FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kiyatkin, EA Wise, RA AF Kiyatkin, EA Wise, RA TI Brain and body hyperthermia associated with heroin self-administration in rats SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain temperature; opiates; heroin; neural activation; drug-taking behavior; thermorecording in behaving animals ID TEGMENTAL AREA NEURONS; CEREBRAL-BLOOD-FLOW; HYPOTHALAMIC TEMPERATURE; CONSCIOUS RAT; COCAINE; REINSTATEMENT; TRANSMISSION; POTENTIALS; MODULATION; PREDICTION AB Intravenous heroin self-administration in trained rats was accompanied by robust brain hyperthermia (+2.0-2.5degreesC); parallel changes were found in the dorsal and ventral striatum, mediodorsal thalamus, and deep temporal muscle. Temperature began to increase at variable latency after a signal of drug availability, increased reliably (similar to0.4degreesC) before the first lever press for heroin, increased further (similar to1.2degreesC) after the first heroin injection, and rose more slowly after the second and third injections to stabilize at an elevated plateau (39-40degreesC) for the remainder of the session. Brain and body temperature declined slowly when drug self-administration was terminated; naloxone precipitated a much more rapid decrease to baseline levels. Changes in temperature were similar across repeated daily sessions, except for the increase associated with the first self-administration of each session, which had progressively shorter latency and greater acceleration. Despite consistent biphasic fluctuations in movement activity associated with heroin self-administrations (gradual increase preceding the lever press, followed by an abrupt hypodynamia after drug infusion), mean brain temperature was very stable at an elevated plateau. Only mean muscle temperature showed evidence of biphasic fluctuations (+/-0.2degreesC) that were time locked to and correlated with lever pressing and associated movements. Drug- and behavior-related changes in brain temperature thus appear to reflect some form of neuronal activation, and, because temperature is a factor capable of affecting numerous neural functions, it may be an important variable in the control of behavior by drugs of abuse. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP NIDA, Behav Neurosci Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ekiyatkin@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 NR 39 TC 25 Z9 25 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2002 VL 22 IS 3 BP 1072 EP 1080 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800056 PM 11826136 ER PT J AU Hough, GE Volman, SF AF Hough, GE Volman, SF TI Short-term and long-term effects of vocal distortion on song maintenance in zebra finches SO JOURNAL OF NEUROSCIENCE LA English DT Article DE zebra finch; auditory feedback; vocal distortion; song; HVc; songbirds; vocal learning ID WHITE-CROWNED SPARROWS; AUDITORY-FEEDBACK; ANTERIOR FOREBRAIN; NEURAL SELECTIVITY; BENGALESE FINCHES; TAENIOPYGIA-GUTTATA; PROJECTION NEURONS; ADULT SONGBIRDS; LEARNED SONG; BIRDSONG AB Adult zebra finch song is irreversibly altered when birds are deprived of correct feedback by deafening or denervation of the syrinx. To clarify the role of feedback in song maintenance, we developed a reversible technique to distort vocal output without damaging the auditory or vocal systems. We implanted flexible beads adjacent to the syrinx to alter its biomechanics. Immediate song aberrations included low volume, frequency shifts, missing harmonics, and production of click-like syllables. After a few weeks, seven of nine birds stopped producing some syllables. In six of these birds, the gaps left by the silenced syllables gradually shortened, and the lost syllables did not return when beads were removed 16 weeks after treatment began. The nondeleted syllables of all birds regained their preimplant morphology, insofar as could be detected, within 9 d after bead removal. In four other birds, we removed the beads as soon as syllables were deleted, when the silent intervals were still full length. In these birds, all deleted syllables returned within 1 week. Our results indicate that both silenced syllables and syllable morphology can recover as long as the song's temporal structure is maintained, but once altered, changes in the song sequence can be permanent. A hierarchical organization of the song production system has recently been described (Margoliash, 1997). Reversible disruption of song production by our method appears to permanently alter the higher levels of the system that encode song sequence, but not the lower levels that encode individual syllable structure. C1 NIDA, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Ecol Evolut & Organismal Biol, Columbus, OH 43210 USA. RP Hough, GE (reprint author), NIDA, NIH, 6001 Execut Blvd,Room 4282 MSC 9555, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH47330] NR 60 TC 17 Z9 19 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2002 VL 22 IS 3 BP 1177 EP 1186 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800067 PM 11826147 ER PT J AU Bonnot, AS Whelan, PJ Mentis, GZ O'Donovan, MJ AF Bonnot, AS Whelan, PJ Mentis, GZ O'Donovan, MJ TI Spatiotemporal pattern of motoneuron activation in the rostral lumbar and the sacral segments during locomotor-like activity in the neonatal mouse spinal cord SO JOURNAL OF NEUROSCIENCE LA English DT Article DE calcium imaging; motoneuron; locomotion; spinal cord; rhythmogenesis; mouse ID IN-VITRO; RAT; NETWORKS; HINDLIMB; MUSCLES AB We used calcium imaging to visualize the spatiotemporal pattern of motoneuron activity during dorsal root-evoked locomotor-like bursting in the lumbosacral spinal cord of the neonatal mouse. Dorsal root stimuli elicited a tonic discharge in motoneurons on which alternating left-right rhythmic discharges were superimposed. Both the tonic and the rhythmic components could be recorded optically from populations of motoneurons labeled with calcium-green dextran. Optical and electrical recordings revealed that rhythmic signals from different parts of the lumbar (L1, L2) and sacral (S1-S3) segments rose, peaked, and decayed in a rostrocaudal sequence. This pattern gave rise to a rostrocaudal "wave" in the activation of motoneurons during each cycle of locomotor-like activity. A similar rostrocaudal delay was observed during episodes of alternation that occurred in the absence of stimulation, suggesting that this delay was not caused by the train of dorsal root stimuli. It is hypothesized that this behavior may simplify the appropriate sequencing of motoneurons during locomotion. C1 NINCDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Bonnot, AS (reprint author), NINCDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM bonnota@ninds.nih.gov RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 20 TC 34 Z9 34 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 1 PY 2002 VL 22 IS 3 AR RC203 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 518HB UT WOS:000173660800001 PM 11826149 ER PT J AU Amin, ND Albers, W Pant, HC AF Amin, ND Albers, W Pant, HC TI Cyclin-dependent kinase 5 (cdk5) activation requires interaction with three domains of p35 SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cdk5; p35; p16; cyclin-dependent kinase ID DIRECTED PROTEIN-KINASE; NEURONAL-SPECIFIC ACTIVATOR; BRAIN-SPECIFIC ACTIVATOR; BOVINE BRAIN; CDC2-LIKE KINASE; TAU-PROTEIN; REGULATORY SUBUNIT; CRYSTAL-STRUCTURE; PHOSPHORYLATION; DIFFERENTIATION AB Cyclin-dependent kinase 5 (cdk5), in contrast to other members of the cyclin-dependent kinase family, is not activated by cyclins but instead is activated by complexing with neuron-specific activator molecules (p35, p39, and p67). The most effective activator of cdk5 both in vitro and in vivo is p35. We have taken a kinetic approach to study the interaction between p35, its various truncated forms, and cdk5 to understand better the mechanism of its activation. The cdk5 complexes formed with the truncated forms p25 and p21 produced similar maximum active kinase, whereas the cdk5 complexed with full-length p35 and a further truncated form spanning amino acid residues from 138 to 291, with approximate molecular weight of 16 kDa (p16), produced slightly less (80%) activation than p25. P16 was the smallest fragment of p35 that produced activation equal to or greater than that of full-length p35. By examination of further truncations of p16, we found that a small number of residues, 11 and 4 at the N- and C-termini, respectively, of p16, are essential for cdk5 activation. Further truncation, removing both essential N- and C-terminal domains, produces a peptide with markedly higher affinity for cdk5 compared with the peptides that retain either of these domains. Using these inactive truncated peptides as inhibitors, we examined the kinetics of activation. From these studies we conclude that activation involves at least three cdk5-interacting domains, one located at each end of p16 and at least one located in a central domain. The cdk5 activation process is slow: The second-order rate constant for p16 is about 1.2 muM(-1) hr(-1). On the basis of kinetic data, we suggest that cdk5 exists in two conformations. The inactive kinase conformation predominates in the absence of the activator. Activation occurs in two stages: a rapid and reversible interaction of cdk5 with its activator, which involves only one or two binding domains, followed by a slow stabilization of the active conformation as interaction with all three domains is achieved. Published 2002 Wiley-Liss, lnc.(dagger) C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINCDS, Neurochem Lab, NIH, Bldg 36,Room 4D-04,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 44 TC 42 Z9 51 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 1 PY 2002 VL 67 IS 3 BP 354 EP 362 DI 10.1002/jnr.10116 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 517JN UT WOS:000173607500009 PM 11813240 ER PT J AU Lai, Z Brady, RO AF Lai, Z Brady, RO TI Gene transfer into the central nervous system in vivo using a recombinanat lentivirus vector SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE lentivirus vector; injection; gene delivery; central nervous system; fusion protein; transport; striatum; hippocampus ID TEGUMENT PROTEIN VP22; ADENOASSOCIATED VIRUS; NONDIVIDING CELLS; INTERCELLULAR DELIVERY; TRANSDUCTION; BRAIN; PERSISTENCE; EXPRESSION; EFFICIENT; PARTICLES AB Gene transfer vectors derived from human immunodeficiency virus (HIV-1) efficiently transduce nondividing cells and may provide for the delivery of their gene products to discrete regions of the brain. We investigated whether stable gene transduction can be achieved in cells of the central nervous system (CNS) in vivo by a potent lentivirus vector. The herpes simplex virus type 1 protein VP22 has been known to facilitate intercellular protein transport and thereby provides an opportunity to increase the effectiveness of therapeutic genes by enhancing the delivery of their protein products. We developed a lentiviral vector construct expressing enhanced green fluorescent protein (EGFP) fused at its N-terminus to the herpes simplex virus VP22. In order to determine expression of the fusion protein in specific cells such as neurons in the CNS, a neuron-specific promoter was also placed into the construct. The viral vectors were injected directly into the striatum and hippocampus of mouse brains. We found that the lentivirus vector efficiently and stably transduced nondividing cells in the CNS with transgene expression for over 3 months. We also show that the delivery of VP22-EGFP fusion protein encoded by the lentivirus was effectively transported between neuronal cells via axons in vivo. Doubly labeled experiments revealed that our lentiviral vector is capable of delivering gene products to neurons and astrocytes in CNS. The data also demonstrate that up to 90% of the CNS cells transduced by our lentiviral vector under the control of the neuronal promoter are neurons. Published 2002 Wiley-Liss, Inc.(dagger) C1 NINCDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Lai, Z (reprint author), NINCDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D-04, Bethesda, MD 20892 USA. NR 30 TC 53 Z9 62 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 1 PY 2002 VL 67 IS 3 BP 363 EP 371 DI 10.1002/jnr.10137 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 517JN UT WOS:000173607500010 PM 11813241 ER PT J AU Velasco, I Tapia, R AF Velasco, I Tapia, R TI High extracellular gamma-aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE glutamate uptake; GABA uptake; neurotoxicity; neuronal culture; pyrrolidine dicarboxylate ID EXCITOTOXIC CELL-DEATH; RAT CORTICAL CULTURES; HIPPOCAMPAL-NEURONS; GLUCOSE DEPRIVATION; CEREBRAL-ISCHEMIA; QUANTAL BIOASSAY; IN-VITRO; GABA; INHIBITION; NEUROTOXICITY AB The glutamate uptake inhibitor L-trans-2,4-pyrrolidine-dicarboxylate (PDC) induces glutamate accumulation and neuronal damage in cultured cells. We have used dissociated cortical cells in culture to study whether the toxicity induced by inhibiting glutamate uptake with PDC could be blocked by the simultaneous inhibition of gamma-aminobutyric acid (GABA) uptake, because both types of transporters are affected during an ischemic event. After 6 hr of exposure to 100 muM GABA or to four different GABA uptake inhibitors, the concentration of extracellular GABA was augmented from the basal 2 muM value to about 25 muM and 5 muM, respectively. These increases, however, did not result in protection against the neuronal damage induced by the accumulation of extracellular glutamate because of the simultaneous exposure to PDC. In contrast, when 100 muM GABA and an inhibitor of GABA uptake were added, after 6 hr the concentrations of GABA reached 50 muM, and neurons were protected from PDC-induced toxicity. The addition of the GABA(A) and GABA(B) receptor agonists muscimol and baclofen also partially protected against PDC-induced damage. The results suggest that the excitotoxic damage resulting from chronic gradual elevation of extracellular glutamate may be prevented by high concentrations of extracellular GABA, an effect mediated by activation of GABA(A) and GABA(B) receptors. (C) 2002 Wiley-Liss, Inc. C1 Univ Nacl Autonoma Mexico, Dept Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico. RP Velasco, I (reprint author), NINCDS, Mol Biol Lab, NIH, 36 Convent Dr,Bldg 36,Room 3C12, Bethesda, MD 20892 USA. RI Velasco, Ivan/D-3593-2014 OI Velasco, Ivan/0000-0002-8953-6578 NR 29 TC 16 Z9 17 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 1 PY 2002 VL 67 IS 3 BP 406 EP 410 DI 10.1002/jnr.10114 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 517JN UT WOS:000173607500015 PM 11813246 ER PT J AU Baser, ME Makariou, EV Parry, DM AF Baser, ME Makariou, EV Parry, DM TI Predictors of vestibular schwannoma growth in patients with neurofibromatosis Type 2 SO JOURNAL OF NEUROSURGERY LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-for-Human-Genetics CY OCT 03-07, 2000 CL PHILADELPHIA, PA SP Amer Soc Human Genet DE natural history; neurogenetics; neurofibromatosis Type 2; vestibular schwannoma ID GERM-LINE MUTATIONS; ACOUSTIC NEUROMAS; PHENOTYPIC VARIABILITY; GENE; NF2; DISEASE; SEVERITY; TUMORS AB Object. The results of two longitudinal studies of growth rates of vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) differ as to whether VS growth rates decrease or increase with increasing patient age. The authors undertook this study to assess the relationship between VS growth rates and patient age and type of constitutional NF2 mutation they also examined variability in VS growth rates among multiple patients in families with NF2. Methods. Gadolinium-enhanced magnetic resonance images obtained in 18 patients with inherited NF2 from 11 unrelated families were retrospectively analyzed. The patients had been observed for a median of 4 years. Volumes of the VSs were measured using a two-component box model (intrameatal and extrameatal parts measured separately). Single-strand conformation polymorphism analysis and Southern blot analysis were used to identify constitutional NF2 mutations. Growth rates of the VSs were highly variable, but tended to decrease with increasing patient age both at onset of signs or symptoms of NF2 (r(2) = 0.35, p = 0.026) and at diagnosis (r(2) = 0.33, p = 0.012). The VS growth rates did not vary significantly with the type of constitutional NF2 mutation or the number of non-VS cerebral or spinal tumors. The VS growth rates were highly variable within families and did not correspond to clinical indices of NF2 disease severity, such as patient age at symptom onset and the number of non-VS cerebral and spinal tumors. Conclusions. The growth rates of VSs in patients with NF2 are highly variable, but tend to decrease with increasing patient age. Clinical treatment of multiple patients in families with NF2 cannot be based on the expectations of similar VS growth rates, even when other clinical aspects of disease severity are similar. C1 Georgetown Univ, Med Ctr, Dept Radiol, Washington, DC 20007 USA. Natl Canc Inst, Genet Epidemiol Branch, Bethesda, MD USA. RP 2257 Fox Hills Dr, Los Angeles, CA 90064 USA. EM baser@earthlink.net NR 24 TC 50 Z9 52 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 2002 VL 96 IS 2 BP 217 EP 222 DI 10.3171/jns.2002.96.2.0217 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 517BU UT WOS:000173591900003 PM 11838793 ER PT J AU Dalai, SK Pesnicak, L Miller, GF Straus, SE AF Dalai, SK Pesnicak, L Miller, GF Straus, SE TI Prophylactic and therapeutic effects of human immunoglobulin on the pathobiology of HSV-1 infection, latency, and reactivation in mice SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE human immunoglobulin; HSV-1 infection; reactivation; encephalitis ID HERPES-SIMPLEX VIRUS; IN-VIVO REACTIVATION; TRIGEMINAL GANGLIA; VIRAL SPREAD; ANTIBODY; TYPE-1; NEURONS; NUMBER; MODEL; ENCEPHALITIS AB Pooled human immunoglobulin (IgG) was evaluated as prophylaxis and treatment of HSV-1 infection in mice. We compared the effects of IgG on the course of acute infection and spread of virus through the nervous system, as well as on the establishment, maintenance, and reactivation of virus from latency. Balb/c mice received a single 3.75 mg intraperitoneal injection of I-G 24 h before or 24 h, 48 h, or 72 h after ocular infection with 10(6) pfu of HSV-1 strain McKrae. Treatment with IgG protected against death in a time-dependent manner (P < 0.001 for -24 h vs. +48 h and +72 h IgG treatment groups). Viral shedding from the eyes was reduced more in mice treated with IgG at -24 h or +24 h relative to animals treated at +48 h. Viral titers in the eyes were reduced in mice treated with IgG at +24 h, but not at +48 h. In ganglia, virus recovery was reduced (P < 0.05) in mice treated at -24 h, +24 h, or +48 h relative to untreated mice, or ones treated at +72 h. In brains, similar results were observed in mice treated at -24 h, +24 h, or +48 h relative to +72 h. Upon explantation, virus reactivated from all ganglia of all surviving mice regardless of treatment group. DNA quantitation showed that mice pretreated with I-G tended towards lower quantities of latent genome copies compared to +24 h treatment and +48 h treatment. UV irradiation induced reactivation in vivo in 16/40 pretreated mice, 20/29 mice treated at +24 h, and in 8/8 mice treated at +48 h (P = 0.03 and P = 0.004, for comparisons at -24 h vs. +24 h, and -24 h vs. +48 h, respectively). Histopathological studies revealed that mice pretreated and treated with I-G had milder encephalitis and reduced virus spread compared to untreated mice. Pooled human IgG attenuates the spread of, and morbidity from, HSV-1 if given before and within 2 days after ocular infection. C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), NIH, Vet Resources Program, Off Res Serv, 10 Ctr Dr,Rm 11N228, Bethesda, MD 20892 USA. NR 22 TC 19 Z9 19 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 2002 VL 8 IS 1 BP 35 EP 44 DI 10.1080/135502802317247794 PG 10 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 527CV UT WOS:000174169200005 PM 11847590 ER PT J AU Kubota, R Soldan, SS Martin, R Jacobson, S AF Kubota, R Soldan, SS Martin, R Jacobson, S TI Selected cytotoxic T lymphocytes with high specificity for HTLV-1 in cerebrospinal fluid from a HAM/TSP patient SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE human T lymphotropic virus type I (HTLV-I); HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP); cerebrospinal fluid; cytotoxic T lymphocyte; T-cell specificity ID VIRUS TYPE-I; TROPICAL SPASTIC PARAPARESIS; ALTERED PEPTIDE LIGAND; MULTIPLE-SCLEROSIS; NEUROLOGICAL DISEASE; PERIPHERAL-BLOOD; MYELOPATHY; CELLS; PROTEIN; HETEROGENEITY AB Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the spinal cord in which HTLV-I Tax-specific cytotoxic T lymphocytes (CTL) have been suggested to be immunopathogenic. However, it is unknown whether the HTLV-I-specific CTL in the central nervous system differ from those in the periphery. We investigated functional T-cell receptor diversity in HTLV-1 Taxii-19-specific CTL clones derived from peripheral blood and cerebrospinal fluid (CSF) of a HAM/TSP patient using analogue peptides of the viral antigen. CTL responses to the analogue peptides varied between T-cell clones, however, CTL clones from CSF showed limited recognition of the peptides when compared to those from peripheral blood. This suggests that CTL with highly focused specificity for HTLV-I Tax accumulate in the CSF and may contribute to the pathogenesis of HAM/TSP. Furthermore, this study provides a rationale for analogue peptide-based immunotherapeutic strategies focusing on the immunopathogenic T-cells in HTLV-I-associated neurologic disease. C1 NINCDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINCDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 22 Z9 22 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD FEB PY 2002 VL 8 IS 1 BP 53 EP 57 DI 10.1080/135502802317247811 PG 5 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 527CV UT WOS:000174169200007 PM 11847592 ER PT J AU de Sousa, SOM Mesquita, RA Pinto, DS Gutkind, S AF de Sousa, SOM Mesquita, RA Pinto, DS Gutkind, S TI Immunolocalization of c-Fos and c-Jun in human oral mucosa and in oral squamous cell carcinoma SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE AP1; c-Jun; c-Fos; oral squamous cell carcinoma ID EXPRESSION; GENES AB Background: Studies have addressed the relevance of c-Jun and c-Fos proteins in cancer development. In the present study, the expression of c-Jun and c-Fos, the major components of transcription factor activator protein (AP1), were evaluated to determine possible alterations to these factors in oral squamous cell carcinoma (OSCC). Methods: Fifteen cases of normal oral mucosa and 20 cases of OSCC were retrieved from the Archives of the Surgical Pathology Service at the University of Sao Paulo. The samples of normal oral mucosa or OSCC originated from different oral mucosal sites. Tissues were submitted for immunohistochemical analysis to detect c-Jun and c-Fos proteins. The OSCC was classified as well, intermediate or poorly differentiated. Results: The results showed that both c-Jun and c-Fos are expressed in normal oral mucosa and in OSCC. In normal mucosa, immunoreactivity for c-Jun was detected in the cytoplasm of the upper basal layers, while in OSCC, c-Jun was detected in the nuclei of the cells. C-Fos expression was observed in the nuclei of cells, both in normal mucosa and in OSCC, but its expression varied according to the cell layer in normal mucosa, and the differentiation of OSCC. Conclusions: The nuclear expression of c-Jun in OSCC, in contrast to its cytoplasmic expression in normal oral mucosa, indicates that c-Jun may have a role in the development of oral cancer. In contrast, the absence of both c-Jun and c-Fos in poorly differentiated carcinoma might be useful in understanding the cell cycle events important in uncontrolled cell growth. C1 Univ Sao Paulo, Sch Dent, Dept Oral Pathol, BR-05508900 Sao Paulo, Brazil. Univ Fed Minas Gerais, Dept Oral Pathol, Belo Morizonte, MG, Brazil. Natl Inst Dent & Cranio Facial Res, Oral & Pharyngeal Branch, NIH, Bethesda, MD USA. RP de Sousa, SOM (reprint author), Univ Sao Paulo, Fac Odontol, Disciplina Patol Bucal, Av Prof Lineu Prestes 2227, BR-05508900 Sao Paulo, Brazil. RI Gutkind, J. Silvio/A-1053-2009; Sousa, Suzana/H-6154-2012; Pinto, Decio/B-6041-2011; Mesquita, Ricardo Alves de/H-3256-2014 OI Pinto, Decio/0000-0001-6198-5155; Mesquita, Ricardo Alves de/0000-0003-3207-4007 NR 13 TC 23 Z9 23 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD FEB PY 2002 VL 31 IS 2 BP 78 EP 81 PG 4 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 529LV UT WOS:000174301700003 PM 11896827 ER PT J AU Alexander, D AF Alexander, D TI The new NIH loan repayment program for pediatric research and for clinical research SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Editorial Material C1 Natl Inst Hlth, NICHHD, Bethesda, MD 20892 USA. RP Alexander, D (reprint author), Natl Inst Hlth, NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD FEB PY 2002 VL 34 IS 2 BP 116 EP 116 DI 10.1097/00005176-200202000-00004 PG 1 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 520LX UT WOS:000173784300004 ER PT J AU Wang, WC Helms, RW Lynn, HS Redding-Lallinger, R Gee, BE Obene-Frempong, K Smith-Whitley, K Waclawiw, MA Vichinsky, EP Styles, LA Ware, RE Kinney, TR AF Wang, WC Helms, RW Lynn, HS Redding-Lallinger, R Gee, BE Obene-Frempong, K Smith-Whitley, K Waclawiw, MA Vichinsky, EP Styles, LA Ware, RE Kinney, TR TI Effect of hydroxyurea on growth in children with sickle cell anemia: Results of the HUG-KIDS Study SO JOURNAL OF PEDIATRICS LA English DT Article ID RESTING ENERGY-EXPENDITURE; POLYCYTHEMIA-VERA; METABOLIC-RATE; DISEASE; THERAPY; AGE; MUTAGENICITY; RETARDATION; PERFORMANCE; MATURATION AB Objectives: Although hydroxy urea is effective in treating adults with sickle-cell anemia (SCA), there is concern that it may adversely affect growth in children. We report the growth characteristics of patients in the Phase I-II Pediatric hydroxy-urea trial (HUG-KIDS) before and during treatment at the maximum tolerated dose for one year. Study design: Children and adolescents with SCA (n = 68), aged 5 to 16 years at baseline, reached the maximum tolerated dose and had serial height, weght, and Tanner stage measurements. Data from the Cooperative Study of Sickle Cell Disease (CSSCD) were used for comparison. Mixed-effects models were used to compare serial measurements as a function of age and group. Results: In girls, there were no significant differences in height or weight among the pretreatment, on-treatment, and CSSCD groups. Compared with the CSSCD group, HUG-KIDS boys were heavier starting at age 9 years, and pretreatment HUG-KIDS boys were taller starting at age 7 years. The Tanner stage transitions took place at appropriate ages. Conclusions: Hydroxyurea treatment had no adverse effect on height or weight gain or pubertal development in school-aged children with SCA. C1 St Jude Childrens Res Hosp, Div Hematol, Memphis, TN 38105 USA. Rho Fed Syst Div Inc, Chapel Hill, NC USA. Univ N Carolina, Med Ctr, Chapel Hill, NC 27515 USA. Duke Univ, Med Ctr, Durham, NC USA. Morehouse Med Ctr, Atlanta, GA USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NHLBI, Bethesda, MD 20892 USA. Childrens Hosp, Oakland, CA 94609 USA. RP Wang, WC (reprint author), St Jude Childrens Res Hosp, Div Hematol, 332 N Lauderdale, Memphis, TN 38105 USA. NR 48 TC 47 Z9 52 U1 1 U2 5 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 2002 VL 140 IS 2 BP 225 EP 229 DI 10.1067/mpd.2002.121383 PG 5 WC Pediatrics SC Pediatrics GA 527PK UT WOS:000174194500015 PM 11865275 ER PT J AU Sun, MK Xu, H Alkon, DL AF Sun, MK Xu, H Alkon, DL TI Pharmacological protection of synaptic function, spatial learning, and memory from transient hypoxia in rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ROSTRAL VENTROLATERAL MEDULLA; ALZHEIMERS-DISEASE; NMDA RECEPTORS; IN-VITRO; NEURONS; IMPAIRMENT; CA1; DAMAGE; CELLS; HIPPOCAMPUS AB Hypoxia significantly reduced cholinergic theta activity in rat CA1 field and intracellular theta in the CA1 pyramidal cells, recorded in hippocampal slices. The hypoxic responses of the hippocampal CA1 pyramidal cells to a brief hypoxia consisted of a short period of "synaptic arrest", observed as an elimination of excitatory postsynaptic current under voltage clamp and recovered immediately as oxygenation was reinitiated. The hypoxic synaptic arrest was not associated with reduced postsynaptic responses of the pyramidal cells to externally applied L-glutamate, suggesting that the synaptic arrest might result from a presynaptic mechanism. The hypoxic synaptic arrest was abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific adenosine A(1) receptor antagonist. Blocking adenosine A(1) receptors also eliminated effects of hypoxia on the hippocampal CA1 field theta activity and intracellular theta of the CA1 pyramidal cells. In behaving rats, brief hypoxia impaired their water maze performance in both the escape latency and probe tests. The impairment was prevented by intralateral cerebroventricular injections of DPCPX. These results suggest that hypoxia releases adenosine and produces an inhibition of synaptic transmission and intracellular signal cascade(s) involved in generation/maintenance of hippocampal CA1 theta activity. This protection of synaptic efficacy and spatial learning through adenosine A(1) receptor antagonism may represent an effective therapeutic strategy to eliminate functional interruption due to transient hypoxic, episodes and/or chronic hypoxia secondary to compromise of respiratory function. C1 Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. NINCDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. RP Sun, MK (reprint author), Blanchette Rockefeller Neurosci Inst, Johns Hopkins Acad & Res Bldg,Room 319,9601 Med C, Rockville, MD 20850 USA. NR 41 TC 39 Z9 42 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2002 VL 300 IS 2 BP 408 EP 416 DI 10.1124/jpet.300.2.408 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 515WD UT WOS:000173518900008 PM 11805198 ER PT J AU Brown, SG Townsend-Nicholson, A Jacobson, KA Burnstock, G King, BF AF Brown, SG Townsend-Nicholson, A Jacobson, KA Burnstock, G King, BF TI Heteromultimeric P2X(1/2) receptors show a novel sensitivity to extracellular pH SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GATED ION CHANNELS; SENSORY NEURONS; P2X(2) RECEPTOR; FOLLICULAR OOCYTES; STRUCTURAL MOTIF; XENOPUS-LAEVIS; ATP-RESPONSES; P-2X RECEPTOR; RAT P2X(2); PURINOCEPTOR AB Rat P2X(1) and P2X(2) subunits were coexpressed in defolliculated Xenopus oocytes and the resultant P2X receptors studied under voltage-clamp conditions. Extracellular ATP elicited biphasic inward currents, involving an initial rapidly inactivating (P2X(1)-like) component and a later slowly inactivating (P2X(2)-like) component. The maximum amplitude of P2X(1)-like ATP responses was increased in some cells by lowering extracellular pH (from 7.5 to 6.5), whereas P2X(2)-like responses and those of homomeric rP2X(1) and rP2X(2) receptors were not changed by this treatment. Concentration-response (C/R) curves for ATP for pH-enhanced P2X(1)-like responses were biphasic, and clearly distinct from monophasic ATP C/R curves for homomeric rP2X(1) and rP2X(2) receptors. Under acidic (pH 5.5 and 6.5) and alkaline (pH 8.5) conditions, ATP C/R curves for P2X(1)-like responses showed increases in agonist potency and efficacy, compared with data at pH 7.5, but the same was not true of homomeric rP2X(1) and rP2X(2) receptors. ATP C/R curves for P2X(2)-like responses overlay C/R curves for homomeric rP2X(2) receptors, and determinations of agonist potency and efficacy were identical for P2X(2)-like and P2X(2) responses at all pH levels tested. Our results show that P2X(1)-like responses possessed the kinetics of homomeric P2X(1) receptors but an acid sensitivity different from homomeric P2X(1) and P2X(2) receptors. In contrast, the P2X(2)-like responses exactly matched the profile expected of homomeric P2X(2) receptors. Thus, coexpression of P2X(1) and P2X(2) subunits yielded a mixed population of homomeric and heteromeric P2X receptors, with a subpopulation of novel pH-sensitive P2X receptors showing identifiably unique properties that indicated the formation of heteromeric P2X(1/2) ion channels. C1 Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, Hampstead, England. UCL, Dept Biochem & Mol Biol, London, England. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP King, BF (reprint author), Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, Royal Free Campus,Rowland Hill St, London NW3 2PF, England. EM b.king@ucl.ac.uk RI Townsend-Nicholson, Andrea/B-8506-2009; Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031127-01] NR 40 TC 56 Z9 58 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2002 VL 300 IS 2 BP 673 EP 680 DI 10.1124/jpet.300.2.673 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 515WD UT WOS:000173518900042 PM 11805232 ER PT J AU Ritchie, JWA Hayashi, Y Shi, YB Taylor, PM AF Ritchie, JWA Hayashi, Y Shi, YB Taylor, PM TI A role for amino acid transporters in cellular TH action SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Univ Dundee, Sch Life Sci, Dundee DD 5EH, Scotland. Nagoya Univ, Environm Med Res Inst, Nagoya, Aichi 4648601, Japan. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RI Taylor, Peter/A-4667-2010; Ritchie, James/B-9377-2013 NR 2 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB PY 2002 VL 539 SU S BP 11P EP 12P PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 534YW UT WOS:000174618200016 ER PT J AU Zhang, J Yancey, MK Henderson, CE AF Zhang, J Yancey, MK Henderson, CE TI US national trends in Labor induction, 1989-1998 SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article DE labor, induced; birth certificates; labor ID ELECTIVE INDUCTION; CESAREAN DELIVERY; CERTIFICATE; HOSPITALS; BIRTH; WOMEN; RISK; TERM AB OBJECTIVE: To examine the epidemiology of labor induction in the United States. STUDY DESIGN: We used U.S. natality data from 1989 to 1998 and examined the I-ate of labor induction by year, geographic region, maternal characteristics and pregnancy complications. RESULTS: Between 1990 and 1998, the rate of labor induction increased from 9.5% to 19.4% of all births nationwide. However, the induction rate varied widely by state. White race, higher education and early initiation of prenatal care were associated with a higher rate of induction. For all gestational ages, a significantly increased induction rate occurred during the study period. The increase for clinically indicated induction was significantly slower than the overall increase, suggesting that elective induction has risen much more rapidly. CONCLUSION: The rate of induction of labor more than doubled in the U.S. nationwide in the decade from 1989 to 1998. The increased use of labor induction may be attributable to both clinically indicated and elective induction. C1 NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Tripler Army Med Ctr, Dept Obstet, Honolulu, HI 96859 USA. Tripler Army Med Ctr, Dept Gynecol, Honolulu, HI 96859 USA. Albert Einstein Coll Med, Dept Obstet & Gynecol, Bronx, NY 10467 USA. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 15 TC 69 Z9 71 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD FEB PY 2002 VL 47 IS 2 BP 120 EP 124 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 525EM UT WOS:000174055800005 PM 11883350 ER PT J AU Chung, IJ Hill, KG Hawkins, JD Gilchrist, LD Nagin, DS AF Chung, IJ Hill, KG Hawkins, JD Gilchrist, LD Nagin, DS TI Childhood predictors of offense trajectories SO JOURNAL OF RESEARCH IN CRIME AND DELINQUENCY LA English DT Article ID PHYSICAL AGGRESSION; LIFE-COURSE; DEVELOPMENTAL TRAJECTORIES; ANTISOCIAL-BEHAVIOR; CRIMINAL CAREERS; DELINQUENCY; DESISTANCE; BOYS; AGE; HYPERACTIVITY AB Previous research has shown heterogeneity in offense trajectories. Using data from the Seattle Social Development Project, a longitudinal study of 808 youths followed since 1985, this study seeks to identify childhood predictors of different offense trajectories. Five offense trajectories were identified using semiparametric, group-based modeling: nonoffenders, late onsetters, desisters, escalators, and chronic offenders. Multinomial logistic regressions were then employed to examine childhood predictors measured at ages 10 to 12 that distinguish these five groups. Results indicated that among initial nonoffenders at age 13, late onsetters were distinguished from nonoffenders by individual factors. Among youth already delinquent at age 13, escalators were distinguished from desisters by peer school, and neighborhood factors. C1 Univ Washington, Social Dev Res Grp, Seattle, WA 98115 USA. Univ Washington, Sch Social Work, Seattle, WA 98115 USA. Seattle Social Dev Project, Seattle, WA USA. Natl Inst Drug Abuse, NIDA, Seattle, WA USA. NIH, Prevent Res Ctr, Bethesda, MD USA. Carnegie Mellon Univ, H John Heinz III Sch Publ Policy & Management, Pittsburgh, PA 15213 USA. RP Chung, IJ (reprint author), Univ Washington, Social Dev Res Grp, 9725 3rd Ave NE,Suite 401, Seattle, WA 98115 USA. EM ichung@u.washington.edu RI Hill, Karl/C-3688-2015; OI Hill, Karl/0000-0001-8342-1561; Chung, Ick Joong/0000-0002-3426-7956 NR 62 TC 90 Z9 93 U1 2 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-4278 EI 1552-731X J9 J RES CRIME DELINQ JI J. Res. Crime Delinq. PD FEB PY 2002 VL 39 IS 1 BP 60 EP 90 PG 31 WC Criminology & Penology SC Criminology & Penology GA 511HN UT WOS:000173258700003 ER PT J AU Kurahara, D Tokuda, A Grandinetti, A Najita, J Ho, C Yamamoto, K Reddy, DV Macpherson, K Iwamuro, M Yamaga, K AF Kurahara, D Tokuda, A Grandinetti, A Najita, J Ho, C Yamamoto, K Reddy, DV Macpherson, K Iwamuro, M Yamaga, K TI Ethnic differences in risk for pediatric rheumatic illness in a culturally diverse population SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE pediatric rheumatology; epidemiology; ethnic groups; juvenile rheumatoid arthritis; systemic lupus erythematosus; acute rheumatic fever ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EPIDEMIOLOGY; ARTHRITIS; HAWAII; FEVER; CLASSIFICATION; PREVALENCE; CRITERIA; CHILDREN; DISEASES AB Objective. To analyze the differences of occurrence of pediatric rheumatic disease among various ethnic groups in a culturally diverse isolated geographic area. Methods. A retrospective study of pediatric rheumatic diseases in a multiethnic area during a 6 year period. Results. A group of 922 patients was categorized based on predominant ethnicity, and their risk of having acute rheumatic fever (ARF), juvenile rheumatoid arthritis (JRA), and systemic lupus erythematosus (SLE) was studied. Odds ratios (OR) were computed for each illness with Caucasians as the reference group. Results indicated that Polynesians were overrepresented among patients with ARF, having elevated OR that were significantly different from Caucasians (22.5-120.7, p < 0.0001). For SLE, the a highest OR were obtained for Samoans, Filipinos, and Japanese. In contrast, for JRA, Filipinos and Japanese had OR less than one, and no Samoans were diagnosed with JRA, possibly indicating a protective effect against developing JRA. Conclusion. This unique retrospective study examined the ethnic variations of expression of certain rheumatic diseases in an isolated region. Results reveal that certain ethnic groups are at risk for ARF and SLE, but are protected against JRA. These findings suggest investigating possible immunogenetic similarities and differences in these illnesses. C1 Univ Hawaii, John A Burns Sch Med, Dept Trop Med & Med Microbiol, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. Univ Hawaii, Clin Res Ctr, NIH, Honolulu, HI 96822 USA. Kapiolani Med Ctr Women & Children, John A Burns Sch Med, Honolulu, HI USA. RP Kurahara, D (reprint author), 734-1319 Punahou St, Honolulu, HI 96826 USA. FU NCRR NIH HHS [P20 RR11091] NR 23 TC 26 Z9 26 U1 1 U2 1 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 2002 VL 29 IS 2 BP 379 EP 383 PG 5 WC Rheumatology SC Rheumatology GA 517PC UT WOS:000173618300030 PM 11838859 ER PT J AU Johnson, CC Li, DL Perry, CL Elder, JP Feldman, HA Kelder, SH Stone, EJ AF Johnson, CC Li, DL Perry, CL Elder, JP Feldman, HA Kelder, SH Stone, EJ TI Fifth through eighth grade longitudinal predictors of tobacco use among a racially diverse cohort: CATCH SO JOURNAL OF SCHOOL HEALTH LA English DT Article ID PHYSICAL-ACTIVITY; CIGARETTE-SMOKING; CARDIOVASCULAR HEALTH; ADOLESCENT TRIAL; BEHAVIOR; PROMOTION; OUTCOMES; STUDENTS; WEIGHT; CHILD AB CATCH provides multiethnic cohort data from third to eighth grades from four US geographic, regions. This study examined smoking behaviors and predictors from fifth and eighth grades by ethnicity, gender, and geographic location through self-report data obtained from the cohort (N = 3,654). Overall, eighth grade prevalence for ever smoked was about 44%, 30-day prevalence was about 20%, 7-day prevalence 13.3%, and daily prevalence 7.4%. Prevalence was similar for Caucasians (21.5%) nd Latinos (21.6%) and lowest for African Americans (13.1%). The 30-day prevalence for smokeless tobacco was higher for boys than for girls (9.8% vs 5.1%). Tobacco use by parents, siblings, and friends, and easy accessibility in the home in fifth grade, were significant predictors for smoking in eighth grade. Results did not differ by race, gender, or geographic location. The strongest correlate of smoking in eighth grade was having a best friend who smoked. Intention not to smoke in fifth grade predicted nonsmoking in eighth grade. Predictor strength across ethnic groups in different geographic regions was impressive. The social environment of young people continues to be an important instigator of smoking onset. The connection between intention and behavior over time suggests students' intentions not to smoke reflect decision - making at an early age. C1 Tulane Univ, Sch Publ Hlth & Trop Med, Dept Community Hlth Sci, New Orleans, LA 70112 USA. New England Res Inst, Watertown, MA 02472 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55454 USA. San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92123 USA. Childrens Hosp, Clin Res Program, Boston, MA 02460 USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Ctr Hlth Promot Res & Dev, Houston, TX 77225 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Johnson, CC (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Community Hlth Sci, 1440 Canal St,Room 2309, New Orleans, LA 70112 USA. FU NHLBI NIH HHS [HL-39852, HL-39880, HL-39927, HL-39906, HL-39870] NR 32 TC 37 Z9 40 U1 0 U2 4 PU AMER SCHOOL HEALTH ASSOC PI KENT PA PO BOX 708, KENT, OH 44240 USA SN 0022-4391 J9 J SCHOOL HEALTH JI J. Sch. Health PD FEB PY 2002 VL 72 IS 2 BP 58 EP 64 PG 7 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services; Public, Environmental & Occupational Health SC Education & Educational Research; Health Care Sciences & Services; Public, Environmental & Occupational Health GA 529BR UT WOS:000174280600003 PM 11905130 ER PT J AU Miller, JL Watkin, KL Chen, MF AF Miller, JL Watkin, KL Chen, MF TI Muscle, adipose, and connective tissue variations in intrinsic musculature of the adult human tongue SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE tongue; histology; connective tissue; collagen; elastin ID EMPIRICAL ULTRASONIC PROPERTIES; SKELETAL-MUSCLE; MAMMALIAN-TISSUES; ORAL CAVITY; MORPHOLOGY; BIOMECHANICS; COMPILATION; TENTACLES; MOVEMENT; ANATOMY AB The purpose of this investigation was to identify the composition and organization of lingual tissues underlying the histostructural and biomechanical Functions of the adult human tongue. The small-scale structures of three intrinsic muscle regions, their principal cells, structural complexities, and differences in underlying tissue composition were compared to other skeletal muscle systems and the results discussed in relation to lingual morphology. Analysis of pixel color distributions determined the percent area concentration of each stained tissue component. Results indicated that muscle content increased from anterior to posterior (p < .0001). Greater adipose (p = .005) and connective tissue (p < .002) concentrations occurred in anterior regions. Dense Collagen sheaths and elastic fibers found anteriorly occurred with less magnitude in medial and posterior sites. The unique elastin, Collagen, and adipose connective tissue distributions found in intrinsic sampling sites are discussed in terms of understanding lingual biomechanics in both normal and pathologic states. C1 McGill Univ, Dept Pathol, Montreal, PQ, Canada. Univ Illinois, Urbana, IL 61801 USA. RP Miller, JL (reprint author), NIH, Warren G Magnuson Clin Ctr, 6S235,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 70 TC 27 Z9 29 U1 0 U2 5 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD FEB PY 2002 VL 45 IS 1 BP 51 EP 65 DI 10.1044/1092-4388(2002/004) PG 15 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 520YZ UT WOS:000173812500004 PM 14748638 ER PT J AU Shyamala, G Chou, YC Louie, SG Guzman, RC Smith, GH Nandi, S AF Shyamala, G Chou, YC Louie, SG Guzman, RC Smith, GH Nandi, S TI Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE estrogen receptors; progesterone receptors; mammary glands ID EPIDERMAL GROWTH-FACTOR; TRUNCATED INT3 GENE; HUMAN-BREAST; PRECANCEROUS BREAST; MOUSE; MORPHOGENESIS; EPITHELIUM; DIFFERENTIATION; TURNOVER; CANCER AB At present, there is an extensive body of literature documenting the participation of estrogen receptors (ER) and progesterone receptors (PR) in mammary gene expression. Yet, the precise roles of these receptors in regulating mammary development, carcinogenesis and the growth of a subset of tumors still remain unclear. Mammary glands are composed of various cell types with different developmental potentials. Further, ultimately, that it is their mutual interactions which dictate the behavior of mammary epithelial cells. Therefore, to resolve the roles of ER and PR in normal mammary growth, differentiation and carcinogenesis, analyses for the expression of these receptors at the level of individual cell types is of paramount importance. Accordingly, in the present studies using immunolocalization techniques, we document the ontogeny and cellular distribution of ER and PR during mammary development and in response to ovarian hormones and aging. In addition, we discuss the potential biological significances of the expression patterns of ER and PR during various physiological states. We believe that the observations reported here should provide a conceptual framework(s) for elucidating the roles of ER and PR in normal and neoplastic mammary tissues. (C) 2002 Published by Elsevier Science Ltd. C1 Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Cell & Mol Biol, Berkeley, CA 94720 USA. BRL, Mammary Biol Program, Natl Canc Inst, Bethesda, MD 20892 USA. RP Shyamala, G (reprint author), Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. FU NCI NIH HHS [CA 66541, CA 72598] NR 60 TC 72 Z9 74 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD FEB PY 2002 VL 80 IS 2 SI SI BP 137 EP 148 AR PII S0960-0760(01)00182-0 DI 10.1016/S0960-0760(01)00182-0 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 539AN UT WOS:000174847400002 PM 11897499 ER PT J AU Shinohara, H Morita, S Kawai, M Miyamoto, A Sonoda, T Pastan, I Tanigawa, N AF Shinohara, H Morita, S Kawai, M Miyamoto, A Sonoda, T Pastan, I Tanigawa, N TI Expression of HER2 in human gastric cancer cells directly correlates with antitumor activity of a recombinant disulfide-stabilized anti-HER2 immunotoxin SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE human epidermal growth factor receptor 2(HER2); immunotoxin; gastric cancer; liver metastasis; peritoneal dissemination ID HER2/NEU-OVEREXPRESSING METASTATIC BREAST; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODY; PHASE-II; AMPLIFICATION; CARCINOMA; STOMACH; PROTEIN; MICE; GENE AB Background. Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein have been associated with an unfavorable prognosis. We determined the efficacy of an anti-HER2 immunotoxin, erb-38 [e23(dsFv)PE38], against human gastric cancer cells. Methods. Immunotoxin was made by fusing the disulfide-stabilized Fv fragments (dsFv) of a monoclonal antibody e23 to a truncated mutant Of M-r 38 Pseudomonas exotoxin (PE38) that lacks its cell-binding domain. Results. The immunotoxin-mediated cytotoxicity directly correlated with the expression levels of the HER2 gene and protein in human gastric cancer cells. Interestingly, MKN-45P cells, a variant line of MKN-45 producing peritoneal dissemination and ascites in vivo, expressed a higher level of HER2 and were more sensitive to erb-38 than MKN-45 cells. RFB-4, a control anti-CD22 immunotoxin, was cytotoxic against none of the tested human gastric cancer cells, also suggesting that the lysis mediated by erb-38 was specific for HER2 expression. Three consecutive iv injections of erb-38 at doses of 0.5 or 5 mug/body eradicated experimental liver metastases and peritoneal disseminations produced by MKN-45P in a dose-dependent manner. Conclusions. We conclude that an erb-38 anti-HER2 immunotoxin has specific antitumor activities against human gastric cancer cells overexpressing HER2. (C) 2001 Elsevier Science. C1 Osaka Med Coll, Dept Gen & Gastroenterol Surg, Takatsuki, Osaka 5698686, Japan. NIH, Natl Canc Inst, Mol Biol Lab, Bethesda, MD 20892 USA. RP Shinohara, H (reprint author), Osaka Med Coll, Dept Gen & Gastroenterol Surg, 2-7 Daigaku Machi, Takatsuki, Osaka 5698686, Japan. NR 31 TC 24 Z9 25 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD FEB PY 2002 VL 102 IS 2 BP 169 EP 177 DI 10.1006/jsre.2001.6305 PG 9 WC Surgery SC Surgery GA 517LN UT WOS:000173612200017 PM 11796015 ER PT J AU Gerring, JP Slomine, B Vasa, RA Grados, M Chen, A Rising, W Christensen, JR Denckla, MB Ernst, M AF Gerring, JP Slomine, B Vasa, RA Grados, M Chen, A Rising, W Christensen, JR Denckla, MB Ernst, M TI Clinical predictors of posttraumatic stress disorder after closed head injury in children SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE posttraumatic stress disorder; posttraumatic stress symptoms; closed head injury ID TRAUMATIC BRAIN INJURY; AMNESIA TEST; SYMPTOMATOLOGY; ADOLESCENTS; ORIENTATION; ACCIDENTS; SEQUELAE; SCALE; RISK AB Objective: To describe injury, demographic, and neuropsychiatric characteristics of children who develop posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS) after closed head injury (CHI). Method: Ninety-five children with severe CHI and amnesia for the event were prospectively followed for 1 year. Structured interviews were administered twice to the parents: shortly after injury to cover the child's premorbid status, and 1 year after injury. The child was also interviewed twice: shortly after injury to cover current status, and 1 year after injury. Outcome measures were diagnostic status (PTSD by parent or child) and symptom severity (PTSS by parent or child). Results: Twelve children developed PTSD by 1 year after injury, 5 according to parent report, 5 according to child report, and 2 according to both parent and child report. Predictors of PTSD at 1 year post-CHI included female gender and early post-CHI anxiety symptoms. Predictors of PTSS at 1 year post-CHI were (1) premorbid psychosocial adversity, premorbid anxiety symptoms, and injury severity; and (2) early post-CHI depression symptoms and nonanxiety psychiatric diagnoses. Conclusions: PTSD developed in 13% of children with severe CHI accompanied by traumatic amnesia. Predictors of PTSD and PTSS after CHI, according to parent and child report, are consistent with predictors of PTSD and PTSS that develop after non-head injury trauma. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Duke Univ, Clin Res Inst, Durham, NC USA. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Gerring, JP (reprint author), Kennedy Krieger Inst, 707 N Broadway, Baltimore, MD 21205 USA. FU NCRR NIH HHS [MO-RR00052]; NIMH NIH HHS [K20 MH-00997] NR 35 TC 35 Z9 35 U1 2 U2 3 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 2002 VL 41 IS 2 BP 157 EP 165 DI 10.1097/00004583-200202000-00009 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 514PZ UT WOS:000173451400009 PM 11837405 ER PT J AU Thompson, FE Subar, AF Brown, CC Smith, AF Sharbaugh, CO Jobe, JB Mittl, B Gibson, JT Ziegler, RG AF Thompson, FE Subar, AF Brown, CC Smith, AF Sharbaugh, CO Jobe, JB Mittl, B Gibson, JT Ziegler, RG TI Cognitive research enhances accuracy of food frequency questionnaire reports: Results of an experimental validation study SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CONSUMPTION AB Objective To test whether changing a food frequency questionnaire (FFQ) on the basis of cognitive theory and testing results in greater accuracy. Accuracy was examined for 4 design issues: a) Grouping: asking about foods in a single vs multiple separate questions; b) different forms of a food: asking consumption frequency of each form of a food (eg, skim, 2%, whole milk) vs a nesting approach-asking frequency of the main food (eg, milk) and proportion of times each form was consumed; c) additions (eg, sugar to coffee): asking independent of the main food vs nested under the main foods; d) units: asking frequency and portion size vs frequency of units (eg, cups of coffee). Design Participants in two randomly assigned groups completed 30 consecutive daily food reports (DFRs), followed by 1 of 2 FFQs that asked about foods consumed in the past month. One was a new, cognitively-based National Cancer Institute (NCI) Diet History Questionnaire; the other was the 1992 NCI-Block Health Habits and History Questionnaire. Subjects/setting 623 participants, age range 25 to 70 years, from metropolitan Washington, DC. Statistical analyses performed Accuracy was assessed by comparing DFR and FFQ responses using categorical (percent agreement) and continuous (rank order correlation, discrepancy scores) agreement statistics. Results Grouping: accuracy was greater using separate questions. Different forms of food: accuracy was greater using nesting. Additions: neither approach was consistently superior; accuracy of the addition report was affected by accuracy of the main food report. Units: both approaches were similarly accurate. Conclusions Accuracy of FFQ reporting can be improved by restructuring questions based on cognitive theory and testing. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, BMCCE Sect, Biometry Branch, Bethesda, MD 20892 USA. Cleveland State Univ, Dept Psychol, Cleveland, OH 44115 USA. Westat Corp, Rockville, MD USA. NIA, Adult Psychol Dev Branch, Bethesda, MD 20892 USA. NIA, Social Res Program, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Thompson, FE (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, EPN 4016,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. NR 14 TC 129 Z9 129 U1 3 U2 11 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD FEB PY 2002 VL 102 IS 2 BP 212 EP + DI 10.1016/S0002-8223(02)90050-7 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 518JN UT WOS:000173664600015 PM 11846115 ER PT J AU Story, M Snyder, P Anliker, J Cunningham-Sabo, L Weber, JL Ring, K Platero, H Stone, EJ AF Story, M Snyder, P Anliker, J Cunningham-Sabo, L Weber, JL Ring, K Platero, H Stone, EJ TI Nutrient content of school meals in elementary schools on American Indian reservations SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID CHILDREN; OBESITY; PROGRAM; CATCH C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55454 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ New Mexico, Dept Pediat, Ctr Hlth Promot & Dis Prevent, Hlth Sci Ctr, Albuquerque, NM 87131 USA. Univ Arkansas Med Sci, Dept Pediat, Ctr Appl Res & Evaluat, Little Rock, AR 72205 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Story, M (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. FU NHLBI NIH HHS [U02-HL-50867, U01-HL-50885, U01-HL-50905, U01-HL-50907, U01-HL-50869] NR 26 TC 4 Z9 4 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD FEB PY 2002 VL 102 IS 2 BP 253 EP 256 DI 10.1016/S0002-8223(02)90060-X PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 518JN UT WOS:000173664600024 PM 11846122 ER PT J AU Wu, AW Young, Y Dawson, NV Brant, L Galanos, AN Broste, S Landefeld, SC Harrell, FE Lynn, J AF Wu, AW Young, Y Dawson, NV Brant, L Galanos, AN Broste, S Landefeld, SC Harrell, FE Lynn, J TI Estimates of future physical functioning by seriously ill hospitalized patients, their families, and their physicians SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE prognosis; functional status; survey; physician ID SUPPORT PROGNOSTIC MODEL; SURVIVAL; ADULTS; PREDICTIONS AB OBJECTIVES: To compare prognostic estimates made by seriously ill hospitalized patients, their surrogates, and their physicians about the patients' activities of daily living (ADLs) 2 months after admission; compare the accuracy of their estimates; and identify factors associated with the optimism and accuracy of these estimates. DESIGN: Prospective cohort study. SETTING: Five teaching hospitals. PARTICIPANTS: A subset (n = 716) of patients in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. MEASUREMENTS: Prognostic estimates of ADL function. RESULTS: Physicians were less likely than patients or surrogates to give very high or very low estimates for future functioning. Seven of ten (69.3%) patients who survived 2 months estimated that they, would be functionally independent at Month 2, compared with 58.5% of their surrogates and 49.2% of their physicians. Agreement on prognosis was highest between patients and surrogates (64.2%) and lowest between patients and physicians (48.4%). Factors significantly associated with an optimistic estimate of independent functioning were better baseline ADL function, male gender, and higher level of education. Patients were significantly more accurate than surrogates and even more so than physicians in predicting independent functioning at Month 2. Worse baseline function and higher income were significantly associated with accurate estimation. CONCLUSION: At hospital admission, seriously ill patients were more optimistic about their prognosis for physical functioning at 2 months, and more accurate in their estimates, than surrogates and physicians. Physicians tended to underestimate the prognosis for future functioning. Physicians should consider patients' and families' estimates before giving advice about treatment options and discharge planning. C1 Johns Hopkins Univ, HSRDC, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Metrohlth Med Ctr, MetroHlth Syst, Cleveland, OH USA. NIA, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Durham, NC USA. Medtronic Inc, Minneapolis, MN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. RAND Corp, Ctr Improve Care Dying, Arlington, VA USA. RP Wu, AW (reprint author), Johns Hopkins Univ, HSRDC, Bloomberg Sch Publ Hlth, 624 N Broadway, Baltimore, MD 21205 USA. NR 27 TC 3 Z9 3 U1 1 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2002 VL 50 IS 2 BP 230 EP 237 DI 10.1046/j.1532-5415.2002.50053.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 520EL UT WOS:000173767600003 PM 12028203 ER PT J AU McDermott, MM Ferrucci, L Simonsick, EM Balfour, J Fried, L Ling, S Gibson, D Guralnik, JM AF McDermott, MM Ferrucci, L Simonsick, EM Balfour, J Fried, L Ling, S Gibson, D Guralnik, JM TI The ankle brachial index and change in lower extremity functioning over time: The women's health and aging study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE ankle brachial index; peripheral arterial disease; functional impairment ID PERIPHERAL ARTERIAL-DISEASE; DISABLED OLDER WOMEN; INTERMITTENT CLAUDICATION; CARDIOVASCULAR HEALTH; SUBSEQUENT DISABILITY; PHYSICAL-DISABILITY; ELDERLY WOMEN; LEG SYMPTOMS; ADULTS; PROGRESSION AB OBJECTIVES: To define the association between baseline ankle brachial index (ABI) level and subsequent onset of severe disability. DESIGN: Prospective cohort study. SETTING: Baltimore community. PARTICIPANTS: Eight hundred forty-seven disabled women aged 65 and older participating in the Women's Health and Aging Study. MEASUREMENTS: At baseline, participants underwent measurement of ABI and lower extremity functioning. Measures of lower extremity functioning included patient's report of their ability to walk one-quarter of a mile, number of city blocks walked last week, number of stair flights climbed last week, and performance-based measures including walking speed over 4 meters, five repeated chair stands, and a summary performance score. Functioning was remeasured every 6 months for 3 years. Definitions of severe disability were developed a priori; and participants who met these definitions at baseline were excluded from subsequent analyses. RESULTS: Participants with an ABI of less than 0.60 at baseline had significantly higher cumulative probabilities of developing severe disability than participants with a baseline ABI of 0.90 to 1.50 for walking-specific outcomes (ability to walk a quarter of a mile, number of city blocks walked last week, and walking velocity) but not for the remaining functional outcomes. In age-adjusted Cox proportional hazards analyses, hazard ratios for participants with a baseline ABI of less than 0.60 were 1.63 for becoming unable to walk a quarter of a mile (P =.044), 2.00 for developing severe disability in the number of blocks walked last week (P =.004), and 1.61 for developing severe disability in walking speed (P =.041), compared with participants with a baseline ABI of 0.90 to 1.50. Adjusting for age, race, baseline performance, and comorbidities, an ABI of less than 0.60 remained associated with becoming severely disabled in the number of blocks walked last week (hazard ratio = 1.97, P =.009) and nearly significantly associated with becoming unable to walk a quarter of a mile (hazard ratio = 1.54, P =.09). In fully adjusted random effects models, a baseline ABI of less than 0.60 was associated with significantly greater decline in walking speed per year (P =.019) and nearly significantly greater decline in number of blocks walked last week per year (P =.053) compared with a baseline ABI of 0.90. to 1.50. CONCLUSION: In community-dwelling disabled older women, a low ABI is associated with a greater incidence of severe disability in walking-specific but not other lower extremity functional outcomes, compared with persons with a normal ABI over 3 years. C1 Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. I Fraticini Natl Res Inst, INRCA, Dept Geriatr, Florence, Italy. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP McDermott, MM (reprint author), Northwestern Univ, Sch Med, Dept Med, 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. NR 36 TC 34 Z9 38 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2002 VL 50 IS 2 BP 238 EP 246 DI 10.1046/j.1532-5415.2002.50054.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 520EL UT WOS:000173767600004 PM 12028204 ER PT J AU McDermott, MM Greenland, P Ferrucci, L Criqui, MH Liu, K Sharma, L Chan, C Celic, L Priyanath, A Guralnik, JM AF McDermott, MM Greenland, P Ferrucci, L Criqui, MH Liu, K Sharma, L Chan, C Celic, L Priyanath, A Guralnik, JM TI Lower extremity performance is associated with daily life physical activity in individuals with and without peripheral arterial disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the Gerontological-Society-of-America CY NOV 18, 2000 CL WASHINGTON, D.C. SP Gerontol Soc Amer DE peripheral vascular disease; peripheral arterial disease; physical activity; disability; intermittent claudication ID OLDER ADULTS; RANDOMIZED TRIAL; CARDIOVASCULAR HEALTH; SUBSEQUENT DISABILITY; PREVENTING DISABILITY; CALTRAC ACCELEROMETER; WOMENS HEALTH; PRIMARY-CARE; QUESTIONNAIRES; PREDICTOR AB OBJECTIVES: To determine whether persons with poorer lower extremity functioning have reduced physical activity levels. DESIGN: Cross-sectional. SETTING: Three Chicago-area medical centers. PARTICIPANTS: Two hundred twenty-five people with lower extremity peripheral arterial disease (PAD) and 121 individuals without PAD. MEASUREMENTS: The summary performance score (SPS) was determined for all participants. The SPS combines data on walking velocity, time for five repeated chair rises, and standing balance. Each test is scored on a 0 to 4 scale (4 = best). Scores are summed to create the SPS (0-12 scale, 12 = best). All participants wore a vertical accelerometer for 7 days to measure physical activity. RESULTS: The SPS was associated linearly with 7-day physical activity levels of participants with (P <.0001) and without PAD (P <.0001). This relationship was maintained even after restricting analyses to subsets of participants who reported that they could walk a quarter of a mile and up and down stairs without difficulty (P <.001) and were able to walk for 6-minutes without stopping (P <.001). In multiple linear regression analyses, the SPS was associated with physical activity in participants with (P <.01) and without PAD (P <.001), adjusting for age, sex, race; comorbidities, ankle brachial index, neuropathy, and leg-symptoms. CONCLUSION: In people with and without PAD who have impaired lower extremity performance, reduced physical activity levels may contribute to subsequent disability. Future study is needed to determine whether interventions to increase physical activity can prevent functional decline in persons with a low SPS. C1 Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. I Fraticini Natl Res Inst, INRCA, Dept Geriatr, Florence, Italy. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP McDermott, MM (reprint author), Northwestern Univ, Sch Med, Dept Med, 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. FU NCRR NIH HHS [RR-00048]; PHS HHS [R01-58099] NR 31 TC 49 Z9 50 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2002 VL 50 IS 2 BP 247 EP 255 DI 10.1046/j.1532-5415.2002.50055.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 520EL UT WOS:000173767600005 PM 12028205 ER PT J AU Woods, AS Koomen, JM Ruotolo, BT Gillig, KJ Russel, DH Fuhrer, K Gonin, M Egan, TF Schultz, JA AF Woods, AS Koomen, JM Ruotolo, BT Gillig, KJ Russel, DH Fuhrer, K Gonin, M Egan, TF Schultz, JA TI A study of peptide-peptide using MALDI ion mobility o-TOF and ESI mass spectrometry SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID ASSISTED-LASER-DESORPTION/IONIZATION; PHASE AB Matrix-assisted laser desorption ionization ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI-IM-oTOF MS) is evaluated as a tool for studying non-covalent complex (NCX) formation between peptides. The NCX formed between dynorphin 1-7 and Mini Gastrin I is used as a model system for comparison to previous MALDI experiments (Woods, A. S.; Huestis, M. A. J. Am, Soc. Mass Spectrom. 2001, 12, 88-96). The dynorphin 1-7/Mini Gastrin I complex is stable after more than a ms drift time through the He filled mobility cell. Furthermore, the effects of solution pH on NCX ion signal intensity is measured both by MALDI-IM-MS analysis and by nanoelectrospray mass spectrometry. When compared to the previous MALDI study this work shows that all three techniques give similar results. In addition, fragmentation can be observed from of the non-covalent complex parent ion that occurs prior to TOF mass analysis but after mobility separation, thus providing NCX composition information. C1 NIDA, Intramural Res Program, Chem & Drug Metab, NIH, Baltimore, MD 21224 USA. Texas A&M Univ, Lab Biol Mass Spectrometry, College Stn, TX USA. Ionwerks Inc, Houston, TX USA. RP Woods, AS (reprint author), NIDA, Intramural Res Program, Chem & Drug Metab, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Koomen, John/D-1844-2013; Ruotolo, Brandon/F-2669-2013 OI Ruotolo, Brandon/0000-0002-6084-2328 FU NIGMS NIH HHS [2 R44 GM57736-02] NR 22 TC 45 Z9 47 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD FEB PY 2002 VL 13 IS 2 BP 166 EP 169 DI 10.1016/S1044-0305(01)00348-8 PG 4 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 517BE UT WOS:000173590600007 PM 11838019 ER PT J AU Stewart, JH Nguyen, DM Chen, GA Schrump, DS AF Stewart, JH Nguyen, DM Chen, GA Schrump, DS TI Induction of apoptosis in malignant pleural mesothelioma cells by activation of the Fas (Apo-1/CD95) death-signal pathway SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 81st Annual Meeting of the American-Association-for-Thoracic-Surgery CY MAY 06-09, 2001 CL SAN DIEGO, CALIFORNIA SP Amer Assoc Thorac Surg ID CARCINOMA-CELLS; TUMOR-CELLS; MEDIATED APOPTOSIS; OSTEOSARCOMA CELL; T-LYMPHOCYTES; CANCER CELLS; LIGAND; LINES; CYTOTOXICITY; EXPRESSION AB Objective: Although well characterized in several solid tumors, the effects of Fas/Fas ligand interactions in malignant pleural mesothelioma cells have not been defined. The present study was undertaken to examine the functional status of the Fas/Fas ligand pathway in malignant pleural mesothelioma cells and to determine the feasibility of targeting this death-signal pathway for molecular intervention in patients with mesotheliomas. Methods: Fas expression in primary normal human bronchial epithelial cells and 6 malignant pleural mesothelioma cell lines was quantified by means of flow cytometry. The caspase components of the Fas-mediated apoptotic pathway were evaluated by means of Western blot techniques. Soluble Fas ligand-mediated cytotoxicity and apoptosis were evaluated by means of MTS and TUNEL assays, respectively. Cisplatin (3 mug/mL) and lymphokine-activated killer cells were used to enhance mesothelioma sensitivity to soluble Fas ligand. An H2373 nude mouse xenograft model of malignant pleural mesothelioma was established to assess the in vivo effects of soluble Fas ligand. Results: Four of 6 malignant pleural mesothelioma lines exhibited high levels of Fas expression, and 2 of 4 were inherently susceptible to soluble Fas ligand-mediated cytotoxicity (soluble Fas ligand 50% inhibitory concentration, <15 ng/mL). Two soluble Fas ligand refractory cell lines (H2052 and H513) exhibited high levels of Fas receptor. Pretreatment with cisplatin resulted in a reduction of 50% inhibitory concentration from infinity to 4.17 &PLUSMN; 0.14 ng/mL and 10.23 &PLUSMN; 1.58 ng/mL, respectively. Two additional soluble Fas ligand refractory cell lines (H2595 and REN) expressed low levels of Fas. Exposure of these cells to lymphokine-activated killer cells or lymphokine-activated killer cell-conditioned medium followed by a 24-hour treatment with cisplatin resulted in a significant reduction in 50% inhibitory concentration of soluble Fas ligand and pronounced induction of apoptosis. Intraperitoneally administered soluble Fas ligand mediated regression of H2373 xenografts. Conclusion: The Fas/Fas ligand pathway in mesothelioma cells is either intrinsically intact or can be rendered functional with chemotherapeutic agents or immune effector cells. These preclinical data support further evaluation of strategies to enhance Fas-mediated apoptosis in mesotheliomas. C1 NCI, NIH, Thorac Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. RP Nguyen, DM (reprint author), NCI, NIH, Thorac Oncol Sect, Surg Branch, Bldg 10,Room 2B07,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [K08 CA131482] NR 26 TC 16 Z9 23 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2002 VL 123 IS 2 BP 295 EP 302 DI 10.1067/mtc.2002.119882 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 520PN UT WOS:000173790400014 PM 11828289 ER PT J AU Schmidt, M Chiorini, JA Afione, S Kotin, R AF Schmidt, M Chiorini, JA Afione, S Kotin, R TI Adeno-associated virus type 2 Rep78 inhibition of PKA and PRKX: Fine mapping and analysis of mechanism SO JOURNAL OF VIROLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; HEAT-STABLE INHIBITOR; CATALYTIC SUBUNIT; DNA HELICASE; BIOCHEMICAL-CHARACTERIZATION; CELLULAR-TRANSFORMATION; REGULATORY PROTEINS; CYCLIC-AMP; REPLICATION; GENE AB Hormones and neurotransmitters utilize cyclic AMP (cAMP) as a second messenger in signal transduction pathways to regulate cell growth and division, differentiation, gene expression, and metabolism. Adeno-associated virus type 2 (AAV-2) nonstructural protein Rep78 inhibits members of the cAMP signal transduction pathway, the protein kinases PKA and PRKX. We mapped the kinase binding and inhibition domain of Rep78 for PRKX to amino acids (aa) 526 to 561 and that for PKA to aa 526 to 621. These polypeptides were as potent as full-length Rep78 in kinase inhibition, which suggests that the kinase-inhibitory domain is entirely contained in these Rep peptides. Steady-state kinetic analysis of Rep78-mediated inhibition of PKA and PRKX showed that Rep78 appears to increase the K-m value of the peptide kinase substrate, while the maximal velocity of the reaction was unaffected. This indicates that Rep78 acts as a competitive inhibitor with respect to the peptide kinase substrate. We detected homology between a cellular pseudosubstrate inhibitor of PKA, the protein kinase inhibitor PKI, and the PRKX and PKA inhibition domains of Rep78. Due to this homology and the competitive inhibition mechanism of Rep78, we propose that Rep78 inhibits PKA and PRKX kinase activity by pseudosubstrate inhibition. C1 NHLBI, Biochem Genet Lab, NIH, Bethesda, MD 20892 USA. RP NHLBI, Biochem Genet Lab, NIH, Bldg 10,Rm 7D05, Bethesda, MD 20892 USA. EM kotinr@nhlbi.nih.gov RI kotin, robert/B-8954-2008 NR 52 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 3 BP 1033 EP 1042 DI 10.1128/JVI.76.3.1033-1042.2002 PG 10 WC Virology SC Virology GA 511TM UT WOS:000173281700013 PM 11773379 ER PT J AU Schmidt, AC Wenzke, DR McAuliffe, JM St Claire, M Elkins, WR Murphy, BR Collins, PL AF Schmidt, AC Wenzke, DR McAuliffe, JM St Claire, M Elkins, WR Murphy, BR Collins, PL TI Mucosal immunization of rhesus monkeys against respiratory syncytial virus subgroups A and B and human parainfluenza virus type 3 by using a live cDNA-derived vaccine based on a host range-attenuated bovine parainfluenza virus type 3 vector backbone SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; HEMAGGLUTININ-NEURAMINIDASE; DEVELOPING-COUNTRIES; REASSORTANT VIRUSES; GLYCOPROTEIN GENE; RSV RECOMBINANTS; F-GLYCOPROTEIN; PARA-INFLUENZA; FOREIGN GENE; A VIRUS AB Reverse genetics was used to develop a two-component, trivalent live attenuated vaccine against human parainfluenza virus type 3 (HPIV3) and respiratory syncytial virus (RSV) subgroups A and B. The backbone for each of the two components of this vaccine was the attenuated recombinant bovine/human PIV3 (rB/ HPIV3), a recombinant BPIV3 in which the bovine HN and F protective antigens are replaced by their HPIV3 counterparts (48). This chimera retains the well-characterized host range attenuation phenotype of BPIV3, which appears to be appropriate for immunization of young infants. The open reading frames (ORFs) for the G and F major protective antigens of RSV subgroup A and B were each placed under the control of PIV3 transcription signals and inserted individually or in homologous pairs as supernumerary genes in the promoter proximal position of rB/HPIV3. The level of replication of rB/HPIV3-RSV chimeric viruses in the respiratory tract of rhesus monkeys was similar to that of their parent virus rB/HPIV3, and each of the chimeras induced a robust immune response to both RSV and HPIV3. RSV-neutralizing antibody titers induced by rB/HPIV3-RSV chimeric viruses were equivalent to those induced by infection with wild-type RSV, and HPIV3-specific antibody responses were similar to, or slightly less than, after infection with the rB/HPIV3 vector itself. This study describes a novel vaccine strategy against RSV in which vaccine viruses with a common attenuated backbone, specifically rB/HPIV3 derivatives expressing the G and/or F major protective antigens of RSV subgroup A and of RSV subgroup B, are used to immunize by the intranasal route against RSV and HPIV3, which are the first and second most important viral agents of pediatric respiratory tract disease worldwide. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD 20850 USA. RP Schmidt, AC (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 7,Rm 130,7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-000030, AI-000087] NR 66 TC 59 Z9 61 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 3 BP 1089 EP 1099 DI 10.1128/JVI.76.3.1089-1099.2002 PG 11 WC Virology SC Virology GA 511TM UT WOS:000173281700019 PM 11773385 ER PT J AU Yoshimura, K Kato, R Kavlick, MF Nguyen, A Maroun, V Maeda, K Hussain, KA Ghosh, AK Gulnik, SV Erickson, JW Mitsuya, H AF Yoshimura, K Kato, R Kavlick, MF Nguyen, A Maroun, V Maeda, K Hussain, KA Ghosh, AK Gulnik, SV Erickson, JW Mitsuya, H TI A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site SO JOURNAL OF VIROLOGY LA English DT Article ID ORALLY BIOAVAILABLE INHIBITOR; STRUCTURE-BASED DESIGN; IN-VITRO SELECTION; HIV-1 PROTEASE; ANTIRETROVIRAL THERAPY; VARIANTS RESISTANT; CROSS-RESISTANCE; DRUG-RESISTANCE; PLUS INDINAVIR; INFECTION AB We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 muM). UIC-94003 was also potent against multi-PI-resistant HIV-1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 muM). Upon selection of HIV-1 in the presence of UIC-94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and wide spectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1. C1 NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8608556, Japan. Univ Illinois, Dept Chem, Chicago, IL 60607 USA. NCI, Frederick Canc Res & Dev Ctr, Struct Biochem Program, SAIC, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, HIV Clin Interface Lab, Dev Therapeut Program,SAIC, Frederick, MD 21702 USA. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bldg 10,Rm 5A11, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [R01 GM053386, R37 GM053386, GM 53386] NR 39 TC 106 Z9 108 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 3 BP 1349 EP 1358 DI 10.1128/JVI.76.3.1349-1258.2002 PG 10 WC Virology SC Virology GA 511TM UT WOS:000173281700043 PM 11773409 ER PT J AU Kuhn, U Terunuma, A Pfutzner, W Foster, RA Vogel, JC AF Kuhn, U Terunuma, A Pfutzner, W Foster, RA Vogel, JC TI In vivo assessment of gene delivery to keratinocytes by lentiviral vectors SO JOURNAL OF VIROLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; MURINE LEUKEMIA-VIRUS; LONG-TERM EXPRESSION; IN-VIVO; NONDIVIDING CELLS; HIGH-TITER; TRANSGENE EXPRESSION; STABLE TRANSDUCTION; ORGANOTYPIC CULTURE; RETROVIRAL VECTORS AB For skin gene therapy, introduction of a desired gene into keratinocyte progenitor or stem cells could overcome the problem of achieving persistent gene expression in a significant percentage of keratinocytes. Although keratinocyte stem cells have not yet been completely characterized and purified for gene targeting purposes, lentiviral vectors may be superior to retroviral vectors at gene introduction into these stem cells, which are believed to divide and cycle slowly. Our initial in vitro studies demonstrate that lentiviral vectors are able to efficiently transduce nondividing keratinocytes, unlike retroviral vectors, and do not require the lentiviral accessory genes for keratinocyte transduction. When lentiviral vectors expressing green fluorescent protein (GFP) were directly injected into the dermis of human skin grafted onto immunocompromised mice, transduction of dividing basal and nondividing suprabasal. keratinocytes could be demonstrated, which was not the case when control retroviral vectors were used. However, flow cytometry analysis demonstrated low transduction efficiency, and histological analysis at later time points provided no evidence for progenitor cell targeting. In an alternative in vivo method, human keratinocytes were transduced in tissue culture (ex vivo) with either lentiviral or retroviral vectors and grafted as skin equivalents onto immunocompromised mice. GFP expression was analyzed in these human skin grafts after several cycles of epidermal turnover, and both the lentiviral and retroviral vector-transduced grafts had similar percentages of GFP-expressing keratinocytes. This ex vivo grafting study provides a good in vivo assessment of gene introduction into progenitor cells and suggests that lentiviral vectors are not necessarily superior to retroviral vectors at introducing genes into keratinocyte progenitor cells during in vitro culture. C1 Natl Canc Inst, NIH, Dermatol Branch, Bethesda, MD 20892 USA. RP Vogel, JC (reprint author), Natl Canc Inst, NIH, Dermatol Branch, Bldg 10,Room 12N260,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 58 TC 40 Z9 44 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 3 BP 1496 EP 1504 DI 10.1128/JVI.76.3.1496-1504.2002 PG 9 WC Virology SC Virology GA 511TM UT WOS:000173281700056 PM 11773422 ER PT J AU Nishigaki, K Hanson, C Thompson, D Yugawa, T Hisasue, M Tsujimoto, H Ruscetti, S AF Nishigaki, K Hanson, C Thompson, D Yugawa, T Hisasue, M Tsujimoto, H Ruscetti, S TI Analysis of the disease potential of a recombinant retrovirus containing friend murine leukemia virus sequences and a unique long terminal repeat from feline leukemia virus SO JOURNAL OF VIROLOGY LA English DT Article ID 3' END; MCF VIRUS; GENE; PATHOGENESIS; SPECIFICITY; DETERMINANT; CONTAINS; ADJACENT; GENOME; REGION AB We have molecularly cloned a feline leukemia virus (FeLV) (clone 33) from a domestic cat with acute myeloid leukemia (AML). The long terminal repeat (LTR) of this virus, like the LTRs present in FeLV proviruses from other cats with AML, contains an unusual structure in its U3 region upstream of the enhancer (URE) consisting of three tandem direct repeats of 47 bp. To test the disease potential and specificity of this unique FeLV LTR, we replaced the U3 region of the LTR of the erythroleukemia-inducing Friend murine leukemia virus (F-MuLV) with that of FeLV clone 33. When the resulting virus, F33V, was injected into newborn mice, almost all of the mice eventually developed hematopoietic malignancies, with a significant percentage being in the myeloid lineage. This is in contrast to mice injected with an F-MuLV recombinant containing the U3 region of another FeLV that lacks repetitive URE sequences, none of which developed myeloid malignancies. Examination of tumor proviruses from F33V-infected mice failed to detect any changes in FeLV U3 sequences other than that in the URE. Like F-MuLV-infected mice, those infected with the F-MuLV/FeLV recombinants were able to generate and replicate mink cell focus-inducing viruses. Our studies are consistent with the idea that the presence of repetitive sequences upstream of the enhancer in the LTR of FeLV may favor the activation of this promoter in myeloid cells and contribute to the development of malignancies in this hematopoietic lineage. C1 NCI, Basic Res Labs, Frederick, MD 21702 USA. Univ Tokyo, Grad Sch Agr & Life Sci, Dept Vet Internal Med, Bunkyo Ku, Tokyo 113, Japan. RP Ruscetti, S (reprint author), NCI, Basic Res Labs, Bldg 469,Room 205, Frederick, MD 21702 USA. NR 30 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 3 BP 1527 EP 1532 DI 10.1128/JVI.76.3.1527-1532.2002 PG 6 WC Virology SC Virology GA 511TM UT WOS:000173281700061 PM 11773427 ER PT J AU Fearns, R Peeples, ME Collins, PL AF Fearns, R Peeples, ME Collins, PL TI Mapping the transcription and replication promoters of respiratory syncytial virus SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; RNA REPLICATION; GENOMIC RNA; N-PROTEIN; PRODUCTIVE INITIATION; MESSENGER-RNA; IN-VITRO; POLYMERASE; MUTATIONS; SEQUENCE AB An important, unresolved issue in mononegavirus biology is whether or not transcription is initiated by the same promoter as RNA replication. In this study, residues important for respiratory syncytial virus (RSV) transcription and RNA replication were identified by subjecting the first 26 nucleotides of genome RNA to saturation mutagenesis. This analysis was performed using a genome analog that allowed transcription and RNA replication to be dissociated from each other and monitored as independent events in an intracellular assay. This analysis showed that nucleotides 3C, 5C, 8U, 9U, 10U, and 11U were important for transcription and RNA replication. Additional nucleotides (1U, 2G, 6U, and 7U) were important for RNA replication, but not transcription. At position 4, G versus C or U augmented transcription and decreased replication, showing that the naturally occurring assignments in the genomic (4G) and antigenomic (4U) promoters are optimal for transcription and RNA replication, respectively. These data show that RSV transcription and RNA replication each involve a cis-acting signal at the very 3' end of the genome. This signal appears to contain a minimum, common element that functions in both transcription and RNA replication, defined by those substitutions that had similar effects on the two processes. Apart from these common nucleotides, other positions were involved in RNA replication but not transcription or had different effects on the two processes. This indicates that the promoters for transcription and replication involve overlapping sets of nucleotides at the very 3' end of the genome and provides evidence that the nucleotide preferences for the two processes are not identical. C1 NIAID, Infect Dis Lab, NIH, LID, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, NIH, LID, 7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. OI Fearns, Rachel/0000-0003-0783-7498 NR 44 TC 41 Z9 43 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 4 BP 1663 EP 1672 DI 10.1128/JVI.76.4.1663-1672.2002 PG 10 WC Virology SC Virology GA 514TT UT WOS:000173457700014 PM 11799161 ER PT J AU Oh, J Julias, JG Ferris, AL Hughes, SH AF Oh, J Julias, JG Ferris, AL Hughes, SH TI Construction and characterization of a replication-competent retroviral shuttle vector plasmid SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA VIRUS; DOMINANT SELECTABLE MARKER; PHLEOMYCIN RESISTANCE; MUTATIONAL HOTSPOTS; MAMMALIAN-CELLS; BROAD-SPECTRUM; BLE GENE; TRANSFORMATION; DNA; HYPERMUTATIONS AB We constructed two versions of an RCASBP-based retroviral shuttle vector, RSVP (RCASBP shuttle vector plasmid), containing either the zeocin or blasticidin resistance gene. In this vector, the drug resistance gene is expressed in avian cells from the long terminal repeat (LTR) promoter, whereas in bacteria the resistance gene is expressed from a bacterial promoter. The vector contains a bacterial origin of replication (ColE1) to allow circular viral DNA to replicate as a plasmid in bacteria. The vector also contains the lac operator sequence, which binds to the lac repressor protein, providing a simple and rapid way to purify the vector DNA. The RSVP plasmid contains the following sequence starting with the 5' end: LTR, gag, pol, env, drug resistance gene, lac operator, ColE1, LTR. After this plasmid was transfected into DF-1 cells, we were able to rescue the circularized unintegrated viral DNA from RSVP simply by transforming the Hirt DNA into Escherichia coli. Furthermore, we were able to rescue the integrated provirus. DNA from infected cells was digested with an appropriate restriction enzyme (ClaI) and the vector-containing segments were enriched using lac repressor protein and then self-ligated. These enriched fractions were used to transform E. coli. The transformation was successful and we did recover integration sites, but higher-efficiency rescue was obtained with electroporation. The vector is relatively stable upon passage in avian cells. Southern blot analyses of genomic DNAs derived from successive viral passages under nonselective conditions showed that the cassette (drug resistance gene-lac operator-ColE1) insert was present in the vector up to the third viral passage for both resistance genes, which suggests that the RSVP vectors are stable for approximately three viral passages. Together, these results showed that RSVP vectors are useful tools for cloning unintegrated or integrated viral DNAs. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B, Frederick, MD 21702 USA. NR 25 TC 18 Z9 18 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2002 VL 76 IS 4 BP 1762 EP 1768 DI 10.1128/JVI.76.4.1762-1768.2002 PG 7 WC Virology SC Virology GA 514TT UT WOS:000173457700024 PM 11799171 ER PT J AU Spangler, EL Patel, N Speer, D Hyman, M Hengemihle, J Markowska, A Ingram, DK AF Spangler, EL Patel, N Speer, D Hyman, M Hengemihle, J Markowska, A Ingram, DK TI Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM): Age and strain comparisons of SAM P8 and R1 SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID 14-UNIT T-MAZE; MEMORY; RATS; ACQUISITION; RETENTION; MICE; PERFORMANCE; SCOPOLAMINE; IMPAIRMENT; DEFICITS AB Two strains of the senescence accelerated mouse, P8 and R1,were tested in footshock-motivated passive avoidance (PA; P8, 3-21 months; R1, 3-24 months) and 14-unit T-maze (P8 and R1, 9, and 15 months) tasks. For PA, entry to a dark chamber from a lighted chamber was followed by a brief shock. Latency to enter the dark chamber 24 hours later served as a measure of retention. Two days of active avoidance training in a straight runway preceded 2 days (8 trials/day) of testing in the 14-unit T-maze. For PA retention, older P8 mice entered the dark chamber more quickly than older R1 mice, whereas no differences were observed between young P8 or R1 mice. In the 14-unit T-maze, age-related learning performance deficits were reflected in higher error scores for older mice. P8 mice were actually superior learners; that is, they had lower error scores compared with those of age-matched R1 counterparts. Although PA learning results were in agreement with other reports, results obtained in the 14-unit T-maze were not consistent with previous reports of learning impairments in the P8 senescence accelerated mouse. C1 NIA, GRC, Nathan W Shock Labs, Mol Physiol & Genet Sect, Baltimore, MD 21224 USA. NIA, Neurosci Lab, Behav Neurosci Sect, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Psychol, Baltimore, MD 21218 USA. RP Ingram, DK (reprint author), NIA, GRC, Nathan W Shock Labs, Mol Physiol & Genet Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ingramd@grc.nia.nih.gov NR 27 TC 12 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2002 VL 57 IS 2 BP B61 EP B68 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 523ZP UT WOS:000173987700004 PM 11818425 ER PT J AU Rao, V Wawrousek, E Tamm, ER Zigler, S AF Rao, V Wawrousek, E Tamm, ER Zigler, S TI Rho GTPase inactivation impairs lens growth and integrity SO LABORATORY INVESTIGATION LA English DT Article ID HUMAN ENDOTHELIAL-CELLS; A-CRYSTALLIN PROMOTER; TRANSGENIC MICE; ACTIN CYTOSKELETON; BINDING PROTEINS; DIFFERENTIATION; GENE; MORPHOGENESIS; EXPRESSION; BOTULINUM AB To elucidate the significance of Rho GTPase signaling on lens growth and structural integrity, we have selectively inactivated Rho GTPase in the ocular lens. To achieve this tissue-specific inactivation, a transgene encoding the C3-exoenzyme from Clostridium botulinum has been expressed in mice under transcriptional control of the lens-specific alphaA-crystallin promoter. C3-exoenzyme is known to selectively inactivate all Rho GTPase isoforms by ADP-ribosylating an asparagine residue at position 41. Mice expressing the C3-exoenzyme transgene exhibited selective ocular defects, including cataract and microphthalmia. Extralenticular effects included ocular hemorrhage (blood accumulation in the anterior and posterior chambers of the eye) and abnormalities of the iris including focal attachments to lens and cornea (synechiae), C3-transgene expression was found only in the lens and not in the other ocular tissues as determined by RT-PCR analysis. Histologic examination of the eyes of C3 transgenic mice from two independent lines revealed extensive abnormalities of the lens, including defective fiber cell differentiation and elongation, ruptured posterior lens capsule, and thickened anterior lens capsule. Electron microscopic analysis of hemorrhaged C3 eyes showed abnormalities in the posterior hyaloid vessels. Collectively these data reveal the importance of Rho GTPase signaling in regulating lens growth and maintenance of lens transparency. C1 Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NEI, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Lehrstuhl 2, Anat Inst, Erlangen, Germany. RP Rao, V (reprint author), Duke Univ, Med Ctr, Dept Ophthalmol, Erwin Rd,POB 3802, Durham, NC 27710 USA. RI Wawrousek, Eric/A-4547-2008 FU NEI NIH HHS [R01-EY12201] NR 31 TC 18 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2002 VL 82 IS 2 BP 231 EP 239 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 525AW UT WOS:000174045900012 PM 11850536 ER PT J AU Szymko-Bennett, YM Russell, LJ Bale, SJ Griffith, AJ AF Szymko-Bennett, YM Russell, LJ Bale, SJ Griffith, AJ TI Auditory manifestations of Keratitis-Ichthyosis-Deafness (KID) syndrome SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Midwinter Meeting of the Association-for-Research-in-Otolaryngology CY FEB 20-24, 2000 CL ST PETERSBURG, FLORIDA SP Assoc Res Otolarynol DE Keratitis-Ichthyosis-Deafness syndrome; hearing; deafness; genodermatosis; genetic ID SENSORINEURAL HEARING-LOSS; PALMOPLANTAR KERATODERMA; IMPEDANCE AUDIOMETRY; MISSENSE MUTATION; CONNEXIN-26; PATIENT; ERYTHROKERATODERMIA; HISTOPATHOLOGY; HYPERKERATOSIS; HEREDITARY AB Objective. Evaluation of the auditory manifestations of Keratitis-Ichthyosis-Deafness (EM) syndrome, a rare genodermatosis characterized by follicular hyperkeratosis, vascularizing keratitis, and congenital hearing loss. Study Design: Five individuals with sporadic EM syndrome were evaluated in the outpatient audiology clinic at the Warren Grant Magnuson Clinical Center of the National Institutes of Health. Methods. Audiologic examinations included pure-tone audiometry, speech audiometry, and middle ear immittance testing. Auditory brainstein responses and otoacoustic emissions were analyzed in 2 subjects. Results Four subjects had prelingual, bilateral, profound sensorineural hearing loss, whereas the fifth subject had significant residual hearing that exhibited no progression on serial audiograms. All 5 subjects had a history of nonerosive keratosis obturans and cutaneous cysts in the external ear canals that prevented continuous use of ear molds. Conclusions: The sensorineural hearing loss in KID syndrome is generally prelingual and profound. This combination of auditory and cutaneous phenotypes is similar to those previously reported for MOD syndrome. KID syndrome presents a difficult challenge for communication rehabilitation because keratitis may impair the perception of sign and spoken language, and the cutaneous manifestations routinely curtail use of external amplification devices. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. McGill Univ, Ctr Hlth, Montreal Childrens Hosp, Montreal, PQ, Canada. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Szymko-Bennett, YM (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court,Room 2A02, Rockville, MD 20850 USA. FU NIDCD NIH HHS [Z01 DC 00055-01, Z01 DC00054-01] NR 73 TC 21 Z9 22 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 2002 VL 112 IS 2 BP 272 EP 280 DI 10.1097/00005537-200202000-00014 PG 9 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 520HL UT WOS:000173775500014 PM 11889383 ER PT J AU Mann, EA Burnett, T Cornell, S Ludlow, CL AF Mann, EA Burnett, T Cornell, S Ludlow, CL TI The effect of neuromuscular stimulation of the genioglossus on the hypopharyngeal airway SO LARYNGOSCOPE LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; HYPOGLOSSAL NERVE-STIMULATION; ELECTRICAL-STIMULATION AB Objectives: To determine the effects of neuromuscular stimulation (NS) of the genioglossus muscle on hypopharyngeal airway size. Study Design. Fourteen consecutively recruited healthy volunteers underwent percutaneous electrical NS of the genioglossus muscle. Methods: Bipolar hooked wires were inserted percutaneously into the genioglossus muscle and used for NS. The anterior-posterior diameter of the hypopharynx was measured at the level of the superior edge of the epiglottis at baseline and during NS from recorded video endoscopic examinations. Results: NS of the genioglossus muscle resulted in a significant increase in the diameter of the hypopharyngeal airway (P = .002) compared with baseline, ranging from a 33% to 284% increase in airway diameter. Three of the 14 patients demonstrated modest decreases in airway diameter, likely the result of faulty electrode placement in surrounding tongue retrusive muscles. Conclusions: NS of the genioglossus muscle was effective in increasing the hypopharyngeal airway and may provide a useful alternative to direct stimulation of the hypoglossal nerve with a nerve cuff electrode in the development of neuroprosthetic treatments for obstructive sleep apnea. C1 NINCDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Mann, EA (reprint author), NINCDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bldg 10,Room 5D38,10 Ctr Dr,MSC 1416, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 21 TC 37 Z9 40 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 2002 VL 112 IS 2 BP 351 EP 356 DI 10.1097/00005537-200202000-00027 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 520HL UT WOS:000173775500027 PM 11889396 ER PT J AU Pombo-de-Oliveira, MS Dobbin, JA Loureiro, P Borducchi, D Maia, RC Fernandes, MA Cavalcanti, GB Takemoto, S Franchini, G AF Pombo-de-Oliveira, MS Dobbin, JA Loureiro, P Borducchi, D Maia, RC Fernandes, MA Cavalcanti, GB Takemoto, S Franchini, G TI Genetic mutation and early onset of T-cell leukemia in pediatric patients infected at birth with HTLV-I SO LEUKEMIA RESEARCH LA English DT Article DE T-cell leukemia; pediatric patients; HTLV-I ID VIRUS TYPE-I; LYMPHOMA; LEUKEMIA/LYMPHOMA; TRANSMISSION; ADOLESCENT; DERMATITIS; DIVERSITY; CHILDHOOD; FEATURES; DISEASE AB T-cell leukemia/lymphoma (T-c LL) associated with prior infection with HTLV-I is rarely described in children. We present herein, the clinical, morphological, and virologic features of T-c LL, which occurred in eight pediatric cases with similar features of ATLL described in adults. There were three girls and five boys with age ranging from 2 to 18 years. Lymphoadenopathy, hepatosplenomegaly and marked skin lesions were presented in all cases. Five patients had hypercalcemia. The diagnostic criteria of T-c LL were based on both morphological and immunophenotypical analyses characterized by T-cell markers positively. Seven cases were cCD3 +, CD4/CD25 +, whereas CD1a and TdT were negative in all cases tested. HTLV-I antibodies were detected in all cases. HTLV-I provirus integration of at least one provirus was seen in all cases tested by molecular analysis. Mother-to-child transmission of HTLV-I was demonstrated in six cases. Interestingly, a homozygous deletion in p16 gene locus was observed in all four cases studied, while exons 7 and 8 of p53 were deleted in one child. The deletion of the p16(INK4A)/p14(ARF) or mutation of p53, key regulatory protein of cell cycle checkpoint in G1/S progression, found in five of the eight pediatric patients suggests that in these cases genetic lesions associated with HTLV-I infection may predispose for an early onset of leukemia. