF Shevach, EM TI Regulatory T cells in autoimmmunity SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE suppressor T cells; immune regulation; organ-specific autoimmunity; gastritis ID IMMUNOLOGICAL SELF-TOLERANCE; NONOBESE DIABETIC MICE; MYELIN BASIC-PROTEIN; THYMECTOMY AUTOIMMUNE GASTRITIS; INDUCE WASTING DISEASE; GROWTH-FACTOR-BETA; ATHYMIC NUDE-MICE; NEONATAL THYMECTOMY; NOD MICE; POSITIVE SELECTION AB Clonal deletion of autoreactive T cells in the thymus is not the sole mechanism for the induction of tolerance to self-antigens since partial depletion of peripheral CD4(+) T cells from neonatal and adult animals results in the development of organ-specific autoimmunity. Reconstitution of these immunodeficient animals with populations of regulatory CD4(+)T cells prevents the development of autoimmunity. The lineage of regulatory CD4(+) T cells is generated in the thymus and can be distinguished from effector cells by the expression of unique membrane antigens. The target antigens for these suppressor populations and their mechanisms of action remain poorly defined. Depletion of regulatory T cells may be useful in the induction of immunity to weak antigens, such as tumor-specific antigens. Conversely, enhancement of regulatory T cell function may be a useful adjunct to the therapy of autoimmune diseases and for prevention of allograft rejection. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 77 TC 1008 Z9 1054 U1 11 U2 38 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2000 VL 18 BP 423 EP 449 DI 10.1146/annurev.immunol.18.1.423 PG 27 WC Immunology SC Immunology GA 317PX UT WOS:000087236500016 PM 10837065 ER PT J AU Staudt, LM Brown, PO AF Staudt, LM Brown, PO TI Genomic views of the immune system SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE genomics; microarray; gene expression ID DEPENDENT DIABETES-MELLITUS; GERMINAL-CENTER FORMATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; COLLAGEN-INDUCED ARTHRITIS; GENE-EXPRESSION PATTERNS; OLIGONUCLEOTIDE ARRAYS; MULTIPLE-SCLEROSIS; WIDE SEARCH; LUPUS-ERYTHEMATOSUS; SUSCEPTIBILITY LOCI AB Genomic-scale experimentation aims to view biological processes as a whole, yet with molecular precision. Using massively parallel DNA microarray technology, the mRNA expression of tens of thousands of genes can be measured simultaneously. Mathematical distillation of this flood of gene expression data reveals a deep molecular and biological logic underlying gene expression programs during cellular differentiation and activation. Genes that encode components of the same multi-subunit protein complex are often coordinately regulated. Coordinate regulation is also observed among genes whose products function in a common differentiation program or in the same physiological response pathway. Recent application of gene expression profiling to the immune system has shown that lymphocyte differentiation and activation are accompanied by changes of hundreds of genes in parallel. The databases of gene expression emerging from these studies of normal immune responses will be used to interpret the pathological changes in gene expression that accompany autoimmunity, immune deficiencies, and cancers of immune cells. C1 NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Biochem, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. RP NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. EM lstaudt@box-l.nih.gov; pbrown@cmgm.stanford.edu NR 109 TC 134 Z9 137 U1 1 U2 2 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 EI 1545-3278 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2000 VL 18 BP 829 EP 859 DI 10.1146/annurev.immunol.18.1.829 PG 37 WC Immunology SC Immunology GA 317PX UT WOS:000087236500028 PM 10837077 ER PT J AU Gurunathan, S Klinman, DM Seder, RA AF Gurunathan, S Klinman, DM Seder, RA TI DNA vaccines: Immunology, application, and optimization SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE CpG sequences; plasmid DNA ID CYTOTOXIC T-LYMPHOCYTES; IMMUNODEFICIENCY-VIRUS TYPE-1; HEPATITIS-B VIRUS; HUMORAL IMMUNE-RESPONSES; ANTIGEN-PRESENTING CELLS; DIRECT GENE-TRANSFER; CPG-CONTAINING OLIGODEOXYNUCLEOTIDES; DEOXYRIBONUCLEIC-ACID VACCINES; SYSTEMIC LUPUS-ERYTHEMATOSUS; INDUCE AUTOIMMUNE-DISEASE AB The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Sect Retroviral Immunol, Bethesda, MD 20892 USA. RP Gurunathan, S (reprint author), NIAID, Clin Invest Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Liu, Xia/L-9425-2013 NR 245 TC 871 Z9 954 U1 11 U2 155 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2000 VL 18 BP 927 EP 974 DI 10.1146/annurev.immunol.18.1.927 PG 48 WC Immunology SC Immunology GA 317PX UT WOS:000087236500030 PM 10837079 ER PT J AU Kolenbrander, PE AF Kolenbrander, PE TI Oral microbial communities: Biofilms, interactions, and genetic systems SO ANNUAL REVIEW OF MICROBIOLOGY LA English DT Review DE spatial organization; oral bacteria genetic systems; communication; bacterial cell interactions ID SPIROCHETE TREPONEMA-DENTICOLA; PORPHYROMONAS-GINGIVALIS INVASION; HUMAN DENTAL PLAQUE; BACTERIUM STREPTOCOCCUS-GORDONII; ACTINOMYCES-VISCOSUS T14V; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; FUSOBACTERIUM-NUCLEATUM; EPITHELIAL-CELLS; ESCHERICHIA-COLI; EIKENELLA-CORRODENS AB Oral microbial-plaque communities are biofilms composed of numerous genetically distinct types of bacteria that live in close juxtaposition on host surfaces. These bacteria communicate through physical interactions called coaggregation and coadhesion, as well as other physiological and metabolic interactions. Streptococci and actinomyces are the major initial colonizers of the tooth surface, and the interactions between them and their substrata help establish the early biofilm community. Fusobacteria play a central role as physical bridges that mediate coaggregation of cells and as physiological bridges that promote anaerobic microenvironments which protect coaggregating strict anaerobes in an aerobic atmosphere. New technologies for investigating bacterial populations with 16S rDNA probes have uncovered previously uncultured bacteria and have offered an approach to in situ examination of the spatial arrangement of the participant cells in oral-plaque biofilms. Flow cells with saliva-coated surfaces are particularly useful for studies of biofilm formation and observation. The predicted sequential nature of colonization of the tooth surface by members of different genera can be investigated by using these new technologies and imaging the cells in situ with confocal scanning laser microscopy. Members of at least seven genera now can be subjected to genetic studies owing to the discovery of gene-transfer systems in these genera. Identification of contact-inducible genes in streptococci offers an avenue to explore bacterial responses to their environment and leads the way toward understanding communication among inhabitants of a multispecies biofilm. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Kolenbrander, PE (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 134 TC 409 Z9 436 U1 14 U2 100 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4227 J9 ANNU REV MICROBIOL JI Annu. Rev. Microbiol. PY 2000 VL 54 BP 413 EP 437 DI 10.1146/annurev.micro.54.1.413 PG 27 WC Microbiology SC Microbiology GA 373DC UT WOS:000165272300013 PM 11018133 ER PT J AU Carmel-Harel, O Storz, G AF Carmel-Harel, O Storz, G TI Roles of the glutathione- and thioredoxin-dependent reduction systems in the Escherichia coli and Saccharomyces cerevisiae responses to oxidative stress SO ANNUAL REVIEW OF MICROBIOLOGY LA English DT Review DE glutaredoxin; reductase; peroxidase; OxyR; SoxR; YAP1 ID ALKYL HYDROPEROXIDE REDUCTASE; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; YAP-1 TRANSCRIPTIONAL REGULATION; THIOL-SPECIFIC ANTIOXIDANT; DISULFIDE BOND FORMATION; IN-VIVO TRANSCRIPTION; SALMONELLA-TYPHIMURIUM; HYDROGEN-PEROXIDE; DEFICIENT MUTANTS; SOXR PROTEIN AB The glutathione- and thioredoxin-dependent reduction systems are responsible for maintaining the reduced environment of the Escherichia coli and Saccharomyces cerevisiae cytosol. Here we examine the roles of these two cellular reduction systems in the bacterial and yeast defenses against oxidative stress. The transcription of a subset of the genes encoding glutathione biosynthetic enzymes, glutathione reductases, glutaredoxins, thioredoxins, and thioredoxin reductases, as well as glutathione- and thioredoxin-dependent peroxidases is clearly induced by oxidative stress in both organisms. However, only some strains carrying mutations in single genes are hypersensitive to oxidants. This is due, in part, to the redundant effects of the gene products and the overlap between the two reduction systems. The construction of strains carrying mutations in multiple genes is helping to elucidate the different roles of glutathione and thioredoxin, and studies with such strains have recently revealed that these two reduction systems modulate the activities of the E. coli OxyR and SoxR and the S. cerevisiae Yaplp transcriptional regulators of the adaptive responses to oxidative stress. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Carmel-Harel, O (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. OI Storz, Gisela/0000-0001-6698-1241 NR 107 TC 407 Z9 423 U1 5 U2 43 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4227 J9 ANNU REV MICROBIOL JI Annu. Rev. Microbiol. PY 2000 VL 54 BP 439 EP 461 DI 10.1146/annurev.micro.54.1.439 PG 25 WC Microbiology SC Microbiology GA 373DC UT WOS:000165272300014 PM 11018134 ER PT J AU Kastner, S Ungerleider, LG AF Kastner, S Ungerleider, LG TI Mechanisms of visual attention in the human cortex SO ANNUAL REVIEW OF NEUROSCIENCE LA English DT Review DE vision; selective attention; functional brain imaging; neglect; object recognition ID POSITRON EMISSION TOMOGRAPHY; INFERIOR TEMPORAL CORTEX; POSTERIOR PARIETAL CORTEX; PRIMATE PREFRONTAL CORTEX; HUMAN EXTRASTRIATE CORTEX; SPATIAL SELECTIVE ATTENTION; STATE DEPENDENT ACTIVITY; MONKEY CEREBRAL-CORTEX; HUMAN FUSIFORM GYRUS; FRONTAL EYE FIELDS AB A typical scene contains many different objects that, because of the limited processing capacity of the visual system, compete for neural representation. The competition among multiple objects in visual cortex can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that, both in the absence and in the presence of visual stimulation, biasing signals due to selective attention can modulate neural activity in visual cortex in several ways. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals derives from a network of areas in frontal and parietal cortex. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Kastner, S (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RI Winstein, Carolee/A-8375-2008 NR 180 TC 1178 Z9 1194 U1 29 U2 165 PU ANNUAL REVIEWS INC PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0147-006X J9 ANNU REV NEUROSCI JI Annu. Rev. Neurosci. PY 2000 VL 23 BP 315 EP 341 PG 31 WC Neurosciences SC Neurosciences & Neurology GA 308UD UT WOS:000086730500011 PM 10845067 ER PT J AU Sokoloff, L AF Sokoloff, L TI In vivo veritas: Probing brain function through the use of quantitative in vivo biochemical techniques SO ANNUAL REVIEW OF PHYSIOLOGY LA English DT Review DE local cerebral blood flow; local cerebral energy metabolism; functional brain imaging; deoxyglucose method; metabolic mapping of neural pathways ID CEREBRAL GLUCOSE-UTILIZATION; METABOLIC-RATE; DEOXYGLUCOSE; SYSTEM C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. RP Sokoloff, L (reprint author), NIMH, Cerebral Metab Lab, Bldg 36, Bethesda, MD 20892 USA. NR 29 TC 4 Z9 4 U1 0 U2 1 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4278 J9 ANNU REV PHYSIOL JI Annu. Rev. Physiol. PY 2000 VL 62 BP 1 EP 24 DI 10.1146/annurev.physiol.62.1.1 PG 24 WC Physiology SC Physiology GA 341KF UT WOS:000088589000002 PM 10845082 ER PT J AU Nakamura, K Sun, Y Yokoyama, Y Ferris, D Singh, N Ichikawa, T Shinozuka, K Kunitomo, M Colburn, N AF Nakamura, K Sun, Y Yokoyama, Y Ferris, D Singh, N Ichikawa, T Shinozuka, K Kunitomo, M Colburn, N TI Phosphorylation status and function of p53 are inversely related to protein kinase C activation SO ANTICANCER RESEARCH LA English DT Article DE phospho-p53; TPA; H7; MDM2 ID TUMOR-SUPPRESSOR PROTEIN; WILD-TYPE P53; IN-VITRO; CELLS; TRANSACTIVATION; PROMOTER; VARIANTS; SITES; VIVO AB The role of phosphorylation in the regulation of p53 protein function is little understood We have addressed the role of protein kinase C (PKC) in the phosphorylation. Exposure to the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) -2-methylpiperazine dihydrochloride (H7) increased the phosphorylation of wild type p53 protein, whereas exposure to the tumor promoter phorbol ester, 12-O-retradecanoyl-phorbol-13-acetate (TPA), decreased it in vivo following 3 hours incubation with mouse epidermal JB6 cells. Exposure to the c-AMP dependent protein kinase (PKA) activator, forskolin, did not decrease the phosphorylation of p53 protein. In the transient transfection/luciferase reporter transactivation assay,H7 modestly increased the mouse double minute (MDM) 2 reporter transactivation activity of p53 protein after 24 hours treatment, and TPA completely blocked it. These results suggest that the accelerated phosphorylation of wild type p53 protein is inversely related to PKC activation, and that p53 phosphorylation may have some relation to transcription factor function. C1 NCI, Frederick Canc Res & Dev Ctr, Gene Regulat Sect, Lab Biochem Physiol, Ft Detrick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Ft Detrick, MD 21702 USA. Warner Lambert Co, Parke Davis Pharmaceut Res Div, Dept Mol Biol, Ann Arbor, MI 48105 USA. Mukogawa Womens Univ, Interdisciplinary Res Inst Biosci, Nishinomiya, Hyogo 6638558, Japan. Mukogawa Womens Univ, Fac Pharmaceut Sci, Dept Pharmacol, Nishinomiya, Hyogo 6638179, Japan. RP Nakamura, K (reprint author), NCI, Frederick Canc Res & Dev Ctr, Gene Regulat Sect, Lab Biochem Physiol, Ft Detrick, MD 21702 USA. NR 30 TC 12 Z9 12 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN-FEB PY 2000 VL 20 IS 1A BP 1 EP 5 PG 5 WC Oncology SC Oncology GA 301TN UT WOS:000086326500001 PM 10769627 ER PT J AU Elmore, E Luc, TT Li, HR Buckmeier, JA Steele, VE Kelloff, GJ Redpath, JL AF Elmore, E Luc, TT Li, HR Buckmeier, JA Steele, VE Kelloff, GJ Redpath, JL TI Correlation of chemopreventive efficacy data from the human epidermal cell assay with in vivo data SO ANTICANCER RESEARCH LA English DT Article DE cancer prevention efficacy; in vitro/in vivo correlation; human keratinocytes; growth inhibition; involucrin expression; cytotoxicity; in vitro alternatives AB Continuous exposure to low doses of potentially mutagenic and carcinogenic chemicals over the human lifetime makes the identification of agents, which could reduce the ensuing risk of cancer, beneficial The Human Epidermal Cell (HEC) Assay includes multiple exposures to low, non-toxic doses of propane sultone, which increases cellular growth and inhibits differentiation, and co-exposure to potential chemopreventive agents to determine their ability to inhibit the increased growth or increase differentiation. Original data are presented on the efficacy of twenty potential cancer chemopreventive agents were screened for efficacy in the HEC Assay. Efficacy was determined by the ability of agents at nontoxic concentrations, to reverse either of the propane sultone-induced biomarkers, enhanced growth and reduced involucrin expression. Based on the number of positive concentrations and the lack of toxicity, 1,2-dithiol-3-thione, oltipraz, and a synthetic retinoid Ro 16-9100, were the most active. Eleven of seventeen positive agents were active for both endpoints. S-Allylcysteine was only active for the growth inhibition endpoint, and DFMO, lycopene, perillyl alcohol ursodiol, and black tea polyphenols were only active for the involucrin endpoint. The three agents that have been shown to be negative in animal models, diphenhydramine, d-mannitol, and nordihydroguaiaretic acid, were correctly identified as negative by the assay. When the data from previous studies (Elmore et al, Anticancer Res, 19: 909-918, 1999) are included, a positive response in one or more endpoints of the HEC Assay correlates 100% (26/26) with a positive response in one or more of the animal cancer prevention models (8). The available data suggest that the HEC Assay response is highly predictive of efficacy in animals in vivo with an overall accuracy of 90%. Future studies will include data with additional negative agents. The con elation of the HEC Assay data with data from in vivo studies in animal models, which utilize multiple carcinogens and multiple target organs, would suggest that this in vitro assay has the ability to identify agents with the potential to prevent carcinogen-induced cancer. While our ultimate goal is to identify agents with potential efficacy for preventing human cancer, sufficient