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Inst Nacl Canc, Lab Marcadores Celulares, BR-20230130 Rio De Janeiro, Brazil. Inst Nacl Canc, Serv Hematol, BR-20230130 Rio De Janeiro, Brazil. HEMOPE, Serv Hematol, Recife, PE, Brazil. Univ Fed Sao Paulo, Dept Hematol, Sao Paulo, Brazil. NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pombo-de-Oliveira, MS (reprint author), Inst Nacl Canc, Lab Marcadores Celulares, Praca Cruz Vermelha 23, BR-20230130 Rio De Janeiro, Brazil. RI Pombo-de-Oliveira, Maria S./I-8884-2014; maia, raquel/L-4869-2015 OI Pombo-de-Oliveira, Maria S./0000-0003-3986-8993; maia, raquel/0000-0003-0225-471X NR 34 TC 16 Z9 18 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2002 VL 26 IS 2 BP 155 EP 161 DI 10.1016/S0145-2126(01)00108-4 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 520HC UT WOS:000173774400004 PM 11755465 ER PT J AU Shiffman, ML Brown, RS Olthoff, KM Everson, G Miller, C Siegler, M Hoofnagle, JH AF Shiffman, ML Brown, RS Olthoff, KM Everson, G Miller, C Siegler, M Hoofnagle, JH TI Living donor liver transplantation: Summary of a Conference at the National Institutes of Health SO LIVER TRANSPLANTATION LA English DT Review ID FULMINANT HEPATIC-FAILURE; C VIRUS-INFECTION; RIGHT LOBE GRAFTS; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; INTERLEUKIN-6-DEFICIENT MICE; COMPUTED-TOMOGRAPHY; SURGICAL ANATOMY; RAT-LIVER; REGENERATION AB Living donor liver transplantation for adults was developed only recently in an attempt to increase the pool of donor organs; to reduce morbidity and mortality, and to improve the long-term survival of patients in need of liver transplant. Within a few brief years, this procedure has gained widespread support by both the public and transplant community. The procedure will soon be performed by nearly 80% of all liver transplant programs in the United States. Unfortunately, the long-term risks of the procedure to the recipient and especially the donor remain undefined. In response to the rapid growth and enthusiasm for this procedure, the National Institutes of Health sponsored a workshop, the goals of which were to review the scientific, medical, and nonmedical issues associated with living donor liver transplantation, and to define questions for future basic and clinical investigations which could improve the success and applicability of this procedure. C1 Virginia Commonwealth Univ, Coll Med, Hepatol Sect, Richmond, VA 23298 USA. Columbia Univ, Coll Phys & Surg, Liver Transplant Program, New York, NY 10027 USA. Univ Penn, Div Transplant Surg, Philadelphia, PA 19104 USA. Univ Colorado, Hlth Sci Ctr, Hepatol Sect, Denver, CO USA. Mt Sinai Hosp, Recanati Miller Transplant Inst, New York, NY 10029 USA. Univ Chicago, MacLean Ctr Clin Med Eth, Chicago, IL 60637 USA. NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Shiffman, ML (reprint author), Virginia Commonwealth Univ, Coll Med, Hepatol Sect, Box 980341, Richmond, VA 23298 USA. NR 114 TC 87 Z9 94 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD FEB PY 2002 VL 8 IS 2 BP 174 EP 188 DI 10.1053/jlts.2002.30981 PG 15 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 524JG UT WOS:000174009000015 PM 11862598 ER PT J AU Metayer, C Wang, ZY Kleinerman, RA Wang, LD Brenner, AV Cui, HX Cao, JS Lubin, JH AF Metayer, C Wang, ZY Kleinerman, RA Wang, LD Brenner, AV Cui, HX Cao, JS Lubin, JH TI Cooking oil fumes and risk of lung cancer in women in rural Gansu, China SO LUNG CANCER LA English DT Article DE case-control studies; cooking oil fumes; lung neoplasms; females; China ID ENVIRONMENTAL TOBACCO-SMOKE; NONSMOKING WOMEN; AIR-POLLUTION; STYLE COOKING; XUAN-WEI; SHANGHAI; IDENTIFICATION; 1,3-BUTADIENE; GENOTOXICITY; EXPOSURE AB Cooking oil fumes have been suggested to increase the risk of lung cancer in Chinese women by exposing them to mutagenic substances. We investigated the association between lung cancer and locally made rapeseed and linseed oils in a population-based case-control study in Gansu Province, China. Two hundred and thirty-three incident, female lung cancer cases diagnosed from 1994-98 were identified. A control group of 459 women was selected from census lists and were frequency matched on age and prefecture. Interviewers obtained information on cooking practices and cooking oil use. The odds ratio (OR) for lung cancer associated with ever-use of rapeseed oil, alone or in combination with linseed oil, was 1.67 (95% CI 1.0-2.5), compared to use of linseed oil alone. ORs for stir-frying with either linseed or rapeseed oil 15-29, 30 and greater than or equal to31 times per month were 1.96, 1.73, and 2.24, respectively (trend, P = 0.03), relative to a lower frequency of stir-frying. Lung cancer risks also increased with total number of years cooking (trend, P < 0.09). Women exposed to cooking fumes from rapeseed oil appeared to be at increased risk of lung cancer, and there was some evidence that fumes from linseed oil may have also contributed to the risk. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Minist Publ Hlth, Lab Ind Hyg, Beijing 100088, Peoples R China. Minist Hlth, Beijing 100044, Peoples R China. RP Kleinerman, RA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rockville EPS-7044, Bethesda, MD 20892 USA. OI Kleinerman, Ruth/0000-0001-7415-2478 FU NCI NIH HHS [N01 CP 81121, N01 CP 50509] NR 34 TC 81 Z9 90 U1 0 U2 16 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0169-5002 J9 LUNG CANCER-J IASLC JI Lung Cancer PD FEB PY 2002 VL 35 IS 2 BP 111 EP 117 AR PII S0169-5002(01)00412-3 DI 10.1016/S0169-5002(01)00412-3 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 525JH UT WOS:000174065400002 PM 11804682 ER PT J AU Gillis, P Moiny, F Brooks, RA AF Gillis, P Moiny, F Brooks, RA TI On T-2-shortening by strongly magnetized spheres: A partial refocusing model SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion; susceptibility; T-2-shortening; gradients; superparamagnetic particles ID TRANSVERSE RELAXATION; MR CONTRAST; NMR SIGNAL; SUSCEPTIBILITY; TISSUES; DIFFUSION; BEHAVIOR; BLOOD AB Computer simulations of water transverse relaxation induced by superparamagnetic particles are shown to disagree with the available theories, covering the slow diffusion domain. Understanding these new simulations, not in the slow diffusion domain, thus requires a new theoretical approach. A "partial refocusing model" is introduced for this purpose; it is based on a spatial division between an inner region where the gradients are too strong for the refocusing pulses to be efficient and an outer region where they are efficient. This model agrees with published simulations of relaxation induced by magnetic dipoles approximated as points. The validity domains of the various models are also compared. Magn Reson Med 47:257-263, 2002. (C) 2002 Wiley-Liss, Inc. C1 Univ Mons Hainaut, Biol Phys Dept, B-7000 Mons, Belgium. NINCDS, Neuroimaging Branch, NIH, Bethesda, MD USA. RP Gillis, P (reprint author), Univ Mons Hainaut, Biol Phys Dept, B-7000 Mons, Belgium. NR 16 TC 161 Z9 164 U1 3 U2 31 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 257 EP 263 DI 10.1002/mrm.10059 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700006 PM 11810668 ER PT J AU Shapiro, EM Borthakur, A Gougoutas, A Reddy, R AF Shapiro, EM Borthakur, A Gougoutas, A Reddy, R TI Na-23 MRI accurately measures fixed charge density in articular cartilage SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PROTEOGLYCAN DEPLETION; IN-VIVO; RABBIT KNEE; SODIUM MRI; GD-DTPA; DEGRADATION; GLYCOSAMINOGLYCAN; REPLENISHMENT; VISUALIZATION AB One of the initiating steps of osteoarthritis is the loss of proteoglycan (PG) molecules from the cartilage matrix. One method for assessing cartilage integrity, therefore, is to measure the PG content or fixed charge density (FCD) of cartilage. This report shows the feasibility of calculating FCD by Na-23 MRI and introduces MRI protocols for human studies, in vivo. Na-23 MRI was used to measure the sodium concentration inside bovine patellar cartilage. The sodium concentration was then converted to FCD (mM) by considering ideal Donnan equilibrium. These FCD measurements were compared to FCD measurements obtained through standard dimethylmethylene blue PG assays. There was a high correlation (slope = 0.89, r(2) = 0.81) between the FCD measurements obtained by Na-23 MRI and those obtained by the PG assays. These methods were then employed in quantifying the FCD of articular cartilage of human volunteers in vivo. Two imaging protocols were compared: one using a birdcage coil, the other using a transmit/receive surface coil. Both methodologies gave similar results, with the average sodium concentration of normal human patellar cartilage ranging from similar to240 to 260 mM. This corresponds to FCDs of -158 mM to -182 mM. Magn Reson Med 47:284-291, 2002. (C) 2002 Wiley-Liss, Inc. C1 Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Shapiro, EM (reprint author), NINCDS, NIH, Lab Funct & Mol Imaging, 10 Ctr Dr,B10-B1D118, Bethesda, MD 20892 USA. OI Reddy, Ravinder/0000-0003-4580-2392 FU NCRR NIH HHS [P41 RR002305-236874, P41 RR002305, RR02305]; NIAMS NIH HHS [R01 AR045242, R01-AR45242-01] NR 43 TC 156 Z9 160 U1 2 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 284 EP 291 DI 10.1002/mrm.10054 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700009 PM 11810671 ER PT J AU Kellman, P Arai, AE McVeigh, ER Aletras, AH AF Kellman, P Arai, AE McVeigh, ER Aletras, AH TI Phase-sensitive inversion recovery for detecting myocardial infarction using gadolinium-delayed hyperenhancement SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE phase-sensitive reconstruction; inversion recovery; myocardial infarction; delayed hyperenhancement; intensity correction; cardiac imaging ID MAGNETIC-RESONANCE IMAGES; MR-IMAGES; INTENSITY CORRECTION; SIGNAL; CONTRAST; NOISE; RECONSTRUCTION; ARRAY AB After administration of gadolinium, infarcted myocardium exhibits delayed hyperenhancement and can be imaged using an inversion recovery (IR) sequence. The performance of such a method when using magnitude-reconstructed images is highly sensitive to the inversion recovery time (TI) selected. Using phase-sensitive reconstruction, it is possible to use a nominal value of TI, eliminate several breath-holds otherwise needed to find the precise null time for normal myocardium, and achieve a consistent contrast. Phase-sensitive detection is used to remove the background phase while preserving the sign of the desired magnetization during IR. Experimental results are presented which demonstrate the benefits of both phase-sensitive IR image reconstruction and surface coil intensity normalization for detecting myocardial infarction (MI). The phase-sensitive reconstruction method reduces the variation in apparent infarct size that is observed in the magnitude images as TI is changed. Phase-sensitive detection also has the advantage of decreasing the sensitivity to changes in tissue T, with increasing delay from contrast agent injection. Magn Reson Med 47:372-383, 2002. Published 2002 Wiley-Liss, Inc.dagger C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. OI Aletras, Anthony/0000-0002-3786-3817 FU Intramural NIH HHS [Z01 HL004608-08] NR 28 TC 276 Z9 281 U1 1 U2 14 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 372 EP 383 DI 10.1002/mrm.10051 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700020 PM 11810682 ER PT J AU Brooks, RA AF Brooks, RA TI T-2-shortening by strongly magnetized spheres: A chemical exchange model SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE chemical exchange; susceptibility; T-2 shortening; gradients; magnetized spheres AB It is shown that a chemical exchange model can reproduce nuclear magnetic relaxation caused by diffusion of water molecules near strongly magnetized particles. The agreement is based on the similarity (but not equivalence) of the respective "visit-limiting" mechanisms in the echo-limited regime. The model leads to a single equation that predicts relaxation behavior in both the motional-averaging and visit-limited regimes. When combined with the static-dephasing regime equation, the result is a simple theory (for spheres) that covers the entire range of diffusion times. Magn Reson Med 47:388-391, 2002. Published 2002 Wiley-Liss, Inc.dagger C1 NINCDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. RP Brooks, RA (reprint author), 15501 Sweetbirch Court, Rockville, MD 20853 USA. NR 11 TC 66 Z9 66 U1 1 U2 16 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 388 EP 391 DI 10.1002/mrm.10064 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700022 PM 11810684 ER PT J AU Basser, PJ AF Basser, PJ TI Relationships between diffusion tensor and q-space MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE q-space; NMR; diffusion tensor; MRI; DTI; DT-MRI; DSI ID FIELD-GRADIENT; SPIN-ECHO; RESTRICTED DIFFUSION; SELF-DIFFUSION; B-MATRIX; BRAIN; NMR; WATER; APPROXIMATION; SPECTROSCOPY AB Fundamental relationships between diffusion tensor (DT) and 3D q-space MRI are derived which establish conditions when these two complementary MR methods are equivalent. It is shown that the displacement distribution measured by q-space MRI in both the large displacement (i.e., large r) and the long-wavelength (i.e., small q) limits is the same 3D Gaussian displacement distribution assumed in DT-MRI. In these limiting cases, q-space MR yields a dispersion tensor that is identical to the effective DT, D, measured in DT-MRI. An experiment is then proposed to measure D using q-space methods. These findings establish that the effective DT, measured in DT-MRI, characterizes molecule motions on a coarse length-scale. Finally, the feasibility of and requirements for performing 3D q-space MRI on a clinical scanner are considered. Magn Reson Med 47: 392-397, 2002. Published 2002 Wiley-Liss, Inc.dagger C1 NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bldg 13,Rm 3W16,13 South Dr, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 39 TC 87 Z9 94 U1 1 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2002 VL 47 IS 2 BP 392 EP 397 DI 10.1002/mrm.10052 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 516WA UT WOS:000173578700023 PM 11810685 ER PT J AU Goldstein, AM Chidambaram, A Halpern, A Holly, EA Guerry, D Sagebiel, R Elder, DE Tucker, MA AF Goldstein, AM Chidambaram, A Halpern, A Holly, EA Guerry, D Sagebiel, R Elder, DE Tucker, MA TI Rarity of CDK4 germline mutations in familial melanoma SO MELANOMA RESEARCH LA English DT Article DE Arg24Cys mutation; CMM; cyclin-dependent kinase 4; penetrance ID CLINIC-BASED POPULATION; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; DYSPLASTIC NEVI; PRONE FAMILIES; CDKN2A; GENES; PREVALENCE; P16 AB To date, two genes have been implicated in melanoma pathogenesis. The first, CDKN2A, is a tumour suppressor gene with germline mutations detected in 20% of melanoma-prone families. The second, CDK4, Is an oncogene with co-segregating germline mutations detected in only three kindreds worldwide. We examined 16 American melanoma-prone families for mutations in all coding exons of CDK4 and screened additional members of two previously reported families with the Arg24Cys germline CDK4 mutation to evaluate the penetrance of the mutation. No new CDK4 mutations were identified. In the two Arg24Cys families, the penetrance was estimated to be 63%. Overall, 12 out of 12 Invasive melanoma patients, none out of one in situ melanoma patient, five out of 13 dysplastic naevi patients, two out of 15 unaffected family members, and none out of 10 spouses carried the Arg24Cys mutation. Dysplastic naevi did not strongly co-segregate with the Arg24Cys mutation. Thus the phenotype observed in melanoma-prone CDK4 families appears to be more complex than just the CDK4 mutation. Both genetic and environmental factors are likely to contribute to the occurrence of melanoma and dysplastic naevi in these families. In summary, although CDK4 is a melanoma susceptibility gene, it plays a minor role in hereditary melanoma. (C) 2002 Lippincott Williams Wilkins. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Univ Penn, Sch Med, Pigmented Les Study Grp, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Melanoma Clin, San Francisco, CA USA. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Plaza S,Room 7004,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 20 TC 40 Z9 42 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD FEB PY 2002 VL 12 IS 1 BP 51 EP 55 DI 10.1097/00008390-200202000-00008 PG 5 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 524LT UT WOS:000174015400007 PM 11828258 ER PT J AU Martinelli, AM Agazio, J Flaherty, N Ephraim, PM AF Martinelli, AM Agazio, J Flaherty, N Ephraim, PM TI Testing a model of exposure to environmental tobacco smoke in military women with children SO MILITARY MEDICINE LA English DT Article ID SELF-EFFICACY; CIGARETTE-SMOKING; NON-JOINERS; CESSATION; BEHAVIOR; RELAPSE; INFANTS AB The purpose of this study was to test a model of exposure to environmental tobacco smoke (ETS) in military women and their children. The convenience sample consisted of 238 women, 81 smokers and 157 nonsmokers, with a mean age of 37 years (SD = 9.9). Participants were either on active duty or were reservists and/or military dependents. Model constructs, some of which were adapted from the transtheoretical model of behavior change, measured personal and situational factors, pros and cons of ETS exposure, self-efficacy to resist ETS, mother's expectation for child's ETS exposure, and mother's self-efficacy to reduce child's ETS exposure. The mediating variable was the mother's daily ETS exposure, and the outcome variable was the child's daily ETS exposure. The trimmed model showed that 32% of the variance in mother's daily exposure (mediating variable) was accounted for by living with a smoker, having high ETS "pros" (as opposed to ETS "cons"), having less self-efficacy to resist ETS, and having greater self-efficacy to reduce the child's exposure. There was a significant, positive relationship (r = 0.51, p = 0.01) between the mother's and child's daily ETS exposure (outcome variable). C1 NIDA, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Martinelli, AM (reprint author), NIDA, NIH, Bethesda, MD 20892 USA. NR 30 TC 3 Z9 3 U1 0 U2 0 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD FEB PY 2002 VL 167 IS 2 BP 113 EP 120 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 653DN UT WOS:000181420100006 PM 11873532 ER PT J AU Nees, DW Wawrousek, EF Robison, WG Piatigorsky, J AF Nees, DW Wawrousek, EF Robison, WG Piatigorsky, J TI Structurally normal corneas in aldehyde dehydrogenase 3a1-deficient mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MAJOR SOLUBLE-PROTEIN; EYE LENS TRANSPARENCY; ULTRAVIOLET-LIGHT; ALPHA-CRYSTALLIN; BOVINE CORNEA; RECRUITMENT; EPITHELIUM; ENZYMES; SQUID; IDENTIFICATION AB We have constructed an ALDH3a1 null mouse to investigate the role of this enzyme that comprises nearly one-half of the total water-soluble protein in the mouse corneal epithelium. ALDH3a1-deficient mice are viable and fertile, have a corneal epithelium with a water-soluble protein content approximately half that of wild-type mice, and contain no ALDH3a1 as determined by zymograms and immunoblots. Despite the loss of protein content and ALDH3a1 activity, the ALDH3a1(-/-) mouse corneas appear indistinguishable from wild-type corneas when examined by histological analysis and electron microscopy and are transparent as determined by light and slit lamp microscopy. There is no evidence for a compensating protein or enzyme. Even though the function of ALDH3a1 in the mouse cornea remains unknown, our data indicate that its enzymatic activity is unnecessary for corneal clarity and maintenance, at least under laboratory conditions. C1 NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, 6 Ctr Dr,Room 201, Bethesda, MD 20892 USA. RI Wawrousek, Eric/A-4547-2008 NR 50 TC 40 Z9 41 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2002 VL 22 IS 3 BP 849 EP 855 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 511FE UT WOS:000173253300013 PM 11784860 ER PT J AU Herblot, S Aplan, PD Hoang, T AF Herblot, S Aplan, PD Hoang, T TI Gradient of E2A activity in B-cell development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LOOP-HELIX PROTEIN; MURINE BONE-MARROW; TRANSGENIC MICE; DNA-BINDING; IN-VIVO; TRANSCRIPTION FACTORS; SCL GENE; THYMOCYTE DEVELOPMENT; EXPRESSION AB The E2A locus is a frequent target of chromosomal translocations in B-cell acute lymphoblastic leukemia (B-ALL). E2A encodes two products, E12 and E47, that are part of the basic helix-loop-helix (bHLH) family of transcription factors and are central in B lineage differentiation. E2A haplo-insufficiency hinders progression through three major checkpoints in B-cell development: commitment into the B lineage, at the pro-B to pre-B transition, and in the induction of immunoglobulin M (IgM) expression required for a functional BCR. These observations underscore the importance of E2A gene dosage in B-cell development. Here we show that a higher proportion of pro-B cells in E2A(+/-) mice is in the cell cycle compared to that in wild-type littermates. This increase correlates with lower P21(waf/cip1) levels, indicating that E2A has an antiproliferative function in B-cell progenitors. Ectopic expression in the B lineage of SCL/Tall, a tissue-specific bHLH factor that inhibits E2A function, blocks commitment into the B lineage without affecting progression through later stages of differentiation. Furthermore, ectopic SCL expression exacerbates E2A haplo-insufficiency in B-cell differentiation, indicating that SCL genetically interacts with E2A. Taken together, these observations provide evidence for a gradient of E2A activity that increases from the pre-pro-B to the pre-B stage and suggest a model in which low levels of E2A (as in pro-B cells) are sufficient to control cell growth, while high levels (in pre-B cells) are required for cell differentiation. The antiproliferative function of E2A further suggests that in B-ALL associated with t(1;19) and t(17;19), the disruption of one E2A allele contributes to leukemogenesis, in addition to other anomalies induced by E2A fusion proteins. C1 Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Program Mol Biol, Montreal, PQ H3C 3J7, Canada. Natl Canc Inst, Dept Genet, Med Branch, Div Clin Sci, Gaithersburg, MD 20877 USA. RP Hoang, T (reprint author), Clin Res Inst Montreal, 110 Ave Pins OUest, Montreal, PQ H2W 1R7, Canada. RI Aplan, Peter/K-9064-2016 NR 59 TC 63 Z9 63 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2002 VL 22 IS 3 BP 886 EP 900 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 511FE UT WOS:000173253300017 PM 11784864 ER PT J AU Ponnio, T Burton, Q Pereira, FA Wu, DK Conneely, OM AF Ponnio, T Burton, Q Pereira, FA Wu, DK Conneely, OM TI The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MICE LACKING; MYXOID CHONDROSARCOMA; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; NERVOUS-SYSTEM; GENE; SUPERFAMILY; NUR77; MORPHOGENESIS; APOPTOSIS AB Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. RP Conneely, OM (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. OI Pereira, Fred/0000-0003-2100-0280 FU NIDCD NIH HHS [R55 DC004585, R01 DC004585]; NIDDK NIH HHS [DK57743, DK52429, P01 DK057743] NR 46 TC 57 Z9 61 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2002 VL 22 IS 3 BP 935 EP 945 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 511FE UT WOS:000173253300021 PM 11784868 ER PT J AU Choi, J Nannenga, B Demidov, ON Bulavin, DV Cooney, A Brayton, C Zhang, YX Mbawuike, IN Bradley, A Appella, E Donehower, LA AF Choi, J Nannenga, B Demidov, ON Bulavin, DV Cooney, A Brayton, C Zhang, YX Mbawuike, IN Bradley, A Appella, E Donehower, LA TI Mice deficient for the wild-type p53-induced phosphatase gene (Wip1) exhibit defects in reproductive organs, immune function, and cell cycle control SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID P53-DEFICIENT MICE; P53; GROWTH; DNA; RADIATION; PATHWAY AB The Wip1 gene is a serine/threonine phosphatase that is induced in a p53-dependent manner by DNA-damaging agents. We show here that Wip1 message is expressed in moderate levels in all organs, but is present at very high levels in the testes, particularly in the postmeiotic round spermatid compartment of the seminiferous tubules. We have confirmed that Wip1 mRNA is induced by ionizing radiation in mouse tissues in a p53-dependent manner. To further determine the normal biological function of Wip1 in mammalian organisms, we have generated Wip1-deficient mice. Wip1 null mice are viable but show a variety of postnatal abnormalities, including variable male runting, male reproductive organ atrophy, reduced male fertility, and reduced male longevity. Mice lacking Wip1 show increased susceptibility to pathogens and diminished T- and B-cell function. Fibroblasts derived from Wipl null embryos have decreased proliferation rates and appear to be compromised in entering mitosis. The data are consistent with an important role for Wip1 in spermatogenesis, lymphoid cell function, and cell cycle regulation. C1 Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Ctr Comparat Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. NCI, Cell Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Donehower, LA (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, 1 Baylor Plaza, Houston, TX 77030 USA. FU NCI NIH HHS [CA54897] NR 27 TC 104 Z9 108 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2002 VL 22 IS 4 BP 1094 EP 1105 DI 10.1128/MCB.22.4.1094-1105.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 514JL UT WOS:000173435600011 PM 11809801 ER PT J AU Lemkine, GF Mantero, S Migne, C Raji, A Goula, D Normandie, P Levi, G Demeneix, BA AF Lemkine, GF Mantero, S Migne, C Raji, A Goula, D Normandie, P Levi, G Demeneix, BA TI Preferential transfection of adult mouse neural stem cells and their immediate progeny in vivo with polyethylenimine SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MAMMALIAN BRAIN; GENE-TRANSFER; SUBVENTRICULAR ZONE; SUBEPENDYMAL CELLS; NEURONAL MIGRATION; FOREBRAIN; DEATH; PROLIFERATION; PATHWAYS AB The subventricular zone of the adult mammalian brain harbors the neural stem cell population with potential neural regeneration and repair capacity. We describe a nonviral technique to preferentially transfect in vivo the adult neural stem cell population and its immediate progeny based on intraventricular injection of PEI/DNA complexes. The transfected population was identified by cellular and ultra-structural evidence showing their proliferating status and expression of the specific markers GFAP and nestin. Stable activation of the lacZ reporter by cre-recombinase transfection in R26R mice demonstrated survival and migration of stem cell derivatives three months after injection. Apoptosis is thought to be the most common fate of the stem cell progeny. Overexpression of Bcl-X-L increased number and survival time of transduced progenitors and decreased the frequency of cells immunopositive for activated Caspase-3. This method thus provides selective targeting of the stem cell population and should allow an in-depth understanding of their biology. C1 Museum Natl Hist Nat, Lab Physiol Gen & Comparee, UMR CNRS 8572, F-75231 Paris 5, France. Natl Canc Inst, IST, Lab Mol Morphogenesis, Genoa, Italy. INRA, Unite 806, EA 2703, Museum Natl Hist Nat,Inst Biol Physicochim, Paris, France. Univ Mohammed 5, Fac Sci, Dept Biol, Rabat, Morocco. RP Demeneix, BA (reprint author), Museum Natl Hist Nat, Lab Physiol Gen & Comparee, UMR CNRS 8572, 7 Rue Cuvier, F-75231 Paris 5, France. RI Levi, Giovanni/B-4416-2013; Lemkine, Gregory/O-3279-2016; OI Mantero, Stefano/0000-0003-0608-2724 FU Telethon [D.076] NR 28 TC 28 Z9 30 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD FEB PY 2002 VL 19 IS 2 BP 165 EP 174 DI 10.1006/mcne.2001.1084 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 527YB UT WOS:000174214600004 PM 11860270 ER PT J AU Wei, Q Adelstein, RS AF Wei, Q Adelstein, RS TI Pitx2a expression alters actin-myosin cytoskeleton and migration of HeLa cells through Rho GTPase signaling SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID LEFT-RIGHT ASYMMETRY; TRANSCRIPTION FACTOR SNAIL; CERVICAL-CARCINOMA CELLS; EXCHANGE FACTOR DOMAINS; RAC1 SMALL GTPASES; RIEGER-SYNDROME; PHOSPHATIDYLINOSITOL 3-KINASE; EPITHELIAL-CELLS; HOMEOBOX GENE; HEAVY-CHAIN AB We ectopically expressed the transcription factor Pitx2a, one of the Pitx2 isoforms, in HeLa cells by using a tetracycline-inducible expression system and examined whether Pitx2a was capable of modulating Rho GTPase signaling and altering the cell's cytoskeleton. Ectopic expression of Pitx2a induced actin-myosin reorganization, leading to increased cell spreading, suppression of cell migration, and the strengthening of cell-cell adhesion, marked by the accumulation and localization of beta-catenin and N-cadherin to the sites of cell-cell contacts. Moreover, Pitx2a expression resulted in activation of the Rho GTPases Rac1 and RhoA, and the dominant negative Rac1 mutant N17Rac1 inhibited cell spreading and disrupted localization of P-catenin to the sites of cell-cell contacts. Both reorganization of actin-myosin and cell spreading require phosphatidylinositol 3-kinase activity, which is also necessary for activation of the Rho GTPase proteins. Pitx2a induced the expression of Trio, a guanine nucleotide exchange factor for Rac1 and RhoA, which preceded cell spreading, and the expression of Trio protein was down-regulated after the changes in cell spreading and cell morphology were initiated. In addition, Pitx2a also induces cell cycle arrest at G0/G1, most likely due to the accumulation of the tumor suppressor proteins p53 and p21. Our data indicate that the transcriptional activities initiated in the nucleus by Pitx2a result in profound changes in HeLa cell morphology, migration, and proliferation. C1 NIH, NHLBI, Mol Cardiol Lab, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NIH, NHLBI, Mol Cardiol Lab, Bethesda, MD 20892 USA. OI Adelstein, Robert/0000-0002-8683-2144 NR 86 TC 46 Z9 48 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2002 VL 13 IS 2 BP 683 EP 697 DI 10.1091/mbc.01-07-0358 PG 15 WC Cell Biology SC Cell Biology GA 524WW UT WOS:000174036700025 PM 11854422 ER PT J AU Bradshaw, TD Bibby, MC Double, JA Fichtner, I Cooper, PA Alley, MC Donohue, S Stinson, SF Tomaszewjski, JE Sausville, EA Stevens, MFG AF Bradshaw, TD Bibby, MC Double, JA Fichtner, I Cooper, PA Alley, MC Donohue, S Stinson, SF Tomaszewjski, JE Sausville, EA Stevens, MFG TI Preclinical evaluation of amino acid Prodrugs of novel antitumor 2-(4-amino-3-methylphenyl)benzothiazoles SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID IN-VITRO; BIOLOGICAL PROPERTIES; 2-(4-AMINOPHENYL)BENZOTHIAZOLES; BENZOTHIAZOLES; CELLS; VIVO AB Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly selective, potent antitumor properties in vitro and in vivo. Elucidation of the mechanism of action of this structurally simple class of compounds has occurred in parallel with selection of a candidate clinical agent. Antitumor benzothiazoles induce and are biotransformed by cytochrome P 450 1A1 to putative active, as well as inactive metabolites. Metabolic inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus. Amino acid conjugation to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles has been used to overcome limitations posed by drug lipophilicity. Water soluble, chemically stable prodrugs rapidly and quantitatively revert to their parent amine in mice, rats, and dogs in vivo. Plasma concentrations of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (2) regenerated from the lysylamide prodrug (2b), sufficient to elicit cytocidal activity against ZR-75-1 and T47D human mammary carcinoma cell lines persist >6 h. The growth of breast (MCF-7) and ovarian (IGROV-1) xenograft tumors is significantly retarded by 2b. Manageable toxic side effects are reported from preclinically efficacious doses of 2b. Cytochrome P 450 1A1 protein expression, selectively induced in sensitive carcinoma cells, was detected in MCF-7 and IGROV-1 tumors 24 h after treatment of mice with 2b (20 mg/kg). The lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole is potentially suitable for clinical evaluation. C1 Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. Max Delbruck Ctr Mol Med, D-13122 Berlin, Germany. Univ Bradford, Sch Life Sci, Canc Res Unit, Bradford BD7 1DP, W Yorkshire, England. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Frederick, MD 21702 USA. RP Bradshaw, TD (reprint author), Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Univ Pk, Nottingham NG7 2RD, England. NR 15 TC 69 Z9 73 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2002 VL 1 IS 4 BP 239 EP 246 PG 8 WC Oncology SC Oncology GA 606MB UT WOS:000178736800001 PM 12467219 ER PT J AU Montell, C Birnbaumer, L Flockerzi, V Bindels, RJ Brudorf, EA Caterina, MJ Clapham, DE Harteneck, C Heller, S Julius, D Kojima, I Mori, Y Penner, R Prawitt, D Scharenberg, AM Schultz, G Shimizu, N Zhu, MX AF Montell, C Birnbaumer, L Flockerzi, V Bindels, RJ Brudorf, EA Caterina, MJ Clapham, DE Harteneck, C Heller, S Julius, D Kojima, I Mori, Y Penner, R Prawitt, D Scharenberg, AM Schultz, G Shimizu, N Zhu, MX TI A unified nomenclature for the superfamily of TRP cation channels SO MOLECULAR CELL LA English DT Letter C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Ohio State Univ, Neurobiotechnol Ctr, Columbus, OH 43210 USA. Keio Univ, Sch Med, Dept Mol Biol, Tokyo 1608582, Japan. Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98105 USA. Johannes Gutenberg Univ Mainz, Childrens Hosp, D-55101 Mainz, Germany. Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96813 USA. Univ Hawaii, Queens Med Ctr, Ctr Biomed Res, Honolulu, HI 96813 USA. Natl Inst Physiol Sci, Ctr Integrat Biosci, Okazaki, Aichi 4448585, Japan. Gunma Univ, Dept Cell Biol, Maebashi, Gumma 3718512, Japan. Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Free Univ Berlin, Inst Pharmakol, D-14195 Berlin, Germany. Harvard Univ, Sch Med, Boston, MA 02115 USA. UCL, Dept Biol, HUGO Gene Nomenclature Comm, London NW1 2HE, England. Univ Nijmegen, Med Ctr, Dept Cell Physiol, NL-6500 HB Nijmegen, Netherlands. Univ Saarland, Inst Pharmakol & Toxikol, D-66421 Homburg, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. RP Montell, C (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. EM cmontell@jhmi.edu RI Bindels, Rene/B-9824-2013; OI Bindels, Rene/0000-0003-1167-1339; Montell, Craig/0000-0001-5637-1482 NR 0 TC 408 Z9 445 U1 5 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB PY 2002 VL 9 IS 2 BP 229 EP 231 DI 10.1016/S1097-2765(02)00448-3 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522ZN UT WOS:000173927000007 PM 11864597 ER PT J AU Zhou, G Li, HM DeCamp, D Chen, S Shu, HJ Gong, Y Flaig, M Gillespie, JW Hu, N Taylor, PR Emmert-Buck, MR Liotta, LA Petricoin, EF Zhao, YM AF Zhou, G Li, HM DeCamp, D Chen, S Shu, HJ Gong, Y Flaig, M Gillespie, JW Hu, N Taylor, PR Emmert-Buck, MR Liotta, LA Petricoin, EF Zhao, YM TI 2D differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID IMMOBILIZED PH GRADIENTS; 2-DIMENSIONAL ELECTROPHORESIS; MASS-SPECTROMETRY; SAMPLE PREPARATION; MESSENGER-RNA; CURRENT STATE; PROTEOMICS; YEAST AB The reproducibility of conventional two-dimensional (2D) gel electrophoresis can be improved using differential in-gel electrophoresis (DIGE), a new emerging technology for proteomic analysis. In DIGE, two pools of proteins are labeled with 1-(5-carboxypentyl)-1'-propylindocarbocyanine halide (Cy3) N-hydroxy-succinimidyl ester and 1-(5carboxypentyl)-1'-methylindodi-carbocyanine halide (Cy5) N-hydroxysuccinimidyl ester fluorescent dyes, respectively. The labeled proteins are mixed and separated in the same 2D gel. 2D DIGE was applied to quantify the differences in protein expression between laser capture microdissection-procured esophageal carcinoma cells and normal epithelial cells and to define cancer-specific and normal-specific protein markers. Analysis of the 2D images from protein lysates of similar to 250,000 cancer cells and normal cells identified 1038 protein spots in cancer cell lysates and 1088 protein spots in normal cell lysates. Of the detected proteins, 58 spots were up-regulated by >3-fold and 107 were down-regulated by >3-fold in cancer cells. In addition to previously identified down-regulated protein annexin I, tumor rejection antigen (gp96) was found up-regulated in esophageal squamous cell cancer. Global quantification of protein expression between laser capture-microdissected patient-matched cancer cells and normal cells using 2D DIGE in combination with mass spectrometry is a powerful tool for the molecular characterization of cancer progression and identification of cancer-specific protein markers. Molecular & Cellular Proteomics 1:117-124, 2002. C1 Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA. US FDA, Tissue Proteom Unit, Ctr Biol Evaluat & Res, Bethesda, MD 20857 USA. NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20857 USA. NCI, Urol Oncol Branch, Pathol Lab, NIH, Bethesda, MD 20857 USA. NCI, Canc Prevent Studies Branch, NIH, Bethesda, MD 20857 USA. RP Zhao, YM (reprint author), Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. RI Li, Hongmei/L-2595-2013 OI Li, Hongmei/0000-0002-4952-1734 NR 25 TC 276 Z9 317 U1 2 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD FEB PY 2002 VL 1 IS 2 BP 117 EP 124 DI 10.1074/mcp.M100015-MCP200 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 654UT UT WOS:000181515000004 PM 12096129 ER PT J AU Hill, SA Grant, CCR AF Hill, SA Grant, CCR TI Recombinational error and deletion formation in Neisseria gonorrhoeae: a role for RecJ in the production of pilE(L) deletions SO MOLECULAR GENETICS AND GENOMICS LA English DT Article DE deletions; repeats; RecJ; pilE; recombination ID PILIN ANTIGENIC VARIATION; ESCHERICHIA-COLI; GENE CONVERSION; DNA TRANSFORMATION; DIRECT REPEATS; PILUS GENES; PROTEIN-II; CHROMOSOME; SEQUENCE; PHASE AB Genetic linkage within Neisseria gonorrhoeae populations is in equilibrium., yet the physical linkage map indicates a relatively stable chromosome structure, despite an apparently vast potential for mispairing between repeated sequences (e.g. between the multiple pil or opa alleles, or through mispairing of any of the numerous small repeated sequences that are liberally scattered throughout the chromosome). Therefore, the stability of the physical linkage map suggests that aberrant recombination between repeated sequences is a rare event. This study was undertaken to explore some of the parameters that may govern deletion events between short direct oligonucleotide repeats. using a chromosomal locus that appears to be especially prone to deletions (the pilin expression locus. pilE). In this report., we demonstrate that deletion formation at pilE occurs primarily through recombinational error following a pilE/pilS interaction, illegitimate (i.e. RecA-independent) events can occur, but they are infrequent. In contrast, when genetically engineered opa deletion substrates were constructed and placed in the chromosome, deletions at the opa loci were infrequent even under rec(+) conditions. A model is presented in which the gonococcal RecA and RecJ proteins promote pilE deletions through a recombination event that is templated or stabilised by a pilE/pilS interaction. C1 No Illinois Univ, Dept Biol Sci, De Kalb, IL 60115 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP Hill, SA (reprint author), No Illinois Univ, Dept Biol Sci, De Kalb, IL 60115 USA. NR 55 TC 11 Z9 11 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1617-4615 J9 MOL GENET GENOMICS JI Mol. Genet. Genomics PD FEB PY 2002 VL 266 IS 6 BP 962 EP 972 DI 10.1007/s00438-001-0618-5 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 535AJ UT WOS:000174621700007 PM 11862490 ER PT J AU Borrego, F Kabat, J Kim, DK Lieto, L Maasho, K Pena, J Solana, R Coligan, JE AF Borrego, F Kabat, J Kim, DK Lieto, L Maasho, K Pena, J Solana, R Coligan, JE TI Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells SO MOLECULAR IMMUNOLOGY LA English DT Review DE NK cells; inhibitory receptor; KIR; CD94/NKG2; ILT ID HUMAN T-LYMPHOCYTES; HLA-C MOLECULES; INHIBITORY RECEPTOR; GENE-COMPLEX; TYROSINE PHOSPHORYLATION; CRYSTAL-STRUCTURE; AMINO-ACID; IMMUNOGLOBULIN SUPERFAMILY; ACTIVATING RECEPTORS; CD94/NKG2 RECEPTORS AB Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte la-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class la) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules. In this review we will discuss the molecular structure, specificity, cellular expression patterns, and function of these HLA class I receptors, as well as the chromosomal location and genetic organization. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIAID, Lab Allerg Dis, Receptor Cell Biol Sect, NIH, Rockville, MD 20852 USA. Univ Cordoba, Sch Med Reina Sofia, Dept Immunol, E-14004 Cordoba, Spain. RP Coligan, JE (reprint author), NIAID, Lab Allerg Dis, Receptor Cell Biol Sect, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. NR 224 TC 163 Z9 170 U1 1 U2 8 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 PY 2002 VL 38 IS 9 BP 637 EP 660 AR PII S0161-5890(01)00107-9 DI 10.1016/S0161-5890(01)00107-9 PG 24 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 528WD UT WOS:000174266500001 PM 11858820 ER PT J AU Rangarajan, S Woodgate, R Goodman, MF AF Rangarajan, S Woodgate, R Goodman, MF TI Replication restart in UV-irradiated Escherichia coli involving pols II, III, V, PriA, RecA and RecFOR proteins SO MOLECULAR MICROBIOLOGY LA English DT Article ID DNA-POLYMERASE-II; SINGLE-STRANDED-DNA; SOS RESPONSE; GENETIC-RECOMBINATION; MUTAGENESIS PROTEINS; ADAPTIVE MUTATION; REPAIR; BINDING; DAMAGE; MUTANT AB In Escherichia coli, UV-irradiated cells resume DNA synthesis after a transient inhibition by a process called replication restart. To elucidate the role of several key proteins involved in this process, we have analysed the time dependence of replication restart in strains carrying a combination of mutations in lexA, recA, polB (pol II), umuDC (pol V), priA, dnaC, recF, recO or recR. We find that both pol 11 and the origin-independent primosome-assembling function of PriA are essential for the immediate recovery of DNA synthesis after UV irradiation. In their absence, translesion replication or 'replication readthrough' occurs approximate to 50 min after UV and is pol V-dependent. In a wild-type, lexA(+) background, mutations in recF, recO or recR block both pathways. Similar results were obtained with a lexA(Def) recF strain. However, lexA(Def) recO or lexA(Def) recR strains, although unable to facilitate PriA-pol II-dependent restart, were able to perform pol V-dependent readthrough. The defects in restart attributed to mutations in recF, recO or recR were suppressed in a recA730 lexA(Def) strain expressing constitutively activated RecA (RecA(star)). Our data suggest that in a wild-type background, RecF, O and R are important for the induction of the SOS response and the formation of RecA(star)-dependent recombination intermediates necessary for PriA/Pol II-dependent replication restart. In contrast, only RecF is required for the activation of RecA that leads to the formation of pol V (UmuD'C-2) and facilitates replication readthrough. C1 Univ So Calif, Dept Chem & Biol Sci, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Chem & Biol Sci, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. FU NIGMS NIH HHS [GM42554] NR 78 TC 68 Z9 70 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2002 VL 43 IS 3 BP 617 EP 628 DI 10.1046/j.1365-2958.2002.02747.