human data are not yet available to make this correlation. C1 Univ Calif Irvine, Dept Radiat Oncol, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA. Univ Calif Irvine, Ctr Canc, Irvine, CA 92697 USA. NCI, DCP, Chemoprevent Branch, NIH, Bethesda, MD 20892 USA. RP Elmore, E (reprint author), Univ Calif Irvine, Dept Radiat Oncol, B149, Irvine, CA 92697 USA. FU NCI NIH HHS [N01-CN-65115] NR 9 TC 5 Z9 5 U1 1 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN-FEB PY 2000 VL 20 IS 1A BP 27 EP 32 PG 6 WC Oncology SC Oncology GA 301TN UT WOS:000086326500005 PM 10769631 ER PT J AU Silverman, RH Dong, BH Maitra, RK Player, MR Torrence, PF AF Silverman, RH Dong, BH Maitra, RK Player, MR Torrence, PF TI Selective RNA cleavage by isolated RNase L activated with 2-5A antisense chimeric oligonucleotides SO ANTISENSE TECHNOLOGY, PT A SE METHODS IN ENZYMOLOGY LA English DT Review ID INTERFERON-TREATED CELLS; 2-5A-DEPENDENT RNASE; TARGETING RNA; 2',5'-OLIGOADENYLATES; RIBONUCLEASE; DEGRADATION; SYSTEM C1 Cleveland Clin Fdn, Lerner Res Inst, Dept Canc, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Lerner Res Inst, HIV Core Facil, Cleveland, OH 44195 USA. 3 Dimens Pharmaceut Inc, Exton, PA 19341 USA. NIDDKD, Sect Biomed Chem, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Silverman, RH (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Canc, 9500 Euclid Ave, Cleveland, OH 44195 USA. FU NCI NIH HHS [1 PO1 CA 62220, CA44059] NR 25 TC 9 Z9 9 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 313 BP 522 EP 533 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BP58C UT WOS:000085567400031 PM 10595377 ER PT J AU Bost, F McKay, R Dean, NM Potapova, O Mercola, D AF Bost, F McKay, R Dean, NM Potapova, O Mercola, D TI Antisense methods for discrimination of phenotypic properties of closely related gene products: Jun kinase family SO ANTISENSE TECHNOLOGY, PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; C-ALPHA EXPRESSION; PROTEIN-KINASE; SIGNAL-TRANSDUCTION; ACTIVATION DOMAIN; INDUCED APOPTOSIS; RAF KINASE; HA-RAS; CELLS; PHOSPHORYLATION C1 Sidney Kimmel Canc Ctr, San Diego, CA 92121 USA. ISIS Pharmaceut Inc, Carlsbad, CA 92008 USA. NIA, Biol Chem Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA. RP Bost, F (reprint author), Sidney Kimmel Canc Ctr, San Diego, CA 92121 USA. FU NCI NIH HHS [CA56834, CA76173] NR 50 TC 11 Z9 12 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 314 BP 342 EP 362 PG 21 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BP58D UT WOS:000085569700024 PM 10565024 ER PT J AU Xu, ZQ Kern, ER Westbrook, L Allen, LB Buckheit, RW Tseng, CKH Jenta, T Flavin, MT AF Xu, ZQ Kern, ER Westbrook, L Allen, LB Buckheit, RW Tseng, CKH Jenta, T Flavin, MT TI Plant-derived and semi-synthetic calanolide compounds with in vitro activity against both human immunodeficiency virus type 1 and human cytomegalovirus SO ANTIVIRAL CHEMISTRY & CHEMOTHERAPY LA English DT Article DE calanolide; HIV; HCMV ID INHIBITORY NATURAL-PRODUCTS; REVERSE-TRANSCRIPTASE; NONNUCLEOSIDE INHIBITORS; AIDS PATIENTS; RETINITIS; GANCICLOVIR; FOSCARNET; INFECTION; (+)-CALANOLIDE-A; COMBINATION AB Plant-derived and semi-synthetic calanolide compounds with anti-human immunodeficiency virus type 1 (HIV-1) activity were tested for antihuman cytomegalovirus (HCMV) activity in both cytopathic effect inhibition and plaque reduction assays. The results indicated that the anti-HCMV activity of calanolide compounds does not correlate with their activity against HIV-1. The semi-synthetic 12-keto derivatives tended to be more active against HCMV than the corresponding 12-OH congeners, which were more active against HIV-1. It appeared that the 7,8-unsaturated double bond in the chromene ring played a certain role in maintaining activities against both HCMV and HIV-1. Saturation of the double bond increased the EC50 values against both viruses, with concomitant increase in toxicity. The calanolide compounds reported here are the first non-nucleoside analogues capable of inhibiting both HIV-1 and HCMV and, therefore, may be useful chemoprophylactic agents for HCMV in HIV-infected people or vice versa. C1 MediChem Res & Sarawak MediChem Pharmaceut, Argonne, IL 60439 USA. Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. So Res Inst, Birmingham, AL 35255 USA. So Res Inst, Frederick Res Ctr, Frederick, MD 21701 USA. NIAID, Virol Branch, Bethesda, MD 20892 USA. RP Xu, ZQ (reprint author), MediChem Res & Sarawak MediChem Pharmaceut, Argonne, IL 60439 USA. FU NIAID NIH HHS [1R43 AI41785-01] NR 41 TC 7 Z9 9 U1 0 U2 1 PU INT MEDICAL PRESS PI LONDON PA 125 HIGH HOLBORN, LONDON WC1V 6QA, ENGLAND SN 0956-3202 J9 ANTIVIR CHEM CHEMOTH JI Antivir. Chem. Chemother. PD JAN PY 2000 VL 11 IS 1 BP 23 EP 29 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Virology GA 280ZU UT WOS:000085134300002 PM 10693651 ER PT J AU Morse, GD Reichman, RC Fischl, MA Para, M Leedom, J Powderly, W Demeter, LM Resnick, L Bassiakos, Y Timpone, J Cox, S Batts, D AF Morse, GD Reichman, RC Fischl, MA Para, M Leedom, J Powderly, W Demeter, LM Resnick, L Bassiakos, Y Timpone, J Cox, S Batts, D CA ACTG 187 199 Study Teams TI Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies SO ANTIVIRAL RESEARCH LA English DT Article DE concentration-targeted phase I trials; atevirdine mesylate; patients with HIV; dosage studies; pharmacokinetic studies ID VIRUS TYPE-1 REPLICATION; REVERSE-TRANSCRIPTASE INHIBITORS; IMMUNODEFICIENCY; ZIDOVUDINE; DIDANOSINE; COMBINATION; DERIVATIVES; ABSORPTION; POTENT; VITRO AB Rationale: To determine the dosage requirements and pharmacokinetics of atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkylated metabolite (N-ATV) during phase I studies in patients receiving atevirdine alone or in combination with zidovudine. Design: Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which atevirdine was administered every 8 h with weekly dosage adjustments to attain targeted trough plasma atevirdine concentrations. Setting: Five Adult AIDS Clinical Trials Units. Patients: Fifty patients (ACTG 199, n = 20 and ACTG 187; n = 30) with HIV-1 infection and less than or equal to 500 CD4+ lymphocytes/mm(3). Intervention: ACTG 199: 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5-10 mu M) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31 mu M). il Measurements: ACTG 199. atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) Drier to and at 6 and 12 weeks during combination therapy. ACTG 187. atevirdine and N-ATV trough concentrations over a 12 week period. Intensive pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during atevirdine monotherapy in female patients, Results: Atevirdine plasma concentrations demonstrated considerable interpatient variability which was minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to achieve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained the target, was group I (5-11 mu M): 2.7 +/- 2.4 weeks (92%); group II (12-21 mu M): 2.6 +/- 1.8 (64%); and group III (22-31 mu M): 7.0 +/- 5.6 weeks (27%). In ACTG 199 it was 3.2 +/- 5.2 weeks (95%) to achieve a 5-10 mu M trough. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absorption with C-max at 0.5-1 h, delayed absorption with C-max at 3-4 h; minimal C-max to C-min fluctuation and C-max to C-min ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized on day one by rapid appearance of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. Al steady-stare N-ATV patterns demonstrated minimal C-max to C-min fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. Conclusions: Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition was reflected in the range of daily doses required to attain the targeted trough concentrations. Atevirdine metabolism did not appear to reach saturation during chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV ratios in plasma and saturation was not an explanation for the variation in dosing requirements. No apparent differences were noted between males and females, and atevirdine did not appear to influence zidovudine disposition. Published by Elsevier Science B.V. C1 SUNY Buffalo, Dept Pharm Practice & Med, Lab Antiviral Res, Buffalo, NY 14260 USA. Univ Rochester, Sch Med & Dent, Dept Med, Infect Dis Unit, Rochester, NY USA. Univ Miami, Dept Med, Miami, FL USA. Ohio State Univ, Div Infect Dis, Columbus, OH 43210 USA. Univ So Calif, Dept Med, Infect Dis Sect, Los Angeles, CA USA. Washington Univ, St Louis, MO USA. Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. NIAID, NIH, Bethesda, MD 20892 USA. Pharmacia & Upjohn Inc, Kalamazoo, MI 49001 USA. FSTRF, Stat Data Anal Ctr, Amherst, NY USA. RP Morse, GD (reprint author), SUNY Buffalo, Dept Pharm Practice & Med, Lab Antiviral Res, 247 Cooke Hall, Buffalo, NY 14260 USA. FU NIAID NIH HHS [AI25924, AI27658, AI27675] NR 24 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2000 VL 45 IS 1 BP 47 EP 58 DI 10.1016/S0166-3542(99)00073-X PG 12 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 284MK UT WOS:000085336000005 PM 10774589 ER PT B AU Zahn-Waxler, C AF Zahn-Waxler, C BE Davidson, RJ TI The development of empathy, guilt, and internalization of distress: Implications for gender differences in internalizing and externalizing problems SO ANXIETY, DEPRESSION, AND EMOTION SE SERIES IN AFFECTIVE SCIENCE LA English DT Proceedings Paper CT 1st Wisconsin Symposium on Emotion CY APR, 1995 CL UNIV WISCONSIN, MADISON, WI HO UNIV WISCONSIN ID MANIC-DEPRESSIVE PARENT; HIGH-SCHOOL-STUDENTS; AGE 15 YEARS; SEX-DIFFERENCES; YOUNG-CHILDREN; CONDUCT DISORDER; AUTOBIOGRAPHICAL MEMORY; PRESCHOOL-CHILDREN; BEHAVIOR PROBLEMS; WELL MOTHERS C1 NIMH, Bethesda, MD 20892 USA. NR 241 TC 38 Z9 38 U1 6 U2 13 PU OXFORD UNIV PRESS PI NEW YORK PA 198 MADISON AVENUE, NEW YORK, NY 10016 USA BN 0-19-513358-7 J9 SER AFFECTIVE SCI PY 2000 BP 222 EP 265 PG 44 WC Psychology, Biological SC Psychology GA BR81Q UT WOS:000167657700011 ER PT J AU Hughes, FM Cidlowski, JA AF Hughes, FM Cidlowski, JA TI Apoptotic nuclease assays SO APOPTOSIS SE METHODS IN ENZYMOLOGY LA English DT Review ID RECOMBINANT CYCLOPHILIN-A; ACID CLEAVAGE ACTIVITY; RAT THYMOCYTES; ENDONUCLEASE; IDENTIFICATION; DNA; INDUCTION C1 Univ N Carolina, Charlotte, NC 28223 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Hughes, FM (reprint author), Univ N Carolina, Charlotte, NC 28223 USA. NR 18 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 322 BP 47 EP 62 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ66B UT WOS:000089101300005 PM 10914004 ER PT J AU Stennicke, HR Salvesen, GS AF Stennicke, HR Salvesen, GS TI Caspase assays SO APOPTOSIS SE METHODS IN ENZYMOLOGY LA English DT Review ID APOPTOSIS; SPECIFICITIES; PROTEOLYSIS; PROTEASES; CLEAVAGE; KINETICS; FAMILY C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Burnham Inst, La Jolla, CA 92037 USA. RP Stennicke, HR (reprint author), NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. NR 12 TC 75 Z9 80 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 322 BP 91 EP 100 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ66B UT WOS:000089101300008 PM 10914007 ER PT J AU Scaffidi, C Kischkel, FC Krammer, PH Peter, ME AF Scaffidi, C Kischkel, FC Krammer, PH Peter, ME TI Analysis of the CD95 (APO-1/Fas) death-inducing signaling complex by high-resolution two-dimensional gel electrophoresis SO APOPTOSIS SE METHODS IN ENZYMOLOGY LA English DT Review ID DRUG-INDUCED APOPTOSIS; RECEPTOR/LIGAND SYSTEM; MONOCLONAL-ANTIBODY; CELL-DEATH; PROTEINS; FLICE; INVOLVEMENT; ACTIVATION; INTERACTS; FAS/APO-1 C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Genentech Inc, Dept Mol Oncol, San Francisco, CA 96305 USA. German Canc Res Ctr, Tumor Immunol Program, D-69120 Heidelberg, Germany. Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. RP Scaffidi, C (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RI Watzl, Carsten/B-4911-2013 OI Watzl, Carsten/0000-0001-5195-0995 NR 21 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 322 BP 363 EP 373 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ66B UT WOS:000089101300031 PM 10914030 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI Volume regulation and ion transport during apoptosis SO APOPTOSIS SE METHODS IN ENZYMOLOGY LA English DT Review ID ACTIVATION; K+ C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Bortner, CD (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 8 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 322 BP 421 EP + PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ66B UT WOS:000089101300039 PM 10914038 ER PT J AU Melino, G Candi, E Steinert, PM AF Melino, G Candi, E Steinert, PM TI Assays for transglutaminases in cell death SO APOPTOSIS SE METHODS IN ENZYMOLOGY LA English DT Review ID RECESSIVE LAMELLAR ICHTHYOSIS; HUMAN EPIDERMAL-KERATINOCYTES; PIG LIVER TRANSGLUTAMINASE; HUMAN NEUROBLASTOMA-CELLS; COAGULATION-FACTOR-XIII; GTP-BINDING PROTEIN; TISSUE TRANSGLUTAMINASE; GUINEA-PIG; INTERMEDIATE FILAMENTS; CATALYTIC PROPERTIES C1 Univ Rome Tor Vergata, IDI, IRCCS, Biochem Lab, I-00133 Rome, Italy. Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, I-00133 Rome, Italy. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Melino, G (reprint author), Univ Rome Tor Vergata, IDI, IRCCS, Biochem Lab, I-00133 Rome, Italy. NR 79 TC 35 Z9 35 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 322 BP 433 EP 472 PG 40 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BQ66B UT WOS:000089101300040 PM 10914039 ER PT J AU Hirschberg, K Phair, RD Lippincott-Schwartz, J AF Hirschberg, K Phair, RD Lippincott-Schwartz, J TI Kinetic analysis of intracellular trafficking in single living cells with vesicular stomatitis virus protein G-green fluorescent protein hybrids SO APPLICATIONS OF CHIMERIC GENES AND HYBRID PROTEINS PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID TO-GOLGI TRANSPORT; ER; VISUALIZATION; GLYCOPROTEIN C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. BioInformat Serv, Rockville, MD 20854 USA. RP Hirschberg, K (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NR 13 TC 19 Z9 19 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 327 BP 69 EP 89 PG 21 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR04N UT WOS:000165500500006 PM 11044975 ER PT J AU Leonard, WJ AF Leonard, WJ TI Use of chimeric receptor molecules to dissect signal transduction mechanisms SO APPLICATIONS OF CHIMERIC GENES AND HYBRID PROTEINS PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID HUMAN INTERLEUKIN-2 RECEPTOR; MEMBRANE-PROXIMAL REGION; T-CELL PROLIFERATION; BETA-CHAIN; CYTOPLASMIC DOMAINS; KINASE ACTIVATION; GAMMA(C) CHAIN; ALPHA-CHAIN; SUFFICIENT; SEQUENCES C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 327 BP 228 EP 239 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR04N UT WOS:000165500500017 PM 11044986 ER PT J AU Reuther, GW Buss, JE Quilliam, LA Clark, GJ Der, CJ AF Reuther, GW Buss, JE Quilliam, LA Clark, GJ Der, CJ TI Analysis of function and regulation of proteins that mediate signal transduction by use of lipid-modified plasma membrane-targeting sequences SO APPLICATIONS OF CHIMERIC GENES AND HYBRID PROTEINS PT B SE METHODS IN ENZYMOLOGY LA English DT Review ID SERINE-THREONINE KINASE; TRANSFORMING ACTIVITY; PHOSPHATIDYLINOSITOL 3-KINASE; EXCHANGE FACTOR; GROWTH-FACTOR; RAS-PROTEINS; INCREASING COMPLEXITY; NEGATIVE REGULATION; COUPLED RECEPTORS; ALPHA-SUBUNITS C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA. Iowa State Univ, Dept Biochem & Biophys, Ames, IA 50011 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. NCI, Med Branch, Div Clin Sci, Dept Cell & Canc Biol, Rockville, MD 20850 USA. RP Reuther, GW (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA. RI Quilliam, Lawrence/B-6447-2015 FU NCI NIH HHS [CA72644, CA42978, CA63139] NR 83 TC 18 Z9 18 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2000 VL 327 BP 331 EP 350 PG 20 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BR04N UT WOS:000165500500026 PM 11044995 ER PT J AU Paul, S Kalaga, RS Gololobov, G Brenneman, D AF Paul, S Kalaga, RS Gololobov, G Brenneman, D TI Natural catalytic immunity is not restricted to autoantigenic substrates - Identification of a human immunodeficiency virus gp 120-cleaving antibody light chain SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article; Proceedings Paper CT Satellite Conference on Catalytic and Superantibodies of the 10th International Congress of Immunology CY OCT 29-NOV 01, 1998 CL NEW DELHI, INDIA DE HIV-1; AIDS; gp120; catalytic antibody; light chain ID VASOACTIVE-INTESTINAL-PEPTIDE; BENCE-JONES PROTEINS; AIDS PATHOGENESIS; ENVELOPE; AUTOANTIBODIES; CLEAVAGE; SPECIFICITY; BINDING; STATE; MICE AB The autoimmune repertoire is well known from previous studies to be capable of producing catalytic antibodies directed to self-antigens. In the present study, we explored the ability of 26 monoclonal light chains (L chains) from multiple myeloma patients to cleave radiolabeled gp120, a foreign protein. One L chain with this activity was identified. I-125-gp120 and unlabeled gp120 were cleaved at several sites by the L chain, as shown by SDS-polyacrylamide gel electrophoresis, autoradiography, and immunoblotting, respectively. The apparent dissociation constant of the L chain was 130-145 nM, indicating high-affinity gp120 recognition. I-125-albumin was not cleaved by the L, chain, and various proteins and peptides did not inhibit gp120 cleavage by the L, chain, suggesting that the activity is not a nonspecific phenomenon. The substrate recognition determinants maybe conserved in different HIV-1 strains, because gp120 isolated from strains SF2, MN, and IIIB was found to be cleaved by the L, chain. Micromolar concentrations of a synthetic peptide corresponding to residues 23-30 of gp120 inhibited the cleavage of 125I-gp120, suggesting that these residues are components of the epitope recognized by the L, chain. The toxic effect of gp120 in neuronal cultures was reduced by about 100-fold by pretreatment of the protein with the L chain. These observations open the possibility of utilizing gp120-cleaving antibodies in the treatment of AIDS. C1 Univ Texas, Sch Med, Dept Pathol, Houston, TX 77030 USA. Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE 68198 USA. NIH, Sect Dev & Mol Pharmacol, Bethesda, MD 20892 USA. RP Paul, S (reprint author), Univ Texas, Sch Med, Dept Pathol, 6431 Fannin, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL59746, HL44126]; NIAID NIH HHS [AI31268] NR 30 TC 23 Z9 25 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD JAN-MAR PY 2000 VL 83 IS 1-3 BP 71 EP 82 DI 10.1385/ABAB:83:1-3:71 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 312NH UT WOS:000086949000012 PM 10826950 ER PT J AU Upadhya, SC Tirumalai, PS Boyd, MR Mori, T Ravindranath, V AF Upadhya, SC Tirumalai, PS Boyd, MR Mori, T Ravindranath, V TI Cytochrome P4502E (CYP2E) in brain: Constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE cytochrome P450; chlorzoxazone; drug metabolism; brain; ethanol; monooxygenase; human ID RAT-BRAIN; CHLORZOXAZONE; METABOLISM; PROTEINS; CELL; 2E1; DNA AB Cytochrome P4502E (P4502E), the major ethanol-inducible P450 metabolizes ethanol to acetaldehyde and bioactivates procarcinogens to ultimate carcinogens. Metabolism of ethanol to acetaldehyde in the brain could be deleterious since it can react with cytoskeletal proteins, forming adducts, In the present study, rats were administered ethanol chronically to evaluate its effect on chlorzoxazone hydroxylation in rat brain regions. Chlorzoxazone hydroxylation in brains from the treated rats was induced in hippocampus and cortex, downregulated in brainstem, and unchanged in cerebellum, striatum, and thalamus. The presence of functionally active P4502E was also seen in human brain regions obtained at autopsy from traffic accident victims. Northern blot analysis of rat and human brain poly(A)(+) RNA hybridized with cDNA to rat CYP2E1 revealed the constitutive presence of a corresponding transcript in rat and human brain. Localization of CYP2E by fluorescence in situ hybridization demonstrated the constitutive expression of CYP2E preferentially in the neuronal cells in rat and human brain. CYP2E expression was seen in neurons within the cerebral cortex, Purkinje and granule cell layers of cerebellum, granule cell layer of dentate gyrus, and pyramidal neurons of CA1, CA2, and CA3 subfields of hippocampus in both rat and human brain. The present studies demonstrate constitutive expression of P4502E1 in brain, its differential induction in rat brain regions by chronic ethanol treatment, and its topographic distribution in rat and human brain. (C) 2000 Academic Press. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Frederick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. FU NIMH NIH HHS [MH55494] NR 26 TC 77 Z9 80 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2000 VL 373 IS 1 BP 23 EP 34 DI 10.1006/abbi.1999.1477 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 282QP UT WOS:000085229800004 PM 10620320 ER PT J AU Chamberlin, ME Ubagai, T Pao, VY Pearlstein, RA Chou, JY AF Chamberlin, ME Ubagai, T Pao, VY Pearlstein, RA Chou, JY TI Structural requirements for catalysis and dimerization of human methionine adenosyltransferase I/III SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE methionine adenosyltransferase; enzyme's active site; model of human methionine adenosyltransferase; cross-linking; subunit dimerization ID S-ADENOSYLMETHIONINE SYNTHETASE; MOLECULAR MECHANISMS; EXPRESSION; PURIFICATION; DEFICIENCY; CLONING; PROGRAM; LIVER; GENE; ADP AB We have used site-directed mutagenesis to probe the structural requirements for catalysis and dimerization of human hepatic methionine adenosyltransferase (hMAT). We built a homology model of the dimeric hMAT III inferred by the crystal structure of the highly homologous Escherichia coli MAT dimer. The active sites of both enzymes comprise the same amino acids and are located in the inter-subunit interface. All of the amino acids predicted to be in the hMAT III active site were mutated, as well as residues in a conserved ATP binding region. All of the mutations except one severely affected catalytic activity. On the other hand, dimerization was affected only by single mutations of three different residues, all on one monomer. The homology model suggested that the side chains of these residues stabilized the monomer and participated in a bridge between subunits consisting of a network of metal and phosphate ions. In agreement with this observation, we demonstrated that dimerization cannot occur in the absence of phosphate. (C) 2000 Academic Press. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Mol Modeling, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. NR 26 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2000 VL 373 IS 1 BP 56 EP 62 DI 10.1006/abbi.1999.1542 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 282QP UT WOS:000085229800007 PM 10620323 ER PT J AU Yanovski, SZ AF Yanovski, SZ TI Eating disorders, race, and mythology SO ARCHIVES OF FAMILY MEDICINE LA English DT Editorial Material ID BINGE; EPIDEMIOLOGY C1 NIDDKD, Obes & Eating Disorders Program, Bethesda, MD 20892 USA. RP Yanovski, SZ (reprint author), NIDDKD, Obes & Eating Disorders Program, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1063-3987 J9 ARCH FAM MED JI Arch. Fam. Med. PD JAN PY 2000 VL 9 IS 1 BP 88 EP 88 DI 10.1001/archfami.9.1.88 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 277KL UT WOS:000084932700020 PM 10664649 ER PT J AU Hyman, SE AF Hyman, SE TI The millennium of mind, brain, and behavior SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Editorial Material AB Psychiatry enters the new millennium poised to answer many of its central questions. Given the complexity of the human brain and its interactions with our world, these questions are among the most difficult ever addressed by human science. How is the human brain built? How does it change over the life span? What are the precise genetic and environmental risk factors for mental illnesses? What are the pathophysiologic processes that produce the symptoms and disabilities? How do our treatments, including psychotherapy, work? What objective markers can we discover to monitor the progression of the pathogenic processes and the effects of treatment? How will we discover preventive measures and cures that will be effective in diverse populations and settings? Parallel to the pursuit of its public health agenda, psychiatry will grow closer to neuroscience, behavioral science, and neurology. In so doing, those who practice these disciplines will be better positioned to ask meaningful questions about the relationship among mind, brain, and behavior, and to finally overcome the pervasive Cartesianism that continues to incubate stigma and ignorance about mental illness. C1 NIMH, Rockville, MD 20857 USA. RP Hyman, SE (reprint author), NIMH, 5600 Fishers Ln, Rockville, MD 20857 USA. NR 0 TC 32 Z9 35 U1 1 U2 5 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 JAN PY 2000 VL 57 IS 1 BP 88 EP 89 DI 10.1001/archpsyc.57.1.88 PG 2 WC Psychiatry SC Psychiatry GA 270WK UT WOS:000084560000012 PM 10632239 ER PT J AU Nirenberg, M AF Nirenberg, M TI The initial strategy for assembly of part of the central nervous system SO ARCHIVES OF NEUROLOGY LA English DT Article C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, 36 Convent Dr,MSC 4036,Bldg 36,Room 1C-06, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JAN PY 2000 VL 57 IS 1 BP 51 EP 51 DI 10.1001/archneur.57.1.51 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 272QD UT WOS:000084661700006 PM 10634433 ER PT J AU Brady, RO AF Brady, RO TI Neurogene therapy for the 21st century SO ARCHIVES OF NEUROLOGY LA English DT Article ID INHERITED ENZYME DEFICIENCY; MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; REPLACEMENT THERAPY; GAUCHERS-DISEASE C1 NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NIH, Bldg 10,Room 3D04,10 Ctr Dr,MSC 1260, Bethesda, MD 20892 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD JAN PY 2000 VL 57 IS 1 BP 54 EP 54 DI 10.1001/archneur.57.1.54 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 272QD UT WOS:000084661700010 PM 10634437 ER PT J AU Battey, JF Luecke, DH AF Battey, JF Luecke, DH TI New leadership and new initiatives at the National Institute on Deafness and Other Communication Disorders SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material C1 Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 31 Ctr Dr,MSC 2320, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD JAN PY 2000 VL 126 IS 1 BP 17 EP 19 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 272BM UT WOS:000084630700003 PM 10628705 ER PT J AU Henson, DE Albores-Saavedra, J Compton, CC AF Henson, DE Albores-Saavedra, J Compton, CC CA Coll Amer Pathologists TI Protocol for the examination of specimens from patients with carcinomas of the extrahepatic bile ducts, exclusive of sarcomas and carcinoid tumors - A basis for checklists SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID BILIARY-TRACT; PROGNOSTIC FACTORS; INVASION C1 NCI, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Henson, DE (reprint author), Care of Schramm J, Coll Amer Pathologists, 325 Waukegan Rd, Northfield, IL 60093 USA. NR 20 TC 7 Z9 7 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JAN PY 2000 VL 124 IS 1 BP 26 EP 29 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 276CB UT WOS:000084857100006 PM 10629127 ER PT J AU Henson, DE Albores-Saavedra, J Compton, CC AF Henson, DE Albores-Saavedra, J Compton, CC CA Coll Amer Pathologists TI Protocol for the examination of specimens from patients with carcinomas of the gallbladder, including those showing focal endocrine differentiation - A basis for checklists SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID OAT-CELL CARCINOMA; PROGNOSTIC FACTORS; HYPERPLASIA; INSITU C1 NCI, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Henson, DE (reprint author), Care of Schramm J, Coll Amer Pathologists, 325 Waukegan Rd, Northfield, IL 60093 USA. NR 26 TC 6 Z9 7 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JAN PY 2000 VL 124 IS 1 BP 37 EP 40 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 276CB UT WOS:000084857100008 PM 10629129 ER PT J AU Nemchinov, LG Shamloul, AM Zemtchik, EZ Verderevskaya, TD Hadidi, A AF Nemchinov, LG Shamloul, AM Zemtchik, EZ Verderevskaya, TD Hadidi, A TI Apricot latent virus: a new species in the genus Foveavirus SO ARCHIVES OF VIROLOGY LA English DT Article ID CLONING; DISEASE; PCR AB Extraction of viral double-stranded RNA from peach leaves infected with Apricot Intent virus (ALV) followed by molecular cloning; of synthesized cDNA and its sequencing, suggested that ALV is a new virus, whose coat protein (CP) coding region contains Apple stem pitting virus (ASPV)-related sequences. The sequenced portion of the ALV genome (1444 nt) includes the putative CP gene and the 3' non-translated region. The 5' portion of this fragment (1-651 nt) is highly distinct whereas the 3/ portion is 77% identical to the corresponding region of ASPV. Molecular hybridization experiments using a cRNA probe to ASPV with ALV-infected leaf tissue extracts also revealed that the genome of ALV contains nucleotide sequences related to that of ASPV. Western blots of tissue extracts indicated that ALV coat protein reacted with polyclonal antiserum against ASPV; however, the ALV CP differs in size from that of ASPV. ALV was graft-transmitted to several Prunus rootstocks. Based on the available sequence data, serological observations and bioassays we propose that ALV is a new species in the genus Foveavirus, typified by ASPV. ALV-specific PCR-primers and viral-specific cRNA probes developed in this investigation may be useful for detecting the virus and for studying its epidemiology and geographical distribution. C1 Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, Bethesda, MD 20891 USA. USDA ARS, Fruit Lab, Beltsville, MD USA. Inst Hort Res, Chisinau, Moldova. RP Nemchinov, LG (reprint author), Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, Bethesda, MD 20891 USA. NR 14 TC 12 Z9 14 U1 0 U2 1 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PY 2000 VL 145 IS 9 BP 1801 EP 1813 DI 10.1007/s007050070057 PG 13 WC Virology SC Virology GA 358XL UT WOS:000089582400004 PM 11043942 ER PT J AU Willian, S Tracy, S Chapman, N Leser, S Romero, J Shapiro, B Currey, K AF Willian, S Tracy, S Chapman, N Leser, S Romero, J Shapiro, B Currey, K TI Mutations in a conserved enteroviral RNA oligonucleotide sequence affect positive strand viral RNA synthesis SO ARCHIVES OF VIROLOGY LA English DT Article ID INFECTIOUS CDNA COPY; COXSACKIEVIRUS B3; POLIOVIRUS RNA; NONCODING REGION; VIRUS; REPLICATION; GENOME; CARDIOVIRULENT; TRANSLATION; HYBRIDIZATION AB We showed earlier that a transition mutation U234C, located within the completely conserved 5 nucleotide (nt) tract 5'-CGUUA (nt232-236) in the 5' non-translated region (NTR) of the coxsackievirus B3 (CVB3) genome, attenuated CVB3 cardiovirulence in mice. To further explore the role of the sequence, we induced two single and one double transversion mutations in the conserved 5mer in a cardiovirulent CVB3 genome. The mutated sites partially or totally reverted to parental wild-type when progeny viruses were passaged at 37 degreesC, but remained stable when transfection and subsequent passages were performed at 33.5 degreesC. Viral replication in cell culture was attenuated at 37 degreesC or 39.5 degreesC relative to replication at 33.5 degreesC. While Western blot analysis demonstrated the level of protein translation consistent with virus replication, the ratios of positive to negative strand viral RNA at 37 degreesC in murine cells demonstrated a 2-5 fold diminution from those measured at 33.5 degreesC. Mutant CVB3 strains failed to replicate productively when inoculated into mice. The biological data are consistent with an hypothesis that proposes a lesion with primary effects at the level of positive strand viral RNA synthesis that results in attenuation of viral replication at physiologic temperature. C1 Univ Nebraska, Med Ctr 986495, Enterovirus Res Lab, Dept Pathol & Microbiol, Omaha, NE 68198 USA. Creighton Univ Nebraska Univ, Med Ctr, Combined Div Pediat Infect Dis, Omaha, NE 68198 USA. NCI, Frederick Canc Res & Dev Ctr, DBS, Lab Math Biol, Frederick, MD USA. Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. RP Tracy, S (reprint author), Univ Nebraska, Med Ctr 986495, Enterovirus Res Lab, Dept Pathol & Microbiol, 600 S 42nd St, Omaha, NE 68198 USA. NR 52 TC 12 Z9 13 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PY 2000 VL 145 IS 10 BP 2061 EP 2086 DI 10.1007/s007050070040 PG 26 WC Virology SC Virology GA 366PT UT WOS:000090014300006 PM 11087092 ER PT J AU Jeong, KS Nam, YS Venkatesan, S AF Jeong, KS Nam, YS Venkatesan, S TI Deletions near the N-terminus of HIV-1 Rev reduce RNA binding affinity and dominantly interfere with Rev function irrespective of the RNA target SO ARCHIVES OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RESPONSIVE ELEMENT RNA; GENE-EXPRESSION REQUIRES; NUCLEAR EXPORT SIGNAL; VIRAL MESSENGER-RNA; HUMAN T-CELLS; TYPE-1 REV; ACTIVATION DOMAIN; TRANS-ACTIVATOR; I REX AB The contributions of the near N-terminal residues of Rev protein of HIV were investigated by analyzing N-terminal deletions of Rev in the context of a Rev/MS-C fusion protein that can bind and activate both the Rev responsive element (RRE) and the MS2 phage translational operator RNAs. Rev/MS-C fusion proteins deleted for residues 3-19 of Rev retained trans-activation potential for both RRE and MS2 targets. Coincidentally, peptides spanning residues 17-87 or 22-85 were functionally competent for trans-activation of RRE containing HIV-1 gag mRNA. Deletion of residues 18-24 of Rev in the Rev/MS-C fusion protein abolished the activation potential for both RRE and MS2 targets, although this mutant was competent for specific RNA binding, protein multimerization, and nuclear and nucleolar localization. Four mutants dominantly interfering with Rev activation of RRE were mapped near the N-terminus of Rev; (i) between residues 18 and 24, (ii) 25-34, (iii) 43-50, and (iv) 51-60. Of these, the mutant lacking residues 18-24 was a novel trans-dominant inhibitor of Rev and Rev/MS-C for activation of RRE or MS2 RNA, while the oligomerization domain mutants mapping between residues 25-34 or 51-60 inhibited the activation of RRE rather than MS2 RNA. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Venkatesan, S (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 10,Room 6A05, Bethesda, MD 20892 USA. NR 64 TC 6 Z9 8 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PY 2000 VL 145 IS 12 BP 2443 EP 2467 DI 10.1007/s007050070001 PG 25 WC Virology SC Virology GA 399RZ UT WOS:000166827300001 PM 11205098 ER PT J AU Nemchinov, LG Liang, TJ Rifaat, MM Mazyad, HM Hadidi, A Keith, JM AF Nemchinov, LG Liang, TJ Rifaat, MM Mazyad, HM Hadidi, A Keith, JM TI Development of a plant-derived subunit vaccine candidate against hepatitis C virus SO ARCHIVES OF VIROLOGY LA English DT Article ID TOXIN-B SUBUNIT; HYPERVARIABLE REGION-1; HYPERIMMUNE SERUM; E2 GLYCOPROTEIN; ANTIBODIES; CHIMPANZEES; SEQUENCE; PROTEIN; BINDING; IDENTIFICATION AB Hepatitis C virus (HCV) is a major cause of acute and chronic hepatitis with over 180 million cases worldwide. Vaccine development for HCV has been difficult. Presently, the virus cannot be grown in tissue culture and there is no vaccine or effective therapy against this virus. In this research, we describe the development of an experimental plant-derived subunit vaccine against HCV. A tobamoviral vector was engineered to encode a consensus sequence of hypervariable region 1 (HVR1), a potential neutralizing epitope of HCV, genetically fused to the C-terminal of the B subunit of cholera toxin (CTB). This epitope was selected from among the amino acid sequences of HVR1 "mimotopes" previously derived by phage display technology. The nucleotide sequence encoding this epitope was designed utilizing optimal plant codons. This mimotope is capable of inducing cross-neutralizing antibodies against different variants of the virus. Plants infected with recombinant tobacco mosaic virus (TMV) engineered to express the HVR1/CTB chimeric protein, contained intact TMV particles and produced the HVR1 consensus peptide fused to the functionally active, pentameric B subunit of cholera toxin. Plant-derived HVR1/CTB reacted with HVR1-specific monoclonal antibodies and immune sera from individuals infected with virus from four of the major genotypes of HCV. Intranasal immunization of mice with a crude plant extract containing the recombinant HVR1/CTB protein elicited both anti-CTB serum antibody and anti-HVR1 serum antibody which specifically bound to HCV virus-like particles. Using plant-virus transient expression to produce this unique chimeric antigen will facilitate the development and production of an experimental HCV vaccine. A plant-derived recombinant HCV vaccine can potentially reduce expenses normally associated with production and delivery of conventional vaccines. C1 Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. Agr Res Ctr, Plant Pathol Res Inst, Giza, Egypt. USDA, Beltsville, MD 20705 USA. RP Nemchinov, LG (reprint author), Natl Inst Dent & Craniofacial Res, Vaccine & Therapeut Dev Sect, Oral Infect & Immun Branch, NIH, 30 Convent Dr MSC 4350, Bethesda, MD 20892 USA. NR 29 TC 66 Z9 80 U1 1 U2 3 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PY 2000 VL 145 IS 12 BP 2557 EP 2573 DI 10.1007/s007050070008 PG 17 WC Virology SC Virology GA 399RZ UT WOS:000166827300008 PM 11205105 ER PT J AU Demaimay, R Chesebro, B Caughey, B AF Demaimay, R Chesebro, B Caughey, B TI Inhibition of formation of protease-resistant prion protein by Trypan Blue, Sirius Red and other Congo Red analogs SO ARCHIVES OF VIROLOGY LA English DT Article; Proceedings Paper CT Symposium on the Characterization and Diagnosis of Prion Diseases CY SEP 23-25, 1999 CL TUBINGEN, GERMANY ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE-INFECTED HAMSTERS; INCUBATION PERIOD; PRP ACCUMULATION; AMPHOTERICIN-B; MOUSE; PHTHALOCYANINES; REPLICATION; PORPHYRINS; DELAYS AB Five compounds related to Congo Red were found to inhibit generation of protease-resistant prion protein in a cell-free system. In this assay Trypan Blue, Evans Blue, Sirius Red F3B, Primuline and Thioflavin-S were all more inhibitory than Congo Red itself. In scrapie-infected mouse neuroblastoma cells one compound, Sirius Red F3B, was capable of blocking the formation of protease-resistant prion protein to a similar extent as Congo Red; however, the other four compounds were less effective. Some of these compounds should be considered for testing in TSE disease models in live animals. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 20 TC 5 Z9 6 U1 0 U2 1 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PY 2000 SU 16 BP 277 EP 283 PG 7 WC Virology SC Virology GA 392PR UT WOS:000166420600027 PM 11214931 ER PT J AU Leppala, JM Virtamo, J Fogelholm, R Huttunen, JK Albanes, D Taylor, PR Heinonen, OP AF Leppala, JM Virtamo, J Fogelholm, R Huttunen, JK Albanes, D Taylor, PR Heinonen, OP TI Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE alpha-tocopherol; beta-carotene; cerebral infarction; intracerebral hemorrhage; subarachnoid hemorrhage ID CARDIOVASCULAR-DISEASE; ATHEROSCLEROTIC PLAQUE; PLATELET-FUNCTION; VITAMIN-C; PLASMA; LASER; MEN AB Observational data suggest that diets rich in fruits and vegetables and with high serum levels of antioxidants are associated with decreased incidence and mortality of stroke. We studied the effects of alpha-tocopherol and beta-carotene supplementation. The incidence and mortality of stroke were examined in 28 519 male cigarette smokers aged 50 to 69 years without history of stroke who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). The daily supplementation was 50 mg alpha-tocopherol, 20 mg beta-carotene, bath, or placebo. The median follow-up was 6.0 years. A total of 1057 men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively (total 160). alpha-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI - 3% to 132%, P = 0.07) but decreased that of cerebral infarction 14% (95% CI -25% to - 1%, P = 0.03), whereas beta-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, P = 0.01). alpha-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, P = 0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. alpha-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of alpha-tocopherol. beta-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available. C1 Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Clin Neurosci, Helsinki, Finland. Univ Helsinki, Cent Hosp, Natl Publ Hlth Inst, Helsinki, Finland. NCI, Bethesda, MD 20892 USA. RP Leppala, JM (reprint author), Univ Helsinki, Dept Publ Hlth, POB 41,Mannerheimintie 172, FIN-00014 Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01CN45165] NR 22 TC 106 Z9 112 U1 0 U2 6 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 JAN PY 2000 VL 20 IS 1 BP 230 EP 235 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 282RP UT WOS:000085232500031 PM 10634823 ER PT J AU Ortmann, RA Cheng, T Visconti, R Frucht, DM O'Shea, JJ AF Ortmann, RA Cheng, T Visconti, R Frucht, DM O'Shea, JJ TI Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation SO ARTHRITIS RESEARCH LA English DT Review DE cytokines; signaling; Jak; Stat; immunoregulation ID SEVERE COMBINED IMMUNODEFICIENCY; PROTEIN-TYROSINE KINASE; CELL ANTIGEN-RECEPTOR; GROWTH-HORMONE RECEPTOR; INTERFERON-ALPHA/BETA RECEPTOR; STAT3 SERINE PHOSPHORYLATION; COLONY-STIMULATING FACTOR; PERIPHERAL T-CELLS; MICE LACKING JAK3; MOTH-EATEN MICE AB Cytokines play a critical role in the normal development and function of the immune system. On the other hand, many rheumatologic diseases are characterized by poorly controlled responses to or dysregulated production of these mediators. Over the past decade tremendous strides have been made in clarifying how cytokines transmit signals via pathways using the Janus kinase (Jak) protein tyrosine kinases and the Signal transducer and activator of transcription (Stat) proteins. More recently, research has focused on several distinct proteins responsible for inhibiting these pathways. It is hoped that further elucidation of cytokine signaling through these pathways will not only allow for a better comprehension of the etiopathogenesis of rheumatologic illnesses, but may also direct future treatment options. C1 NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, NIH Scholars Program, Bethesda, MD 20817 USA. RP Ortmann, RA (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N262, Bethesda, MD 20892 USA. RI Visconti, Roberta/C-5299-2009 NR 238 TC 28 Z9 34 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2000 VL 2 IS 1 BP 16 EP 32 DI 10.1186/ar66 PG 17 WC Rheumatology SC Rheumatology GA 408ZF UT WOS:000167356500003 PM 11094415 ER PT J AU Goldbach-Mansky, R Lee, JM Hoxworth, JM Smith, D Duray, P Schumacher, HR Yarboro, CH Klippel, J Kleiner, D El-Gabalawy, HS AF Goldbach-Mansky, R Lee, JM Hoxworth, JM Smith, D Duray, P Schumacher, HR Yarboro, CH Klippel, J Kleiner, D El-Gabalawy, HS TI Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis SO ARTHRITIS RESEARCH LA English DT Review DE early synovitis; erosion; metalloproteinase; matrix metalloproteinase-2; rheumatoid arthritis ID EARLY RHEUMATOID-ARTHRITIS; TISSUE INHIBITOR; IV COLLAGENASE; GELATINASE-B; PLASMINOGEN-ACTIVATOR; COLON-CANCER; EXPRESSION; FIBROBLASTS; PLASMA; TIMP-2 AB Serum and synovial tissue expression of the matrix metalloproteinase (MMP)-2 and -9 and their molecular regulators, MMP-14 and TIMP-2 was examined in 28 patients with inflammatory early synovitis and 4 healthy volunteers and correlated with the presence of erosions in the patients. Immunohistological staining of MMP-2, MMP-14 and TIMP-2 localized to corresponding areas in the synovial lining layer and was almost absent in normal synovium. Patients with radiographic erosions had significantly higher levels of active MMP-2 than patients with no erosions, suggesting that activated MMP-2 levels in synovial tissue may be a marker for a more aggressive synovial lesion. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Pathol, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Vet Affairs, Philadelphia, PA USA. RP El-Gabalawy, HS (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9S205, Bethesda, MD 20892 USA. OI Hoxworth, Joseph/0000-0002-7179-5846; Kleiner, David/0000-0003-3442-4453 NR 53 TC 60 Z9 64 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2000 VL 2 IS 2 BP 145 EP 153 DI 10.1186/ar79 PG 9 WC Rheumatology SC Rheumatology GA 408ZP UT WOS:000167357300008 PM 11062605 ER PT J AU Goldbach-Mansky, R Lee, J McCoy, A Hoxworth, J Yarboro, C Smolen, JS Steiner, G Rosen, A Zhang, C Menard, HA Zhou, ZJ Palosuo, T Van Venrooij, WJ Wilder, RL Klippel, JH Schumacher, HR El-Gabalawy, HS AF Goldbach-Mansky, R Lee, J McCoy, A Hoxworth, J Yarboro, C Smolen, JS Steiner, G Rosen, A Zhang, C Menard, HA Zhou, ZJ Palosuo, T Van Venrooij, WJ Wilder, RL Klippel, JH Schumacher, HR El-Gabalawy, HS TI Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset SO ARTHRITIS RESEARCH LA English DT Review DE autoantibodies; early synovitis; human leukocyte antigen; rheumatoid arthritis; spondylarthropathy ID HUMAN EPIDERMIS FILAGGRIN; ANTIKERATIN ANTIBODIES; ANTIFILAGGRIN AUTOANTIBODIES; ANTIPERINUCLEAR FACTOR; MARKER; PURIFICATION; DISEASE; SERA; RA33 AB An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro) filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-Sa identified a subset of predominantly male RA patients with severe, erosive disease. Anti-Sa, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses. C1 Univ Vienna, Dept Med, Div Rheumatol, Vienna, Austria. Johns Hopkins Sch Med, Dept Med, Div Rheumatol, Baltimore, MD USA. Univ Sherbrooke, Ctr Univ Sante Estrie, Div Rheumatol, Sherbrooke, PQ J1K 2R1, Canada. Natl Publ Hlth Inst, Immunobiol Lab, Helsinki, Finland. Katholieke Univ Nijmegen, Nijmegen, Netherlands. Univ Penn, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP El-Gabalawy, HS (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. OI Hoxworth, Joseph/0000-0002-7179-5846 NR 30 TC 246 Z9 278 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2000 VL 2 IS 3 BP 236 EP 243 DI 10.1186/ar93 PG 8 WC Rheumatology SC Rheumatology GA 408ZU UT WOS:000167357700013 PM 11056669 ER PT J AU Nanki, T Lipsky, PE AF Nanki, T Lipsky, PE TI Cytokine, activation marker, and chemokine receptor expression by individual CD4(+) memory T cells in rheumatoid arthritis synovium SO ARTHRITIS RESEARCH LA English DT Review DE chemokine receptor; cytokine; rheumatoid arthritis; T lymphocyte ID DIFFERENTIAL EXPRESSION; PERIPHERAL-BLOOD; MESSENGER-RNA; SINGLE-CELL; SUBSETS; TISSUE; LYMPHOCYTES; CCR5; TH1; RESPONSIVENESS AB IL-10, IL-13, IFN-gamma, tumor necrosis factor (TNF)-alpha, LT-alpha, CD154, and TNF-related activation-induced cytokine (TRANCE) were expressed by 2-20% of rheumatoid arthritis (RA) synovial tissue CD4(+) memory T cells, whereas CD4(+) cells that produced IL-2, IL-4, or IL-6 were not detected. Expression of none of these molecules by individual CD4+ cells correlated with the exception of TRANCE and IL-10, and TRANCE and TNF-alpha. A correlation between expression of IL-10 and CCR7, LT-alpha and CCR6, IFN-gamma and CCR5, and TRANCE and CXCR4 was also detected. C1 Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX USA. Univ Texas, SW Med Ctr, Harold C Simmons Arthrit Res Ctr, Dallas, TX USA. RP Lipsky, PE (reprint author), NIAMSD, Bldg 10,Room 9N228,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. NR 27 TC 41 Z9 46 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2000 VL 2 IS 5 BP 415 EP 423 DI 10.1186/ar120 PG 9 WC Rheumatology SC Rheumatology GA 409TF UT WOS:000167401200012 PM 11056676 ER PT J AU Phillips, SJ AF Phillips, SJ TI FDA reform legislation and its effect on clinical trials SO ASAIO JOURNAL LA English DT Editorial Material C1 Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Phillips, SJ (reprint author), Natl Lib Med, NIH, Bldg 38,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1058-2916 J9 ASAIO J JI Asaio J. PD JAN-FEB PY 2000 VL 46 IS 1 BP 19 EP 20 DI 10.1097/00002480-200001000-00006 PG 2 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 392UK UT WOS:000166430800006 PM 10667708 ER PT S AU Kirk, KL Herbert, B Lu, SF Jayachandran, B Padgett, WL Olufunke, O Daly, JW Haufe, G Laue, KW AF Kirk, KL Herbert, B Lu, SF Jayachandran, B Padgett, WL Olufunke, O Daly, JW Haufe, G Laue, KW BE Ramachandran, PV TI Chemical and biochemical approaches to the enantiomers of chiral fluorinated catecholamines and amino acids SO ASYMMETRIC FLUOROORGANIC CHEMISTRY: SYNTHESIS, APPLICATIONS, AND FUTURE DIRECTIONS SE ACS SYMPOSIUM SERIES LA English DT Article; Proceedings Paper CT 216th National Meeting of the American-Chemical-Society CY AUG 21-27, 1998 CL BOSTON, MASSACHUSETTS SP Amer Chem Soc, Div Polymer Mat, Sci & Engn Inc, Div Polymer Mat, Exxon Res & Engn CO, Amer Chem Soc, Petr Res Fund, Amer Chem Soc, Div Fluorine Chem, Amer Chem Soc, Div Organ Chem, Amer Chem Soc, Corp Associates, Dow Agrosci, Monsanto Co, Eastman Kodak Co, Schering Plough, Merck Res Labs, Cent Glass Int Inc, Daikin Ind, Kanto Denka Kogyo Co, Asahi Glass Co, Div Agr & Food Chem ID ASYMMETRIC-SYNTHESIS; ORGANIC-SYNTHESIS AB Several routes to the enantiomers of FNEs (5) and FDOPSs (9) have been explored. From these studies two asymmetric routes to FNEs 5b and 5d have been developed. A catalytic enantioselective oxazaborolidine reduction and a chiral (salen)Ti-IV catalyzed asymmetric silocyanation were used in the key stereo-defining steps of the respective routes. The syntheses that we carried out to demonstrate efficacy are complimentary in that they provided the targets with opposite configuration. Excellent progress has also been made towards the synthesis of(2S,3R)-FDOPS (9b and 9d) using an Evans aldol approach. Binding studies revealed that the R-configuration of FNEs was essential for marked effects on the affinity towards adrenergic receptors, These studies also revealed that fluorination at the 2-position of NE reduced activity at the alpha-receptors and enhanced activity at beta-receptors, while fluorination at the 6-position reduced activity at the beta-receptors. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20817 USA. Univ Munster, Inst Organ Chem, D-48149 Munster, Germany. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20817 USA. NR 36 TC 2 Z9 2 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 SIXTEENTH ST NW, WASHINGTON, DC 20036 USA SN 0097-6156 BN 0-8412-3639-9 J9 ACS SYM SER PY 2000 VL 746 BP 194 EP 209 PG 16 WC Chemistry, Multidisciplinary SC Chemistry GA BP75Q UT WOS:000086073000014 ER EF