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 525FM UT WOS:000174058300007 PM 11929519 ER PT J AU Shah, BH Catt, KJ AF Shah, BH Catt, KJ TI Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: Roles of protein kinase c delta, Src/proline-rich tyrosine kinase 2, and epidermal growth factor receptor trans-activation SO MOLECULAR PHARMACOLOGY LA English DT Article ID VASCULAR SMOOTH-MUSCLE; ADRENAL GLOMERULOSA CELLS; LIVER EPITHELIAL-CELLS; COUPLED RECEPTORS; EGF RECEPTOR; INTRACELLULAR CA2+; G(I) PROTEINS; PYK2; TRANSACTIVATION; PATHWAYS AB Agonist activation of endogenous angiotensin II (Ang II) AT(1) receptors expressed in hepatic C9 cells markedly stimulated inositol phosphate production, phosphorylation of the proline-rich tyrosine kinase PyK-2, and ERK activation. Ang II caused activation of protein kinase C delta (PKCdelta) in C9 cells, and its stimulatory actions on Pyk2 and extracellularly regulated kinase (ERK) phosphorylation were abolished by PKC depletion and selective inhibition of PKCdelta by rottlerin, but not by Ca2+-chelators. These effects, and the similar actions of the Src kinase inhibitor PP2 indicate the involvement of PKCdelta and Src kinase in ERK activation. In C9 cells, phorbol-12-myristate-13-acetate (PMA) caused much greater phosphorylation of Pyk2 and ERK than the Ca2+ ionophore lonomycin, and the effects of PMA and Ang II were abolished in PKC-depleted cells. Ang II increased the association of Pyk2 with Src and with the epidermal growth factor receptor (EGF-R). EGF caused much greater tyrosine phosphorylation of the EGF-R than Ang II and PMA. Ang II-induced activation of ERK, but not Pyk2, was prevented by inhibition of EGF receptor phosphorylation by AG 1478 and of Src kinase by PP1. Ang II also increased the association of the adaptor protein Grb2 with the EGF-R. These findings indicate that Src and Pyk2 act upstream of the EGF-R and that the majority of Ang II-induced ERK phosphorylation is dependent on trans-activation of the EGF-R. Ang II-induced ERK activation in C9 cells is initiated by a PKCdelta-dependent but Ca2+-independent mechanism and is mediated by the Src/Pyk2 complex through trans-activation of the EGF-R. C1 NICHHD, ERRB, NIH, Bethesda, MD 20892 USA. RP Catt, KJ (reprint author), NICHHD, ERRB, NIH, Bld 49,Rm 6A36, Bethesda, MD 20892 USA. NR 40 TC 70 Z9 72 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2002 VL 61 IS 2 BP 343 EP 351 DI 10.1124/mol.61.2.343 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 515VY UT WOS:000173518400013 PM 11809859 ER PT J AU Frank, JA Richert, N Lewis, B Bash, C Howard, T Civil, R Stone, R Eaton, J McFarland, H Leist, T AF Frank, JA Richert, N Lewis, B Bash, C Howard, T Civil, R Stone, R Eaton, J McFarland, H Leist, T TI A pilot study of recombinant insulin-like growth factor-1 in seven multiple sclerosis patients SO MULTIPLE SCLEROSIS LA English DT Article DE contrast; insulin-like growth factor; magnetization transfer; MRI; multiple sclerosis; proton MRS; T1 hypointensities; white matter lesion load ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PLACEBO-CONTROLLED TRIAL; FACTOR-I TREATMENT; MAGNETIC-RESONANCE; INTERFERON BETA-1B; DOUBLE-BLIND; CLINICAL DEFICITS; LESION SEVERITY; BRAIN; DISEASE AB The purpose of this open-label, crossover study was to determine the safety and efficacy of recombinant insulin-like growth factor-1 (rhIGF-1) using magnetic resonance imaging (MRI) and clinical measures of disease activity in seven multiple sclerosis (MS) patients. Monthly clinical and MRI examinations were performed during a 24-week baseline and a 24-week treatment period with rhIGF-1, The primary outcome measure was contrast enhancing lesion (CEL) frequency on treatment compared to baseline. Secondary outcome measures included clinical and MRI measures of disease activity including: white matter lesion food (WMLL), magnetization transfer ratio (MTR), TI-Hypointensity volume, cervical spine cross-sectional area and proton magnetic resonance spectroscopic (MRS) imaging for determining regional metabolite ratios. rhIGF-1 (Cephalon) was administered at a dose of 50 mg subcutaneously twice a day for 6 months, rhIGF-1 was safe and well tolerated with no severe adverse reactions. There was no significant difference between baseline and treatment periods for any MRI or clinical measures of disease activity. Although rhIGF-1 did not after the course of disease in this smog cohort of MS patients, the drug was well tolerated. Further studies using rhIGF-1 alone or in combination with other therapies may be of value because of the proposed mechanism of action of this growth factor on the oligodendrocyte and remyelination. C1 Natl Inst Hlth, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Clin & Regulatory Affairs, W Chester, PA USA. Natl Inst Hlth, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), Natl Inst Hlth, Lab Diagnost Radiol Res, Bldg 10,Room B1N256,10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA. NR 26 TC 55 Z9 58 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2002 VL 8 IS 1 BP 24 EP 29 DI 10.1191/1352458502ms768oa PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 528WK UT WOS:000174267300005 PM 11936485 ER PT J AU McFarland, HF Barkhof, F Antel, J Miller, DH AF McFarland, HF Barkhof, F Antel, J Miller, DH TI The role of MRI as a surrogate outcome measure in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Article DE mri; outcome measure ID MAGNETIC-RESONANCE SPECTROSCOPY; CLINICALLY ISOLATED SYNDROMES; APPEARING WHITE-MATTER; SPINAL-CORD ATROPHY; INTRAMUSCULAR INTERFERON BETA-1A; PROGRESSIVE CEREBRAL ATROPHY; PLACEBO-CONTROLLED TRIAL; T1 WEIGHTED IMAGES; HYPOINTENSE LESIONS; FOLLOW-UP AB The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sclerosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-con trolled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease, The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on clinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration. C1 NINCDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. Vrije Univ Amsterdam, Med Ctr, Dept Radiol, MD MR Ctr, Amsterdam, Netherlands. Montreal Neurol Inst, Dept Neurol, Montreal, PQ, Canada. NMR Res Unit, Inst Neurol, London, England. RP McFarland, HF (reprint author), NINCDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. FU Multiple Sclerosis Society [491] NR 89 TC 76 Z9 79 U1 0 U2 3 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2002 VL 8 IS 1 BP 40 EP 51 DI 10.1191/1352458502ms767xx PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 528WK UT WOS:000174267300008 PM 11936488 ER PT J AU McFarland, HF AF McFarland, HF TI The emerging role of MRI in multiple sclerosis and the new diagnostic criteria SO MULTIPLE SCLEROSIS LA English DT Editorial Material ID PREDICT CONVERSION C1 NINCDS, NIH, Bethesda, MD 20892 USA. RP McFarland, HF (reprint author), NINCDS, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 8 TC 5 Z9 5 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2002 VL 8 IS 1 BP 71 EP 72 DI 10.1177/135245850200800114 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 528WK UT WOS:000174267300012 PM 11936491 ER PT J AU Hara, H Nolan, PM Scott, MO Bucan, M Wakayama, Y Fischbeck, KH AF Hara, H Nolan, PM Scott, MO Bucan, M Wakayama, Y Fischbeck, KH TI Running endurance abnormality in mdx mice SO MUSCLE & NERVE LA English DT Article DE Duchenne muscular dystrophy; dystrophin; mdx mouse; phenotype analysis; running wheel ID DUCHENNE MUSCULAR-DYSTROPHY; MOUSE SKELETAL-MUSCLE; IN-VIVO; FULL-LENGTH; EXPRESSION; WEAKNESS; EXERCISE; GENE; DIAPHRAGM; MUTATION AB The mdx mouse lacks dystrophin and has histological features of Duchenne muscular dystrophy but little weakness in the first year of life. We report here an early deficit in voluntary wheel running, as assayed with a computerized wheel. All mdx mice showed an intermittent running pattern, in contrast to the continuous running seen in controls. The average continuous running time differed significantly between mdx and control mice at all ages tested (5-21 weeks). This assay is noninvasive, has the advantage of unbiased automatic data collection, and should be useful for quantifying the mdx deficit in therapeutic studies. (C) 2002 John Wiley Sons, Inc. C1 Showa Univ, Dept Med, Div Neurol, Fujigaoka Hosp,Aoba Ku, Yokohama, Kanagawa 2270043, Japan. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. NINCDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Hara, H (reprint author), Showa Univ, Dept Med, Div Neurol, Fujigaoka Hosp,Aoba Ku, 1-30 Fujigaoka, Yokohama, Kanagawa 2270043, Japan. OI Nolan, Patrick/0000-0001-5550-0334 NR 30 TC 20 Z9 21 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD FEB PY 2002 VL 25 IS 2 BP 207 EP 211 DI 10.1002/mus.10023 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 517HW UT WOS:000173605900009 PM 11870688 ER PT J AU Tsang, M Friesel, R Kudoh, T Dawid, IB AF Tsang, M Friesel, R Kudoh, T Dawid, IB TI Identification of Sef, a novel modulator of FGF signalling SO NATURE CELL BIOLOGY LA English DT Article ID MIDBRAIN-HINDBRAIN BOUNDARY; GROWTH-FACTOR RECEPTORS; ZEBRAFISH; XENOPUS; EXPRESSION; MESODERM; SPROUTY; TRANSMEMBRANE; INHIBITOR; ORGANIZER AB Fibroblast growth factors (FGFs) are members of a family of some 30 secreted proteins important in the regulation of cellular proliferation, migration, differentiation and survival(1-4). Here we report the identification of a novel modulator of FGF signal transduction, sef, isolated from a zebrafish embryo library through an in situ hybridization screen. The sef gene encodes a transmembrane protein, and belongs to the synexpression group that includes some of the fgf genes. Sef expression is positively regulated by FGF, and ectopic expression of sef in zebrafish or Xenopus laevis embryos specifically inhibits FGF signalling. In co-immunoprecipitation assays, the intracellular domain of Sef interacts with FGF receptors, FGFR1 and FGFR2. Injection of antisense sef morpholino oligos mimicked the phenotypes observed by ectopic fgf8 expression, suggesting that Sef is required to limit FGF signalling during development. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Maine Med Ctr, Res Inst, Ctr Mol Med, Scarborough, ME 04074 USA. RP Dawid, IB (reprint author), NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RI TSANG, Michael/E-2758-2013; Tsang, Michael/I-9305-2014 OI TSANG, Michael/0000-0001-6384-2422; Tsang, Michael/0000-0001-7123-0063 FU NCRR NIH HHS [RR15555]; NHLBI NIH HHS [HL65301]; NIDCR NIH HHS [DE13248] NR 29 TC 207 Z9 214 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD FEB PY 2002 VL 4 IS 2 BP 165 EP 169 DI 10.1038/ncb749 PG 5 WC Cell Biology SC Cell Biology GA 520RJ UT WOS:000173794600022 PM 11802164 ER PT J AU Carpten, J Nupponen, N Isaacs, S Sood, R Robbins, C Xu, J Faruque, M Moses, T Ewing, C Gillanders, E Hu, P Buinovszky, P Makalowska, I Baffoe-Bonnie, A Faith, D Smith, J Stephan, D Wiley, K Brownstein, M Gildea, D Kelly, B Jenkins, R Hostetter, G Matikainen, M Schleutker, J Klinger, K Connors, T Xiang, Y Wang, Z De Marzo, A Papadopoulos, N Kallioniemi, OP Burk, R Meyers, D Gronberg, H Meltzer, P Silverman, R Bailey-Wilson, J Walsh, P Isaacs, W Trent, J AF Carpten, J Nupponen, N Isaacs, S Sood, R Robbins, C Xu, J Faruque, M Moses, T Ewing, C Gillanders, E Hu, P Buinovszky, P Makalowska, I Baffoe-Bonnie, A Faith, D Smith, J Stephan, D Wiley, K Brownstein, M Gildea, D Kelly, B Jenkins, R Hostetter, G Matikainen, M Schleutker, J Klinger, K Connors, T Xiang, Y Wang, Z De Marzo, A Papadopoulos, N Kallioniemi, OP Burk, R Meyers, D Gronberg, H Meltzer, P Silverman, R Bailey-Wilson, J Walsh, P Isaacs, W Trent, J TI Germline mutations in the ribonuclease L gene in families showing linkage with HPC1 SO NATURE GENETICS LA English DT Article ID PROSTATE-CANCER INCIDENCE; 2-5A-DEPENDENT RNASE; INTERFERON ACTION; PROTEIN-SYNTHESIS; EXPRESSION; MORTALITY; CLEAVAGE; TRENDS; CELLS AB Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States(1,2), little is known about inherited factors that influence its genetic predisposition(3-5). Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL)(6-8) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene(10-12). We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Vanderbilt Univ, Div Med Genet, Nashville, TN USA. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Univ Tampere, Canc Genet Lab, Inst Med Technol, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Canc Genet Lab, Inst Med Technol, Tampere, Finland. Genzyme Mol Oncol, Framingham, MA USA. Cleveland Clin Fdn, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44195 USA. Columbia Univ, Dept Pathol, Inst Canc Genet, New York, NY USA. Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Albert Einstein Sch Med, Bronx, NY 10461 USA. Umea Univ, Dept Oncol, Umea, Sweden. RP Trent, J (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RI Brownstein, Michael/B-8609-2009; Kallioniemi, Olli/H-5111-2011; Smith, Jeff/C-3484-2012; Papadopoulos, Nickolas/K-7272-2012; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Bailey-Wilson, Joan/0000-0002-9153-2920 NR 23 TC 350 Z9 361 U1 1 U2 10 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2002 VL 30 IS 2 BP 181 EP 184 DI 10.1038/ng823 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 519CY UT WOS:000173708700018 PM 11799394 ER PT J AU Moser, JM Gibbs, J Jensen, PE Lukacher, AE AF Moser, JM Gibbs, J Jensen, PE Lukacher, AE TI CD94-NKG2A receptors regulate antiviral CD8+T cell responses SO NATURE IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; POLYOMA-VIRUS; INHIBITORY RECEPTORS; VIRAL PERSISTENCE; MOLECULE QA-1(B); TUMOR-INDUCTION; KIR EXPRESSION; MIDDLE-T; IN-VIVO; LYMPHOCYTES AB CD8(+) T lymphocytes mediate immunosurveillance against persistent virus infections and virus-induced neoplasia. Polyoma virus, a highly oncogenic natural mouse DNA virus, establishes persistent infection, but only a few mice are highly susceptible to tumors induced by the virus. Mature antiviral CD8(+) T cells expand in tumor-susceptible mice, but their cytotoxic effector activity is nonfunctional in vivo. Here we show that the natural killer cell inhibitory receptor, CD94-NKG2A, is up-regulated by antiviral CD8(+) T cells during acute polyoma infection and is responsible for down-regulating their antigen-specific cytotoxicity during both viral clearance and virus-induced oncogenesis. C1 Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Lukacher, AE (reprint author), Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. NR 47 TC 149 Z9 154 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2002 VL 3 IS 2 BP 189 EP 195 DI 10.1038/ni757 PG 7 WC Immunology SC Immunology GA 516PJ UT WOS:000173562400020 PM 11812997 ER PT J AU Arikawa-Hirasawa, E Rossi, SG Rotundo, RL Yamada, Y AF Arikawa-Hirasawa, E Rossi, SG Rotundo, RL Yamada, Y TI Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice SO NATURE NEUROSCIENCE LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCAN; COLLAGEN-TAILED ACETYLCHOLINESTERASE; EXTRACELLULAR-MATRIX; BASEMENT-MEMBRANES; SKELETAL-MUSCLE; ALPHA-DYSTROGLYCAN; BASAL LAMINA; CHOLINESTERASE; CARTILAGE; DIAPHRAGM AB The collagen-tailed form of acetylcholinesterase (AChE) is concentrated at the vertebrate neuromuscular junction (NMJ), where it is responsible for rapidly terminating neurotransmission. This unique oligomeric form of AChE, consisting of three tetramers covalently attached to a collagen-like tail, is more highly expressed in innervated regions of skeletal muscle fibers, where it is externalized and attached to the synaptic basal lamina interposed between the nerve terminal and the receptor-rich postsynaptic membrane. Although it is clear that the enzyme is preferentially synthesized in regions of muscle contacted by the motoneuron, the molecular events underlying its localization to the NMJ are not known. Here we show that perlecan, a multifunctional heparan sulfate proteoglycan concentrated at the NMJ, is the unique acceptor molecule for collagen-tailed AChE at sites of nerve-muscle contact and is the principal mechanism for localizing AChE to the synaptic basal lamina. C1 Univ Miami, Sch Med, Dept Cell Biol & Anat, Miami, FL 33136 USA. Univ Miami, Sch Med, Neurosci Program, Miami, FL 33136 USA. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Rotundo, RL (reprint author), Univ Miami, Sch Med, Dept Cell Biol & Anat, 1600 NW 10th Ave, Miami, FL 33136 USA. FU NIA NIH HHS [R01 AG005917] NR 39 TC 102 Z9 108 U1 1 U2 2 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 2002 VL 5 IS 2 BP 119 EP 123 DI 10.1038/nn801 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 516NB UT WOS:000173558400013 PM 11802174 ER PT J AU Pierce, SK AF Pierce, SK TI Lipid rafts and B-cell activation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID GPI-ANCHORED PROTEINS; ANTIGEN RECEPTOR; T-CELL; CUTTING EDGE; IMMUNOLOGICAL SYNAPSE; LYMPHOCYTE RESPONSES; SIGNAL-TRANSDUCTION; CD19/CD21 COMPLEX; TYROSINE KINASE; PLASMA-MEMBRANE AB The B-cell antigen receptor acts during B-cell activation both to initiate signalling cascades and to transport antigen into the cell for subsequent processing and presentation. Recent evidence indicates that membrane microdomains, termed lipid rafts, have a role in B-cell activation as platforms for B-cell receptor (BCR) signalling and might also act in antigen trafficking. Lipid rafts might facilitate the regulation of the BCR during B-cell development by B-cell co-receptors, and during viral infection. So, lipid rafts seem to be an important new piece of the B-cell signalling puzzle. C1 NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, NIH, Immunogenet Lab, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. NR 56 TC 211 Z9 217 U1 4 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD FEB PY 2002 VL 2 IS 2 BP 96 EP 105 DI 10.1038/nri726 PG 10 WC Immunology SC Immunology GA 635KQ UT WOS:000180398400023 PM 11910900 ER PT J AU Zhou, H Meyer, A Starke, K Gomeza, J Wess, J Trendelenburg, AU AF Zhou, H Meyer, A Starke, K Gomeza, J Wess, J Trendelenburg, AU TI Heterogeneity of release-inhibiting muscarinic autoreceptors in heart atria and urinary bladder: a study with M2- and M4-receptor-deficient mice SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article DE parasympathetic neurons; acetylcholine release; autoreceptors; presynaptic receptors; muscarinic receptors; M-2-receptors; M-4-receptors; knockout mice ID MODULATING ACETYLCHOLINE-RELEASE; RECEPTOR KNOCKOUT MICE; GUINEA-PIG TRACHEA; SEPTOHIPPOCAMPAL CHOLINERGIC SYSTEM; H-3 ACETYLCHOLINE; POSTNATAL-DEVELOPMENT; IN-VITRO; RAT; AUTOINHIBITION; CLASSIFICATION AB Release-inhibiting muscarinic autoreceptors were studied in heart atria and the urinary bladder of NMRI mice, M-2-receptor-deficient mice, M-4-receptor-deficient mice, and wildtype mice sharing the genetic background of the knockout animals. Segments of the tissues were preincubated with H-3-choline and then superfused and stimulated electrically. In atrial segments taken from adult mice and stimulated with 120 pulses at 1 Hz, the muscarinic receptor agonist oxotremorine-M reduced the evoked overflow of tritium. Its concentration-response curves in atria from NMRI, M-2-wildtype, M-4-wildtype and M-2-knockout mice were similar, with maximal inhibition by about 75%. In atria from M-4-knockout mice, the maximal inhibitory effect of oxotremorine-M was reduced to 57%. The concentration-response curves of oxotremorine-M were shifted to the right by ipratropium, methoctramine and pirenzepine. Methoctramine and pirenzepine were approximately equipotent antagonists in all strains except in M-4-knockout atria in which methoctramine was more potent than pirenzepine. When atria from adult NMRI mice were stimulated by 360 pulses at 3 Hz, ipratropium increased the evoked overflow of tritium both in the absence and in the presence of physostigmine (0.1 muM). In atria taken from 1-day-old NMRI mice, oxotremorine-M failed to reduce the evoked overflow of tritium. In bladder segments taken from adult mice, superfused with medium containing oxotremorine-M (1 muM), and stimulated by 360 pulses at 3 Hz, ipratropium increased the evoked overflow of tritium. Its concentration-response curves in preparations from NMRI, M-2-wildtype, M-4-wildtype and M-2-knockout mice were similar. There was one exception: ipratropium failed to cause an increase in bladder pieces from M-4-knockout mice. Methoctramine and pirenzepine also increased the evoked overflow of tritium in all strains except the M-4-knockout, The two antagonists were approximately equipotent in NMRI, M-4-wildtype and M-2-knockout preparations but methoetramine was less potent than pirenzepine in M-2-wildtype preparations. When bladder pieces from adult NMRI mice were superfused with oxotremorine-M-free medium and stimulated by 360 pulses at 3 Hz, ipratropium increased the evoked overflow of tritium in the presence of physostigmine (0.1 muM) but not in its absence. In bladder segments taken from 1-day-old NMRI mice and superfused with medium containing oxotremorine-M (1 muM), ipratropium increased the evoked overflow of tritium in the same way as in adult tissue. It is concluded that NMRI mice and the two wildtype strains are similar in their muscarinic autoreceptors. In atria, the autoreceptors are heterogeneous. Some are M-4. The non-M-4-autoreceptors probably are M-2. In the bladder, the autoreceptors are exclusively M-4. In both tissues, the autoreceptors are activated by previously released acetylcholine under appropriate conditions. C1 Inst Exptl & Klin Pharmakol & Toxikol, D-79104 Freiburg, Germany. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Starke, K (reprint author), Inst Exptl & Klin Pharmakol & Toxikol, Hermann Herder Str 5, D-79104 Freiburg, Germany. NR 43 TC 18 Z9 20 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD FEB PY 2002 VL 365 IS 2 BP 112 EP 122 DI 10.1007/s00210-001-0517-7 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 528HA UT WOS:000174237300005 PM 11819029 ER PT J AU Coelho, VDM Villa-Verde, DMS Farias-De-Oliveira, DA de Brito, JM Dardenne, M Savino, W AF Coelho, VDM Villa-Verde, DMS Farias-De-Oliveira, DA de Brito, JM Dardenne, M Savino, W TI Functional insulin-like growth factor-1/insulin-like growth factor-1 receptor-mediated circuit in human and murine thymic epithelial cells SO NEUROENDOCRINOLOGY LA English DT Article DE insulin-like growth factors; insulin-like growth factor receptors; growth hormone; thymus; thymocytes; extracellular matrix; neuroimmune interactions; lymphocytes; mouse; human ID EXTRACELLULAR-MATRIX COMPONENTS; FACTOR-I; HUMAN THYMOCYTES; GENE-EXPRESSION; NURSE CELLS; HORMONE; MICROENVIRONMENT; LOCALIZATION; ENHANCEMENT; INVITRO AB Interactions between thymocytes and thymic epithelial cell (TEC) can be modulated by growth hormone via insulin-like growth factor-1 (IGF-1). In this study, we showed IGF-1 and IGF-1 receptor mRNA expression by human and murine TEC and thymocytes. Functionally, IGF-1 stimulates extracellular matrix production by human TEC. Moreover, pretreatment of murine TEC with IGF-1 increases their adhesion to thymocytes. Interestingly, we observed an increase in the frequency of CD4-CD8-CD90+ T cells which adhered to pretreated TEC, supporting the concept that IGF-1 may also act indirectly on intrathymic T cell differentiation and migration through the thymic epithelium. Copyright (C) 2002 S. KargerAG. C1 Univ Paris 05, CNRS UMR 8603, Hop Necker Enfants Malad, F-75015 Paris, France. Inst Oswaldo Cruz, Oswaldo Cruz Fdn, Dept Immunol, Lab Thymus Res, BR-20001 Rio De Janeiro, Brazil. NIA, Immunol Lab, Baltimore, MD 21224 USA. Univ Fed Rio de Janeiro, Inst Biomed Sci, Dept Histol & Embryol, Rio De Janeiro, Brazil. RP Savino, W (reprint author), Univ Paris 05, CNRS UMR 8603, Hop Necker Enfants Malad, 161 Rue Sevres, F-75015 Paris, France. RI Brito, Jose/E-2384-2016 NR 58 TC 10 Z9 11 U1 1 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD FEB PY 2002 VL 75 IS 2 BP 139 EP 150 PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 529KP UT WOS:000174298900007 ER PT J AU Pine, DS Grun, J Maguire, EA Burgess, N Zarahn, E Koda, V Fyer, A Szeszko, PR Bilder, RM AF Pine, DS Grun, J Maguire, EA Burgess, N Zarahn, E Koda, V Fyer, A Szeszko, PR Bilder, RM TI Neurodevelopmental aspects of spatial navigation: A virtual reality fMRI study SO NEUROIMAGE LA English DT Article DE navigation; development; adolescence; neuroscience; fMRI ID WORKING-MEMORY; FUNCTIONAL MRI; PREFRONTAL CORTEX; BRAIN ACTIVATION; CHILDREN; NEUROANATOMY; CEREBELLAR; ADULTHOOD; TASK; PET AB Navigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network. (C) 2002 Elsevier Science. C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Hillside Hosp, New York, NY USA. Nathan S Kline Inst Psychiat Res, Ctr Adv Brain Imaging, Orangeburg, NY 10962 USA. UCL, Dept Anat, London, England. UCL, Inst Cognit Neurosci, London, England. UCL, Inst Neurol, Wellcome Dept Cognit Neurol, London, England. RP NIMH, Intramural Res Program, Bldg 10,Room 4N-222,MSC1381, Bethesda, MD 20892 USA. RI Burgess, Neil/B-2420-2009; Szeszko, Philip/G-9336-2013; Bilder, Robert/A-8894-2008 OI Burgess, Neil/0000-0003-0646-6584; Bilder, Robert/0000-0001-5085-7852 FU NIMH NIH HHS [MH-43878, MH-01391] NR 57 TC 60 Z9 60 U1 1 U2 23 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2002 VL 15 IS 2 BP 396 EP 406 DI 10.1006/nimg.2001.0988 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 518XC UT WOS:000173692500009 PM 11798274 ER PT J AU Shen, DG Moffat, S Resnick, SM Davatzikos, C AF Shen, DG Moffat, S Resnick, SM Davatzikos, C TI Measuring size and shape of the hippocampus in MR images using a deformable shape model SO NEUROIMAGE LA English DT Article ID MESIAL TEMPORAL SCLEROSIS; LOBE EPILEPSY; BRAIN IMAGES; SEGMENTATION; MORPHOMETRY; GEOMETRY AB A method for segmentation and quantification of the shape and size of the hippocampus is proposed, based on an automated image analysis algorithm. The algorithm uses a deformable shape model to locate the hippocampus in magnetic resonance images and to determine a geometric representation of its boundary. The deformable model combines three types of information. First, it employs information about the geometric properties of the hippocampal boundary, from a local and relatively finer scale to a more global and relatively coarser scale. Second, the model includes a statistical characterization of normal shape variation across individuals, serving as prior knowledge to the algorithm. Third, the algorithm utilizes a number of manually defined boundary points, which can help guide the model deformation to the appropriate boundaries, wherever these boundaries are weak or not clearly defined in MR images. Excellent agreement is demonstrated between the algorithm and manual segmentations by well-trained raters, with a correlation coefficient equal to 0.97 and algorithm/rater differences statistically equivalent to interrater differences for manual definitions. (C) 2002 Elsevier Science. C1 Johns Hopkins Univ, Sch Med, Ctr Biomed Image Comp, Dept Radiol, Baltimore, MD 21287 USA. NIA, Lab Personal & Cognit, Bethesda, MD 20892 USA. RP Johns Hopkins Univ, Sch Med, Ctr Biomed Image Comp, Dept Radiol, Baltimore, MD 21287 USA. FU NIA NIH HHS [NIH-AG-93-07, R01-AG14971] NR 32 TC 84 Z9 84 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2002 VL 15 IS 2 BP 422 EP 434 DI 10.1006/nimg.2001.0987 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 518XC UT WOS:000173692500011 PM 11798276 ER PT J AU Kim, M Jeong, HJ Kao, CHK Yao, ZS Paik, DS Pie, JE Kobayashi, H Waldmann, TA Carrasquillo, JA Paik, CH AF Kim, M Jeong, HJ Kao, CHK Yao, ZS Paik, DS Pie, JE Kobayashi, H Waldmann, TA Carrasquillo, JA Paik, CH TI Improved renal clearance and tumor targeting of Tc-99m-labeled anti-Tac monoclonal antibody Fab by chemical modifications SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Tc-99m-MAG3-antibody fragments; acylation; rapid renal clearance; tumor targeting ID STABILIZED FV FRAGMENT; AMINO-ACID INFUSION; SOMATOSTATIN ANALOG; BIODISTRIBUTION; TC-99M; CATABOLISM; REDUCTION; THERAPY; CANCER; RATS AB This study was undertaken to improve the renal clearance and tumor targeting properties of Tc-99m-labeled humanized anti-Tac (HuTac) monoclonal antibody Fab fragments using two chemical approaches: 1) labeling with a renal secretion agent Tc-99m-mercaptoacetyltrialycine (MAG3) and 2) lowering its isoelectric point (pI) by acylation. HuTac Fab (3.3 mg/mL) was reacted with a trifluorophenyl ester (TFP) of Tc-99m-MAG3 alone or was additionally reacted with TFP-glycolate to reduce the pI. In Balb/c mice, Tc-99m-MAG3-Fab (pI > 9.3) rapidly accumulated in the kidneys (177% injected dose [ID]/g at 15 min) and then gradually cleared out of the kidneys. In contrast, the glycolation (pI 4.6-6.6) drastically reduced the renal uptake (31% ID/g) and also the whole-body retention (82% ID vs 101% for the nonglycolated) at 15 min, indicating that the glycolated Tc-99m-MAG3-Fab (pI 4.6-6.6) was rapidly excreted. The glycolated remained in the blood longer than the nonglycolated (1.2% vs 0.3% ID/g at 360 min), but this effect was less drastic than the effect shown on the renal uptake. In nude mice bearing receptor-positive (ATAC4) tumors, the glycolated (99m)-Tc-MAG3-Fab increased the peak tumor uptake to 14.8% ID/g from 8.3% ID/g for Tc-99m-MAG3-Fab, whereas the glycolation resulted in a drastic reduction of the renal uptake at 15 min. We demonstrated that the renal clearance and the tumor targeting of Fab could be optimized by chemical modifications. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), Korea Univ, Sch Med, Dept Biochem & Mol Biol, Seoul 136705, South Korea. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 45 TC 13 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD FEB PY 2002 VL 29 IS 2 BP 139 EP 146 DI 10.1016/S0969-8051(01)00296-7 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 521EX UT WOS:000173827200001 PM 11823118 ER PT J AU Selzer, RR Nyaga, S Tuo, JS May, A Muftuoglu, M Christiansen, M Citterio, E Brosh, RM Bohr, VA AF Selzer, RR Nyaga, S Tuo, JS May, A Muftuoglu, M Christiansen, M Citterio, E Brosh, RM Bohr, VA TI Differential requirement for the ATPase domain of the Cockayne syndrome group B gene in the processing of UV-induced DNA damage and 8-oxoguanine lesions in human cells SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; NUCLEOTIDE EXCISION-REPAIR; HAMSTER OVARY CELLS; XERODERMA-PIGMENTOSUM; PREFERENTIAL REPAIR; ELONGATION COMPLEXES; PUTATIVE HELICASES; STIMULATED ATPASE; INDUCED APOPTOSIS AB Cockayne syndrome (CS) is a rare inherited human genetic disorder characterized by UV sensitivity, developmental abnormalities and premature aging. The cellular and molecular phenotypes of CS include increased sensitivity to oxidative and UV-induced DNA lesions. The CSB protein is thought to play a pivotal role in transcription-coupled repair and CS-B cells are defective in the repair of the transcribed strand of active genes, both after exposure to UV and in the presence of oxidative DNA lesions. A previous study has indicated that a conserved helicase ATPase motif II residue is essential for the function of the CSB protein in responding to UV-induced DNA damage in a hamster cell line. Due to the limitations in studying a complex human disorder in another species, this study introduced the site-directed mutation of the ATPase motif II in the human CSB gene in an isogenic human cell line. The CSB mutant allele was tested for genetic complementation of UV-sensitive phenotypes in the human CS-B cell line CS1AN.S3.G2. In addition, the incision of an 8-oxoguanine lesion by extracts of the CS-B cell lines stably transfected with the wild-type or ATPase mutant CSB gene has been investigated. The ATPase motif II point mutation (E646Q) abolished the function of the CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery and apoptosis. Interestingly, whole-cell extract prepared from these mutant cells retained wild-type incision activity on an oligonucleotide containing a single 8-oxoguanine lesion, whereas the absence of the CSB gene altogether resulted in reduced incision activity relative to wild-type. These results suggest damage-specific functional requirements for CSB in the repair of UV-induced and oxidative lesions in human cells. The transfection of the mutant or wild-type CSB gene into the CS1AN.S3.G2 cells did not alter the expression of the subset of genes examined by cDNA array analysis. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Hacettepe Univ, Sch Med, Dept Biochem, Ankara, Turkey. Aarhus Univ, Dept Biol Mol & Struct, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. Erasmus Univ, Dept Cell Biol & Genet, Ctr Med Genet, NL-3000 DR Rotterdam, Netherlands. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 53 TC 49 Z9 51 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 2002 VL 30 IS 3 BP 782 EP 793 DI 10.1093/nar/30.3.782 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 517WK UT WOS:000173633300024 PM 11809892 ER PT J AU Reid, BC Alberg, AJ Klassen, AC Rozier, RG Garcia, I Winn, DM Samet, JM AF Reid, BC Alberg, AJ Klassen, AC Rozier, RG Garcia, I Winn, DM Samet, JM TI A comparison of three comorbidity indexes in a head and neck cancer population SO ORAL ONCOLOGY LA English DT Article DE comorbidity; survival; epidemiology; head and neck neoplasms; age > 65 years ID SEVERITY STAGING SYSTEM; 5-YEAR SURVIVAL RATES; ADMINISTRATIVE DATA; CO-MORBIDITY; VALIDATION; MORTALITY; MEDICARE AB We explored differences in prognostic ability for mortality of the established and validated Charlson comorbidity index with two other comorbidity indexes developed for this study. Our study was limited to persons diagnosed with HNCA between 1985 and 1993 in a database formed by a linkage of files from the National Cancer Institute's Surveillance, Epidemiology, and End Results Pro-ram with Health Care Finance Administration Medicare files (n=9386). Adjusted relative risks (RR) and 95% confidence intervals (95%CI) for comorbidity index scores of I or more compared to 0 were (RR = 1.50, 95% Cl 1.43-1.68) Charlson index, (RR = 1.53 95% CI 1.42-1.66) HNCA index, and (RR = 1.49, 95% CI 1.32-1.68) ATC index, respectively. The Charlson and HNCA indexes displayed dose-response patterns (P-value for trend <0.0001). Although the ATC index appears promising, the HNCA and Charlson indexes had similar adjusted RR's, dose-response patterns, P-values, and chi-square scores and appear particularly well-suited to the measurement of comorbidity. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Maryland, Sch Dent, Dept Oral Hlth Care Delivery, Baltimore, MD 21201 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Univ N Carolina, Sch Publ Hlth, Dept Hlth Policy & Adm, Chapel Hill, NC 27599 USA. NIDCR, NIH, Off Director, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Reid, BC (reprint author), Univ Maryland, Sch Dent, Dept Oral Hlth Care Delivery, Rm 3E-04 666 W Baltimore St, Baltimore, MD 21201 USA. FU NCI NIH HHS [CA73790]; NIDCR NIH HHS [T32 DE-7255] NR 23 TC 27 Z9 27 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD FEB PY 2002 VL 38 IS 2 BP 187 EP 194 AR PII S1368-8375(01)00044-6 DI 10.1016/S1368-8375(01)00044-6 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 533XD UT WOS:000174554800010 PM 11854067 ER PT J AU Yogev, R Lee, S Wiznia, A Nachman, S Stanley, K Pelton, S Mofenson, L Fiscus, S Jimenez, E Rathore, MH Smith, ME Song, LY McIntosh, K AF Yogev, R Lee, S Wiznia, A Nachman, S Stanley, K Pelton, S Mofenson, L Fiscus, S Jimenez, E Rathore, MH Smith, ME Song, LY McIntosh, K CA Pediat AIDS Clinical Trials Grp 33 TI Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE human immunodeficiency virus; children; stavudine; nevirapine; ritonavir; zidovudine; lamivudine; protease inhibitor; nucleoside analogue reverse transcriptase inhibitor ID TYPE-1 RNA; VIRAL LOAD; HIV-1-INFECTED CHILDREN; CONTROLLED TRIAL; HIV-1 INFECTION; PLASMA; DISEASE; QUANTITATION; INFANTS; ZIDOVUDINE AB Background. The efficacy and tolerance of switching from zidovudine (ZDV) and lamivudine (3TC) in clinically stable HIV-infected children with incomplete viral suppression to stavudine (d4T), nevirapine (NVP) and ritonavir (RTV) has not been determined. Aim. To evaluate the safety, tolerance, antiviral activity and immunologic changes after the change to a three drug combination. Methods. During a clinical trial in which HI[V. infected antiretroviral-experienced children were initially randomized to receive d4T/RTV, ZDV/3TC/RTV or ZDV/3TC (Step 1), 48 children who had HIV RNA :greater than or equal to10 000 copies/ml after greater than or equal to12 weeks of ZDV/3TC therapy in Step 1 were switched to d4T/NVP/RTV in Step 2. The proportion of children receiving therapy with HIV RNA :less than or equal to400 copies/ml at Study Weeks 24 and 48 receiving d4T/NVP/RTV in Step 2 were compared with children receiving RTV-containing regimens in Step 1. Results. At 24 weeks of treatment with d4T/ NVP/RTV in Step 2,48% (23 of 48) of children had HIV RNA less than or equal to400 copies/ml. compared with 34% (31 of 92) and 47% (44 of 93) receiving d4T/RTV or ZDV/3TC/RTV for 24 weeks in Step 1; at 48 weeks virologic response was 44, 27 and 42% in Step 2 d4T/NVP/RTV, Step 1 d4T/RTV and Step 1 ZDV/ 3TC/RTV arms, respectively. Conclusions. A delay of 7 to 12 months in the initiation of protease inhibitor-containing combination therapy in children receiving dual nucleoside analogue therapy did not adversely affect the RNA response during the first 48 weeks of treatment. C1 Childrens Mem Hosp, Div Infect Dis, Chicago, IL 60614 USA. Boston Med Ctr, Sect Pediat Infect Dis, Boston, MA USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Jacobi Med Ctr, Dept Pediat, Bronx, NY USA. SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Div Aids, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. San Juan City Hosp, Dept Pediat, Suan Juan, PR USA. Univ Florida, Hlth Sci Ctr, Dept Pediat, Jacksonville, FL 32209 USA. RP Yogev, R (reprint author), Childrens Mem Hosp, Div Infect Dis, 2300 Childrens Plaza,Box 155, Chicago, IL 60614 USA. OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [AI-27559, AI41110]; PHS HHS [97PVC06] NR 27 TC 7 Z9 7 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2002 VL 21 IS 2 BP 119 EP 125 DI 10.1097/00006454-200202000-00007 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 524ZT UT WOS:000174043300006 PM 11840078 ER PT J AU Huizing, M Scher, CD Strovel, E Fitzpatrick, DL Hartnell, LM Anikster, Y Gahl, WA AF Huizing, M Scher, CD Strovel, E Fitzpatrick, DL Hartnell, LM Anikster, Y Gahl, WA TI Nonsense mutations in ADTB3A cause complete deficiency of the beta 3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2 SO PEDIATRIC RESEARCH LA English DT Article ID PLATELET DENSE GRANULES; PALE EAR EP; OCULOCUTANEOUS ALBINISM; LOCUS HETEROGENEITY; VESICLE FORMATION; AP-3 ADAPTER; HPS GENE; PROTEIN; TRAFFICKING; MELANOSOMES AB Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disease consisting of oculocutaneous albinism and a storage pool deficiency resulting from absent platelet dense bodies. The disorder is genetically heterogeneous. The majority of patients, including members of a large genetic isolate in northwest Puerto Rico, have mutations in HPS1 Another gene, ADTB3A, was shown to cause HPS-2 in two brothers having compound heterozygous mutations that allowed for residual production of the gene product, the beta3A subunit of adaptor complex-3 (AP-3). This heterotetrameric complex serves as a coat protein-mediating formation of intracellular vesicles, e.g. the melanosome and platelet dense body, from membranes of the transGolgi network. We determined the genomic organization of the human ADTB3A gene, with intron/exon boundaries, and describe a third patient with beta3A deficiency. This 5-y-old boy has two nonsense mutations, C1578T (R-->X) and G2028T (E-->X), which produce no ADTB3A mRNA and no beta3A protein. The associated mu3 subunit of AP-3 is also entirely absent. In fibroblasts, the cell biologic concomitant of this deficiency is robust and aberrant trafficking through the plasma membrane of LAMP-3, an integral lysosomal membrane protein normally carried directly to the lysosome. The clinical concomitant is a severe, G-CSF-responsive neutropenia. in addition to oculocutaneous albinism and platelet storage pool deficiency. Our findings expand the molecular, cellular, and clinical spectrum of HPS-2 and call for an increased index of suspicion for this diagnosis among patients with features of albinism, bleeding, and neutropenia. C1 NICHHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Tulane Univ, Sch Med, Dept Pediat, Hematol Oncol Sect, New Orleans, LA 70112 USA. RP Gahl, WA (reprint author), NICHHD, NIH, 10 Ctr Dr,MSC 1830,Bldg 10,Room 9S-241, Bethesda, MD 20892 USA. NR 41 TC 81 Z9 84 U1 0 U2 3 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 2002 VL 51 IS 2 BP 150 EP 158 DI 10.1203/00006450-200202000-00006 PG 9 WC Pediatrics SC Pediatrics GA 515KF UT WOS:000173493900006 PM 11809908 ER PT J AU Overpeck, MD Brenner, RA Cosgrove, C Trumble, AC Kochanek, K MacDorman, M AF Overpeck, MD Brenner, RA Cosgrove, C Trumble, AC Kochanek, K MacDorman, M TI National underascertainment of sudden unexpected infant deaths associated with deaths of unknown cause SO PEDIATRICS LA English DT Article DE SIDS; infant injury fatalities; infant homicide; underascertainment; risk factors; child fatality reviews ID UNITED-STATES; CHILD-ABUSE; MORTALITY; HOMICIDE; INJURY; RISK AB Objective. To investigate underascertainment of unexpected infant deaths at the national level as a result of probable classification as attributable to unknown cause. Methods. Using linked birth and death certificates for all US birth cohorts from 1983-1991 and 1995-1996, we identified 53 470 sudden infant death syndrome (SIDS) fatalities, 9071 unintentional injury deaths, 3473 injury deaths classified with intentional or suspicious intent, and 8097 deaths with unknown underlying cause. For these deaths, we compared relative risks (RRs) for maternal and infant variables available on birth certificates known to be predictive of SIDS, unintentional injury, and homicides. Variables available on death certificates were compared for unlinked and linked records. Factors related to state and national management of cases pending final cause determination are reviewed. Results. For deaths from unknown cause, rates were consistently high among the same risk groups that have been shown to be at increased risk for SIDS, unintentional injury, and homicides. For most risk factors, RRs for deaths attributable to unknown causes were somewhat lower than for RRs for intentional/suspicious injury deaths but higher than for SIDS or unintentional injury, indicating combined contributions from all causes. For example, age at death from unknown cause includes RRs that more strongly resemble patterns of intentional/suspicious injuries than SIDS or unintentional injury. Deaths from unknown cause were more likely to occur during the first week of life for unattended births occurring outside clinical settings or when birth certificates were not found, similar to intentional/suspicious injury deaths. Conclusions. Risk profiles indicate that deaths of unknown cause are likely to represent a mixture of unexpected deaths. The process for determination of cause of unexpected death affects national underascertainment of SIDS and injury deaths. Better coordination among child fatality review teams and local, state, and national officials should reduce underascertainment and improve documentation of circumstances surrounding deaths for prevention efforts. C1 Maternal & Child Hlth Bur, US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Overpeck, MD (reprint author), Maternal & Child Hlth Bur, US Hlth Resources & Serv Adm, 5600 Fishers Ln,Room 18-41, Rockville, MD 20857 USA. NR 37 TC 33 Z9 34 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2002 VL 109 IS 2 BP 274 EP 283 DI 10.1542/peds.109.2.274 PG 10 WC Pediatrics SC Pediatrics GA 517FV UT WOS:000173601200036 PM 11826207 ER PT J AU Lindsay, RS Cook, V Hanson, RL Salbe, AD Tataranni, A Knowler, WC AF Lindsay, RS Cook, V Hanson, RL Salbe, AD Tataranni, A Knowler, WC TI Early excess weight gain of children in the Pima Indian population SO PEDIATRICS LA English DT Article DE Pima; Native American; body mass index; obesity ID BODY-MASS INDEX; OBESITY; GROWTH; ADOLESCENTS; CHILDHOOD; NUTRITION; PREGNANCY; INFANTS; WOMEN AB Objective. To determine the period of childhood in which weight relative to height increases in Pima Indian children and young adults in comparison with the general US population. Methods. Heights and weights of children in the Pima Indian population were derived from either clinical examinations conducted by the Department of Public Health Nursing (from 1-48 months of age), or from examinations in the National Institutes of Health longitudinal survey of health in the Pima population (for birth and ages 5-20 years), and compared with standards for the US population recently published by the National Center for Health Statistics. Results. Weight relative to height (weight-for-length in children aged <24 months, body mass index at ages &GE; 2 years) was significantly higher in Pima children at all ages examined after the first month of life. Compared with reference values, the most dramatic increases in weight relative to height occurred in 2 stages of childhood: mean z scores of weight-for-length increased between 1 month (mean +/- SEM: males: -0.2 +/- 0.19; females: -0.02 +/- 0.14) and 6 months (males: 0.8 +/- 0.04; females: 0.7 +/- 0.04) of age; mean z scores for body mass index increased gradually between 2 years (males: 0.4 +/- 0.06; females: 0.4 +/- 0.08) and 11 years (males: 1.4 +/- 0.08; females: 1.4 +/- 0.08) and remained stable thereafter. Conclusion. Excessive weight gain occurs early in the Pima population with changes relative to reference values most marked in the first 6 months of life and between 2 and 11 years. Interventions toward primary prevention of obesity may need to be targeted at children rather than adults in this population. C1 NIDDKD, NIH, Phoenix, AZ 85014 USA. Gila River Indian Community, Dept Publ Hlth Nursing, Sacaton, AZ USA. RP Lindsay, RS (reprint author), NIDDKD, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 25 TC 26 Z9 27 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2002 VL 109 IS 2 AR e33 DI 10.1542/peds.109.2.e33 PG 6 WC Pediatrics SC Pediatrics GA 517FV UT WOS:000173601200015 PM 11826243 ER PT J AU Mannon, PJ AF Mannon, PJ TI Peptide YY as a growth factor for intestinal epithelium SO PEPTIDES LA English DT Article DE peptide YY; receptor; growth; epidermal growth factor receptor; mitogen-activated protein kinase; epithelium ID PROTEIN-KINASE-C; SMOOTH-MUSCLE CELLS; STIMULATED ION-TRANSPORT; RABBIT DISTAL COLON; NEUROPEPTIDE-Y; FACTOR RECEPTOR; COUPLED RECEPTORS; PERTUSSIS TOXIN; EGF RECEPTOR; SMALL-BOWEL AB Peptide YY is an abundant distal gut hormone that may play a significant role in intestinal epithelial proliferation. Gut epithelial cells express specific receptors for PYY. PYY induces proliferation in intestinal cells in vivo and in vitro. and the Y1 receptor subtype couples to mitogenic signaling pathways. In addition to proposed physiologic effects on gut mucosal maintenance, PYY proliferative effects may be hypothesized to contribute to pathophysiologic consequences of stimulated growth. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Mannon, PJ (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, 10 Ctr Dr,Rm 11N238, Bethesda, MD 20892 USA. NR 74 TC 20 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2002 VL 23 IS 2 BP 383 EP 388 AR PII S0196-9781(01)00615-5 DI 10.1016/S0196-9781(01)00615-5 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 522QD UT WOS:000173907700015 PM 11825653 ER PT J AU Kasuya, Y Lu, ZR Kopeckova, P Tabibi, SE Kopecek, J AF Kasuya, Y Lu, ZR Kopeckova, P Tabibi, SE Kopecek, J TI Influence of the structure of drug moieties on the in vitro efficacy of HPMA copolymer-geldanamycin derivative conjugates SO PHARMACEUTICAL RESEARCH LA English DT Article DE geldanamycin; N-(2-hydroxypropyl)methacrylamide copolymers; ovarian carcinoma; drug delivery system; aqueous two phase system; cathepsin B ID CATHEPSIN-B; N-(2-HYDROXYPROPYL)METHACRYLAMIDE COPOLYMERS; ANTIPROLIFERATIVE ACTIVITY; BOUND ADRIAMYCIN; ANTITUMOR AGENT; BOVINE SPLEEN; LIPOSOMES; MECHANISM; DESIGN; TARGET AB Purpose. To optimize the structure of geldanamycin (GDM) derivative moieties attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via an enzymatically degradable spacer. Methods HPMA copolymers containing different AR-GDM (AR=3-aminopropyl (AP), 6-aminohexyl (AH), and 3-amino-2-hydroxypropyl AP(OH)) were synthesized and characterized. Their cytotoxicity towards the A2780 human ovarian carcinoma cells was evaluated. Results The cytotoxic efficacy of HPMA copolymer-AR-GDM conjugates depended on the structure of AR-GDM. Particularly, HPMA copolymer-bound AH-GDM, which possessed the longest substituent at the 17-position, demonstrated the highest efficacy among the polymer-bound GDM derivatives; however the activity of free AH-GDM was lower than that of the other free AR-GDMs. The relative increase of the activity of macromolecular AH-GDM when compared to AP-GDM or AP(OH)-GDM correlated with the enhanced recognition of AH-GDM terminated oligopeptide side-chains by the active site of the lysosomal enzyme, cathepsin B. Drug stability and further stabilization upon binding to HPMA copolymer also contributed to the observed phenomena. Conclusions AH-GDM was found to be a suitable GDM derivative for the design of a drug delivery system based on HPMA copolymers and enzymatically-degradable spacers. C1 Univ Utah, CCCD, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA. Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. NCI, Pharmaceut Resources Branch, NIH, Bethesda, MD 20892 USA. RP Kopecek, J (reprint author), Univ Utah, CCCD, Dept Pharmaceut & Pharmaceut Chem, Salt Lake City, UT 84112 USA. FU NCI NIH HHS [CA51578] NR 32 TC 28 Z9 29 U1 0 U2 5 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD FEB PY 2002 VL 19 IS 2 BP 115 EP 123 AR UNSP 0724-8741/02/0200-0115/0 DI 10.1023/A:1014216712820 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 525DW UT WOS:000174054300001 PM 11883637 ER PT J AU Inbaraj, JJ Bilski, P Chignell, CF AF Inbaraj, JJ Bilski, P Chignell, CF TI Photophysical and photochemical studies of 2-phenylbenzimidazole and UVB sunscreen 2-phenylbenzimidazole-5-sulfonic acid SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID ELECTRON-SPIN-RESONANCE; CUTANEOUS PHOTOSENSITIZING AGENTS; SINGLET MOLECULAR-OXYGEN; FREE-RADICALS; ENERGY-TRANSFER; SKIN-CANCER; SUPEROXIDE; FLUORESCENCE; PHOTOLYSIS; OXIDATION AB The sunscreen agent 2-phenylbenzimidazole-5-sulfonic acid (PBSA) and its parent 2-phenylbenzimidazole (PBI) cause DNA photodamage via both Type-I and Type-II mechanisms when UVB irradiated. We have studied the photophysical and photochemical properties of these compounds and their ability to photogenerate reactive oxygen species including free radicals. PBI and PBSA exhibit both oxidizing and reducing properties in their excited state. The absorption and fluorescence properties of PBSA depend strongly upon pH, and hence the photochemistry of PBSA was studied in both neutral and alkaline solutions. PBSA showed strong oxidizing properties when UV irradiated in neutral aqueous solution (pH 7.4) in the presence of cysteine, glutathione and azide, as evidenced by the detection of the corresponding S-cysteinyl, glutathiyl and azidyl radicals with the aid of the spin trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO). However, when an aqueous anaerobic solution (pH 10) of PBSA and either nitromethane (NM) or 4-nitrobenzoic acid (4-NBA) were irradiated, the corresponding nitro anion radicals were observed. This finding suggests that both NM and 4-NBA are reduced by direct electron transfer from the excited state PBSA. During UV irradiation of an aerobic solution of PBSA, O-2(.) and (OH)-O-. radical were generated and trapped by DMPO. Further, PBI (in ethanol) and PBSA (in ethylene glycol : water 2: 1 mixture) showed low temperature (77 K) phosphorescence (lambda(max) = 443, 476 and 509 nm) and also an electron paramagnetic resonance half-field transition (DeltaM(s) = +/-2), which is evidence for a triplet state. This triplet produced singlet oxygen (O-1(2)) with quantum yields 0.07 and 0.04 in MeCN for PBI and PBSA, respectively. These studies demonstrate that UV irradiation of PBSA and PBI generates a variety of free radicals and active oxygen species that may be involved in the photodamage of DNA. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Chignell, CF (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. NR 42 TC 46 Z9 47 U1 3 U2 10 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 2002 VL 75 IS 2 BP 107 EP 116 DI 10.1562/0031-8655(2002)075<0107:PAPSOP>2.0.CO;2 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 526CU UT WOS:000174111500004 PM 11883597 ER PT J AU Roberts, JE Kukielczak, BM Hu, DN Miller, DS Bilski, P Sik, RH Motten, AG Chignell, CF AF Roberts, JE Kukielczak, BM Hu, DN Miller, DS Bilski, P Sik, RH Motten, AG Chignell, CF TI The role of A2E in prevention or enhancement of light damage in human retinal pigment epithelial cells SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID SINGLET OXYGEN; BLUE-LIGHT; MACULAR DEGENERATION; LIPOFUSCIN FLUOROPHORE; MOLECULAR-OXYGEN; BINDING PROTEIN; AGE PIGMENT; DNA-DAMAGE; OXIDATION; A2-E AB The process of sight (photostasis) produces, as a by-product, a chromophore called 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1- (2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclo-hexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E), whose function in the eye has not been defined as yet. In youth and adulthood, A2E is removed from human retinal pigment epithelial (h-RPE) cells as it is made, and so it is present in very low concentrations, but with advanced age, it accumulates to concentrations reaching 20 muM. In the present study we have used photophysical techniques and in vitro cellular measurements to explore the role of A2E in h-RPE cells. We have found that A2E has both pro- and antioxidant properties. It generated singlet oxygen (Phi(80) = 0.004) much less efficiently than its precursor traps-retinal (Phi(80) = 0.24). It also quenched ringlet oxygen at a rate (10(8) M-1 s(-1)) equivalent to two other endogenous quenchers of reactive oxygen species in the eye: alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C). The endogenous singlet oxygen quencher lutein, whose quenching rate is two orders of magnitude greater than that of A2E, completely prevented light damage in vitro, suggesting that singlet oxygen does indeed play a role in light-induced damage to aged human retinas. We have used multiphoton confocal microscopy and the comet assay to measure the toxic, phototoxic and protective capacity of A2E in h-RPE cells. At 1-5 muM, A2E protected these cells from UV-induced breaks in DNA; at 20 muM, A2E no longer exerted this protective effect. These results imply that the role of A2E is not simple and may change over the course of a lifetime. A2E itself may play a protective role in the young eye but a toxic role in older eyes. C1 Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. NIEHS, Lab Chem & Pharmacol, Res Triangle Pk, NC 27709 USA. New York Eye & Ear Infirm, Dept Pathol & Lab Med, Tissue Culture Ctr, New York, NY 10003 USA. New York Eye & Ear Infirm, Dept Ophthalmol, Tissue Culture Ctr, New York, NY 10003 USA. RP Roberts, JE (reprint author), Fordham Univ, Dept Nat Sci, 113 W 60th St, New York, NY 10023 USA. NR 74 TC 52 Z9 53 U1 0 U2 5 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 2002 VL 75 IS 2 BP 184 EP 190 DI 10.1562/0031-8655(2002)075<0184:TROAIP>2.0.CO;2 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 526CU UT WOS:000174111500015 PM 11883606 ER PT J AU Cui, KR Li, J Xing, GM Li, JL Wang, LH Wang, YF AF Cui, KR Li, J Xing, GM Li, JL Wang, LH Wang, YF TI Effect of hydrogen peroxide on synthesis of proteins during somatic embryogenesis in Lycium barbarum SO PLANT CELL TISSUE AND ORGAN CULTURE LA English DT Article DE hydrogen peroxide; in vitro translation; Lycium barbarum L.; somatic embryogenesis; synthesis of proteins ID GENE-EXPRESSION; CELL PROLIFERATION; OXIDATIVE BURST; SALICYLIC-ACID; DEFENSE; SIGNAL; TRANSDUCTION; ACCUMULATION; RESISTANCE; INDUCTION AB Direct exposure of calluses of Lycium barbarum L. to an auxin-free medium can induce somatic embryogenesis. The effect of hydrogen peroxide on synthesis of proteins during somatic embryogenesis in Lycium barbarum L. was studied. One-dimensional gel electrophoresis showed that new protein was synthesized by embryogenic callus II (in MS+200 mumol l(-1) H2O2 medium). Therefore, we suggested that there was a synthesis of H2O2-induced protein during somatic embryogenesis of Lycium barbarum L. Cycloheximide and actinomycin D prevented the synthesis of the new protein (H2O2-induced) effectively. The results of two-dimensional gel electrophoresis showed that the differences in the protein patterns between embryogenic callus occurred at 35similar to55 kDa with a pI-level of about 5similar to6. Changes at the transcriptional level in embryogenic callus I and II were analyzed by comparing in vitro translation patterns. The results showed that several new in vitro-translated proteins were found in embryogenic callus treated with hydrogen peroxide. It suggests that the exogenous added H2O2 induced genes expression at the mRNA level during somatic embryogenesis of Lycium barbarum L. C1 Lanzhou Univ, State Key Lab Arid Agroecol, Lanzhou 730000, Peoples R China. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP ARS, Mol Plant Pathol Lab, USDA, Beltsville, MD 20705 USA. EM cuiusda@hotmail.com NR 35 TC 6 Z9 11 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6857 EI 1573-5044 J9 PLANT CELL TISS ORG JI Plant Cell Tissue Organ Cult. PD FEB PY 2002 VL 68 IS 2 BP 187 EP 193 PG 7 WC Biotechnology & Applied Microbiology; Plant Sciences SC Biotechnology & Applied Microbiology; Plant Sciences GA 512XN UT WOS:000173349000009 ER PT J AU Kane, AA Butman, JA Mullick, R Skopec, M Choyke, P AF Kane, AA Butman, JA Mullick, R Skopec, M Choyke, P TI A new method for the study of velopharyngeal function using gated magnetic resonance imaging SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID VOCAL-TRACT; BREATH-HOLD; MRI; QUANTIFICATION AB The purpose of this project was to assess the feasibility of imaging the velopharynx of adult volunteers during repetitive speech, using gated magnetic resonance imaging (MRI). Although a number of investigators have used conventional MRI in the study of the human vocal tract, the mismatch between the lengthy time necessary to acquire sufficiently detailed images and the rapidity of movement of the vocal tract during speech has forced investigators to acquire images either while the subject is at rest or during sustained utterances. The technique used here acquired a portion of each image during repetitive Utterances, building the full image over multiple utterance cycles. The velopharyngeal portal was imaged on a 1.5-Tesla GE Signa LX 8.2 platform With gated fast spoiled gradient echo protocol. An external 1-Hertz trigger was fed to the cardiac gate. Subjects synchronized utterance of consonant-vowel syllables to a flashing light synchronized with the external trigger. Each acquisition of 30 phases per second at a single-slice location took 22 to 29 seconds. Four consonant-vowel syllables (/pa/, /ma/, /sa/, and /ka/) were evaluated. Subjects vocalized throughout the acquisition, beginning 5 to 6 seconds beforehand to establish a regular rhythm. Imaging of the velopharyngeal portal was performed for sagittal, velopharyngeal axial (aligned perpendicular to the "knee" of the velum), axial, and coronal planes. Volumes were obtained by sequential acquisition of six to 10 slices (each with 30 phases) in the axial or sagittal planes during repetition of the /pa/ syllable. Spatiotemporal volumes of the single-slice data were sectioned to provide time-motion images (analogous to M-mode echocardiograms). Three-dimensional dynamic Volume renderings of palate motion were displayed interactively (Vortex; CieMed, Singapore). A method suitable for the collection and visualization of four-dimensional information regarding monosyllabic speech using gated MRI was developed. These techniques were applied to a Population of adult volunteer subjects with no history of speech problems and two patients with a history of cleft lip and palate. The techniques allowed good real-time visualization of velopharyngeal anatomy during its entire range of motion and was also able to image pathology-specific anatomic differences in the subjects with cleft lip and cleft palate. These methods may be applicable to a wide spectrum of problems in speech physiology research and for clinical decision-making regarding surgery for speech and outcomes analysis. C1 NIH, Imaging Sci Training Program, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kane, AA (reprint author), Washington Univ, Sch Med, St Louis Childrens Hosp, Cleft Palate & Craniofacial Deform Inst,Div Plast, 1 Childrens Pl,Suite 11 W 7, St Louis, MO 63110 USA. EM kanea@msnotes.wustl.edu RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 NR 24 TC 31 Z9 31 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2002 VL 109 IS 2 BP 472 EP 481 DI 10.1097/00006534-200202000-00010 PG 10 WC Surgery SC Surgery GA 518PX UT WOS:000173678000010 PM 11818823 ER PT J AU Kloczkowski, A AF Kloczkowski, A TI Application of statistical mechanics to the analysis of various physical properties of elastomeric networks - a review SO POLYMER LA English DT Review DE elastomeric networks; physical properties; statistical mechanics ID AMORPHOUS POLYMER NETWORKS; EXCLUDED VOLUME INTERACTION; DIFFUSED-CONSTRAINT THEORY; RUBBER ELASTICITY THEORY; GAUSSIAN MOLECULES; NEUTRON-SCATTERING; RODLIKE PARTICLES; CARBON-BLACK; STRAIN BIREFRINGENCE; PHANTOM NETWORKS AB This paper examines the application of the statistical mechanics to the analysis of various physical properties of the elastomeric networks. The equilibrium properties of rubber-like networks are discussed, and also some dynamic properties, such as the relaxation spectrum of Gaussian networks. The paper covers a large spectrum of properties of polymer networks such as: fluctuations and chain dimensions in unimodal and bimodal network, effects of entanglements and constraints on the elastic properties of the network, segmental orientation, liquid-crystalline networks, small angle neutron scattering from networks, strain birefringence, elastic properties of filled networks, strain induced crystallization etc. The paper shows that the statistical mechanics can be successfully used to the analysis of almost all physical properties of rubber-like networks. (C) 2001 Published by Elsevier Science Ltd. C1 NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. RP NCI, Lab Expt & Computat Biol, NIH, 12 South Dr,Bldg 12B,Rm B116, Bethesda, MD 20892 USA. EM kloczkoa@mail.nih.gov RI Kloczkowski, Andrzej/B-9868-2012 NR 154 TC 27 Z9 27 U1 4 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0032-3861 EI 1873-2291 J9 POLYMER JI Polymer PD FEB PY 2002 VL 43 IS 4 BP 1503 EP 1525 DI 10.1016/S0032-3861(01)00588-2 PG 23 WC Polymer Science SC Polymer Science GA 503WJ UT WOS:000172824400056 ER PT J AU Frankel, AE Bugge, TH Liu, SH Vallera, DA Leppla, SH AF Frankel, AE Bugge, TH Liu, SH Vallera, DA Leppla, SH TI Peptide toxins directed at the matrix dissolution systems of cancer cells SO PROTEIN AND PEPTIDE LETTERS LA English DT Article ID AMINO-TERMINAL FRAGMENT; PLASMINOGEN-ACTIVATOR; UROKINASE RECEPTOR; BACILLUS-ANTHRACIS; PROTECTIVE ANTIGEN; CRYSTAL-STRUCTURE; LETHAL FACTOR; CHIMERIC TOXIN; LIGAND-BINDING; TUMOR INVASION AB Growth and spread of tumors requires a variety of membrane and extracellular proteases to modify membrane integrins, dissolve the surrounding matrix and release critical growth factors from both the tumor cell surface and surrounding structures. The two major protease systems involved in this process are the matrix metalloproteases and the serine proteases. Genes and gene products for both protease systems are overexpressed in a variety of neoplasms. Thus, these enzymes serve as excellent targets for the delivery of potent cytotoxic molecules to tumors. A number of peptide toxins have been engineered to bind to tumor cells with high levels of surface proteases and their receptors including anthrax toxins, Pseudomonas exotoxin, saporin and diphtheria toxin. These recombinant fusion proteins provide a novel class of anti-cancer agents that will enter clinical trials in the next several years. C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. NR 46 TC 22 Z9 22 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8665 J9 PROTEIN PEPTIDE LETT JI Protein Pept. Lett. PD FEB PY 2002 VL 9 IS 1 BP 1 EP 14 DI 10.2174/0929866023409048 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 521QF UT WOS:000173851700001 PM 12141918 ER PT J AU Kapust, RB Routzahn, KM Waugh, DS AF Kapust, RB Routzahn, KM Waugh, DS TI Processive degradation of nascent polypeptides, triggered by tandem AGA codons, limits the accumulation of recombinant tobacco etch virus protease in Escherichia coli BL21(DE3) SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article ID HIGH-LEVEL EXPRESSION; MALTOSE-BINDING-PROTEIN; FUSION PROTEINS; TRANSFER-RNA; TAGGING SYSTEM; MESSENGER-RNA; GENE-PRODUCT; PURIFICATION; CLEAVAGE; ARGININE AB Due to its high degree of sequence specificity, the catalytic domain of the nuclear inclusion protease from tobacco etch virus (TEV protease) is a useful reagent for cleaving genetically engineered fusion proteins. However, the overproduction of TEV protease in Escherichia coli has been hampered in the past by low yield and poor solubility. Here we demonstrate that the low yield can be attributed to the presence of arginine codons in the TEV protease coding sequence that are rarely used in E. coli and specifically to a tandem pair of AGA codons. The yield of protease can be improved by replacing these rare arginine codons with synonymous ones or by increasing the supply of cognate tRNA that is available to the cell. Furthermore, we show that when ribosomes become stalled at rare arginine codons in the TEV protease mRNA, the nascent polypeptides are targeted for proteolytic degradation in BL21(DE3) cells by a mechanism that does not involve tmRNA-mediated peptide tagging. (C) 2002 Elsevier Science (USA). C1 NCI, Macromol Crystallog Lab, Prot Engn Sect, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Prot Engn Sect, POB B, Frederick, MD 21702 USA. NR 47 TC 25 Z9 26 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE 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 2002 VL 24 IS 1 BP 61 EP 70 DI 10.1006/prep.2001.1545 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 518UW UT WOS:000173687100009 PM 11812224 ER PT J AU Ma, BY Shatsky, M Wolfson, HJ Nussinov, R AF Ma, BY Shatsky, M Wolfson, HJ Nussinov, R TI Multiple diverse ligands binding at a single protein site: A matter of pre-existing populations SO PROTEIN SCIENCE LA English DT Review DE multiple ligand binding; single site binding; hinge bending; combinatorial libraries; flexible docking; populations; flexible structural comparison ID EFFICIENT COMPUTATIONAL ALGORITHMS; CRYSTAL-STRUCTURES; TISSUE FACTOR; TRIOSEPHOSPHATE ISOMERASE; FUNCTIONAL EPITOPES; DOMAIN FLEXIBILITY; CYTOCHROME-C; DRUG DESIGN; INDUCED-FIT; HOT-SPOTS AB Here, we comment on the steadily increasing body of data showing that proteins with specificity actually bind ligands of diverse shapes, sizes, and composition. Such a phenomenon is not surprising when one considers that binding is a dynamic process with populations in equilibrium and that the shape of the binding site is strongly influenced by the molecular partner. It derives implicitly from the concept of populations. All proteins, specific and nonspecific, exist in ensembles of substates. If the library of ligands in solution is large enough, favorably matching ligands with altered shapes and sizes can be expected to bind, with a redistribution of the protein populations. Point mutations at spatially distant sites may exert large conformational rearrangements and hinge effects, consistent with mutations away from the binding site leading to population shifts and (cross-)drug resistance. A similar effect is observed in protein superfamilies, in which different sequences with similar topologies display similar large-scale dynamic motions. The hinges are frequently at analogous sites, yet with different substrate specificity. Similar topologies yield similar conformational isomers, although with different distributions of population times, owing to the change in the conditions, that is, the change in the sequences. In turn, different distributions relate to binding of different sizes and shapes. Hence, the binding site shape and size are defined by the ligand. They are not independent entities of fixed proportions and cannot be analyzed independently of the binding partner. Such a proposition derives from viewing proteins as dynamic distributions, presenting to the incoming ligands a range of binding site shapes. It illustrates how presumably specific binding molecules can bind multiple ligands. In terms of drug design, the ability of a single receptor to recognize many dissimilar ligands shows the need to consider more diverse molecules. It provides a rationale for higher affinity inhibitors that are not derived from substrates at their transition states and indicates flexible docking schemes. C1 NCI, Lab Expt & Computat Biol, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. NCI, Intramural Res Support Program, SAIC, Frederick Canc Res & Dev Ctr,Lab Expt & Computat, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Computat Biol, Frederick Canc Res & Dev Ctr, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 79 TC 273 Z9 277 U1 1 U2 13 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2002 VL 11 IS 2 BP 184 EP 197 DI 10.1110/ps.21302 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 512ZD UT WOS:000173352700001 PM 11790828 ER PT J AU Freedberg, DI Ishima, R Jacob, J Wang, YX Kustanovich, I Louis, JM Torchia, DA AF Freedberg, DI Ishima, R Jacob, J Wang, YX Kustanovich, I Louis, JM Torchia, DA TI Rapid structural fluctuations of the free HIV protease flaps in solution: Relationship to crystal structures and comparison with predictions of dynamics calculations SO PROTEIN SCIENCE LA English DT Article DE AIDS; NMR; secondary structure; relaxation; hydrogen bonds ID CHEMICAL-SHIFT ANISOTROPY; MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; N-15 NMR RELAXATION; MOLECULAR-DYNAMICS; DIMERIZATION INTERFACE; RETROVIRAL PROTEASES; ROTATIONAL DIFFUSION; HYDROGEN-BONDS; INHIBITOR AB Crystal structures have shown that the HIV-1 protease flaps, domains that control access to the active site, are closed when the active site is occupied by a ligand. Although flap structures ranging from closed to semi-open are observed in the free protease, crystal structures reveal that even the semi-open flaps block access to the active site, indicating that the flaps are mobile in solution. The goals of this paper are to characterize the secondary structure and fast (sub-ns) dynamics of the flaps of the free protease in solution, to relate these results to X-ray structures and to compare them with predictions of dynamics calculations. To this end we have obtained nearly complete backbone and many sidechain signal assignments of a fully active free-protease construct that is stabilized against autoproteolysis by three point mutations. The secondary structure of this protein was characterized using the chemical shift index, measurements of (3h)J(NC') couplings across hydrogen bonds, and NOESY connectivities. Analysis of these measurements indicates that the protease secondary structure becomes irregular near the flap tips, residues 49-53. Model-free analysis of N-15 relaxation parameters, T-1, T-2 (T-1p) and (15) N-{H-1} NOE, shows that residues in the flap tips are flexible on the sub-ns time scale, in contrast with previous observations on the inhibitor-bound protease. These results are compared with theoretical predictions of flap dynamics and the possible biological significance of the sub-ns time scale dynamics of the flap tips is discussed. C1 Natl Inst Dent & Craniofacial Res, Mol Struct Biol Unit, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Inst Life Sci, Wolfson Ctr Appl Struct Biol, IL-91904 Jerusalem, Israel. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Torchia, DA (reprint author), Bldg 30,Room 113,MSC4307, Bethesda, MD 20892 USA. NR 46 TC 148 Z9 148 U1 1 U2 4 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2002 VL 11 IS 2 BP 221 EP 232 DI 10.1110/ps.33202 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 512ZD UT WOS:000173352700005 PM 11790832 ER PT J AU Panchenko, AR Bryant, SH AF Panchenko, AR Bryant, SH TI A comparison of position-specific score matrices based on sequence and structure alignments SO PROTEIN SCIENCE LA English DT Article DE profile search; protein structure alignment; alignment accuracy ID HIDDEN MARKOV-MODELS; SECONDARY STRUCTURE; PROTEINS; DATABASE; PROFILES; INFORMATION; EVOLUTION; PROGRAMS; CORES AB Sequence comparison methods based on position-specific score matrices (PSSMs) have proven a useful tool for recognition of the divergent members of a protein family and for annotation of functional sites. Here we investigate one of the factors that affects overall performance of PSSMs in a PSI-BLAST search, the algorithm used to construct the seed alignment upon which the PSSM is based. We compare PSSMs based on alignments constructed by global sequence similarity (ClustalW and ClustalW-pairwise), local sequence similarity (BLAST), and local structure similarity (VAST). To assess performance with respect to identification of conserved functional or structural sites, we examine the accuracy of the three-dimensional molecular models predicted by PSSM-sequence alignments. Using the known structures of those sequences as the standard of truth, we find that model accuracy varies with the algorithm used for seed alignment construction in the pattern local-structure (VAST) > local-sequence (BLAST) > global-sequence (ClustalW). Using structural similarity of query and database proteins as the standard of truth, we find that PSSM recognition sensitivity depends primarily on the diversity of the sequences included in the alignment, with an optimum around 30-50% average pairwise identity. We discuss these observations, and suggest a strategy for constructing seed alignments that optimize PSSM-sequence alignment accuracy and recognition sensitivity. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RP Bryant, SH (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bldg 38A,Room 8B805,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 37 TC 23 Z9 25 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2002 VL 11 IS 2 BP 361 EP 370 DI 10.1110/ps.19902 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 512ZD UT WOS:000173352700019 PM 11790846 ER PT J AU Evdokimov, AG Tropea, JE Routzahn, KM Waugh, DS AF Evdokimov, AG Tropea, JE Routzahn, KM Waugh, DS TI Crystal structure of the Yersinia pestis GTPase activator YopE SO PROTEIN SCIENCE LA English DT Article DE GAP; GTPase-activating protein; plague; cytotoxin; cytoskeleton; Rho ID RHO-GTPASES; PROTEIN; BACTERIAL; CRYSTALLIZATION; REPLACEMENT; REFINEMENT; SALMONELLA; VIRULENCE; SECRETION; TARGETS AB Yersinia pestis, the causative agent of bubonic plague, evades the immune response of the infected organism by using a type III (contact-dependent) secretion system to deliver effector proteins into the cytosol of mammalian cells, where they interfere with signaling pathways that regulate inflammation and cytoskeleton dynamics. The cytotoxic effector YopE functions as a potent GTPase-activating protein (GAP) for Rho family GTP-binding proteins, including RhoA, Rac1, and Cdc42. Down-regulation of these molecular switches results in the loss of cell motility and inhibition of phagocytosis, enabling Y. pestis to thrive on the surface of macrophages. We have determined the crystal structure of the GAP domain of YopE (YopE(GAP); residues 90-219) at 2.2-Angstrom resolution. Apart from the fact that it is composed almost entirely of alpha-helices, YopE(GAP) shows no obvious structural similarity with eukaryotic RhoGAP domains. Moreover, unlike the catalytically equivalent arginine fingers of the eukaryotic GAPs, which are invariably contained within flexible loops. the critical arginine in YopE(GAP) (Arg144) is part of an alpha-helix. The structure of YopE(GAP) is strikingly similar to the GAP domains from Pseudomonas aeruginosa (ExoS(GAP)) and Salmonella enterica (SptP(GAP)), despite the fact that the three amino acid sequences are not highly conserved. A comparison of the YopE(GAP) structure with those of the Rac1-ExoS(GAP) and Rac1-SptP complexes indicates that few, if any, significant conformational changes occur in YopE(GAP) when it interacts with its G protein targets. The structure of YopE(GAP) may provide an avenue for the development of novel therapeutic agents to combat plague. C1 NCI, Macromol Crystallog Lab, Prot Engn Sect, Frederick, MD 21702 USA. NCI, Canc Res Ctr, Struct Biol Core Facil, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), NCI, Macromol Crystallog Lab, Prot Engn Sect, POB B, Frederick, MD 21702 USA. NR 36 TC 43 Z9 44 U1 2 U2 2 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2002 VL 11 IS 2 BP 401 EP 408 DI 10.1110/ps.34102 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 512ZD UT WOS:000173352700023 PM 11790850 ER PT J AU Barrientos, LG Louis, JM Hung, J Smith, TH O'Keefe, BR Gardella, RS Mori, T Boyd, MR Gronenborn, AM AF Barrientos, LG Louis, JM Hung, J Smith, TH O'Keefe, BR Gardella, RS Mori, T Boyd, MR Gronenborn, AM TI Design and initial characterization of a circular permuted variant of the potent HIV-inactivating protein cyanovirin-N SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE cyanovirin-N; HIV-1; protein folding; circular permutation ID STRUCTURAL INTEGRITY; POLYPEPTIDE-CHAINS; PERMUTATION; STABILITY; SEQUENCE; DOMAIN; GP120; FORMS AB A circular permuted variant of the potent human immunodeficiency virus (HIV)-inactivating protein cyanovirin-N (CV-N) was constructed. New N- and C-termini were introduced into an exposed helical loop, and the original termini were linked using residues of the original loop. Since the three-dimensional structure of wild-type cyanovirin-N is a pseudodimer, the mutant essentially exhibits a swap between the two pseudo-symmetrically related halves. The expressed protein, which accumulates in the insoluble fraction, was purified, and conditions for in vitro refolding were established. During refolding, a transient dimeric species is also formed that converts to a monomer. Similar to the wild-type CV-N, the monomeric circular permuted protein exhibits reversible thermal unfolding and urea denaturation. The mutant is moderately less stable than the wild-type protein, but it displays significantly reduced anti-HIV activity. Using nuclear magnetic resonance spectroscopy, we demonstrate that this circular permuted monomeric molecule adopts the same fold as the wild-type protein. Characterization of these two architecturally very similar molecules allows us to embark, for the first time, on a structure guided focused mutational study, aimed at delineating crucial features for the extraordinary difference in the activity of these molecules. Proteins 2002;46:153-160. 2001 Wiley-Liss, Inc. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Drug Discovery Res & Dev, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. NCI, SAIC, Frederick, MD 21701 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 130, Bethesda, MD 20892 USA. NR 22 TC 18 Z9 18 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 0887-3585 J9 PROTEINS JI Proteins PD FEB 1 PY 2002 VL 46 IS 2 BP 153 EP 160 DI 10.1002/prot.10024 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 508KW UT WOS:000173088500002 PM 11807943 ER PT J AU Stone, HB McBride, WH Coleman, CN AF Stone, HB McBride, WH Coleman, CN TI Modifying Normal Tissue Damage Postirradiation report of a workshop sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland - September 6-8, 2000 - Meeting report SO RADIATION RESEARCH LA English DT Review ID GROWTH-FACTOR-BETA; BONE-MARROW TRANSPLANTATION; ANGIOTENSIN-CONVERTING ENZYME; INDUCED PULMONARY FIBROSIS; COLLAGEN VASCULAR-DISEASE; HYPERBARIC-OXYGEN THERAPY; SQUAMOUS-CELL CARCINOMA; TOTAL-BODY IRRADIATION; EFFECTS WORKING GROUP; INDUCED LUNG-DISEASE AB Late effects that develop in normal tissues adjacent to the tumor site in the months to years after radiotherapy can reduce the quality of life of cancer survivors. They can be dose-limiting and debilitating or life-threatening. There is now evidence that some late effects may be preventable or partially reversible. A workshop, "Modifying Normal Tissue Damage Postirradiation", was sponsored by the Radiation Research Program of the National Cancer Institute to identify the current status of and research needs and opportunities in this area. Mechanistic, genetic and physiological studies of the development of late effects are needed and will provide a rational basis for development of treatments. Interdisciplinary teams will be needed to carry out this research, including pathologists, physiologists, geneticists, molecular biologists, experts in functional imaging, wound healing, burn injury, molecular biology, and medical oncology, in addition to radiation biologists, physicists and oncologists. The participants emphasized the need for developing and choosing appropriate models, and for radiation dose-response studies to determine whether interventions remain effective at the radiation doses used clinically. Both preclinical and clinical studies require long-term follow-up, and easier-to-use, more objective clinical scoring systems must be developed and standardized. New developments in biomedical imaging should provide useful tools in all these endeavors. The ultimate goals are to improve the quality of life and efficacy of treatment for cancer patients treated with radiotherapy. (C) 2002 by Radiation Research Society. C1 NCI, Radiat Res Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Med Ctr, Dept Expt Radiat Oncol, Los Angeles, CA 90095 USA. NCI, Radiat Oncol Sci Program, Bethesda, MD 20892 USA. RP Stone, HB (reprint author), NCI, Radiat Res Program, 6310 Execut Blvd,6010, Bethesda, MD 20892 USA. NR 159 TC 58 Z9 58 U1 0 U2 1 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2002 VL 157 IS 2 BP 204 EP 223 DI 10.1667/0033-7587(2002)157[0204:MNTDP]2.0.CO;2 PG 20 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 516MW UT WOS:000173557900012 PM 11835685 ER PT J AU Yongbi, MN Fera, F Yang, YH Frank, JA Duyn, JH AF Yongbi, MN Fera, F Yang, YH Frank, JA Duyn, JH TI Pulsed arterial spin labeling: Comparison of multisection baseline and functional MR imaging perfusion signal at 1.5 and 3.0 T: Initial results in six subjects SO RADIOLOGY LA English DT Article DE brain, diffusion; brain, MR; brain, perfusion; magnetic resonance (MR), functional imaging; magnetic resonance (MR), perfusion study ID CEREBRAL BLOOD-FLOW; HUMAN BRAIN; MAGNETIC-RESONANCE; FAIR TECHNIQUE; INVERSION; DEMENTIA AB Flow-alternating inversion-recovery magnetic resonance imaging was performed at 3.0 T to measure cerebral perfusion during rest and motor activation in six healthy adult volunteers. Results were compared with those at 1.5 T. The mean signal-to-noise ratio for both gray matter and white matter perfusion measured with and without vascular suppression at 3.0 T was significantly (P < .01) higher (n = 6) than that at 1.5 T. Brain perfusion activation maps collected during a motor task showed a substantially larger number of activated pixels (>80%) at 3.0 T, with activation in the supplementary motor area in the 3.0-T data that was not present on 1.5-T perfusion maps. C1 NIH, Ctr Clin, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. Cornell Univ, Coll Med, Funct Neuro Imaging Lab, Dept Psychiat, New York, NY USA. CNR, Inst Expt Med & Biotechnol, Cosenza, Italy. RP Duyn, JH (reprint author), NIH, NMR Ctr, Bldg 10,Room B1D109,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 23 TC 38 Z9 40 U1 0 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2002 VL 222 IS 2 BP 569 EP 575 DI 10.1148/radiol.2222001697 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 515NQ UT WOS:000173502500039 PM 11818630 ER PT J AU Krichevsky, O Bonnet, G AF Krichevsky, O Bonnet, G TI Fluorescence correlation spectroscopy: the technique and its applications SO REPORTS ON PROGRESS IN PHYSICS LA English DT Review ID INTENSITY DISTRIBUTION ANALYSIS; SINGLE-MOLECULE FLUORESCENCE; PHOTON-COUNTING HISTOGRAM; TOTAL INTERNAL-REFLECTION; LIVING CELLS; CONFORMATIONAL FLUCTUATIONS; STATISTICAL ACCURACY; 2-PHOTON EXCITATION; ESCHERICHIA-COLI; DYNAMICS AB Fluorescence correlation spectroscopy (FCS) is an experimental technique using statistical analysis of the fluctuations of fluorescence in a system in order to decipher dynamic molecular events, such as diffusion or conformational fluctuations of biomolecules. First introduced by Magde et al to measure the diffusion and binding of ethidium bromide onto double-stranded DNA, the technique has been undergoing a renaissance since 1993 with the implementation of confocal microscopy FCS. Since then, a flurry of experiments has implemented FCS to characterize the photochemistry of dyes, the translational and rotational mobilities of fluorescent molecules, as well as to monitor conformational fluctuations of green fluorescent proteins and DNA molecules. In this review, we present the analytical formalism of an FCS measurement, as well as practical considerations for the design of an FCS setup and experiment. We then review the recent applications of FCS in analytical chemistry, biophysics and cell biology, specifically emphasizing the advantages and pitfalls of the technique compared to alternative spectroscopic tools. We also discuss recent extensions of FCS in single-molecule spectroscopy, offering alternative data processing of fluorescence signals to glean more information on the kinetic processes. C1 Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel. NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Krichevsky, O (reprint author), Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel. NR 112 TC 473 Z9 483 U1 22 U2 191 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0034-4885 J9 REP PROG PHYS JI Rep. Prog. Phys. PD FEB PY 2002 VL 65 IS 2 BP 251 EP 297 AR PII S0034-4885(02)93943-6 DI 10.1088/0034-4885/65/2/203 PG 47 WC Physics, Multidisciplinary SC Physics GA 528GU UT WOS:000174236700003 ER PT J AU Velez, G Chan, CC Csaky, KG AF Velez, G Chan, CC Csaky, KG TI Fluorescein angiographic findings in primary intraocular lymphoma SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE diagnosis; fluorescein angiography; primary intraocular lymphoma ID RETICULUM-CELL SARCOMA; CENTRAL-NERVOUS-SYSTEM; OCULAR LYMPHOMA; DETACHMENTS; DIAGNOSIS AB Purpose: Primary intraocular lymphoma (PIOL), also known as primary central nervous system lymphoma, is a rare yet blinding and fatal disease. Often presenting with ocular involvement, it can masquerade as posterior or intermediate uveitis, thus delaying diagnosis. A noninvasive ancillary test such as fluorescein angiography could be helpful in raising the level of suspicion in the diagnosis of this disease. Methods: Results of fluorescein angiography (FA) and clinical characteristics, of 17 patients (31 eyes) who presented to the National Eye Institute with the diagnosis of PIOL (confirmed by histopathologic analysis) were reviewed. Results: The most common angiographic characteristics included disturbances at the level of the retinal pigment epithelium (RPE), such as granularity (19 eyes [61%]), blockage (17 eyes [55%]), and late staining (14 eyes [45%]). These changes are well correlated to histopathologic findings of lymphoma cells located between the RPE and Bruchs membrane. Perivascular staining or leakage and cystoid macular edema were rare. Other less common findings included pigment epithelial detachments and punctate hyperfluorescent lesions. Clinical characteristics found in eyes for which results of FA were available included vitreitis (29 eyes [94%]), subretinal infiltrates (19 eyes [61%]), and anterior chamber cells (10 eyes [32%]). In some cases, clinical examination did not correlate with FA findings. Conclusions: Although PIOL may present with a normal angiographic phenotype, extensive RPE changes demonstrated by FA, combined with the absence of perivascular staining or leakage and macular edema, may be associated with and distinctive of PIOL. C1 Natl Eye Inst, Lab Immunol, NIH, Bethesda, MD USA. RP Velez, G (reprint author), 85 Washington Pk, Newton, MA 02460 USA. NR 23 TC 31 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2002 VL 22 IS 1 BP 37 EP 43 DI 10.1097/00006982-200202000-00007 PG 7 WC Ophthalmology SC Ophthalmology GA 529BF UT WOS:000174279600007 PM 11884876 ER PT J AU Ardila, GP Angarita, BEV Leon-Sarmiento, FE AF Ardila, GP Angarita, BEV Leon-Sarmiento, FE CA Grp Estudio GENECO TI Prevalence of neurological diseases in Aratoca, a rural area of eastern Colombia SO REVISTA MEDICA DE CHILE LA Spanish DT Article DE epidemiologic studies; epilepsy; migraine; nervous system diseases ID SPASTIC PARAPARESIS; SOUTH-AMERICA; EPILEPSY AB Background. Current health statistics on the prevalence of neurological diseases, in Colombia, are still lacking. Aim: To determine the Prevalence of migraine, cerebrovascular disease, movement disorders, peripheral neuropathies, mental retardation and developmental disorders, epilepsy, dementia and sequels of cranial trauma in a rural population of Colombia, Materials and methods: Me evaluated 544 subjects in Aratoca, a rural place of Santander, placed at 400 kilometers from Bogota. The world health organization (WHO)protocol for neuroepidemiological studies modified by our group, a survey to determine sequels of cranial trauma and the mini mental state examination were used as instruments. People 12 years-old or more and suspected to have a neurological disease was evaluated by adult neurologists and those less than 12 years-old were evaluated by a neuropediatrician. Results: 223 out of 544 subjects surveyed were evaluated by, the clinicians of which 135 bad a neurological disorder. The prevalence of neurological diseases, per thousand inhabitants were as follows., migraine 189.3; epilepsy 33; febrile seizures 25.6; peripheral neuropathy 22,1; mental retardation 18.4; developmental and language disorders 11; dementia 10,5,. cerebrovascular disease 4,7; and movement disorders 3.7. Conclusions: These results will allow to define appropriate control measures, as well as to prevent and treat these prevalent neurological disorders in rural places of Colombia as Aratoca and the like, (Rev, Med Chile 2002; 130: 191-9). C1 Univ Ind Santander, Fac Salud, Dept Med Interna & Ciencias Basicas, Bucaramanga, Colombia. Inst Colombiano Invest Biomed, Bucaramanga, Colombia. Fdn Cardiovasc Oriente Colombiano, Inst Invest, Bucaramanga, Colombia. RP Leon-Sarmiento, FE (reprint author), NINCDS, Brain Stimulat Unit, Med Neurol Branch, NIH, Bldg 10,Room 5N234,10 Ctr Dr MSC 1430, Bethesda, MD 20892 USA. NR 61 TC 0 Z9 0 U1 0 U2 0 PU SOC MEDICA SANTIAGO PI SANTIAGO 9 PA BERNARDA MORIN 488 PROVIDENCIA, CASILLA 168 CORREO 55, SANTIAGO 9, CHILE SN 0034-9887 J9 REV MED CHILE JI Rev. Medica Chile PD FEB PY 2002 VL 130 IS 2 BP 191 EP 199 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 536YY UT WOS:000174730500009 ER PT J AU Long, EO AF Long, EO TI Tumor cell recognition by natural killer cells SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE natural killer; inhibitory receptor; major histocompatibility complex; HLA class I ID T-LYMPHOCYTES; NK CELLS; IN-VIVO; INHIBITORY RECEPTORS; NKG2D RECEPTOR; EXPRESSION; CYTOTOXICITY; ACTIVATION; MOLECULES; MECHANISM AB Natural killer (NK) cells contribute to the immune defense against cancer and viruses. Tumor cells and infected cells that downregulate the HLA class I antigen expression are targets for NK cell responses because NK cell activation is controlled by a repertoire of inhibitory receptors with different HLA class I specificities. The clonal distribution of these inhibitory receptors permits NK cell recognition of target cells that have lost expression of a single HLA-B or HLA-C allotype. Several activation receptors on NK cells have been identified that contribute to tumor cell recognition. One such receptor, NKG2D, is expressed by all NK cells and binds to inducible ligands on tumor cells. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 31 TC 51 Z9 51 U1 1 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2002 VL 12 IS 1 BP 57 EP 61 DI 10.1006/scbi.2001.0398 PG 5 WC Oncology SC Oncology GA 515QN UT WOS:000173507000008 PM 11926413 ER PT J AU Restifo, NP Antony, PA Finkelstein, SE Leitner, WW Surman, DR Theoret, MR Touloukian, CE AF Restifo, NP Antony, PA Finkelstein, SE Leitner, WW Surman, DR Theoret, MR Touloukian, CE TI Assumptions of the tumor 'escape' hypothesis SO SEMINARS IN CANCER BIOLOGY LA English DT Article DE immunotherapy; tolerance; escape; CD8+T cells; CD4+T cells ID DISSEMINATED MURINE LEUKEMIA; I ANTIGEN EXPRESSION; T-CELLS; MELANOMA-CELLS; POINT MUTATION; B2M GENE; IMMUNOTHERAPY; INDUCTION; IMMUNITY; IDENTIFICATION AB The reasons why cancer cells are not destroyed by the immune system are likely to be similar, in most cases, to the reasons why normal cells are not destroyed by the immune system. Unfortunately for tumor immunologists, these reasons have not yet been fully elucidated. What is known, however, is that the lack of autoimmune destruction of normal tissue after immune activation is a finely regulated, highly orchestrated sequence of events. Viewed in this light, it is interesting to conceptualize the derangement of the tumor genome not merely as an engine that enables cancer cells to dodge immune recognition. The dysregulation characteristic of the transformed genome is also what makes tumor immunity, a specialized form of autoimmunity, possible. C1 NCI, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20817 USA. RP Restifo, NP (reprint author), Bldg 10,Rm 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; Leitner, Wolfgang/F-5741-2011; OI Leitner, Wolfgang/0000-0003-3125-5922; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 47 TC 24 Z9 25 U1 1 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2002 VL 12 IS 1 BP 81 EP 86 DI 10.1006/scbi.2001.0399 PG 6 WC Oncology SC Oncology GA 515QN UT WOS:000173507000011 PM 11926416 ER PT J AU Seminario, MC Wange, RL AF Seminario, MC Wange, RL TI Signaling pathways of D3-phosphoinositide-binding kinases in T cells and their regulation by PTEN SO SEMINARS IN IMMUNOLOGY LA English DT Review DE phosphoinositide 3-kinases; phospholipids; PTEN; signaling; T cells ID 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1; PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY; PHOSPHOINOSITIDE 3-KINASE; TUMOR SUPPRESSION; MAMMALIAN TARGET; PLASMA-MEMBRANE; MULTIPLE ROLES; TYROSINE-PHOSPHORYLATION; IN-VIVO; ACTIVATION AB Phosphoinositide 3-kinases (PI3Ks) phosphorylate the D3 position of the myo-inositol ring of inositol phospholipids, producing, amongst others, phosphatidylinositol-(3,4,5)-trisphosphate. This activity is opposed by the lipid phosphatase PTEN, which catalyzes the removal of this phosphate. Stimulation of PI3Ks is elicited by engagement of receptors for antigen, cytokines and chemokines, and by co-stimulatory molecules. Kinases and other enzymes containing pleckstrin homology domains are activated by binding to these phospholipids, affecting a variety of cellular processes that control lymphocyte function, including cell survival, proliferation, chemotaxis and cytoskeletal reorganization., This review highlights the signaling Pathways of these kinases and other enzymes in T cells, their biological effects, and their regulation by PTEN. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Wange, RL (reprint author), NIA, Cellular & Mol Biol Lab, NIH, GRC Bldg,MSC-12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 78 TC 14 Z9 15 U1 1 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2002 VL 14 IS 1 BP 27 EP 36 DI 10.1006/smim.2001.0339 PG 10 WC Immunology SC Immunology GA 533QY UT WOS:000174542800004 PM 11884228 ER PT J AU Wilson, WH Gutierrez, M O'Connor, P Frankel, S Jaffe, E Chabner, BA Grossbard, ML AF Wilson, WH Gutierrez, M O'Connor, P Frankel, S Jaffe, E Chabner, BA Grossbard, ML TI The role of rituximab and chemotherapy in aggressive B-cell lymphoma: A preliminary report of dose-adjusted EPOCH-R SO SEMINARS IN ONCOLOGY LA English DT Review ID NON-HODGKINS-LYMPHOMA; MULTIDRUG-RESISTANCE; HEMATOLOGICAL MALIGNANCIES; MONOCLONAL-ANTIBODY; DRUG-RESISTANCE; P-GLYCOPROTEIN; GLUTATHIONE; ACTIVATION; APOPTOSIS; CYCLE C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Oncol, Boston, MA 02114 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. St Lukes Roosevelt Hosp, Dept Oncol, New York, NY USA. RP Wilson, WH (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 46 Z9 52 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2002 VL 29 IS 1 SU 2 BP 41 EP 47 DI 10.1053/sonc.2002.30151 PG 7 WC Oncology SC Oncology GA 523MT UT WOS:000173958400007 PM 11842388 ER PT J AU Buck, GM Johnson, CD AF Buck, GM Johnson, CD TI Methodologic considerations for population-based research on fetal deaths: Overcoming data gaps SO SEMINARS IN PERINATOLOGY LA English DT Article; Proceedings Paper CT Workshop of the National-Institute-of-Child-Health-and-Human-Development on Stillbirth CY MAR 26, 2001 CL BETHESDA, MARYLAND SP NICHD ID LOW-BIRTH-WEIGHT; PREGNANCY HISTORY; WASHINGTON-STATE; MATERNAL AGE; RISK-FACTORS; STILLBIRTH; RECURRENCE; CERTIFICATES; EPIDEMIOLOGY; MORTALITY C1 NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, Rockville, MD 20852 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Buck, GM (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. OI Buck Louis, Germaine/0000-0002-1774-4490 NR 35 TC 3 Z9 3 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 2002 VL 26 IS 1 BP 31 EP 35 DI 10.1053/sper.2002.29837 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 524GK UT WOS:000174004700006 PM 11876565 ER PT J AU Graubard, BI Korn, EL AF Graubard, BI Korn, EL TI Inference for superpopulation parameters using sample surveys SO STATISTICAL SCIENCE LA English DT Article DE cluster sampling; complex survey data; design-based inference; model-based inference; random effects; stratified sampling ID ORDINARY LEAST-SQUARES; REGRESSION-ANALYSIS; STRATIFIED SAMPLES; SURVEY WEIGHTS; MODEL; DESIGN; CHOICE; POPULATION; SIZE AB Sample survey inference is historically concerned with finite-population parameters, that is, functions (like means and totals) of the observations for the individuals in the population. In scientific applications, however, interest usually focuses on the "superpopulation" parameters associated with a stochastic mechanism hypothesized to generate the observations in the population rather than the finite-population parameters. Two relevant findings discussed in this paper are that (1) with stratified sampling, it is not sufficient to drop finite-population correction factors from standard design-based valiance formulas to obtain appropriate variance formulas for superpopulation inference, and (2) with cluster sampling, standard design-based variance formulas can dramatically underestimate superpopulation variability, even with a small sampling fraction of the final units. A literature review of inference for superpopulation parameters is given, with emphasis on why these findings have not been previously appreciated. Examples are provided for estimating superpopulation means, linear regression coefficients and logistic regression coefficients using U.S. data from the 1987 National Health Interview Survey, the third National Health and Nutrition Examination Survey and the 1986 National Hospital Discharge Survey. C1 NCI, Biostat Branch, Bethesda, MD 20892 USA. NCI, Clin Trials Sect, Biometr Res Branch, Bethesda, MD 20892 USA. RP Graubard, BI (reprint author), NCI, Biostat Branch, EPS-8024, Bethesda, MD 20892 USA. NR 85 TC 27 Z9 27 U1 1 U2 13 PU INST MATHEMATICAL STATISTICS PI BEACHWOOD PA PO BOX 22718, BEACHWOOD, OH 44122 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD FEB PY 2002 VL 17 IS 1 BP 73 EP 96 DI 10.1214/ss/1023798999 PG 24 WC Statistics & Probability SC Mathematics GA 567FL UT WOS:000176474700005 ER PT J AU Moore, DF Altarescu, G Ling, GSF Jeffries, N Frei, KP Weibel, T Charria-Ortiz, G Ferri, R Arai, AE Brady, RO Schiffmann, R AF Moore, DF Altarescu, G Ling, GSF Jeffries, N Frei, KP Weibel, T Charria-Ortiz, G Ferri, R Arai, AE Brady, RO Schiffmann, R TI Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement SO STROKE LA English DT Article DE blood flow velocity; cerebrovascular accident; cerebrovascular disorders; Fabry disease; ultrasonography, Doppler, transcranial ID TRANSCRANIAL DOPPLER SONOGRAPHY; INVOLVEMENT; STORAGE; SYSTEM; ARTERY; VALUES AB Background and Purpose-Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients. Methods-TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes. Results-Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point. Conclusions-Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy. C1 NINCDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Biostat Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Neurol, Washington, DC 20307 USA. RP Schiffmann, R (reprint author), NINCDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 129 Z9 131 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2002 VL 33 IS 2 BP 525 EP 531 DI 10.1161/hs0202.102601 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 518AX UT WOS:000173644900020 PM 11823664 ER PT J AU Baker, H AF Baker, Houston TI Imaging Technology Development Initiatives by the National Cancer Institute's Biomedical Imaging Program SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article AB The extramural research community is invited to compete for grant application funding to perform research and development in Cancer Imaging, which is prominent in the list of Extraordinary Opportunities that the National Cancer Institute (NCI) currently recognizes as likely to yield significant gains in public health. Through its Biomedical Imaging Program (BIP), NCI offers grant support for advances in medical imaging technologies applicable to cancer and pre-cancer research, screening, diagnosis, treatment, and monitoring of treatment progress. Many investigators are familiar with generic NIH Program Announcements to which they may submit investigator-initiated grant applications that support missions of the NIH Institutes and Centers (ICs). However, fewer know about specific grant application initiatives by individual ICs. Active NCI Imaging Initiatives administered by BIP are listed on its website, http://cancer.gov/bip. The short descriptions include additional web-links that lead directly to full-text Program Announcements that provide comprehensive information for investigators who wish to respond with applications. Current initiatives include Exploratory/Developmental Grants for Diagnostic Cancer Imaging (R21), Development of Novel Imaging Technologies (Phased Innovation Award-R21/R33), and Development of Novel Imaging Technologies (SBIR/STTR-R43/R44 and R41/R42). Domestic and foreign investigators from academia, research organizations, and large and small businesses are invited to check specific eligibility requirements found in the details of each program announcement. Investigators contemplating multi-disciplinary imaging technology development projects are encouraged to assemble teams that include necessary expertise either through direct participation or with collaborations and/or sub-contracts, as needed. Brief descriptions of older Program Announcements that are now closed are provided to show the range of initiatives supported by the Biomedical Imaging Program in the recent past. New NCI imaging initiatives are under consideration. C1 NCI, Imaging Technol Dev Branch, Biomed Imaging Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. RP Baker, H (reprint author), NCI, Imaging Technol Dev Branch, Biomed Imaging Program, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. EM bakerhou@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD FEB PY 2002 VL 1 IS 1 BP 89 EP 93 PG 5 WC Oncology SC Oncology GA V28FU UT WOS:000208667500012 ER PT J AU Price, DK Ando, Y Kruger, EA Weiss, M Figg, WD AF Price, DK Ando, Y Kruger, EA Weiss, M Figg, WD TI 5 '-OH-thalidomide, a metabolite of thalidomide, inhibits angiogenesis SO THERAPEUTIC DRUG MONITORING LA English DT Article DE thalidomide; cytochrome P-450; angiogenesis ID REFRACTORY MULTIPLE-MYELOMA; NECROSIS-FACTOR-ALPHA; TERATOGEN METABOLISM; IN-VIVO; ASSAY; CYTOCHROME-P-450; ACTIVATION; MICROSOMES; ANALOGS; GROWTH AB Despite its known teratogenic effects, thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. The exact method of action of thalidomide and its derivatives is still under investigation. Thalidomide undergoes very little metabolism by the cytochrome P-450 system in vitro, but at least two hydroxylated metabolites have been found in humans. The two metabolites are 5-hydroxythalidomide, formed by hydroxylation of the phthalimide ring, possibly via arene oxides, and 5'-hydroxythalidomide, formed by hydroxylation of the glutarimide ring, leading to diastereomeric products. These two metabolites, along with another minor metabolite of thalidomide, were tested in a rat aortic ring assay, a human saphenous vein model, and a tube formation assay to assess the metabolite's ability to inhibit angiogenesis. Of the metabolites tested, only 5'-OH-thalidomide showed biologic activity in the rat aortic ring assay, and none of the metabolites showed activity in the human model. The studies with thalidomide and thalidomide metabolites underline the difficulty and complexity of trying to isolate and evaluate a single biologically active agent. These studies, however, do suggest that at least one metabolite, 5'-OH-thalidomide, has moderate anti-angiogenic activity at high concentrations. Unfortunately, because of the lack of observed activity of 5'-OH-thalidomide in the human saphenous vein assay, it remains unclear whether there is species specificity for the activity of this metabolite. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bldg 10,Room 5A01,MSC1910,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 34 TC 32 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD FEB PY 2002 VL 24 IS 1 BP 104 EP 110 DI 10.1097/00007691-200202000-00017 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 515WL UT WOS:000173519600017 PM 11805730 ER PT J AU Ando, Y Ueoka, H Sugiyama, T Ichiki, M Shimokata, K Hasegawa, Y AF Ando, Y Ueoka, H Sugiyama, T Ichiki, M Shimokata, K Hasegawa, Y TI Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan SO THERAPEUTIC DRUG MONITORING LA English DT Article DE irinotecan; polymorphism; UDP-glucuronosyltransferase; pharmacogenetics; pharmacokinetics ID ACTIVE METABOLITE SN-38; PHASE-I; GILBERTS-SYNDROME; LUNG-CANCER; CPT-11; GLUCURONIDATION; CISPLATIN; CAMPTOTHECIN; POPULATION; RECURRENT AB Irinotecan is a prodrug that is hydrolyzed by carboxylesterase in vivo to forth an active metabolite SN-38. SN-38 is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) to yield its beta-glucuronide (SN-38G). Although irinotecan is widely used, the drug causes unpredictably severe, occasionally fatal, toxicity of leukopenia or diarrhea. Interindividual variation of sensitivity to irinotecan is related to large variations of biotransformation of the active metabolite SN-38, some of which would be caused by genetic polymorphism of UGT1A1, an isozyme responsible for the SN-38 glucuronidation. As a surrogate for the UGT activity, the polymorphic frequency distribution of the area under the concentration-time curve (AUC) ratios of SN-38 to SN-38G (AUC(SN-38)/AUC(SN-38a)) using pooled pharmacokinetic data from four independent study groups in Japan was explored. The data from 100 cancer patients was analyzed, including 14 who were genotyped for UGT1A1 gene in the previous studies. The median ratios of AUC(SN-38)/AUC(SN-38G) was 0.4-0 (interquartile range, 0.30 to 0.55; range, 0.09 to 2.32). Frequency distribution of the AUC(SN-38)/AUC(SN-38G) was skewed to the right without bimodality and the patient population could not be segregated into discrete subgroups that differ in the UGT activity by the AUC ratios. The 4 subjects carrying UGT1A1*28 allele had values of the AUC(SN-38)/AUC(SN-38G) above the 75th percentile of the total population, suggesting a potential pharmacogenetic/pharmacokinetic relationship. Ordinary values with a median of 0.41 (interquartile range, 0.33 to 0.49) were obtained for the UGT1A1*6 heterozygous patient and the 9 UGT1A1*1 homozygous patients (the reference sequence). The large variation in the UGT activity being related to the genetic status would warrant pharmacogenetic-guided dosing of irinotecan. C1 Nagoya Univ, Sch Med, Dept Internal Med 1, Nagoya, Aichi 466, Japan. Okayama Univ, Sch Med, Dept Internal Med 2, Okayama 700, Japan. Kurume Univ, Dept Obstet & Gynecol, Kurume, Fukuoka 830, Japan. Kurume Univ, Dept Internal Med 1, Kurume, Fukuoka 830, Japan. Nagoya Univ, Sch Med, Dept Clin Prevent Med, Nagoya, Aichi 466, Japan. RP Ando, Y (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, NIH, Bldg 10,Rm 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 67 Z9 72 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD FEB PY 2002 VL 24 IS 1 BP 111 EP 116 DI 10.1097/00007691-200202000-00018 PG 6 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 515WL UT WOS:000173519600018 PM 11805731 ER PT J AU Kinnula, VL Lehtonen, S Kaarteenaho-Wiik, R Lakari, E Paakko, P Kang, SW Rhee, SG Soini, Y AF Kinnula, VL Lehtonen, S Kaarteenaho-Wiik, R Lakari, E Paakko, P Kang, SW Rhee, SG Soini, Y TI Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis SO THORAX LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; BRONCHIAL EPITHELIAL-CELLS; TUMOR-NECROSIS-FACTOR; MAMMALIAN PEROXIREDOXIN; ANTIOXIDANT ENZYMES; 100-PERCENT O-2; IN-VITRO; GLUTATHIONE; THIOREDOXIN; LOCALIZATION AB Background: Six proteins of the peroxiredoxin (Prx) family have recently been characterised which have the capacity to decompose hydrogen peroxide in vivo and in vitro. These proteins may have an important role in the protection of human lung against endogenous and exogenous oxidant stress. However, the expression and distribution of these proteins in healthy human lung and diseased lung tissue is unknown. Methods: The cell specific expression of Prxs in healthy lung tissue from four non-smokers and in parenchymal tissue from 10 subjects with pulmonary sarcoidosis was investigated by immunohistochemistry, and expression of these proteins in various cultured lung cells and cells of bronchoalveolar lavage (BAL) fluid of controls and patients with sarcoidosis was assessed by Western blot analysis. Results: All six Prxs could be synthesised in cultured human lung cells, The bronchial epithelium showed moderate to high expression of Prxs I, III, V and VI, the alveolar epithelium expressed mainly Prxs V and VI, and alveolar macrophages expressed mainly Prxs I and III. Granulomas of subjects with sarcoidosis expressed mainly Prxs I and III. Samples of BAL fluid from controls and From subjects with sarcoidosis had very similar findings, except that Prxs II and III had a tendency for increased immunoreactivity in sarcoidosis tissue. Conclusions: Prxs I, III, V, and VI, in particular, have prominent and cell specific expression in human lung tissue. High expression of Prxs I and III in granulomas and alveolar macrophages of sarcoidosis parenchyma may have a significant effect on the oxidant burden and the progression of lung injury in this disease. C1 Oulu Univ, Dept Internal Med, Div Pulm, FIN-90014 Oulu, Finland. Oulu Univ, Dept Pathol, FIN-90014 Oulu, Finland. Oulu Univ Hosp, Oulu, Finland. NIH, Lab Cell Signalling, Bethesda, MD 20892 USA. RP Kinnula, VL (reprint author), Oulu Univ, Dept Internal Med, Div Pulm, POB 50000,Kajaanintie 50A, FIN-90014 Oulu, Finland. NR 36 TC 65 Z9 67 U1 1 U2 2 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD FEB PY 2002 VL 57 IS 2 BP 157 EP 164 DI 10.1136/thorax.57.2.157 PG 8 WC Respiratory System SC Respiratory System GA 520FF UT WOS:000173769800014 PM 11828047 ER PT J AU Noth, U Tuli, R Osyczka, AM Danielson, KG Tuan, RS AF Noth, U Tuli, R Osyczka, AM Danielson, KG Tuan, RS TI In vitro engineered cartilage constructs produced by press-coating biodegradable polymer with human mesenchymal stem cells SO TISSUE ENGINEERING LA English DT Article ID BONE MORPHOGENETIC PROTEIN-2; MARROW STROMAL CELLS; FULL LENGTH CDNA; CHONDROGENIC DIFFERENTIATION; ALLOGRAFT CHONDROCYTES; X COLLAGEN; EXPRESSION; TISSUE; SEQUENCE; FORMS AB Cartilage constructs were fabricated by press-coating D,D-L,L-polylactic acid polymer blocks of 1 x 0.5 x 0.5 cm onto high-density cell pellets of 1.5 x 10(6) human mesenchymal stem cells (mhMSCs) isolated from the femoral head of patients undergoing total hip arthroplasty. Following attachment of the cell pellets to the polymer surfaces, chondrogenesis was induced by culturing the constructs for 3 weeks in a serum-free, chemically defined, chondrogenic differentiation medium supplemented with transforming growth factor beta-1 (TGF-beta1). Histochemical analysis showed that the press-coated pellets formed cell layers composed of morphologically distinct, chondrocyte-like cells, surrounded by a fibrous, sulfated proteoglycan-rich extracellular matrix. Immunohistochemical analysis detected collagen type II and cartilage proteoglycan link protein within the extracellular matrix. Expression of the cartilage-specific marker genes collagen types II, IX, X, and XI, and aggrecan was detected by RT-PCR. Scanning electron microscopy revealed organized and spatially distinct zones of cells within the cell-polymer constructs, with the superficial layer resembling compact hyaline cartilage. The fabrication method of press-coating biodegradable polymers with mhMSCs allows the in vitro production of cartilage constructs without harvesting chondrocytes from intact articular cartilage surfaces. These constructs may be applicable as prototypes for the reconstruction of articular cartilage defects in humans. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 13,Room 3W17,13 South Dr,MSC 5755, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA 71602, R25 CA69277]; NIAMS NIH HHS [AR 44501, AR 45181]; NIDCR NIH HHS [DE 11327, DE 12864] NR 63 TC 93 Z9 102 U1 0 U2 7 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD FEB PY 2002 VL 8 IS 1 BP 131 EP 144 DI 10.1089/107632702753503126 PG 14 WC Cell & Tissue Engineering SC Cell Biology GA 526YG UT WOS:000174157000013 PM 11886661 ER PT J AU Caplen, NJ AF Caplen, NJ TI A new approach to the inhibition of gene expression SO TRENDS IN BIOTECHNOLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; MESSENGER-RNA; C-ELEGANS; INTERFERENCE; POLYMERASE AB The induction of a specific down-regulation in gene expression is an important research tool. Recently, several related processes including post-transcriptional gene silencing (PTGS) and RNA interference (RNAi) have been identified that generate sequence-specific inhibition of gene expression. Although the physiological function of PTGS and RNAi is still being elucidated, these pathways have been used to rapidly determine gene function. The recent observation of RNAi in mammalian cells extends the possible applications of these mechanisms. C1 NIH, NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NIH, NHGRI, Med Genet Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 24 TC 22 Z9 32 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD FEB PY 2002 VL 20 IS 2 BP 49 EP 51 DI 10.1016/S0167-7799(01)01900-X PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 515WQ UT WOS:000173520000002 PM 11814589 ER PT J AU Hagemann, D Xiao, RP AF Hagemann, D Xiao, RP TI Dual site phospholamban phosphorylation and its physiological relevance in the heart SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID CARDIAC SARCOPLASMIC-RETICULUM; BETA-ADRENERGIC STIMULATION; DEPENDENT PROTEIN-KINASE; MYOCARDIAL-CONTRACTILITY; DILATED CARDIOMYOPATHY; CALCIUM-TRANSPORT; INTACT MYOCARDIUM; AMINO-ACIDS; TROPONIN-I; CA2+ PUMP AB Phospholamban (PLB) plays a primary role in regulating cardiac sarcoplasmic reticulum (SR) Ca2+-ATPase activity. Dephosphorylated PLB suppresses the SR Ca2+ pump activity, whereas phosphorylation of PLB leads to deinhibition. A widely accepted sequential model of dual site PLB phosphorylation states that PKA-dependent phosphorylation of Ser(16) is obligatory to phosphorylation of Thr(17) by Ca2+/calmodulin-dependent kinase II, and mainly accounts for beta-adrenergic receptor mediated cardiac relaxation. However, emerging evidence supports independent phosphorylation of Ser(16) and Thr(17) and their independent contributions to cardiac relaxation. Furthermore, concurrent activation of PKA and CaMKII signaling pathways exhibits a robust synergistic effect on phosphorylation of Thr(17), but not of Ser(16). Thus, the synergistic interaction may masquerade as a sequential phosphorylation of Ser(16) and Thr(17) under certain circumstances. Further studies are required to determine the exact process of dual site PLB phosphorylation and its functional roles in healthy and diseased hearts. (Trends Cardiovasc Med 2002; 12:51-56). (C) 2002, Elsevier Science Inc. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 61 TC 68 Z9 69 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD FEB PY 2002 VL 12 IS 2 BP 51 EP 56 AR PII S1050-1738(01)00145-1 DI 10.1016/S1050-1738(01)00145-1 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 523BA UT WOS:000173930400001 PM 11852250 ER PT J AU Thomas, JW Touchman, JW AF Thomas, JW Touchman, JW TI Vertebrate genome sequencing: building a backbone for comparative genomics SO TRENDS IN GENETICS LA English DT Editorial Material ID HUMAN-CHROMOSOME 7; REPETITIVE SEQUENCES; NONCODING SEQUENCES; CONTIG MAP; MOUSE; IDENTIFICATION; EVOLUTION; GENES; HUMAN-CHROMOSOME-19; STRATEGIES AB The human genome sequence provides a reference point from which we can compare ourselves with other organisms. Interspecies comparison is a powerful tool for inferring function from genomic sequence and could ultimately lead to the discovery of what makes humans unique. To date, most comparative sequencing has focused on pair-wise comparisons between human and a limited number of other vertebrates, such as mouse. Targeted approaches now exist for mapping and sequencing vertebrate bacterial artificial chromosomes (BACs) from numerous species, allowing rapid and detailed molecular and phylogenetic investigation of multi-megabase loci. Such targeted sequencing is complementary to current whole-genome sequencing projects, and would benefit greatly from the creation of BAC libraries from a diverse range of vertebrates. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Touchman, JW (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM jefft@nhgri.nih.gov NR 43 TC 42 Z9 43 U1 0 U2 1 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 2002 VL 18 IS 2 BP 104 EP 108 DI 10.1016/S0168-9525(02)02599-4 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 517DR UT WOS:000173596300012 PM 11818143 ER PT J AU Chaudry, GJ Moayeri, M Liu, SH Leppla, SH AF Chaudry, GJ Moayeri, M Liu, SH Leppla, SH TI Quickening the pace of anthrax research: three advances point towards possible therapies SO TRENDS IN MICROBIOLOGY LA English DT Review ID LETHAL FACTOR; BACILLUS-ANTHRACIS; MACROPHAGES; TOXIN; CELLS; SUSCEPTIBILITY; KIF1C AB Anthrax toxin is the dominant virulence factor of Bacillus anthracis and drugs blocking its action could therefore have therapeutic benefit. Three recent papers suggest new ways to inhibit the toxin. Identification of the cell surface toxin receptor could lead to the design of binding competitors and receptor decoys. Determination of the crystal structure of the lethal factor protease will facilitate ongoing efforts to develop protease inhibitors as therapies. Finally, the susceptibility of certain inbred mice to anthrax lethal toxin was associated with mutations in the kinesin-like protein Kif1C, a discovery that could help to explain how anthrax toxin kills animals. C1 Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Chaudry, GJ (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bldg 30,Room 304,MSC4350, Bethesda, MD 20892 USA. RI Chaudry, Ghulam/F-9761-2011 NR 25 TC 29 Z9 36 U1 1 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD FEB PY 2002 VL 10 IS 2 BP 58 EP 62 DI 10.1016/S0966-842X(01)02294-6 PG 5 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 520TT UT WOS:000173798000002 PM 11827799 ER PT J AU Romero, R Kalache, KD Kadar, N AF Romero, R Kalache, KD Kadar, N TI Timing the delivery of the preterm severely growth-restricted fetus: venous Doppler, cardiotocography or the biophysical profile? SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material ID VELOCITY WAVE-FORMS; GESTATIONAL-AGE FETUSES; BLOOD-FLOW VELOCITY; FETAL RENAL-ARTERY; UMBILICAL ARTERY; RETARDED FETUSES; DUCTUS VENOSUS; CEREBRAL DOPPLER; RETARDATION; CORDOCENTESIS C1 NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Perinatal Res Branch, Detroit, MI 48201 USA. RP Romero, R (reprint author), NICHHD, Perinatol Res Branch, NIH, Bethesda, MD 20892 USA. NR 64 TC 41 Z9 46 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2002 VL 19 IS 2 BP 118 EP 121 DI 10.1046/j.0960-7692.2002.00653.x PG 4 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 526HC UT WOS:000174123500002 PM 11876801 ER PT J AU Stec, AA Hommer, R Walker, LC Pannu, HK Fishman, EK Gearhart, JP AF Stec, AA Hommer, R Walker, LC Pannu, HK Fishman, EK Gearhart, JP TI Classic bladder exstrophy in a nonhuman primate: A comparative analysis SO UROLOGY LA English DT Article AB Objectives. To describe the pelvic floor musculature and bony pelvic anatomy in a case of naturally occurring classic bladder exstrophy in a rhesus monkey, the first reported case in the animal population since 1832, and compare the results to exstrophy seen in human newborns. Methods. A 7-day-old male rhesus monkey with classic bladder exstrophy was examined by a pediatric urologist and primate veterinarian before being killed. A multidetector row computed tomography study with three-dimensional reconstruction was obtained, and a comparison computed tomography study of a 17-day-old male human with exstrophy was also reconstructed three dimensionally. The bony pelvis and pelvic floor muscular anatomy of both subjects were then examined and compared. Results. On gross examination, a similar appearance of classic bladder exstrophy in the rhesus monkey and human newborn were noted, including an open exposed bladder, associated penile epispadias, and widely separated pubic bones. The evaluation of the three-dimensional models showed a similar orientation of the bony pelvis in both the rhesus and the human newborn. The iliac wings were significantly rotated outward, and the sacroiliac joint was 10degrees wider than that seen in normal children. The exstrophy pelvic floor in both the rhesus and the newborn was markedly flattened, with approximately 33 0 of the muscle located anterior to the rectum to support the pelvic structures (normal children have 50% of their levator ani anterior to the rectum). Conclusions. By using advancements in imaging modalities, this study illustrated that naturally occurring classic bladder exstrophy in the human newborn and rhesus monkey were identical in both external appearance and internal anatomy. UROLOGY 59: 180-183, 2002. (C) 2002, Elsevier Science Inc. C1 Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. NIH, Anim Control Ctr, Poolesville, MD USA. RP Gearhart, JP (reprint author), Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Div Pediat Urol, 600 N Wolfe St,Marburg 146, Baltimore, MD 21287 USA. NR 15 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2002 VL 59 IS 2 BP 180 EP 183 DI 10.1016/S0090-4295(01)01587-4 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 520QQ UT WOS:000173792900002 PM 11834381 ER PT J AU Etzioni, R Berry, KM Legler, JM Shaw, P AF Etzioni, R Berry, KM Legler, JM Shaw, P TI Prostate-specific antigen testing in black and white men: An analysis of Medicare claims from 1991-1998 SO UROLOGY LA English DT Article ID CANCER INCIDENCE; KNOWLEDGE; TRIAL AB Objectives. To describe the trends in prostate-specific antigen (PSA) use and associated cancer detection among black and white Medicare beneficiaries older than 65 years during the calendar period from January 1991 through December 1998. Methods. Medicare claims data were linked with cancer registry data from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. Data from a 5% random sample of men without a diagnosis of prostate cancer were combined with data from prostate cancer cases diagnosed during the calendar period from 1991 to 1998. PSA tests conducted after a diagnosis of prostate cancer were excluded. Results. PSA use has stabilized among white men, reaching an annual rate of 38% by 1995 and remaining at this level through 1998. The annual rate of use among black men reached 31% by 1998, but was still increasing at that time. By 1996, at least 80% of tests in both blacks and whites were second or later tests. By the end of 1996, 35% of white men and 25% of black men were undergoing testing at least biannually or more frequently. In 1996, 83% of diagnoses in whites and 77% in blacks were preceded by a PSA test. Conclusions. Older black men lag slightly behind older white men in their use of the PSA test; however, annual testing rates in blacks have yet to stabilize. In both race groups, an overwhelming majority of diagnoses are associated with a PSA test, whether for screening or diagnostic purposes. Regular screening rates in blacks are substantially lower than in whites, but the regular screening rates are relatively low in both race groups. Should PSA screening prove efficacious, efforts to promote regular use among both black and white men will likely be needed. UROLOGY 59: 251-255, 2002. (C) 2002, Elsevier Science Inc. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. NCI, Appl Res Branch, Canc Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Etzioni, R (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,MP-665,POB 19024, Seattle, WA 98109 USA. FU NCI NIH HHS [R29 CA70227, U01 CA88160] NR 15 TC 82 Z9 83 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD FEB PY 2002 VL 59 IS 2 BP 251 EP 255 DI 10.1016/S0090-4295(01)01516-3 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 520QQ UT WOS:000173792900018 PM 11834397 ER PT J AU Senior, C Ward, J David, AS AF Senior, C Ward, J David, AS TI Representational momentum and the brain: An investigation into the functional necessity of V5/MT SO VISUAL COGNITION LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; POSITRON-EMISSION-TOMOGRAPHY; MOTION PERCEPTION; IMPLICIT-MOTION; MECHANISMS; PATIENT; OBJECTS; SAFETY AB The mental representation of objects can imply motion and momentum. This can be explored by investigating a distortion in recognition memory for pictures that depict objects "frozen" in mid-air, implying motion. This distortion is called representational momentum (RM). Recent functional neuroimaging studies have suggested that the V5/MT system (the area of the brain thought to be responsible for perceptual processing of motion) is involved in the mediation of RM. The results of these studies are reviewed here. However the presence of functional activity revealed in brain imaging studies does not mean that this part of the brain is necessary for a particular cognitive task. A greater degree of functional necessity can be inferred by disrupting function in that part of the brain. One way in which this can be done is with Transcranial Magnetic Stimulation (TMS, a method of temporarily suspending cortical activity). We extended the findings of the previous fMRI experiments by using TMS in conjunction with an RM paradigm. Repetitive magnetic stimulation to V5/MT during the so-called freeze-frame RM task resulted in an absence of the stereotypical distortion in recognition memory (compared to stimulation at the vertex) for approximately 60% of the subjects. Those subjects that did not show the RM effect with vertex stimulation were excluded from the final analysis. Taken together these initial data converge on the role of the V5/MT system as a necessary substrate for the cognitive representation of motion. C1 Inst Psychiat, Sect Cognit Neuropsychiat, London, England. UCL, Dept Psychol, London, England. RP Senior, C (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM carl@codon.nih.gov RI Ward, Jamie/F-3609-2011; David, Anthony/C-1315-2011 OI David, Anthony/0000-0003-0967-774X NR 27 TC 38 Z9 38 U1 1 U2 7 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1350-6285 J9 VIS COGN JI Vis. Cogn. PD FEB PY 2002 VL 9 IS 1-2 BP 81 EP 92 DI 10.1080/13506280143000331 PG 12 WC Psychology, Experimental SC Psychology GA 508UT UT WOS:000173108600006 ER PT J AU Zhang, LX Levine, S Dent, G Zhan, YT Xing, GQ Okimoto, D Gordon, MK Post, RM Smith, MA AF Zhang, LX Levine, S Dent, G Zhan, YT Xing, GQ Okimoto, D Gordon, MK Post, RM Smith, MA TI Maternal deprivation increases cell death in the infant rat brain SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE apoptosis; nerve growth factor; oligodendrocyte; stress ID PITUITARY-ADRENAL AXIS; DEVELOPING DENTATE GYRUS; STRESS; HIPPOCAMPUS; EXPRESSION; SEPARATION; SURVIVAL; GROWTH; NGF; HYDROCORTISONE AB Prolonged separation from the mother can interfere with normal growth and development and is a significant risk factor for adult psychopathology. In rodents, separation of a pup from its mother increases the behavioral and endocrine responses to stress for the lifetime of the animal, Here we investigated whether maternal deprivation could affect brain development of infant rats via changes in the rate of cell death as measured by labeling the 3' end of DNA fragments using terminal transferase (ApopTag). At postnatal day 12 (P12), the number Of Cells undergoing cell death approximately doubled in the cerebral cortex, cerebellar cortex and in several white matter tracts following 24 h of maternal deprivation. Deprivation strongly increased the number of ApopTag-labeled cells at P6 but not at P20. Stroking the infant rats only partially reversed the effects of maternal deprivation. Increased cell death in white matter tracts correlated with an induction of nerve growth factor which has been previously associated with oligodendrocyte cell death. Cell birth was either unchanged or decreased in response to deprivation. These results indicate that maternal deprivation can alter normal brain development by increasing cell death of neuron and glia, and provides a potential mechanism by which early environmental stressors may influence subsequent behavior. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. Univ Delaware, Dept Psychol, Newark, DE USA. Dupont Merck Pharmaceut Co, CNS Dis Res, Wilmington, DE 19880 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Smith, MA (reprint author), AstraZeneca Pharmaceut, Expt Med, POB 15437, Wilmington, DE 19850 USA. NR 40 TC 72 Z9 75 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD JAN 31 PY 2002 VL 133 IS 1 BP 1 EP 11 AR PII S0926-6410(01)00118-5 DI 10.1016/S0926-6410(01)00118-5 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 529RG UT WOS:000174311900001 ER PT J AU Pankiewicz, KW Lesiak-Watanabe, KB Watanabe, KA Patterson, SE Jayaram, HN Yalowitz, JA Miller, MD Seidman, M Majumdar, A Prehna, G Goldstein, BM AF Pankiewicz, KW Lesiak-Watanabe, KB Watanabe, KA Patterson, SE Jayaram, HN Yalowitz, JA Miller, MD Seidman, M Majumdar, A Prehna, G Goldstein, BM TI Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INOSINE MONOPHOSPHATE DEHYDROGENASE; HUMAN TYPE-I; IMP-DEHYDROGENASE; ERYTHROID-DIFFERENTIATION; MOLECULAR MECHANISMS; INHIBITORY ACTIVITY; SELECTIVE BLOCKER; DINUCLEOTIDE TAD; BLAST CRISIS; TIAZOFURIN AB Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2',3'-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzyl-protected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC50 = 0.7 muM and IC50 = 0.1 muM, respectively) as potently as mycophenolic acid (IC50 = 0.3 muM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias. C1 Pharmasset Inc, Tucker, GA 30084 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. RP Pankiewicz, KW (reprint author), Pharmasset Inc, 1860 Montreal Rd, Tucker, GA 30084 USA. FU NCI NIH HHS [CA-84828]; NIAID NIH HHS [AI-46093] NR 44 TC 51 Z9 53 U1 0 U2 2 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 31 PY 2002 VL 45 IS 3 BP 703 EP 712 DI 10.1021/jm0104116 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 517MZ UT WOS:000173615600017 PM 11806722 ER PT J AU Balboni, G Guerrini, R Salvadori, S Bianchi, C Rizzi, D Bryant, SD Lazarus, LH AF Balboni, G Guerrini, R Salvadori, S Bianchi, C Rizzi, D Bryant, SD Lazarus, LH TI Evaluation of the Dmt-Tic pharmacophore: Conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL EVALUATION; TRANSMEMBRANE DOMAIN; PEPTIDE ANTAGONISTS; ANALOGS; MU; DESIGN; BINDING; DERIVATIVES; SELECTIVITY; NALTRINDOLE AB Analogues of the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore were prepared to test the hypothesis that a "spacer" and a third aromatic center in opioid peptides are required to convert a delta-antagonist into ligands with delta-agonist or with mixed delta-antagonist/mu-agonist properties. Potent delta-agonists and bifunctional compounds with high delta- and mu-opioid receptor affinities were obtained by varying the spacer length [none, NH-CH2, NH-CH2-CH2, Gly-NH-CH2] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]: C-terminal modification primarily affected,mu-opioid receptor affinities, which increased maximally 1700-fold relative to the prototype delta-antagonist H-Dmt-Tic-NH2 and differentially modified bioactivity. In the absence of a spacer (1), the analogue exhibited dual delta-agonism (pEC(50), 7.28) and delta-antagonism (pA(2), 7.90). H-Dmt-Tic-NH-CH2-1H-benzimidazol-2-yl (Bid) (2) became a highly potent delta-agonist (pEC(50), 9.90), slightly greater than deltorphin C (pEC(50), 9.56), with mu-agonism (pE(50), 7.57), while H-Dmt-Tic-Gly-NH-CH2-Bid (4) retained potent delta-antagonism, (pA2, 9.0) but with an order of magnitude less mu-agonism. Similarly, H-Dmt-Tic-Gly-NH-Ph (5) had nearly equivalent high mu-agonism (pEC(50), 8.52) and mu-agonism (pEC(50), -8.59), while H-Dmt-TicGly-NH-CH2-Ph (6) whose spacer was longer by a single methylene group exhibited potent delta-antagonism. (pA2, 9.25) and very high mu-agonism (pEC(50), 8.57). These data confirm that the distance between the Dmt-Tic pharmacophore and a third aromatic nucleus is an important criterion in converting Dint-Tic from a highly potent delta-antagonist into a potent delta-agonist or into ligands with mixed delta- and,mu-opioid properties. C1 NIEHS, LCBRA, Durham, NC 27707 USA. Univ Cagliary, Dept Toxicol, I-09126 Cagliari, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Univ Ferrara, Inst Pharmacol, I-44100 Ferrara, Italy. RP Lazarus, LH (reprint author), NIEHS, LCBRA, Durham, NC 27707 USA. OI Guerrini, Remo/0000-0002-7619-0918 NR 54 TC 81 Z9 82 U1 0 U2 6 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 31 PY 2002 VL 45 IS 3 BP 713 EP 720 DI 10.1021/jm010449i PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 517MZ UT WOS:000173615600018 PM 11806723 ER PT J AU Hutchinson, I Jennings, SA Vishnuvajjala, BR Westwell, AD Stevens, MFG AF Hutchinson, I Jennings, SA Vishnuvajjala, BR Westwell, AD Stevens, MFG TI Antitumor benzothiazoles. 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugs SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VITRO; CANCER AB A series of water-soluble L-lysyl- and L-alanyl-amide prodrugs of the lipophilic antitumor 2-(4-aminophenyl)benzothiazoles has been synthesized to address formulation and bioavailability issues related to the desired parenteral administration of the chosen clinical candidate. The prodrugs exhibit the required pharmaceutical properties of good water solubility (in weak acid) and stability at ambient temperature and degradation to free base in vivo. The lysyl-amide of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (NSC 710305, 6d) has been selected for phase 1 clinical evaluation. C1 Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. NCI, Pharmaceut Resources Branch, Div Canc Treatment & Diag, Rockville, MD 20852 USA. RP Stevens, MFG (reprint author), Univ Nottingham, Sch Pharmaceut Sci, Canc Res Labs, Nottingham NG7 2RD, England. RI Westwell, Andrew/M-8126-2014 OI Westwell, Andrew/0000-0002-5166-9236 NR 15 TC 289 Z9 297 U1 1 U2 16 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 31 PY 2002 VL 45 IS 3 BP 744 EP 747 DI 10.1021/jm011025r PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 517MZ UT WOS:000173615600021 PM 11806726 ER PT J AU Szabo, T Biro, T Gonzalez, AF Palkovits, M Blumberg, PM AF Szabo, T Biro, T Gonzalez, AF Palkovits, M Blumberg, PM TI Pharmacological characterization of vanilloid receptor located in the brain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE [H-3]resiniferatoxin; capsaicin; vanilloid receptor ID LOCUS-COERULEUS NEURONS; ROOT GANGLION NEURONS; CAPSAICIN-RECEPTOR; RESINIFERATOXIN BINDING; H-3 RESINIFERATOXIN; SENSORY NEURONS; SPINAL-CORD; RAT; HEAT; NEUROPEPTIDES AB Specific [H-3]resiniferatoxin (RTX) binding detects the vanilloid receptor type I (VRI). In the present study we demonstrate specific, high-affinity, saturable [H-3]RTX binding in various areas of monkey brain not known to be innervated by primary afferent neurons as well as in spinal cord and dorsal root ganglion neurons of the same origin. Detailed pharmacological characterization and comparison revealed no major difference in binding affinities between the peripheral and the central sites as measured by K-d/K-i values. In general, lower receptor density was measured in selected brain areas than in the periphery. Areas with higher receptor density were detected in the locus ceruleus, preoptic area, and medial basal hypothalamus of the brain. Both capsaicin and the competitive antagonist capsazepine inhibited the specific binding of [H-3]RTX to membrane preparations of the dorsal horn of the spinal cord and dorsal root ganglia with K-i values of 4.3+/-0.32 muM and 2.7+/-0.33 muM, respectively. Inhibition was observed in the central areas (hypothalamus) with K-i values of 0.95+/-0.1 muM for capsaicin and 0.86+/-0.11 muM for capsazepine. Previous biological and pharmacological evidence suggested that vanilloid receptors were present in the brain. Our results demonstrate that the pharmacological properties of both the peripheral and central receptor sites display appropriate pharmacological similarity to represent the same receptor class. The modest differences in ligand affinities for the vanilloid receptor expressed in the brain nuclei and the dorsal root ganglion neurons may correspond to differences in sequence, modification or associated proteins. Published by Elsevier Science B.V. C1 Natl Inst Mental Hlth, Lab Cellular Carcinogenesis & Tumor Promot, Bethesda, MD 20892 USA. Natl Inst Mental Hlth, Lab Cell Biol, Bethesda, MD 20892 USA. RP Blumberg, PM (reprint author), Natl Inst Mental Hlth, Lab Cellular Carcinogenesis & Tumor Promot, Bldg 37 Rm 3A01 37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 NR 43 TC 35 Z9 35 U1 0 U2 3 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 31 PY 2002 VL 98 IS 1-2 BP 51 EP 57 AR PII S0169-328X(01)00313-8 DI 10.1016/S0169-328X(01)00313-8 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 522ZM UT WOS:000173926900005 ER PT J AU Zhang, L Li, BS Ma, W Barker, JL Chang, YH Zhao, WQ Rubinow, DR AF Zhang, L Li, BS Ma, W Barker, JL Chang, YH Zhao, WQ Rubinow, DR TI Dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEAS) regulate apoptosis during neurogenesis by triggering the Akt signaling pathway in opposing ways SO MOLECULAR BRAIN RESEARCH LA English DT Article DE DHEA; DHEAS; neural precursor; Akt kinase; apoptosis ID PROTEIN-KINASE; GROWTH-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; NEURONAL SURVIVAL; EXPRESSION; DIFFERENTIATION; INHIBITION; CULTURES; INSULIN; DEATH AB Dehydroepiandrosterone (DHEA) can function to protect neural precursors and their progeny targeted with toxic insults; however, the molecular mechanisms underlying the neuroprotective effects of DHEA are not understood. We cultured neural precursors from the embryonic forebrain of rats and examined the effects of DHEA and its sulfated derivative (DHEAS) on the activation of the serine-threonine protein kinase Akt, which is widely implicated in cell survival signaling. We found that DHEA activated Akt in neural precursor culture, in association with a decrease in apoptosis. In contrast, DHEAS decreased activated Akt levels and increased apoptosis. The effects of DHEA on neural cell survival and activation of Akt were not blocked by the steroid hormone antagonists flutamide and tamoxifen, but both were blocked by a PI3-K inhibitor, LY294002. These findings suggest that during neurogenesis in the developing cortex, DHEA and DHEAS regulate the survival of neural precursors and progeny through the Akt signaling pathway. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Natl Inst Mental Hlth, Behav Endocrinol Branch, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Lab Neurophysiol, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Bethesda, MD 20892 USA. RP Zhang, L (reprint author), Natl Inst Mental Hlth, Behav Endocrinol Branch, Bldg 36 Rm 2C02, Bethesda, MD 20892 USA. NR 29 TC 29 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JAN 31 PY 2002 VL 98 IS 1-2 BP 58 EP 66 AR PII S0169-328X(01)00315-1 DI 10.1016/S0169-328X(01)00315-1 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 522ZM UT WOS:000173926900006 ER PT J AU Emanuel, EJ Miller, FG AF Emanuel, EJ Miller, FG TI The ethics of placebo-controlled trials - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CLINICAL RESEARCH C1 NIH, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 31 PY 2002 VL 346 IS 5 BP 383 EP 383 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 516GJ UT WOS:000173545300034 ER PT J AU Montagna, C Andrechek, ER Padilla-Nash, H Muller, WJ Ried, T AF Montagna, C Andrechek, ER Padilla-Nash, H Muller, WJ Ried, T TI Centrosome abnormalities, recurring deletions of chromosome 4, and genomic amplification of HER2/neu define mouse mammary gland adenocarcinomas induced by mutant HER2/neu SO ONCOGENE LA English DT Article DE HER2/neu; spectral karyotyping (SKY); breast cancer model; genomic instability; double minutes (DMs); centrosome ID TRANSGENIC MICE; BREAST-CANCER; C-MYC; TUMORS; HYBRIDIZATION; ABERRATIONS; TUMORIGENESIS; INSTABILITY; ONCOGENE; GENES AB The conditional expression of activated HER2/neu gene under its endogenous promoter in the mammary epithelium of the mouse results in accelerated lobular development and focal mammary tumors. Carcinogenesis, however, requires amplification and considerably increased expression levels of oncogenic neu. Deducing from the multiple genetic aberrations required for human breast cancer to develop, we hypothesized that in addition to the over-expression of an activated HER2/neu, secondary aberrations would occur. We have therefore conducted a genomic screen for chromosomal imbalances and translocations using comparative genomic hybridization and spectral karyotyping. The results reveal a moderate degree of chromosomal instability and micronuclei formation in short-term cultures established from primary tumors. Genomic instability appears to be linked to the amplification of functional centrosomes, a phenomenon that we frequently observed in other tumor types. Seventy per cent of the tumors revealed genomic amplification of HER2/neu, often in the form of double minute chromosomes, which correlated with recurring loss of mouse chromosome 4D-E, a region that is orthologous to distal human chromosome 1p. It is likely that this region contains putative tumor suppressor genes whose inactivation is required for tumor formation in this model of human breast cancer. C1 NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD 20892 USA. McMaster Univ, Inst Mol Biol & Biotechnol, Dept Biol, Hamilton, ON L8S 4K1, Canada. RP Ried, T (reprint author), NCI, Ctr Canc Res, Genet Branch, NIH, Bldg 9,Rm 1N105,9 Mem Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [U01 CA105490] NR 33 TC 70 Z9 70 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 31 PY 2002 VL 21 IS 6 BP 890 EP 898 DI 10.1038/sj.onc.1205146 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FC UT WOS:000173427100004 PM 11840334 ER PT J AU Caldwell, MC Hough, C Furer, S Linehan, WM Morin, PJ Gorospe, M AF Caldwell, MC Hough, C Furer, S Linehan, WM Morin, PJ Gorospe, M TI Serial analysis of gene expression in renal carcinoma cells reveals VHL-dependent sensitivity to TNF alpha cytotoxicity SO ONCOGENE LA English DT Article DE VHL; SAGE; renal cell carcinoma; gene expression; TNF alpha ID ENDOTHELIAL GROWTH-FACTOR; HIPPEL-LINDAU PROTEIN; TUMOR-SUPPRESSOR PROTEIN; NECROSIS-FACTOR-ALPHA; APOPTOSIS; ELONGATION; PRODUCT; ARREST; DEATH AB We have used serial analysis of gene expression (SAGE) to investigate the influence of the von Hippel-Lindau (VHL) gene on global gene expression profiles. SAGE libraries were prepared from renal cell carcinoma (RCC) lines that either lack (parental) or express wild-type VHL (wtVHL). Comparison of these libraries revealed some differentially expressed genes (Glut-1, for example) that were known to be influenced by VHL, but the majority of genes had not previously been reported to be affected by the cell's VHL status. The identification of several genes involved in TNFalpha-mediated events prompted us to compare the sensitivity of cells with different VHL status in TNFalpha cytotoxicity assays. Strikingly, VHL-deficient cells were much more resistant to the toxic influence of TNFalpha. We propose that VHL-dependent sensitization of RCC cells to TNFalpha-mediated killing may contribute to VHL's growth suppressive function. C1 NIA, GRC, IRP,NIH, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Gorospe, M (reprint author), NIA, GRC, IRP,NIH, Cellular & Mol Biol Lab, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 26 TC 30 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 31 PY 2002 VL 21 IS 6 BP 929 EP 936 DI 10.1038/sj.onc.1205140 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FC UT WOS:000173427100008 PM 11840338 ER PT J AU Sanchez-Prieto, R Sanchez-Arevalo, VJ Servitja, JM Gutkind, JS AF Sanchez-Prieto, R Sanchez-Arevalo, VJ Servitja, JM Gutkind, JS TI Regulation of p73 by c-Abl through the p38 MAP kinase pathway SO ONCOGENE LA English DT Article DE p73; c-Abl; p38; p53; DNA damage ID ACTIVATED PROTEIN-KINASE; TYROSINE KINASE; DNA-DAMAGE; CELL-DEATH; APOPTOTIC RESPONSE; P53 GENE; STRESS; FAMILY; AGENTS AB p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular differentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These findings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Clin Puerta Hierro, Dept Anat Patol, Unidad Patol Mol, Madrid 28035, Spain. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Sanchez-Arevalo Lobo, Victor Javier/H-1069-2011; Sanchez-Prieto, Ricardo/B-6877-2008; OI Sanchez-Arevalo Lobo, Victor Javier/0000-0002-4561-1505; Sanchez-Prieto, Ricardo/0000-0003-0882-9780; SERVITJA DUQUE, JOAN-MARC/0000-0002-1241-8004 NR 32 TC 85 Z9 86 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 31 PY 2002 VL 21 IS 6 BP 974 EP 979 DI 10.1038/sj.onc.1205134 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FC UT WOS:000173427100013 PM 11840343 ER PT J AU Shapiro, SZ AF Shapiro, SZ TI The HIV/AIDS vaccine researchers' orientation to the process of preparing a USFDA application for an investigational new drug (IND): what it is all about and how you start by preparing for your pre-IND meeting SO VACCINE LA English DT Article C1 NIAID, Div Aids, Vaccine & Prevent Res Program, Bethesda, MD 20892 USA. RP Shapiro, SZ (reprint author), NIAID, Div Aids, Vaccine & Prevent Res Program, 6700-B Rockledge Dr,Room 4108, Bethesda, MD 20892 USA. NR 3 TC 6 Z9 6 U1 0 U2 2 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 2002 VL 20 IS 9-10 BP 1261 EP 1280 AR PII S0264-410X(01)00453-4 DI 10.1016/S0264-410X(01)00453-4 PG 20 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 521TW UT WOS:000173858300002 PM 11818145 ER PT J AU Golding, B Eller, N Levy, L Beining, P Inman, J Matthews, N Scott, DE Golding, H AF Golding, B Eller, N Levy, L Beining, P Inman, J Matthews, N Scott, DE Golding, H TI Mucosal immunity in mice immunized with HIV-1 peptide conjugated to Brucella abortus SO VACCINE LA English DT Article DE mucosal immunity; Brucella abortus; HIV-1 ID T-CELLS; B-ABORTUS; V3 LOOP; RESPONSES; CARRIER; CD4(+); LIPOPOLYSACCHARIDE; VACCINES AB We have previously shown that a V3-loop peptide from HIV-1 envelope conjugated to heat-inactivated Brucella abortus (Ba) (V3-Ba) is capable of inducing antibodies that neutralize HIV-1 and cytotoxic T cells (CTL) that kill HIV-1-infected targets, even in mice that lack CD4(+) T cells. In this paper we show that intranasal (i.n.) immunization elicits neutralizing antibodies and IFN-gamma-secreting T cells at mucosal surfaces. This approach may protect individuals from HIV-1 infection and reduce transmission from infected individuals to their sexual partners and offspring. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol,Lab Plasma Derivat, Rockville, MD 20852 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Viral Prod,Lab Retrovirus Res, Rockville, MD 20852 USA. RP Golding, B (reprint author), US FDA, Ctr Biol Evaluat & Res, Off Blood Res & Review, Div Hematol,Lab Plasma Derivat, Rockville, MD 20852 USA. NR 11 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 31 PY 2002 VL 20 IS 9-10 BP 1445 EP 1450 AR PII S0264-410X(01)00477-7 DI 10.1016/S0264-410X(01)00477-7 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 521TW UT WOS:000173858300022 PM 11818165 ER PT J AU Sakabe, K Teramoto, H Zohar, M Behbahani, B Miyazaki, H Chikumi, H Gutkind, JS AF Sakabe, K Teramoto, H Zohar, M Behbahani, B Miyazaki, H Chikumi, H Gutkind, JS TI Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38 gamma-dependent signaling pathway SO FEBS LETTERS LA English DT Article DE Rit; mitogen-activated protein kinase; p38 gamma; focus formation ID MAP KINASE ISOFORMS; TRANSDUCTION PATHWAY; SELECTIVE ACTIVATION; EXPRESSION AB A novel branch of the Ras family, Rit, was recently identified. Rit exhibits a distinct C-terminus and effector domain, and does not activate mitogen-activated protein kinase (MAPK) but can cooperate with Raf to transform fibroblasts. Here. we found that when overexpressed, activated mutants of Rit transform NIH 3T3 cells efficiently, and stimulate p38gamma but not MAPK, p38alpha, p38beta, p38delta, or ERK5. Furthermore, we provide evidence that p38gamma activation is required for the ability of Rit to stimulate gene expression and cellular transformation. These findings suggest that this unique GTPase stimulates proliferative pathways distinct from those regulated by other Ras family members. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 90000 Rockville Pike,Bldg 30,Room 212, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 15 TC 18 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 30 PY 2002 VL 511 IS 1-3 BP 15 EP 20 DI 10.1016/S0014-5793(01)03264-1 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 517UF UT WOS:000173628000004 PM 11821041 ER PT J AU Lenfant, C AF Lenfant, C TI Strengthening commitment to clinical research - The National Heart, Lung, and Blood Institute's Specialized Centers of Research Program SO CIRCULATION LA English DT Editorial Material DE trials; research; funding C1 NHLBI, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 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 0009-7322 J9 CIRCULATION JI Circulation PD JAN 29 PY 2002 VL 105 IS 4 BP 400 EP 401 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 517FM UT WOS:000173600500011 PM 11815416 ER PT J AU Ferrans, VJ AF Ferrans, VJ TI New insights into the world of matrix metalloproteinases SO CIRCULATION LA English DT Editorial Material DE metalloproteinases; remodeling; atherosclerosis; aneurysm ID ABDOMINAL AORTIC-ANEURYSM; VEIN GRAFTS; ACTIVATION; INHIBITORS; STROMELYSIN-1; MECHANISMS; DISEASE; STRESS; CELLS C1 NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Ferrans, VJ (reprint author), NHLBI, Pathol Sect, NIH, Bldg 10-2N240, Bethesda, MD 20892 USA. NR 20 TC 18 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 29 PY 2002 VL 105 IS 4 BP 405 EP 407 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 517FM UT WOS:000173600500013 PM 11815418 ER PT J AU Cardillo, C Campia, U Kilcoyne, CM Bryant, MB Panza, JA AF Cardillo, C Campia, U Kilcoyne, CM Bryant, MB Panza, JA TI Improved endothelium-dependent vasodilation after blockade of endothelin receptors in patients with essential hypertension SO CIRCULATION LA English DT Article DE endothelin; endothelium; vasodilation; hypertension ID NITRIC-OXIDE; HEART-FAILURE; VASCULAR RELAXATION; L-ARGININE; ANTAGONIST; ACETYLCHOLINE; INHIBITION; CLONING; POTENT; CELLS AB Background-Hypertensive patients have both impaired endothelium-dependent vasodilation and increased activity of the endothelin (ET-1) system, which participate in their increased vascular tone and may predispose them to atherosclerosis. This study investigated the contribution of increased ET-1 activity to the impaired endothelium-dependent vasodilator function of hypertensive patients, Methods and Results-Forearm blood flow (FBF) responses to intraarterial infusion of acetylcholine (ACh 7.5, 15, and 30 mug/min) and sodium nitroprusside (SNP: 0.8, 1.6, and 3.2 mug/min) were assessed by strain-gauge plethysmography before and after nonselective blockade of ETA and ETB receptors by combined infusion of BQ-123 (ETA blocker, 100 nmol/min) and BQ-788 (ETB blocker; 50 nmol/min). During saline administration, the vasodilator response to ACh was significantly blunted in hypertensive patients compared with controls (P<0.001), whereas the vasodilator effect of SNP was not different between groups (P=0.74). Blockade of ET-1 receptors resulted in a significant increase in FBF from baseline in hypertensive patients (P<0.008) but not in controls (P=0. 15). In hypertensive patients, a combined ETA/B blockade resulted in a significant potentiation of the vasodilator response to ACh compared with saline (P=0.01), whereas the response to SNP Was unchanged (P=0.44). In contrast. the response to ACh was not significantly modified by ET-1 receptor antagonism in healthy subjects (P=0.14 compared with saline). Conclusions-These findings indicate that blockade of ET-1 receptors improves endothelium-dependent vasodilator function in hypertensive patients, thereby suggesting that an increased ET-1 activity may play a role in the pathophysiology of this abnormality. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Panza, JA (reprint author), Washington Hosp Ctr, 110 Irving St NW,Suite 2A 74, Washington, DC 20010 USA. NR 31 TC 85 Z9 91 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 29 PY 2002 VL 105 IS 4 BP 452 EP 456 DI 10.1161/hc0402.102989 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 517FM UT WOS:000173600500022 PM 11815427 ER PT J AU Vandewiele, D de Henestrosa, ARF Timms, AR Bridges, BA Woodgate, R AF Vandewiele, D de Henestrosa, ARF Timms, AR Bridges, BA Woodgate, R TI Sequence analysis and phenotypes of five temperature sensitive mutator alleles of dnaE, encoding modified alpha-catalytic subunits of Escherichia coli DNA polymerase III holoenzyme SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE DNA replication; pot V; spontaneous mutagenesis; tn10 transposon; umuDC ID MUTATIONAL SPECIFICITY; ANTIMUTATOR ALLELES; INDUCED MUTAGENESIS; ACTIVE-SITE; MUTANTS; IDENTIFICATION; REPLICATION; GENE; REQUIREMENTS; PURIFICATION AB In the 1970s, several thermosensitive alleles of dnaE (encoding the alpha-catalytic subunit of pol III) were isolated. Genetic characterization of these dnaE mutants revealed that some are mutator alleles at permissive temperature. We have determined the nucleotide changes of five such temperature sensitive mutator alleles (dnaE9, dnaE74, dnaE486, dnaE511, and dnaE1026) and find that most are single missense mutations. The exception is dnaE1026 which is a compound allele consisting of multiple missense mutations. When the previously characterized mutator alleles were moved into a lexA51(Def) recA730 strain, dnaE486, dnaE1026 and dnaE74 conferred a modest similar totwo-six-fold increase in spontaneous mutagenesis when grown at the permissive temperature of 28degreesC, while dnaE9 and dnaE511 actually resulted in a slight decrease in spontaneous mutagenesis. In isogenic DeltaumuDC derivatives, the level of spontaneous mutagenesis dropped significantly, although in each case, the overall mutator effect conferred by the dnaE allele was relatively larger, with all five dnaE alleles conferring an increased spontaneous mutation rate similar to5-22-fold over the isogenic dnaE(+) DeltaumuDC strain. Interestingly, the temperature sensitivity conferred by each allele varied considerably in the lexA51(Def) recA730 background and in many cases, this phenotype was dependent upon the presence of functional pol V (UmuD(2)'C). Our data suggest that pol V can compete effectively with the impaired alpha-subunit for a 3' primer terminus and as a result, a large proportion of the phenotypic effects observed with strains carrying missense temperature sensitive mutations in dnaE can, in fact, be attributed to the actions of pol V rather than pol III. Published by Elsevier Science B.V. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. Univ Sussex, MRC, Cell Mutat Unit, Falmer BN1 9RR, E Sussex, England. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. NR 52 TC 27 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 29 PY 2002 VL 499 IS 1 BP 85 EP 95 DI 10.1016/S0027-5107(01)00268-8 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 517TM UT WOS:000173626000008 PM 11804607 ER PT J AU Lenfant, C AF Lenfant, C TI Reflections on hypertension control rates - A message from the director of the National Heart, Lung, and Blood Institute SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 38 Z9 41 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 28 PY 2002 VL 162 IS 2 BP 131 EP 132 DI 10.1001/archinte.162.2.131 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 514QT UT WOS:000173453100001 PM 11802745 ER PT J AU Emanuel, EJ AF Emanuel, EJ TI Euthanasia and physician-assisted suicide - A review of the empirical data from the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID ACTIVE EUTHANASIA; ONCOLOGY PATIENTS; WASHINGTON-STATE; MEDICAL-STUDENTS; DEATH PRACTICES; ATTITUDES; LIFE; OREGON; CARE; END AB For more than a decade, there has been an intense debate about the ethics and legality of euthanasia and physician-assisted suicide (PAS) in the United States.(1.5) In June 1997, the US Supreme Court unanimously ruled that there is neither a constitutional right nor a constitutional prohibition to euthanasia or PAS.(6,7) This permitted Oregon to experiment with legalizing PAS. During this decade, most other states have consistently opposed legalization. In the weeks after the US Supreme Court decision, the Florida Supreme Court also ruled that there is no constitutional right to PAS.(8) At least 7 state legislatures have voted to explicitly prohibit euthanasia and PAS.' Indeed, a bill to legalize euthanasia or PAS has been considered by a full chamber of a state legislature in only one state, Maine, and that bill was defeated 99 to 42.(10) In November 1998, 70% of the voters of Michigan resoundingly defeated a referendum to legalize PAS, while in November 2000 Maine voters also rejected legalizing PAS.(11) C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 67 TC 93 Z9 93 U1 4 U2 24 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 28 PY 2002 VL 162 IS 2 BP 142 EP 152 DI 10.1001/archinte.162.2.142 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 514QT UT WOS:000173453100003 PM 11802747 ER PT J AU Smith, NL Barzilay, JI Shaffer, D Savage, PJ Heckbert, SR Kuller, LH Kronmal, RA Resnick, HE Psaty, BM AF Smith, NL Barzilay, JI Shaffer, D Savage, PJ Heckbert, SR Kuller, LH Kronmal, RA Resnick, HE Psaty, BM TI Fasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly - The cardiovascular health study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; RANCHO-BERNARDO; MORTALITY; MEN; ATHEROSCLEROSIS; HYPERGLYCEMIA; ASSOCIATION; WHITEHALL; GLYCEMIA; PROGRAM AB Background: The contributions of fasting and 2-hour postchallenge glucose level to cardiovascular events remain ill-defined, especially for nondiabetic adults. This study examined the relative predictive power of fasting and 2-hour glucose level on cardiovascular event risk. Methods: A total of 4014 community-dwelling adults 65 years or older who participated in the baseline visit of the Cardiovascular Health Study and who were without treated diabetes or previous myocardial infarction or stroke were eligible for analyses. Participants with treated diabetes at baseline were excluded. Incident myocardial infarction or stroke, or coronary death, was the outcome of interest. Age-, sex-, and race-adjusted proportional hazards regression models described individual and joint associations between baseline measures of fasting and 2-hour postchallenge glucose level and event risk. Results: There were 764 incident cardiovascular events during 8.5 years of follow-up. Fasting glucose level of 115 mg/dL (6.4 mmol/L) or more was associated with an increased cardiovascular risk (hazard ratio [HR], 1.66 [95% confidence interval (CI), 1.39-1.98]) in adjusted analyses compared with fasting glucose level less than 115 mg/dL. Two-hour glucose level was associated with a linear risk (HR, 1.02 [95% CI, 1.00-1.04] per 10 mg/dL [0.6 mmol/L]) that included an additional increase in risk for 2-hour glucose level of 154 mg/dL (8.5 mmol/L) or more (HR, 1.29 [95% CI, 1.04-1.59]) in adjusted analyses. In joint fasting and 2-hour glucose models, only 2-hour glucose level remained predictive of event risk. Conclusions: Two-hour glucose level was better than fasting glucose level alone at identifying older adults at increased risk of major incident cardiovascular events. C1 Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Kaiser Permanente Georgia, Div Endocrinol, Atlanta, GA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epizootiol, Pittsburgh, PA 15260 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Smith, NL (reprint author), Cardiovasc Hlth Res Unit, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HL-15103, N01-HL35129]; NIA NIH HHS [R01-AG-09556] NR 25 TC 92 Z9 95 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 28 PY 2002 VL 162 IS 2 BP 209 EP 216 DI 10.1001/archinte.162.2.209 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 514QT UT WOS:000173453100011 PM 11802755 ER PT J AU Lavery, JV Singer, PA AF Lavery, JV Singer, PA TI Patients' motivations for physician-assisted suicide - Reply SO LANCET LA English DT Letter C1 NIH, Div Adv Studies & Policy Anal, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Toronto, Joint Ctr Bioeth, Toronto, ON, Canada. RP Lavery, JV (reprint author), NIH, Div Adv Studies & Policy Anal, Fogarty Int Ctr, Bldg 16,Room 211,16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. RI Lavery, James/E-5254-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JAN 26 PY 2002 VL 359 IS 9303 BP 353 EP 353 DI 10.1016/S0140-6736(02)07510-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 517AC UT WOS:000173588100041 ER PT J AU Conrads, TP Issaq, HJ Veenstra, TD AF Conrads, TP Issaq, HJ Veenstra, TD TI New tools for quantitative phosphoproteome analysis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE proteomics; phosphorylation; phosphopeptide; mass spectrometry; stable-isotope labeling; affinity tag ID TRAP MASS-SPECTROMETRY; PROTEIN; PHOSPHORYLATION AB Recent advances in analytical methods, particularly in the area of mass spectrometry, have brought the field of proteomics to the forefront in biological science. The ultimate goal of proteomics-to characterize proteins expressed within a cell under a specific set of conditions-is daunting due to the complexity and dynamic nature the of protein population within the cell. While much of the effort has focused on developing methods to identify expressed proteins, the identification of post-translational modifications is equally important for comprehensive proteome characterization. Of all the known post-translational modifications, phosphorylation arguably plays the largest role in the context of cellular homeostasis. This review discusses some of the recent progress made in the development of techniques not only to identify, but also to quantitatively determine sites of phosphorylation. C1 NCI, Analyt Chem Lab, SAIC Frederick, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Analyt Chem Lab, SAIC Frederick, POB B,Bldg 469,Room 160, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 14 TC 51 Z9 57 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 25 PY 2002 VL 290 IS 3 BP 885 EP 890 DI 10.1006/bbrc.2001.6275 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LF UT WOS:000173611500001 PM 11798155 ER PT J AU Zoberi, I Bradbury, CM Curry, HA Bisht, KS Goswami, PC Roti, JLR Gius, D AF Zoberi, I Bradbury, CM Curry, HA Bisht, KS Goswami, PC Roti, JLR Gius, D TI Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines SO CANCER LETTERS LA English DT Article DE cytotoxicity; cyclooxygenase; cyclooxygenase-1; cell cycle; ionizing radiation ID CYCLOOXYGENASE-2 EXPRESSION; IONIZING-RADIATION; MURINE TUMORS; HEAT-SHOCK; INDOMETHACIN; MISOPROSTOL; ACTIVATION; INHIBITION; CARCINOMA AB Resveratrol is a polyphenol isolated from the skins of grapes that has been shown to significantly alter the cellular physiology of tumor cells. as well as block the process of initiation and progression. At least one mechanism for the intracellular actions of resveratrol involves the suppression of prostaglandin (PG) biosynthesis. The involvement of PGs and other eicosanoids in the development of human cancer is well established. PGs are synthesized from arachidonic acid via the cyclooxygenase pathway and have multiple physiological and pathological functions. In addition, evidence has arisen suggesting that PGs may be implicated in the cytotoxic and/or cytoprotective response of tumor cells to ionizing radiation (IR). As such, we hypothesized that tumor cells may exhibit changes in the cellular response to IR following exposure to resveratrol, a naturally occuring compound that inhibits cyclooxygenase-1 (COX-1) activity. Thus, clonogenic cell survival assays were performed using irradiated HeLa and SiHa cells pretreated with resveratrol prior to IR exposure, and resulted in enhanced tumor cell killing by IR in a dose-dependent manner. Further analysis of COX-1 inhibition indicated that resveratrol pretreatment: (1), inhibited cell division as assayed by growth curves; and (2), induced an early S phase cell cycle checkpoint arrest, as demonstrated by fluorescence-activated cell sorting, as well as bromodeoxyuridine pulse-chase analysis. These results suggest that resveratrol alters both cell cycle progression and the cytotoxic response to IR in two cervical tumor cell lines. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, Sect Canc Biol, St Louis, MO 63110 USA. Univ Iowa, Med Labs B180, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA. RP Gius, D (reprint author), NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bldg 10 Room B3B69, Bethesda, MD 20892 USA. FU NCI NIH HHS [P01 CA75556, 1K08 CA72602-01, 5 R01CA43198-15, 5P01 CA75556-05, CA69593] NR 32 TC 65 Z9 67 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 25 PY 2002 VL 175 IS 2 BP 165 EP 173 DI 10.1016/S0304-3835(01)00719-4 PG 9 WC Oncology SC Oncology GA 511DX UT WOS:000173250300007 PM 11741744 ER PT J AU Lobachev, KS Gordenin, DA Resnick, MA AF Lobachev, KS Gordenin, DA Resnick, MA TI The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements SO CELL LA English DT Article ID DNA DOUBLE-STRAND; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; GENE AMPLIFICATION; MEIOTIC RECOMBINATION; PROTEIN COMPLEX; INVERTED REPEAT; HUMAN GENOME; YEAST-CELLS; MEIOSIS AB Inverted repeats (IRs) that can form a hairpin or cruciform structure are common in the human genome and may be sources of instability. An IR involving the human Alu sequence (Alu-IR) has been studied as a model of such structures in yeast. We found that an Alu-IR is a mitotic recombination hotspot requiring MRE11/RAD50/XRS2 and SAE2. Using a newly developed approach for mapping rare double-strand breaks (DSBs), we established that induction of recombination results from breaks that are terminated by hairpins. Failure of the mre11, rad50, xrs2, and sae2 mutants to process the hairpins blocks recombinational repair of the DSBs and leads to generation of chromosome inverted duplications. Our results suggest an additional role for the Mre11 complex in maintaining genome stability. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. OI Gordenin, Dmitry/0000-0002-8399-1836 NR 64 TC 255 Z9 258 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 25 PY 2002 VL 108 IS 2 BP 183 EP 193 DI 10.1016/S0092-8674(02)00614-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 515XE UT WOS:000173521300006 PM 11832209 ER PT J AU Kino, T Slobodskaya, O Pavlakis, GN Chrousos, GP AF Kino, T Slobodskaya, O Pavlakis, GN Chrousos, GP TI Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREB-BINDING-PROTEIN; THYROID-HORMONE RECEPTOR; RNA-POLYMERASE-II; FACTOR KAPPA-B; GLUCOCORTICOID RECEPTOR; TRANSCRIPTIONAL COACTIVATORS; GENE-EXPRESSION; P300; ACTIVATION; VPR AB We report that p160 nuclear receptor coactivators potentiate the transactivating activity of Tat, the most potent virally encoded transactivator of HIV-1. One of the p160 proteins (GRIP1) is tethered to the HIV-1 long terminal repeat (LTR) through kappaB-responsive elements, most likely via NF-kappaB, with which it also associates through its coactivator motifs (LXXLL motifs, "NR boxes"). Indeed, the Tat-stimulated kappaB-defective HIV-1 LTR had a markedly impaired response to GRIP1, whereas NR box-defective GRIM proteins lost part of their Tat coactivator effect on the HIV-1 LTR. Through its N-terminal basic helix-loop-helix and C-terminal domains, GRIP1 binds to the N-terminal region of Tat and to the host cell protein cyclin T1, respectively, which is normally complexed with CDK9 as P-TEFb. Thus, NF-kappaB is crucial for tethering p160 coactivator molecules to the HIV-1 LTR, allowing full activation of this promoter by Tat. Interestingly, cotransfection of Tat, GRIP1, and cyclin T1 enhanced not only the activity of the HIV-1 LTR, but also the glucocorticoid receptor-mediated stimulation of the mouse mammary tumor virus (MMTV) promoter, suggesting that Tat can also attract the P-TEFb complex to the MMTV LTR through GRIP1. Thus, it appears that the coactivator complexes of the HIV-1 and MMTV LTRs both include p 160 coactivators and use similar coactivator and elongation complexes for their transcription. Tat may function as an adaptor molecule, efficiently stimulating the processes of transcription initiation and elongation through potentiation of the coupling of p160 coactivators and the P-TEFb complex. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Human Retrovirus Sect, Canc Res Ctr, Frederick, MD 21702 USA. RP Kino, T (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42,10 Ctr Dr MSC 1583, Bethesda, MD 20892 USA. NR 47 TC 40 Z9 40 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2396 EP 2405 DI 10.1074/jbc.M106312200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500006 PM 11704662 ER PT J AU Lewis, DEA Adhya, S AF Lewis, DEA Adhya, S TI In vitro repression of the gal promoters by GalR and HU depends on the proper helical phasing of the two operators SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; RNA-POLYMERASE; LAC REPRESSOR; DNA; TRANSCRIPTION; PROTEIN; COMPLEX; PURIFICATION; REQUIREMENT; INHIBITION AB Repression of transcription initiation from the two gal promoters, P1 and P2, requires binding of GalR protein to two Ranking operators, O-E and O-I, binding of HU to a site, hbs, located between the two operators, and supercoiled DNA template. Previous experiments suggested that repression involves the interaction of two DNA-bound GalR proteins, which generates a 113-bp DNA loop encompassing the promoter region. Interaction between two DNA-bound proteins would be allowed if the binding sites on DNA are properly aligned. To test the idea that the observed repression of gal transcription in vitro is mediated by DNA looping, we investigated the effect of changing the relative angular orientation of OE and 01 in the DNA helix. We found that repression is a periodic function of the distance between the two operator sites. Since repression recurred commensurate with DNA helical repeat, we conclude that the observed in vitro repression is mediated by DNA looping and the in vitro conditions reflect the in vivo situation. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Rm 5138, Bethesda, MD 20892 USA. NR 34 TC 42 Z9 42 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2498 EP 2504 DI 10.1074/jcb.M108456200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500018 PM 11700313 ER PT J AU Kimchi-Sarfaty, C Kasir, J Ambudkar, SV Rahamimoff, H AF Kimchi-Sarfaty, C Kasir, J Ambudkar, SV Rahamimoff, H TI Transport activity and surface expression of the Na+-Ca2+ exchanger NCX1 are inhibited by the immunosuppressive agent cyclosporin A and by the nonimmunosuppressive agent PSC833 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NERVOUS-SYSTEM TOXICITY; MAMMALIAN-CELL LINES; FUNCTIONAL EXPRESSION; MULTIDRUG-RESISTANCE; SDZ PSC-833; RNA-POLYMERASE; HELA-CELLS; CLONING; TRANSPLANTATION; PROTEIN AB Cyclosporin A (CsA) treatment of HEK 293 cells expressing the rat heart RHE-1 (NCX1.1, EMBL accession number X68191) or the rat brain RBE-2 (NCX1.5, GenBank(TM) accession number X68813) Na+-Ca2+ exchanger inhibited their transport activity in a concentration-dependent manner. The inhibition was detectable at 2 mum CsA, and exposure of the cells to 20 mum CsA resulted in a decrease of the Na+-dependent Ca2+ uptake to about 20% relative to that of untreated cells. Determination of the surface expression of the exchanger protein revealed a parallel concentration-dependent reduction in the amount of the immunoreactive protein. No reduction was detected in the amount of total immunoreactive exchanger protein in CsA-treated cells relative to untreated ones. Among the different drugs tested, only PSC833, an analog of cyclosporin D, mimicked the effects of CsA. Exposure of the transfected cells to the chemically related cyclosporin D and macrolide drugs (FK506 or rapamycin) had no effect on the transport activity or the surface expression of the Na+-Ca2+ exchanger. Co-expression of the human multidrug transporter P-glycoprotein (of which both drugs are modulators) with the cloned Na+-Ca2+ exchanger revealed that transport activity and surface expression of each transporter in the co-transfected system were similar to those of each transporter alone in both the presence and absence of CsA or PSC833. CsA and PSC833 inhibited the surface expression of the NCX1 protein but did not alter the surface expression of P-glycoprotein. Unlike some P-glycoprotein endoplasmic reticulum-retained mutants (Loo, T. W., and Clarke, D. M. (1997) J. Biol. Chem. 272, 709-712), CsA did not rescue RBE-2/F913-->Stop, an endoplasmic reticulum-retained function-competent mutant of the Na+-Ca2+ exchanger (Kasir, J., Ren, X., Furman, L, and Rahamimoff, H. (1999) J. Biot Chem. 274, 24873-24880) and did not induce its kinesis to the surface membrane, further demonstrating molecular differences between P-glycoprotein and NCX1 mutants for interaction with CsA. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, IL-91120 Jerusalem, Israel. NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Rahamimoff, H (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, POB 12272, IL-91120 Jerusalem, Israel. RI Ambudkar, Suresh/B-5964-2008 NR 49 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2505 EP 2510 DI 10.1074/jbc.M109154200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500019 PM 11700317 ER PT J AU Hepbildikler, ST Sandhoff, R Kolzer, M Proia, RL Sandhoff, K AF Hepbildikler, ST Sandhoff, R Kolzer, M Proia, RL Sandhoff, K TI Physiological substrates for human lysosomal beta-hexosaminidase S SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GM2 ACTIVATOR PROTEIN; HUMAN-FIBROBLASTS; ALPHA-SUBUNIT; GANGLIOSIDOSIS; IDENTIFICATION; DISEASE; CELLS; ACID; MUCOPOLYSACCHARIDOSIS; DEGRADATION AB Human lysosomal beta-hexosaminidases remove terminal beta-glycosidically bound N-acetylhexosamine residues from a number of glycoconjugates. Three different isozymes composed of two noncovalently linked sub-units alpha and beta exist: Hex A (alphabeta), Hex B (betabeta), and Hex S (alphaalpha). While the role of Hex A and B for the degradation of several anionic and neutral glycoconjugates has been well established, the physiological significance of labile Hex S has remained unclear. However, the striking accumulation of anionic oligosaccharides in double knockout mice totally deficient in hexosaminidase activity but not in mice expressing Hex S (Sango, K., McDonald, M. P., Crawley, J. N., Mack, M. L., Tifft, C.J., Skop, E., Starr, C. M., Hoffmann, A., Sandhoff, K., Suzuki, K., and Proia, R. L., (1996) Nat. Genet. 14, 348-352) prompted us to reinvestigate the substrate specificity of Hex S. To identify physiological substrates of Hex S, anionic and neutral oligosaccharides excreted in the urine of the double knockout mice were isolated and analyzed. Using ESI-MS/MS and glycosidase digestion the anionic glycans were identified as products of in. complete dermatan sulfate degradation whereas the neutral storage oligosaccharides were found to be fragments of N-glyean degradation. In vitro, recombinant Hex S was highly active on water-soluble and amphiphilic glycoconjugates including artificial substrates, sulfated GAG fragments, and the sulfated glycosphingolipid SM2. Hydrolysis of membrane-bound SM2 by the recombinant Hex S was synergistically stimulated by the GM2 activator protein and the lysosomal anionic phospholipid bis (monoacylglycero) phosphate. C1 Univ Bonn, Kekule Inst Organ Chem & Biochem, D-53121 Bonn, Germany. Deutsch Krebsforschungszentrum Heidelberg, Abt Zellulare & Mol Pathol, D-69120 Heidelberg, Germany. NIDDK, Genet Dev & Dis Brnach, NIH, Bethesda, MD 20892 USA. RP Sandhoff, K (reprint author), Univ Bonn, Kekule Inst Organ Chem & Biochem, Gerhard Domagk Str 1, D-53121 Bonn, Germany. RI Proia, Richard/A-7908-2012 NR 46 TC 40 Z9 42 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2562 EP 2572 DI 10.1074/jcb.M105457200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500026 PM 11707436 ER PT J AU Young, PJ Day, PM Zhou, J Androphy, EJ Morris, GE Lorson, CL AF Young, PJ Day, PM Zhou, J Androphy, EJ Morris, GE Lorson, CL TI A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DISEASE GENE-PRODUCT; SINGLE NUCLEOTIDE; NUCLEAR EXPORT; COILED BODIES; SMN GENE; BINDING; APOPTOSIS; LOCALIZATION; CELLS; MDM2 AB Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 co-localize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA. C1 Arizona State Univ, Dept Biol, Tempe, AZ 85287 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. NE Wales Inst, Multidisciplinary Res & Innovat Ctr, Biochem Grp, Wrexham LL11 2AW, Clwyd, Wales. RP Lorson, CL (reprint author), Arizona State Univ, Dept Biol, Tempe, AZ 85287 USA. OI Androphy, Elliot/0000-0002-8104-0703 FU NINDS NIH HHS [R01 NS40275, R01 NS41584-01] NR 45 TC 74 Z9 77 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2852 EP 2859 DI 10.1074/jbc.M108769200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500064 PM 11704667 ER PT J AU Murillas, R Simms, KS Hatakeyama, S Weissman, AM Kuehn, MR AF Murillas, R Simms, KS Hatakeyama, S Weissman, AM Kuehn, MR TI Identification of developmentally expressed proteins that functionally interact with Nedd4 ubiquitin ligase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WW DOMAINS; FAMILY; DROSOPHILA; PROTEASOME; RECEPTORS; MACHINERY; MODULES; BINDING; NOTCH; GENE AB Nedd4 is a HECT domain-containing ubiquitin ligase that mediates ubiquitylation and proteasome degradation of target proteins. The molecular basis for the interaction of Nedd4 with substrates lies in its WW domains, which can bind proline-rich (PY) domains in target proteins. Nedd4 is a developmentally expressed protein and may have a fundamental role to play in embryonic processes. However, whether Nedd4 has such a function is currently unknown, in part because few developmentally regulated ubiquitylation substrates have been identified or characterized. We have carried out a yeast two-hybrid screen and identified four proteins expressed in the mid-gestation embryo that are able to interact with Nedd4. Characterization of their functional interaction with Nedd4 in vitro and in vivo demonstrated that three of the four are bona fide Nedd4 binding partners, and two have the capacity to be ubiquitylation substrates. One of these is the first identified nonviral substrate for Nedd4-mediated monoubiquitylation. Interestingly, neither of these two ubiquitylated proteins interacts with Nedd4 through PY-mediated mechanisms. For one of the three Nedd4 binding partners, there was no discernable evidence of ubiquitylation. However, this protein clearly associates with Nedd4 through its PY domains and can alter the location of Nedd4 in cells, suggesting a role other than as a ubiquitylation substrate. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Regulat Prot Funct Lab, NIH, Bethesda, MD 20892 USA. RP Kuehn, MR (reprint author), Bldg 10,Rm 4B-36,10 Ctr Dr, Bethesda, MD 20892 USA. RI Kuehn, Michael/A-4573-2014; Hatakeyama, Shigetsugu/C-8333-2012 OI Kuehn, Michael/0000-0002-7703-9160; Hatakeyama, Shigetsugu/0000-0002-2150-9979 NR 40 TC 39 Z9 43 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 25 PY 2002 VL 277 IS 4 BP 2897 EP 2907 DI 10.1074/jbc.M110047200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CY UT WOS:000173421500069 PM 11717310 ER PT J AU Ma, Y Kiesewetter, DO Jagoda, EM Huang, BX Eckelman, WC AF Ma, Y Kiesewetter, DO Jagoda, EM Huang, BX Eckelman, WC TI Identification of metabolites of fluorine-18-labeled M2 muscarinic receptor agonist, 3-(3-[(3-fluoropropyl)thio]-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1- methylpyridine, produced by human and rat hepatocytes SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 3-(3-{(3-[F-18]fluoropropyl)thio}-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahy dro-1-methylpyridine; FP-TZTP; muscarinic receptor ID ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; XANOMELINE; SUBTYPES AB An accurate, rapid method for the determination of unmetabolized 3-(3-{(3-[F-18]fluoropropyl)thio}-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (FP-TZTP), a selective M2 muscarinic agonist, is necessary in order to obtain quantitative information from positron emission tomography (PET) imaging. Using LC-MS-MS to analyze products from cultured human and rat hepatocytes, we identified metabolites resulting from oxidation of the nitrogen in the tetrahydropyridine ring, sulfur-oxidation, demethylation of the tertiary amine, and oxidation of the tetrahydropyridine ring. From the knowledge of the structure of the metabolites, we have developed a two-step extraction sequence that allows rapid determination of the parent fraction in plasma without time-consuming chromatographic analysis. Published by Elsevier Science B.V. C1 NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Ma, Y (reprint author), NIH, Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. NR 11 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 25 PY 2002 VL 766 IS 2 BP 319 EP 329 DI 10.1016/S0378-4347(01)00517-5 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 511PN UT WOS:000173274900014 PM 11824820 ER PT J AU Chu, RA Bai, YW AF Chu, RA Bai, YW TI Lack of definable nucleation sites in the rate-limiting transition state of barnase under native conditions SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein folding; folding pathway of barnase; hydrogen exchange; burst-phase intermediate ID PROTEIN ENGINEERING PROCEDURE; HYDROGEN-EXCHANGE; FOLDING INTERMEDIATE; RIBONUCLEASE-A; CYTOCHROME-C; WILD-TYPE; PATHWAY; EQUILIBRIUM; KINETICS; STABILITY AB It has been shown that the burst-phase (submillisecond) intermediate of barnase, if it exists, can be only marginally more stable than the fully unfolded state at pH 6.3 and 25degreesC. In the study reported here, no stable burst-phase intermediate could be detected, even in the presence of stabilizing salt (0.4 M Na2SO4). These results suggest that a burst-phase intermediate with even marginal stability does not exist. The absence of such an intermediate in turn suggests the need for re-examination of the rate-limiting transition state (RLTS) under native conditions, which was previously characterized by using a three-state model with a stable intermediate and protein engineering. Surprisingly, mutations throughout the structure of barnase do not significantly affect the folding rate, suggesting a lack of specific favorable interactions among the side-chains in the RLTS. This RLTS is clearly different from that previously characterized under denaturing conditions, indicating that changes take place in the RLTS under native and denaturing conditions. The occurrence of such changes is further supported by the observation that the unfolding rate constants of barnase and its mutants were divergent or convergent as a function of denaturant concentrations. Consistent with changes in the RLTS, a re-analysis of data from native-state hydrogen exchange studies has shown that the logarithm of the unfolding rate constant inflects down under low concentrations of denaturant. Here, we discuss in detail the question of whether changes in the RLTS involve a kinetically silent intermediate that occurs after the initial RLTS. (C) 2002 Academic Press. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. NR 41 TC 18 Z9 18 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 25 PY 2002 VL 315 IS 4 BP 759 EP 770 DI 10.1006/jmbi.2001.5240 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 521JL UT WOS:000173836800022 PM 11812145 ER PT J AU Mattson, MP AF Mattson, MP TI Huntington's disease: Accomplices to neuronal death SO NATURE LA English DT Editorial Material ID CELL-DEATH; PATHOGENESIS; APOPTOSIS C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 13 TC 11 Z9 12 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 24 PY 2002 VL 415 IS 6870 BP 377 EP 379 DI 10.1038/415377a PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514HR UT WOS:000173433600030 PM 11807533 ER PT J AU Walsh, TJ Pappas, P Winston, DJ Lazarus, HM Petersen, F Raffalli, J Yanovich, S Stiff, P Greenberg, R Donowitz, G Lee, J AF Walsh, TJ Pappas, P Winston, DJ Lazarus, HM Petersen, F Raffalli, J Yanovich, S Stiff, P Greenberg, R Donowitz, G Lee, J CA Natl Inst Allergy Infect Dis Mycos TI Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IN-VITRO ACTIVITY; INVASIVE ASPERGILLOSIS; PROGNOSTIC FACTORS; RANDOMIZED TRIAL; PROLONGED FEVER; CANCER-PATIENTS; RISK-FACTORS; AGENTS; FLUCONAZOLE; FUNGI AB Background: Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative. Methods: In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy. Results: A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03). Conclusions: Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever. (N Engl J Med 2002;346:225-34.) Copyright (C) 2002 Massachusetts Medical Society. C1 NCI, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Utah, Salt Lake City, UT USA. New York Med Coll, New York, NY USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Loyola Univ, Med Ctr, Chicago, IL 60611 USA. Univ Kentucky, Lexington, KY USA. Univ Virginia, Charlottesville, VA USA. NIAID, Mycoses Study Grp, Birmingham, AL USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Cooper Hosp, Camden, NJ 08103 USA. Univ Florida, Gainesville, FL USA. Mayo Clin, Rochester, MN USA. Med Ctr Delaware, Newark, DE USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Maisonneuve Rosemont Hosp, Montreal, PQ, Canada. Duke Univ, Durham, NC USA. Univ Ottawa, Ottawa, ON, Canada. Osped ASL Pescara, Pescara, Italy. Univ Arkansas, Little Rock, AR 72204 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-65296] NR 37 TC 589 Z9 635 U1 1 U2 15 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 24 PY 2002 VL 346 IS 4 BP 225 EP 234 DI 10.1056/NEJM200201243460403 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 513UR UT WOS:000173398900002 PM 11807146 ER PT J AU Iams, JD Newman, RB Thom, EA Goldenberg, RL Mueller-Heubach, E Moawad, A Sibai, BM Caritis, SN Miodovnik, M Paul, RH Dombrowski, MP McNellis, D AF Iams, JD Newman, RB Thom, EA Goldenberg, RL Mueller-Heubach, E Moawad, A Sibai, BM Caritis, SN Miodovnik, M Paul, RH Dombrowski, MP McNellis, D CA Natl Inst Child Hlth Human Dev Net TI Frequency of uterine contractions and the risk of spontaneous preterm delivery. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FETAL FIBRONECTIN; LABOR; PREDICTION; LENGTH; WOMEN; TERM AB Background: The measurement of the frequency of uterine contractions has not been useful for reducing the rate of preterm delivery in randomized trials. Nonetheless, ambulatory monitoring of contractions continues to be used in clinical practice. Methods: We assessed the frequency of uterine contractions as a predictor of the risk of spontaneous preterm delivery before 35 weeks of gestation. We enrolled women with singleton pregnancies between 22 and 24 weeks of gestation. The women used a contraction monitor at home to record contraction frequency twice daily on 2 or more days per week from enrollment to delivery or 37 weeks of gestation. Results: We obtained 34,908 hours of successful monitoring recordings from 306 women. Although more contractions were recorded from women who delivered before 35 weeks than from women who delivered at 35 weeks or later, we could identify no threshold frequency that effectively identified women who delivered preterm infants. The sensitivity and positive predictive value of a maximal hourly frequency of contractions of four or more between 4 p.m. and 3:59 a.m. were 9 percent and 25 percent, respectively, at 22 to 24 weeks and 28 percent and 23 percent at 27 to 28 weeks. Other proposed screening tests, such as digital and ultrasound evaluations of the cervix and assays for fetal fibronectin in cervicovaginal secretions, also had low sensitivity and positive predictive value for preterm labor. Conclusions: Although the likelihood of preterm delivery increases with an increased frequency of uterine contractions, measurement of this frequency is not clinically useful for predicting preterm delivery. (N Engl J Med 2002;346:250-5.) Copyright (C) 2001 Massachusetts Medical Society. C1 Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Alabama, Birmingham, AL USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Tennessee, Memphis, TN USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. Univ Cincinnati, Cincinnati, OH USA. Univ Calif Los Angeles, Los Angeles, CA USA. Wayne State Univ, Detroit, MI USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. Univ Oklahoma, Oklahoma City, OK USA. RP Iams, JD (reprint author), Ohio State Univ, Dept Obstet & Gynecol, 1654 Upham Dr, Columbus, OH 43210 USA. OI caritis, steve/0000-0002-2169-0712 FU NICHD NIH HHS [HD 27883, HD 19897, HD 21410, HD 21414, HD 21434, HD 27860, HD 27861, HD 27869, HD 27889, HD 27905, HD 27915, HD 27917] NR 18 TC 98 Z9 98 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 24 PY 2002 VL 346 IS 4 BP 250 EP 255 DI 10.1056/NEJMoa002868 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 513UR UT WOS:000173398900005 PM 11807149 ER PT J AU Cheson, BD AF Cheson, BD TI CHOP plus rituximab - Balancing facts and opinion. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ANTI-CD20 MONOCLONAL-ANTIBODY; NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; CHEMOTHERAPY; IDEC-C2B8; THERAPY; TRIAL C1 NCI, Bethesda, MD 20892 USA. RP Cheson, BD (reprint author), NCI, Bethesda, MD 20892 USA. NR 15 TC 31 Z9 34 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 24 PY 2002 VL 346 IS 4 BP 280 EP 282 DI 10.1056/NEJM200201243460411 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 513UR UT WOS:000173398900010 PM 11807154 ER PT J AU Seo, YR Fishel, ML Amundson, S Kelley, MR Smith, ML AF Seo, YR Fishel, ML Amundson, S Kelley, MR Smith, ML TI Implication of p53 in base excision DNA repair: in vivo evidence SO ONCOGENE LA English DT Article DE p53; DNA-repair; polymerase-beta ID DAMAGE; PROTEIN; CELLS; SENSITIVITY; FIBROBLASTS; EXPRESSION; MUTATIONS; AGENTS; GADD45; REF-1 AB The tumor suppressor p53 plays an important role in response to DNA damage, including DNA repair. One DNA repair pathway, nucleotide excision repair (NER), has been well-documenteav6d to be regulated by p53. It seemed probable that p53 may affect other DNA repair pathways. We employed matched isogenic pairs of cell lines, wild-type or p53-deficient, to investigate this question using methyl methanesulfonate (MMS), a base-damaging agent. Alkylation damage induced by MMS is repaired exclusively by the base excision repair (BER) pathway. Cells carrying mutant or no p53 genes exhibited slow BER of MMS-induced DNA damage, and exhibited MMS-sensitivity. One contributing factor is the abundance of DNA polymerase beta (beta-pol), an enzyme required for BER, which was almost absent in p53 mutant and p53-null cells. Our findings demonstrate an in vivo requirement for p53 in regulating the base excision repair response, a novel finding of great potential importance in understanding the DNA repair branch of the p53 pathway. C1 Indiana Univ, Ctr Canc, Dept Microbiol, Walther Oncol Ctr,Sch Med, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN USA. Indiana Univ, Ctr Canc, Dept Biochem, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Wells Ctr Pediat Oncol, Indianapolis, IN 46202 USA. NCI, Bethesda, MD 20892 USA. RP Smith, ML (reprint author), Indiana Univ, Ctr Canc, Dept Microbiol, Walther Oncol Ctr,Sch Med, 1044 W Walnut,R-155, Indianapolis, IN 46202 USA. NR 29 TC 77 Z9 85 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 24 PY 2002 VL 21 IS 5 BP 731 EP 737 DI 10.1038/sj.onc.1205129 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FB UT WOS:000173427000004 PM 11850801 ER PT J AU Leem, SH Londono-Vallejo, JA Kim, JH Bui, H Tubacher, E Solomon, G Park, JE Horikawa, I Kouprina, N Barrett, JC Larionov, V AF Leem, SH Londono-Vallejo, JA Kim, JH Bui, H Tubacher, E Solomon, G Park, JE Horikawa, I Kouprina, N Barrett, JC Larionov, V TI The human telomerase gene: complete genomic sequence and analysis of tandem repeat polymorphisms in intronic regions SO ONCOGENE LA English DT Article DE hTERT; VNTR; polymorphism ID REVERSE-TRANSCRIPTASE HTERT; EMBRYONIC STEM-CELLS; CATALYTIC SUBUNIT; AFFECTIVE-DISORDERS; VARIABLE NUMBER; C-MYC; PROMOTER; IDENTIFICATION; MINISATELLITE; CLONING AB In this work, the full-length hTERT gene was isolated and the sequence of the previously unknown region in intron 6 as well as that of upstream and downstream hTERT regions was determined. We have shown that intron 6 includes a variable number of tandem repeats (VNTR) of a 38 bp sequence, (hTERT-VNTR 6-1). Eight alleles of hTERT-VNTR 6-1 were identified among 103 unrelated individuals, ranging front 27 to 47 repeats. hTERT-VNTR 2-2 is another new 61 bp minisatellite repeat found in intron 2 of hTERT. At least four alleles of hTERT-VNTR 2-2 can be distinguished. Previous studies have described polymorphisms for minisatellites hTERT-VNTR 2-1, a 42 bp repeat in intron 2, and hTERT-VNTR 6-2, a 36 bp repeat in intron 6. These, together with another minisatellite found in intron 12, add up to five such structures within the hTERT gene. The segregation of hTERT minisatellites was analysed in families, revealing that the VNTRs are transmitted through meiosis following a Mendelian inheritance. Minisatellites in hTERT were also analysed in matching normal and cancer tissues from patients with tumors; in one patient with a kidney tumor, the two VNTRs in intron 6 had undergone concomitant rearrangements. This observation suggests that chromosomal rearrangements implicating these VNTRs may be associated with the activation of telomerase expression in cancer cells. C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. DongA Univ, Dept Biol, Pusan 604714, South Korea. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, NIH, Bldg 49,Room 4A56, Bethesda, MD 20892 USA. NR 46 TC 50 Z9 53 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 24 PY 2002 VL 21 IS 5 BP 769 EP 777 DI 10.1038/sj.onc.1205122 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 514FB UT WOS:000173427000008 PM 11850805 ER PT J AU Muftuoglu, M Selzer, R Tuo, J Brosh, RM Bohr, VA AF Muftuoglu, M Selzer, R Tuo, J Brosh, RM Bohr, VA TI Phenotypic consequences of mutations in the conserved motifs of the putative helicase domain of the human Cockayne Syndrome Group B gene SO GENE LA English DT Article DE nucleotide excision repair; transcription-coupled repair; ultraviolet; 4-nitroquinoline-1-oxide; helicase ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; PCNA COMPLEX-FORMATION; DNA-STIMULATED ATPASE; XERODERMA-PIGMENTOSUM; PREFERENTIAL REPAIR; CRYSTAL-STRUCTURES; INDUCED APOPTOSIS; FACTOR CSB/ERCC6; DAMAGING AGENTS AB Cockayne syndrome (CS) is a human genetic disorder characterized by several neurological and developmental abnormalities. Two genetic complementation groups. CS-A and CS-B. have been identified. The CSB protein belongs to helicase superfamily 2, and to the SWI/ SNF family of proteins, The CSB protein is implicated in transcription-coupled repair (TCR), basal transcription and chromatin remodeling. In addition, CS cells undergo UV-induced apoptosis at much lower doses than normal cells. However, the molecular function of the CSB protein in these biological pathways has remained unclear. Evidence indicates that the integrity of the Walker A and B boxes (motifs I and II) are important for CSB function. but the functional significance of the helicase motifs Ia. III-IV has not been previously examined, In this study single amino acid changes in highly conserved residues of helicase motifs Ia, III. V. VI and a second putative nucleotide-binding motif (NTB) of the CSB protein were generated by site-directed mutagenesis to analyze the genetic function of the CSB protein in survival. RNA synthesis recovery and apoptosis after UV treatment. The survival analysis of these CS-B mutant cell lines was also performed after treatment with the chemical carcinogen, 4-nitroquinoline-1-oxide (4-NQO). The lesions induced by UV light, cyclobutane pyrimidine dimers, are known to be repaired by TCR whereas the lesions induced by 4-NQO are repaired by global genome repair. The results of this study demonstrate that the point mutations in highly conserved residues of helicase motifs Ia. III, V and VI abolished the genetic function of the CSB protein in survival, RNA synthesis recovery and apoptosis after UV treatment. Similarly. the same mutants failed to complement the sensitivity toward 4-NQO. Thus. the integrity of these helicase motifs is important for the biological function of the CSB protein. On the contrary. a point mutation in a C-terminal, second, NTB motif of the CSB protein showed full complementation in the ability to repair damage induced by UV light or 4-NQO, suggesting that this motif is not important for the CSB repair function. (C) 2002 Published by Elsevier Science B.V. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Hacettepe Univ, Sch Med, Dept Biochem, TR-06100 Ankara, Turkey. RP NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 50 TC 34 Z9 34 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD JAN 23 PY 2002 VL 283 IS 1-2 BP 27 EP 40 AR PII S0378-1119(01)00870-8 DI 10.1016/S0378-1119(01)00870-8 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 531AW UT WOS:000174393400004 PM 11867210 ER PT J AU Zhang, JC Liu, WL Tang, DC Chen, L Wang, M Pack, SD Zhuang, ZP Rodgers, GP AF Zhang, JC Liu, WL Tang, DC Chen, L Wang, M Pack, SD Zhuang, ZP Rodgers, GP TI Identification and characterization of a novel member of olfactomedin-related protein family, hGC-1, expressed during myeloid lineage development SO GENE LA English DT Article DE granulocyte colony-stimulating factor; mRNA differential display; two-phase liquid culture; hematopoiesis ID DIFFERENTIAL DISPLAY; GENE; CELLS; GLYCOPROTEIN; RECEPTOR; NEUROEPITHELIUM; THROMBOPOIETIN; PROLIFERATION; PROGENITOR; MATRIX AB We have cloned a novel hematopoietic granulocyte colony-stimulating factor (G-CSF)-induced olfactomedin-related glycoprotein, termed hGC-1 (human G-CSF-stimulated clone-1). mRNA differential display was used in conjunction with a modified two-phase liquid culture system. Cultures were enriched for early precursors of erythroid. myeloid, and megakarocytic lineages. which were isolated after induction with erythropoietin, G-CSF, and thrombopoietin, respectively. RNA from the enriched cells was subjected to differential display analysis to identify lineage-specific expressed genes. One clone specifically induced by G-CSF. hGC-1, was characterized. The 2861 bp cDNA clone of hGC-1 contained an open reading frame of 1530 nucleotides, translating, into a protein of 5 10 amino acids with a signal peptide and six N-linked glycosylation motifs. The protein sequence of hGC-1 showed it to be a glycoprotein of the olfactomedin family. which includes olfactomedin. TIGR. Noelin-2 and latrophilin-1. Olfactomedin-like genes show characteristic tissue-restricted patterns of expression: the specific tissues expressing these genes differ among the family members. hGC-1 was strongly expressed in the prostate. small intestine, and colon. moderately expressed in the bone marrow and stomach, and not detectable in other tissues. In vitro translation and ex vivo expression showed hGC-1 to be an N-linked glycoprotein. The hGC-1 gene locus mapped to chromosome 13q14.3. Together, our findings indicate that hGC-1 is primarily expressed as an extracellular olfactomedin-related glycoprotein during normal myeloid-specific lineage differentiation, suggesting the possibility of a matrix-related function for hGC-1 in differentiation, Published by Elsevier Science B.V. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Mol Pathogenesis Unit, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N115,10 Ctr Dr, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 23 TC 72 Z9 77 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 23 PY 2002 VL 283 IS 1-2 BP 83 EP 93 AR PII S0378-1119(01)00763-6 DI 10.1016/S0378-1119(01)00763-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 531AW UT WOS:000174393400009 PM 11867215 ER PT J AU Trott, JF Wilson, MJ Hovey, RC Shaw, DC Nicholas, KR AF Trott, JF Wilson, MJ Hovey, RC Shaw, DC Nicholas, KR TI Expression of novel lipocalin-like milk protein gene is developmentally-regulated during lactation in the tammar wallaby, Macropus eugenii SO GENE LA English DT Article DE late lactation protein; mammary gland; autocrine regulation; milk composition; marsupial ID BETA-LACTOGLOBULIN; MAMMARY-GLAND; ALPHA-LACTALBUMIN; WHEY PROTEINS; FATTY-ACIDS; BINDING; CLONING; RETINOL; MEMBER; FAMILY AB We ha,e identified a novel whey protein (late lactation protein B: LLPB) that is first secreted in the milk of the tammar wallaby around day 200 of lactation. The LLPB cDNA clone of 843 base pairs encodes a mature protein of 156 amino acids. LLPB shares 65 and 48% nucleotide and deduced amino acid identify. respectively, with a previously identified late lactation protein A (LLPA). Both these proteins share significant amino acid Sequence homology with the lipocalin protein family. Expression of the LLPB gene is induced between day's 200 and 240 of lactation, in contrast to expression of the LLPA gene, which is induced at around 145 days of lactation. Maximal expression of both genes in mammary explants from tammars at 213 days of lactation required a combination of prolactin. insulin and hydrocortisone. Transcripts of LLPA, LLPB and beta-lactoglobulin (TBLG) were localized to the same cells by in situ hybridization. A substantial level of alveolar maturation is required for expression of the LLP genes, unlike TBLG, which is expressed in immature alveoli. We hypothesize that the temporal expression of the LLPB and LLPA genes may be regulated both by endocrine stimuli and factors intrinsic to the mammary gland. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Victorian Inst Anim Sci, Div Mol Biol & Genet, Attwood, Vic 3049, Australia. NCI, Ctr Canc Res, Mol & Cellular Endocrinol Sect, NIH, Bethesda, MD 20892 USA. Australian Natl Univ, John Curtin Sch Med Res, Div Biochem & Mol Biol, Canberra, ACT 2600, Australia. RP Trott, JF (reprint author), Univ Vermont, Dept Anim Sci, Room 204,Terrill Hall, Burlington, VT 05405 USA. NR 42 TC 26 Z9 27 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 23 PY 2002 VL 283 IS 1-2 BP 287 EP 297 AR PII S0378-1119(01)00883-6 DI 10.1016/S0378-1119(01)00883-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 531AW UT WOS:000174393400030 PM 11867236 ER PT J AU Mantelli, M Barile, M Ciotti, P Ghiorzo, P Lantieri, F Pastorino, L Catricala, C Della Torre, G Folco, U Grammatico, P Padovani, L Pasini, B Rovini, D Queirolo, P Rainero, ML Santi, PL Sertoli, RM Goldstein, AM Bianchi-Scarra, G AF Mantelli, M Barile, M Ciotti, P Ghiorzo, P Lantieri, F Pastorino, L Catricala, C Della Torre, G Folco, U Grammatico, P Padovani, L Pasini, B Rovini, D Queirolo, P Rainero, ML Santi, PL Sertoli, RM Goldstein, AM Bianchi-Scarra, G CA Soc Italiana Dermatologia Giovanna TI High prevalence of the G101W germline mutation in the CDKNT2A (P16(ink4a)) gene in 62 Italian malignant melanoma families SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE G101W; CDKN2A; mutation; Italian; melanoma; families ID MULTIPLE PRIMARY MELANOMAS; CDKN2A MUTATIONS; PRONE FAMILIES; PANCREATIC-CANCER; HEREDITARY MELANOMA; P16; CDK4; KINDREDS; RISK; POPULATION AB CDKN2A germline mutation frequency estimates are commonly based on families with several melanoma cases. When we started counseling in a research setting on gene susceptibility analysis in northern and central Italy, however, we mostly found small families with few cases. Here we briefly characterize those kindred, estimate CDKN2A/CDK4 mutation test yields, and provide indications on the possibility of implementing formal DNA testing for melanoma-prone families in Italy. In September 1995 we started genetic counseling in a research setting at our Medical Genetics Center. Screening for CDKN2A/CDK4 mutations was performed on families with two melanoma patients, one of whom was younger than 50 years at onset, the other complying with one of the following: 1) being a first-degree relative, 2) having an additional relative with pancreatic cancer, or 3) having multiple primary melanomas. Sixty-two of 67 (80%) melanoma cases met our criteria. Four previously described CDKN2A mutations (G101W, R24P, V126D, and N71S) were found in 21 of the 62 families (34%) with a high prevalence of G101W (18/21). The percentage of families with two melanoma cases/family harboring a mutation was low (7%, 2/27), but rose to 45% (9/20) if one of the melanoma patients carried multiple melanomas or if pancreatic cancer was present in that family. In the 15 families with three melanoma cases the presence of a mutation was higher (67%, 10/15) and reached 100% in the 4 families with four or more melanoma cases. Our results suggest that CDKN2A/CDK4 counseling-based mutational analysis may be reasonably efficient also for families with two melanoma cases, if one patient carries multiple melanomas or if pancreatic cancer is present in the family. (C) 2001 Wiley-Liss, Inc. C1 Univ Genoa, Dipartimento Oncol Biol & Genet, Genoa, Italy. Univ Roma La Sapienza, Serv Genet Med, Rome, Italy. Ist Nazl Tumori, Div Expt Oncol, I-20133 Milan, Italy. Osped S Corona, Div Oncol, Savona, Italy. IST, Ist Nazl Ric Canc, Genoa, Italy. Osped San Paolo, Div Dermatol, Savona, Italy. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Ist Clin Dermatol, Siena, Italy. Osped Riuniti Bergamo, Dermatol Clin, I-24100 Bergamo, Italy. RP Bianchi-Scarra, G (reprint author), Dipartimento Oncol Clin Biol & Genet, Viale Benedetto XV 6, I-16132 Genoa, Italy. RI Bianchi Scarra, Giovanna/G-8933-2014; Queirolo, Paola/K-6778-2016 OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; Queirolo, Paola/0000-0002-9917-6633 NR 42 TC 57 Z9 58 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 22 PY 2002 VL 107 IS 3 BP 214 EP 221 DI 10.1002/ajmg.10135.abs PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 508YD UT WOS:000173116600006 PM 11807902 ER PT J AU Dimitrova, MN Szczepanowski, RH Ruvinov, SB Peterkofsky, A Ginsburg, A AF Dimitrova, MN Szczepanowski, RH Ruvinov, SB Peterkofsky, A Ginsburg, A TI Interdomain interaction and substrate coupling effects on dimerization and conformational stability of enzyme I of the Escherichia coli phosphoenolpyruvate : sugar phosphotransferase system SO BIOCHEMISTRY LA English DT Article ID N-TERMINAL DOMAIN; DODECAMERIC GLUTAMINE-SYNTHETASE; SALMONELLA-TYPHIMURIUM; SCANNING CALORIMETRY; PHOSPHORYL TRANSFER; TRANSPORT; PROTEIN; HPR; PURIFICATION; TRANSITIONS AB The bacterial PEP:sugar phosphotransferase system couples the phosphorylation and translocation of specific sugars across the membrane. The activity of the first protein in this pathway, enzyme I (EI), is regulated by a monomer-dimer equilibrium where a Mg2+-dependent autophosphorylation by PEP requires the dimer. Dimerization constants for dephospho- and phospho-EI and inactive mutants EI(H189E) and EI(H189A) (in which Glu or Ala is substituted for the active site His189) have been measured under a variety of conditions by sedimentation equilibrium at pH 7.5 and 4 and 20 degreesC. Concurrently, thermal unfolding of these forms of El has been monitored by differential scanning calorimetry and by changes in the intrinsic tryptophanyl residue fluorescence. Phosphorylated EI and EI(H189E) have 10-fold increased dimerization constants [similar to2 x 10(6) (M monomer)-(1)] compared to those of dephospho-EI and EI(H189A) at 20 degreesC. Dimerization is strongly promoted by 1 mM PEP with 2 mM MgCl2 [K-A' greater than or equal to 10(8) M-1 at 4 or 20 degreesC], as demonstrated with EI(H189A) which cannot undergo autophosphorylation. Together, 1 mM PEP and 2 mM Mg2+ also markedly stabilize and couple the unfolding of C- and N-terminal domains of EI(HI89A), increasing the transition temperature (T-m) for unfolding the C-terminal domain by similar to18 degreesC and that for the N-terminal domain by similar to9 degreesC to T-max congruent to 63 degreesC, giving a value of K-D' congruent to 3 muM PEP at 45 degreesC. PEP alone also promotes the dimerization of EI(H189A) but only increases T-m similar to5 degreesC for C-terminal domain unfolding without affecting N-terminal domain unfolding, giving an estimated value of K-D' congruent to 0.2 mM for PEP dissociation in the absence of Mg2+ at 45 degreesC. In contrast, the dimerization constant of phospho-EI at 20 degreesC is the same in the absence and presence of 5 mM PEP and 2 MM MgCl2. Thus, the separation of substrate binding effects from those of phosphorylation by studies with the inactive EI(H189A) has shown that intracellular concentrations of PEP and Mg2+ are important determinants of both the conformational stability and dimerization of dephospho-EI. C1 NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Ginsburg, A (reprint author), NHLBI, Sect Prot Chem, Biochem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 39 TC 18 Z9 19 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 22 PY 2002 VL 41 IS 3 BP 906 EP 913 DI 10.1021/bi011801x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 513JJ UT WOS:000173374500024 PM 11790113 ER PT J AU Laurenzana, EM Balasubramanian, G Weis, C Blaydes, B Newbold, RR Delclos, KB AF Laurenzana, EM Balasubramanian, G Weis, C Blaydes, B Newbold, RR Delclos, KB TI Effect of nonylphenol on serum testosterone levels and testicular steroidogenic enzyme activity in neonatal, pubertal, and adult rats SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE nonylphenol; testosterone; steroidogenesis ID ALKYLPHENOL ETHOXYLATES; REPRODUCTIVE-TRACT; NEWBORN RATS; LEYDIG-CELLS; EXPOSURE; 4-TERT-OCTYLPHENOL; GONADOTROPIN; OCTYLPHENOL; DISRUPTION; EXPRESSION AB Previous dose range-finding studies with nonylphenol (NP) administered to rats in a soy- and alfalfa-free diet showed apparent feminization of several endpoints in male rats at doses of 25 ppm and above. One possible mechanism contributing to these effects is a reduction of testosterone at critical developmental periods. The present study was conducted as an adjunct to a multigeneration study and was designed to examine the effect of NP on testosterone production. Male rats in the F-1 and F-2 generations were exposed through their dams or directly to various dietary doses of NP (0, 25, 200 and 750 ppm) throughout gestation and until sacrifice at either postnatal day 2 (PND2), PND50, or PND140. Male pups in the F, generation were examined only on PND2. At PND2, serum testosterone levels were significantly decreased in all groups exposed to NP in the F-1 generation, but not in the F-2 or F-3 generations. The activity of 17alpha-hydroxylase/C17, 20 lyase (P450c17) in PND2 testicular homogenates was not affected by NP treatment. In F-1 and F-2 PND50 and PND140 rats, NP treatment did not affect serum testosterone levels. The absolute dorsolateral prostate weight was increased in the 200 and 750 ppm dose groups only in the F-1 PND50 rats, however, no significant effects were observed in other male reproductive organs. NP treatment did not affect P450c17 activity in microsomes prepared from testes of F-1 PND50 or PND140 rats. However, P450c17 activity was significantly decreased in testicular microsomes of F-1 PND50 (200 and 750 ppm dose groups) and PND140 (25, 200, and 750 ppm dose groups) rats. A decrease in testicular beta-nicotinamide adenine dinucleotide phosphate (NADPH) P450 reductase was also observed in all PND50 and PND140 NP-exposed rats of the F-1 and F-2 generations. The ability of NP to directly inhibit P450c17 activity in vitro at concentrations of 1-100 muM was also demonstrated. These results indicate that NP call inhibit the activity of enzymes involved in testosterone synthesis, but suggest minimal effects on testosterone or testosterone-dependent endpoints via this mechanism. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Delclos, KB (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, 3900 NCTR Rd HFT-110, Jefferson, AR 72079 USA. NR 43 TC 25 Z9 34 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 22 PY 2002 VL 139 IS 1 BP 23 EP 41 AR PII S0009-2797(01)00291-5 DI 10.1016/S0009-2797(01)00291-5 PG 19 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 522KR UT WOS:000173895600002 PM 11803027 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI MOSC domains: ancient, predicted sulfur-carrier domains, present in diverse metal-sulfur cluster biosynthesis proteins including Molybdenum cofactor sulfurases SO FEMS MICROBIOLOGY LETTERS LA English DT Article ID ESCHERICHIA-COLI; AZOTOBACTER-VINELANDII; MOLYBDOPTERIN COFACTOR; XANTHINE-DEHYDROGENASE; RESISTANT MUTANTS; PSI-BLAST; DROSOPHILA; SEQUENCE; IDENTIFICATION; HYDROXYLASES AB Using computational analysis, a novel superfamily of beta-strand-rich domains was identified in the Molybdenum cofactor sulfurase and several other proteins from both prokaryotes and eukaryotes. These MOSC domains contain an absolutely conserved cysteine and occur either as stand-alone forms such as the bacterial YiiM proteins, or fused to other domains such as a NifS-like catalytic domain in Molybdenum cofactor sulfurase. The MOSC domain is predicted to be a sulfur-carrier domain that receives sulfur abstracted by the pyridoxal phosphate-dependent NifS-like enzymes, on its conserved cysteine, and delivers it for the formation of diverse sulfur-metal clusters. The identification of this domain may clarify the mechanism of biogenesis of various metallo-enzymes including Molybdenum cofactor-containing enzymes that are compromised in human type II xanthinuria. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. OI Anantharaman, Vivek/0000-0001-8395-0009 NR 33 TC 38 Z9 39 U1 0 U2 2 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 22 PY 2002 VL 207 IS 1 BP 55 EP 61 AR PII S0378-1097(01)00515-8 DI 10.1111/j.1574-6968.2002.tb11028.x PG 7 WC Microbiology SC Microbiology GA 530EF UT WOS:000174342100010 PM 11886751 ER PT J AU Domenech, P Pym, AS Cellier, M Barry, CE Cole, ST AF Domenech, P Pym, AS Cellier, M Barry, CE Cole, ST TI Inactivation of the Mycobacterium tuberculosis Nramp orthologue (mntH) does not affect virulence in a mouse model of tuberculosis SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE Mycobacterium tuberculosis; Nramp; cation transporter; manganese; virulence; mntH; macrophage protein; mouse infection ID INTRACELLULAR INFECTIONS; NATURAL-RESISTANCE; ESCHERICHIA-COLI; GENE; TRANSPORTER; MACROPHAGES; SUSCEPTIBILITY; MEMBRANE; GROWTH; MICE AB Mycobacterium tuberculosis is an intracellular pathogen which can survive and multiply within the phagosomal compartment of the macrophage, and in doing so has to withstand the various macrophage defense mechanisms, which include limitation of iron and other metals. Analysis of the complete genome sequence of M. tuberculosis revealed an extensive array of cation transporters, including mntH, an orthologue of the eukaryotic Nramp (natural resistance-associated macrophage protein) gene, that encodes a proton-dependent divalent metal transporter. To assess the effect of this transporter on intracellular survival and pathogenesis, an mntH knock-out mutant of M. tuberculosis H37Rv was created and assayed in bone marrow-derived macrophages and in a murine model of tuberculosis. In neither of these systems was any loss of fitness associated with inactivation of mntH, demonstrating that Nramp orthologues are not important determinants of mycobacterial virulence. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Inst Pasteur, Unite Genet Mol Bacterienne, F-75724 Paris 15, France. NIAID, TB Res Sect, LHD, NIH, Rockville, MD 20852 USA. Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. INRS, Inst Armand Frappier, Laval, PQ H7V 1B7, Canada. RP Cole, ST (reprint author), Inst Pasteur, Unite Genet Mol Bacterienne, 28 Rue Dr Roux, F-75724 Paris 15, France. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 26 TC 28 Z9 28 U1 0 U2 2 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 22 PY 2002 VL 207 IS 1 BP 81 EP 86 AR PII S0378-1097(01)00552-3 DI 10.1016/S0378-1097(01)00552-3 PG 6 WC Microbiology SC Microbiology GA 530EF UT WOS:000174342100014 PM 11886755 ER PT J AU Mouradian, MM AF Mouradian, MM TI Recent advances in the genetics and pathogenesis of Parkinson disease SO NEUROLOGY LA English DT Review ID ALPHA-SYNUCLEIN MUTATIONS; UBIQUITIN-PROTEIN LIGASE; NEURODEGENERATIVE DISORDERS; ALZHEIMERS-DISEASE; LEWY BODIES; HUMAN BRAIN; DOPAMINE; INCLUSIONS; SYSTEM; MICE AB The identification of three genes and several additional loci associated with inherited forms of levodopa-responsive PD has confirmed that this is not a single disorder. Yet, analyses of the structure and function of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the common mechanism leading to neurodegeneration in all known forms of this disease. The three specific genes identified to date-alpha-synuclein, Parkin, and ubiquitin C terminal hydrolase L1-are either closely involved in the proper functioning of the ubiquitin-proteasome pathway or are degraded by this protein-clearing machinery of cells. Knowledge gained from genetically transmitted PD also has clear implications for nonfamilial forms of the disease. Lewy bodies, even in sporadic PD, contain these three gene products, particularly abundant amounts of fibrillar alpha-synuclein. Increased aggregation of alpha-synuclein by oxidative stress, as well as oxidant-induced proteasomal dysfunction, link genetic and potential environmental factors in the onset and progression of the disease. The biochemical and molecular cascades elucidated from genetic studies in PD can provide novel targets for curative therapies. C1 NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Mouradian, MM (reprint author), NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, 10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 62 TC 174 Z9 182 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 22 PY 2002 VL 58 IS 2 BP 179 EP 185 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 513CT UT WOS:000173360900004 PM 11805242 ER PT J AU Ross, JL Stefanatos, GA Kushner, H Zinn, A Bondy, C Roeltgen, D AF Ross, JL Stefanatos, GA Kushner, H Zinn, A Bondy, C Roeltgen, D TI Persistent cognitive deficits in adult women with Turner syndrome SO NEUROLOGY LA English DT Article ID NEURODEVELOPMENTAL CHANGES; X-CHROMOSOME; MEMORY; BRAIN; GIRLS; PHENOTYPE; MONOSOMY; ESTROGEN AB Background: Turner syndrome (TS) has a characteristic neurocognitive profile. Verbal abilities are, in general, normal; however, women with TS, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits could be caused by genetic or endocrine factors. Objective: To evaluate the specific cognitive deficits that appear to persist in adulthood, are not estrogen-responsive, and may be genetically determined. Methods: The cognitive performance of adult women with TS (n = 71) who were estrogen repleted was compared with verbal IQ- and socioeconomic status-matched female controls (n = 50). Sixty-one women with TS had ovarian failure and received estrogen replacement and 10 had preserved endogenous ovarian function and were not receiving estrogen replacement at the time of evaluation. Results: Similar to children and adolescents with TS, adults with TS have normal verbal IQ but have relative difficulty on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function despite estrogen replacement. These deficits are apparent in women with TS despite apparently adequate estrogen effect, either endogenous or by hormone replacement. Conclusion: The cognitive phenotypes of adults with TS, with or without ovarian failure, are similar, indicating that estrogen replacement does not have a major impact on the cognitive deficits of adults with TS. C1 Thomas Jefferson Univ, Dept Pediat, DI Dupont Hosp Children, Philadelphia, PA 19107 USA. Albert Einstein Med Ctr, MossRehab Res Inst, Philadelphia, PA 19141 USA. Biomed Comp Res Inst, Philadelphia, PA USA. Univ Texas, SW Med Ctr, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75230 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75230 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Penn State Coll Med, Dept Med Neurol, Hershey, PA USA. RP Ross, JL (reprint author), Thomas Jefferson Univ, Dept Pediat, 1025 Walnut St, Philadelphia, PA 19107 USA. OI Zinn, Andrew/0000-0002-4935-3291 FU NINDS NIH HHS [NS42777, NS35554, NS29857, NS32531] NR 50 TC 68 Z9 70 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 22 PY 2002 VL 58 IS 2 BP 218 EP 225 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 513CT UT WOS:000173360900009 PM 11805247 ER PT J AU Ferraris, JD Williams, CK Persaud, P Zhang, Z Chen, Y Burg, MB AF Ferraris, JD Williams, CK Persaud, P Zhang, Z Chen, Y Burg, MB TI Activity of the TonEBP/OREBP transactivation domain varies directly with extracellular NaCl concentration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENHANCER-BINDING PROTEIN; TRANSCRIPTIONAL ACTIVATION; OSMOTIC RESPONSE; TONICITY; HYPERTONICITY; GENE AB Hypertonicity-induced binding of the transcription factor TonEBP / OREBP to its cognate DNA element, ORE/TonE, is associated with increased transcription of several osmotically regulated genes, Previously, it was found that hypertonicity rapidly causes nuclear translocation and phosphorylation of TonEBP/OREBP and, more slowly, increases TonEBP/OREBP abundance. Also, the C terminus of TonEBP/OREBP was found to contain a transactivation domain (TAD). We have now tested for tonicity dependence of the TAD activity of the 983 C-terminal amino acids of TonEBP/OREBP. HepG2 cells were cotransfected with a reporter construct and one of several TAD expression vector constructs. The reporter construct contained GAL4 DNA binding elements, a minimal promoter, and the Photinus luciferase gene. TAD expression vectors generate chimeras comprised of the GAL4 DNA binding domain fused to (J) the 983 C-terminal amino acids of TonEBP/OREBP, (it) 17 glutamine residues, (M) the TAD of c-Jun, or (iv) no TAD. All TAD-containing chimeras were functional at normal extracellular osmolality (300 mosmol/kg), but the activity only of the chimera containing the 983 C-terminal amino acids of TonEBP/OREBP varied with extracellular NaCl concentration, decreasing by >80% at 200 mosmol/kg and increasing 8-fold at 500 mosmol/kg. The chimera containing the 983 C-terminal amino acids of TonEBP/OREBP was constitutively localized to the nucleus and showed tonicity-dependent posttranslational modification consistent with phosphorylation. The activity at 500 mosmol/kg was reduced by herbimycin, a tyrosine kinase inhibitor and by 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, a protein kinase CK2 inhibitor. Thus, the 983 C-terminal amino acids of TonEBP/OREBP contain a TAD that is regulated osmotically, apparently by tonicity-dependent phosphorylation. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Ferraris, JD (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. NR 19 TC 95 Z9 98 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 22 PY 2002 VL 99 IS 2 BP 739 EP 744 DI 10.1073/pnas.241637298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100038 PM 11792870 ER PT J AU Broughton, BC Cordonnier, A Kleijer, WJ Jaspers, NGJ Fawcett, H Raams, A Garritsen, VH Stary, A Avril, MF Boudsocq, F Masutani, C Hanaoka, F Fuchs, RP Sarasin, A Lehmann, AR AF Broughton, BC Cordonnier, A Kleijer, WJ Jaspers, NGJ Fawcett, H Raams, A Garritsen, VH Stary, A Avril, MF Boudsocq, F Masutani, C Hanaoka, F Fuchs, RP Sarasin, A Lehmann, AR TI Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSLESION SYNTHESIS; CELL STRAINS; IRRADIATION; REPAIR; GENE AB Xeroderma pigmentosum variant (XP-V) cells are deficient in their ability to synthesize intact daughter DNA strands after UV irradiation. This deficiency results from mutations in the gene encoding DNA polymerase eta, which is required for effecting translesion synthesis (TLS) past UV photoproducts. We have developed a simple cellular procedure to identify XP-V cell strains, and have subsequently analyzed the mutations in 21 patients with XP-V. The 16 mutations that we have identified fall into three categories. Many of them result in severe truncations of the protein and are effectively null alleles. However, we have also identified five missense mutations located in the conserved catalytic domain of the protein. Extracts of cells falling into these two categories are defective in the ability to carry out TLS past sites of DNA damage. Three mutations cause truncations at the C terminus such that the catalytic domains are intact, and extracts from these cells are able to carry out TLS. From our previous work, however we anticipate that protein in these cells will not be localized in the nucleus nor will it be relocalized into replication foci during DNA replication. The spectrum of both missense and truncating mutations is markedly skewed toward the N-terminal half of the protein. Two of the missense mutations are predicted to affect the interaction with DNA, the others are likely to disrupt the three-dimensional structure of the protein. There is a wide variability in clinical features among patients, which is not obviously related to the site or type of mutation. C1 Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RR, E Sussex, England. Ecole Super Biotechnol Strasbourg, CNRS, Unite Propre Rech 9003, F-67400 Strasbourg, France. Erasmus Univ, Dept Clin Genet, NL-3000 DR Rotterdam, Netherlands. Erasmus Univ, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands. CNRS, Unite Propre Rech 2169, Lab Genet Instabil & Canc, F-94801 Villejuif, France. Inst Gustave Roussy, Serv Dermatol, F-94801 Villejuif, France. NIH, Bethesda, MD 20892 USA. Japanese Sci & Technol Corp, Core Res Evolut Sci & Technol, Suita, Osaka 5650871, Japan. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 5650871, Japan. RP Lehmann, AR (reprint author), Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RR, E Sussex, England. RI Masutani, Chikahide/I-6160-2014 NR 26 TC 104 Z9 108 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 22 PY 2002 VL 99 IS 2 BP 815 EP 820 DI 10.1073/pnas.022473899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100051 PM 11773631 ER PT J AU Kang, HL Benzer, S Min, KT AF Kang, HL Benzer, S Min, KT TI Life extension in Drosophila by feeding a drug SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HISTONE DEACETYLASE; GENE-EXPRESSION; CAENORHABDITIS-ELEGANS; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; EXTENDED LIFE; SPAN; MELANOGASTER; OVEREXPRESSION; MUTANT AB We report that feeding Drosophila throughout adulthood with 4-phenylbutyrate (PBA) can significantly increase lifespan, without diminution of locomotor vigor, resistance to stress, or reproductive ability. Treatment for a limited period, either early or late in adult life, is also effective. Flies fed PBA show a global increase in histone acetylation as well as a dramatically altered pattern of gene expression, including induction or repression of numerous genes. The delay in aging may result from the altered physiological state. C1 NINCDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. CALTECH, Div Biol 156 29, Pasadena, CA 91125 USA. RP Min, KT (reprint author), NINCDS, Neurogenet Branch, NIH, MSC1250,10-3B12, Bethesda, MD 20892 USA. RI Marion-Poll, Frederic/D-8882-2011; OI Marion-Poll, Frederic/0000-0001-6824-0180; min, kyung-tai/0000-0003-0983-4258 NR 40 TC 180 Z9 188 U1 2 U2 16 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 22 PY 2002 VL 99 IS 2 BP 838 EP 843 DI 10.1073/pnas.022631999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100055 PM 11792861 ER PT J AU Demirov, DG Ono, A Orenstein, JM Freed, EO AF Demirov, DG Ono, A Orenstein, JM Freed, EO TI Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; VESICULAR STOMATITIS-VIRUS; PROLINE-RICH MOTIF; GAG POLYPROTEIN; LIFE-CYCLE; PARTICLE-PRODUCTION; UBIQUITIN LIGASE; MATRIX PROTEIN; RETROVIRUS AB Efficient budding of HIV-1 from the plasma membrane of infected cells requires the function of a 6-kDa protein known as p6. A highly conserved Pro-Thr-Ala-Pro (PTAP) motif (the "late" or "L" domain), is critical for the virus-budding activity of p6. Recently, it was demonstrated that the product of tumor susceptibility gene 101 (TSG101), which contains at its N terminus a domain highly related to ubiquitin-conjugating (E2) enzymes, binds HIV-1 Gag in a p6-dependent fashion. We examined the impact of overexpressing the N-terminal region of TSG101 on HIV-1 particle assembly and release. We observed that this domain (referred to as TSG-5') potently inhibits virus production. Examination of cells coexpressing HIV-1 Gag and TSG-5' by electron microscopy reveals a defect in virus budding reminiscent of that observed with p6 L domain mutants. In addition, the effect of TSG-5' depends on an intact p6 L domain; the assembly and release of virus-like particles produced by Gag mutants lacking a functional p6 PTAP motif is not significantly affected by TSG-5'. Furthermore, assembly and release of murine leukemia virus and Mason-Pfizer monkey virus are insensitive to TSG-5'. TSG-5' is incorporated into virions, confirming the Gag/TSG101 interaction in virus-producing cells. Mutations that inactivate the p6 L domain block TSG-5' incorporation. These data demonstrate a link between the E2-like domain of TSG101 and HIV-1 L domain function, and indicate that TSG101 derivatives can act as potent and specific inhibitors of HIV-1 replication by blocking virus budding. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. RP Freed, EO (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 48 TC 244 Z9 251 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 22 PY 2002 VL 99 IS 2 BP 955 EP 960 DI 10.1073/pnas.032511899 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100075 PM 11805336 ER PT J AU Boldrick, JC Alizadeh, AA Diehn, M Dudoit, S Liu, CL Belcher, CE Botstein, D Staudt, LM Brown, PO Relman, DA AF Boldrick, JC Alizadeh, AA Diehn, M Dudoit, S Liu, CL Belcher, CE Botstein, D Staudt, LM Brown, PO Relman, DA TI Stereotyped and specific gene expression programs in human innate immune responses to bacteria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BORDETELLA-PERTUSSIS INFECTION; HUMAN MONOCYTES; FILAMENTOUS HEMAGGLUTININ; CELL ACTIVATION; PROTEIN-KINASE; CYCLIC-AMP; KAPPA-B; CAMP; TOLL; RECOGNITION AB The innate immune response is crucial for defense against microbial pathogens. To investigate the molecular choreography of this response, we carried out a systematic examination of the gene expression program in human peripheral blood mononuclear cells responding to bacteria and bacterial products. We found a remarkably stereotyped program of gene expression induced by bacterial lipopolysaccharide and diverse killed bacteria. An intricately choreographed expression program devoted to communication between cells was a prominent feature of the response. Other features suggested a molecular program for commitment of antigen-presenting cells to antigens captured in the context of bacterial infection. Despite the striking similarities, there were qualitative and quantitative differences in the responses to different bacteria. Modulation of this host-response program by bacterial virulence mechanisms was an important source of variation in the response to different bacteria. C1 Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. RP Relman, DA (reprint author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. OI Alizadeh, Arash Ash/0000-0002-5153-5625 FU NIAID NIH HHS [AI39587] NR 39 TC 259 Z9 268 U1 0 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 22 PY 2002 VL 99 IS 2 BP 972 EP 977 DI 10.1073/pnas.231625398 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100078 PM 11805339 ER PT J AU Doyon, J Song, AW Karni, A Lalonde, F Adams, MM Ungerleider, LG AF Doyon, J Song, AW Karni, A Lalonde, F Adams, MM Ungerleider, LG TI Experience-dependent changes in cerebellar contributions to motor sequence learning SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BASAL GANGLIA; VISUOMOTOR SEQUENCE; FRONTAL-CORTEX; MOVEMENTS; STRIATUM; ACQUISITION; PERFORMANCE; ATTENTION; COGNITION; IMPLICIT AB Studies in experimental animals and humans have stressed the role of the cerebellum in motor skill learning. Yet, the relative importance of the cerebellar cortex and deep nuclei, as well as the nature of the dynamic functional changes occurring between these and other motor-related structures during learning, remains in dispute. Using functional magnetic resonance imaging and a motor sequence learning paradigm in humans, we found evidence of an experience-dependent shift of activation from the cerebellar cortex to the dentate nucleus during early learning, and from a cerebellar-cortical to a striatal-cortical network with extended practice. The results indicate that intrinsic modulation within the cerebellum, in concert with activation of motor-related cortical regions, serves to set up a procedurally acquired sequence of movements that is then maintained elsewhere in the brain. C1 Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. NIMH, Natl Inst Hlth, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, Natl Inst Hlth, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. Duke Univ, Brain Imaging & Anal Ctr, Durham, NC 27710 USA. Univ Haifa, Fac Educ, IL-31905 Haifa, Israel. Univ Haifa, Fac Sci & Sci Educ, IL-31905 Haifa, Israel. Brown Univ, Dept Neurosci, Providence, RI 02912 USA. RP Doyon, J (reprint author), Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. NR 41 TC 241 Z9 247 U1 2 U2 15 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 22 PY 2002 VL 99 IS 2 BP 1017 EP 1022 DI 10.1073/pnas.022615199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 514PK UT WOS:000173450100086 PM 11805340 ER PT J AU Yu, H Prisinzano, T Dersch, CM Marcus, J Rothman, RB Jacobson, AE Rice, KC AF Yu, H Prisinzano, T Dersch, CM Marcus, J Rothman, RB Jacobson, AE Rice, KC TI Synthesis and biological activity of 8 beta-substituted hydrocodone indole and hydromorphone indole derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID OPIOID RECEPTOR ANTAGONISTS; SELECTIVITY; ANALOGS; NALTRINDOLE; AFFINITY AB The 8beta-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8beta-methyl group into the indolomorphinan nucleus increased affinity at all opioid receptors. 6,7-Dehydro-4,5alpha-epoxy-8beta-methyl-6,7,2',3'-indolomorphinan (9) was found to be a delta antagonist with subnanomolar affinity (0,7 nM) for the delta-opioid receptor, and to have good delta-selectivity (mu/delta = 322). Published by Elsevier Science Ltd. C1 NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, POB 5180, Baltimore, MD 21224 USA. RI Prisinzano, Thomas/B-7877-2010 NR 16 TC 14 Z9 14 U1 1 U2 3 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 21 PY 2002 VL 12 IS 2 BP 165 EP 168 DI 10.1016/S0960-894X(01)00689-8 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 511KP UT WOS:000173263300014 PM 11755345 ER PT J AU Egron, D Perigaud, C Gosselin, G Aubertin, AM Gatanaga, H Mitsuya, H Zemlicka, J Imbach, JL AF Egron, D Perigaud, C Gosselin, G Aubertin, AM Gatanaga, H Mitsuya, H Zemlicka, J Imbach, JL TI Increase of the adenallene anti-HIV activity in cell culture using its bis(tBuSATE) phosphotriester derivative SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID NUCLEOSIDE ANALOGS; DELIVERY AB The bis(S-pivaloyl-2-thioethyl) phosphotriester derivative of 9-(4'-hydroxy-1',2'-butadienyl)adenine (adenallene) was synthesized. This mononucleotide prodrug proved to be more effective than the parent nucleoside in inhibiting HIV-1 replication in several human T4 lymphoblastoid cell lines. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Montpellier 2, CNRS, UMR 5625, F-34095 Montpellier 5, France. Fac Med Strasbourg, INSERM, U 74, Inst Virol, F-67000 Strasbourg, France. NCI, Expt Retrovirol Sect, Med Branch, Div Clin Sci,NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Dept Chem, Detroit, MI 48201 USA. RP Perigaud, C (reprint author), Univ Montpellier 2, CNRS, UMR 5625, CC 008,Pl E Bataillon, F-34095 Montpellier 5, France. NR 9 TC 7 Z9 9 U1 0 U2 5 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 21 PY 2002 VL 12 IS 2 BP 265 EP 266 DI 10.1016/S0960-894X(01)00728-4 PG 2 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 511KP UT WOS:000173263300037 PM 11755368 ER PT J AU Brooks, LA Sullivan, A O'Nions, J Bell, A Dunne, B Tidy, JA Evans, DJ Osin, P Vousden, KH Gusterson, B Farrell, PJ Storey, A Gasco, M Sakai, T Crook, T AF Brooks, LA Sullivan, A O'Nions, J Bell, A Dunne, B Tidy, JA Evans, DJ Osin, P Vousden, KH Gusterson, B Farrell, PJ Storey, A Gasco, M Sakai, T Crook, T TI E7 proteins from oncogenic human papillomavirus types transactivate p73: role in cervical intraepithelial neoplasia SO BRITISH JOURNAL OF CANCER LA English DT Article DE HPV; p73; cervical cancer ID GENE; P53; CANCER; EXPRESSION; APOPTOSIS; TUMOR; KERATINOCYTES AB In common with other E2F1 responsive genes such as p14(ARF) and B-(myb), the promoter of p73 is shown to be positively regulated in cell lines and primary human keratinocytes by E7 proteins from oncogenic human papillomavirus (HPV) types 16, 18, 31 and 33, but not HPV 6. Mutational analysis revealed that transactivation of the p73 promoter by HPV 16E7 requires association with pRb. Expression of p73 in normal cervical epithelium is confined to the basal and supra-basal layers. In contrast, expression in neoplastic lesions is detected throughout the epithelium and increases with grade of neoplasia, being maximal in squamous cell cancers (SCC). Deregulation of expression of the N-terminal splice variant p73Delta2 was observed in a significant proportion of cancers, but not in normal epithelium. The frequent over-expression of p73Delta2, which has recognized transdominant properties, in malignant and pre-malignant lesions suggests a role in the oncogenic process in cervical epithelium. (C) 2002 The Cancer Research Campaign. C1 St Marys Hosp, Sch Med, Ludwig Inst Canc Res, London W2 1PG, England. Univ Glasgow, Western Infirm, Dept Pathol, Glasgow G11 6NT, Lanark, Scotland. Univ Sheffield, No Gen Hosp, Dept Gynaecol Oncol, Sheffield S5 7AU, S Yorkshire, England. St Marys Hosp, Sch Med, Dept Histopathol, London W2, England. UCL Hosp, Dept Pathol, London WC1, England. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. St Bartholomews & Royal London Sch Med & Dent, Ctr Cutaneous Res, London E1 2AT, England. Azienda Osped S Croce & Carle, UO Oncol Med, I-12100 Cuneo, Italy. Kyoto Prefectural Univ Med, Dept Prevent Med, Kamigyo Ku, Kyoto 6028566, Japan. RP Crook, T (reprint author), St Marys Hosp, Sch Med, Ludwig Inst Canc Res, Norfolk Pl, London W2 1PG, England. EM t.crook@ic.ac.uk RI gusterson, barry/D-3752-2009 NR 22 TC 24 Z9 26 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 21 PY 2002 VL 86 IS 2 BP 263 EP 268 DI 10.1038/sj/bjc/6600033 PG 6 WC Oncology SC Oncology GA 529QR UT WOS:000174310500019 PM 11870517 ER PT J AU Joshi, BH Leland, P Silber, J Kreitman, RJ Pastan, I Berger, M Puri, RK AF Joshi, BH Leland, P Silber, J Kreitman, RJ Pastan, I Berger, M Puri, RK TI IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein SO BRITISH JOURNAL OF CANCER LA English DT Article DE medulloblastoma; IL-4 receptor; subunit composition; immunofluorescence ID AFFINITY INTERLEUKIN-4 RECEPTORS; CARCINOMA CELL-LINES; IN-VIVO; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; SIGNAL-TRANSDUCTION; ANTITUMOR-ACTIVITY; INHIBITS GROWTH; SARCOMA-CELLS; CANCER-CELLS AB Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT-PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha) chains, however common c, a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by I-125-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo. (C) 2002 The Cancer Research Campaign. C1 US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. RP Puri, RK (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, NIH Bld 29B,Room 2NN10,29 Lincoln Dr, Bethesda, MD 20892 USA. NR 33 TC 23 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 21 PY 2002 VL 86 IS 2 BP 285 EP 291 DI 10.1038/sj/bjc/6600034 PG 7 WC Oncology SC Oncology GA 529QR UT WOS:000174310500023 PM 11870521 ER PT J AU Eicher, DM Damjanovich, S Waldmann, TA AF Eicher, DM Damjanovich, S Waldmann, TA TI Oligomerization of IL-2R alpha SO CYTOKINE LA English DT Article DE cell-to-cell interactions; cellular activation; cytokine receptors; cytokines; signal transduction ID HUMAN INTERLEUKIN-2 RECEPTOR; JAK-3 JANUS KINASE; T-CELL; IL-2 RECEPTOR; GAMMA-CHAIN; BETA-CHAIN; SIGNAL-TRANSDUCTION; CYTOPLASMIC DOMAINS; MOLECULAR-CLONING; ZETA-CHAIN AB Interleukin (IL) 2 receptor subunit alpha (IL-2Ralpha) increases the affinity of the IL-2 receptor complex while hetero-association of IL-2Rbeta and gamma(c) chains initiates a proliferative signal. We show here that IL-2Ralpha is necessary for receptor clustering required for augmentation of IL-2 signalling. Cells expressing chimeras incorporating the extracellular domain of IL-2Ra demonstrated IL-2 independent homo-association of the IL-2Ralpha chimera. Singly or co-transfected IL-2Rbeta and gamma(c) chimeras showed no spontaneous or IL-2-inducible oligomerization. Co-transfection of IL-2Ralpha and IL-2Rbeta ( +/-gamma(c)) chimeras diminished spontaneous IL-2Ralpha chimera oligomerization and permitted IL-2-inducible hetero-oligomerization of receptor components. Homo-association of IL-2Ralpha was also demonstrated by fluorescence resonance energy transfer (FRET). The spontaneous homo-oligomerization property of IL-2Ralpha required the membrane proximal region of the receptor (exon 6) by deletion analysis; the IL-2 inducible oligomerization property of IL-2Ralpha required the second "sushi" domain (exon 4). This work provides insight into the mechanics of this complex receptor system and to other receptor complexes in the immune system that send signals by clustering receptor subunits. (C) 2002 Elsevier Science Ltd. C1 Case Western Reserve Univ, Sch Med, Div Hematol Oncol, Ireland Canc Ctr,Univ Hosp Cleveland, Cleveland, OH 44106 USA. Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Eicher, DM (reprint author), Case Western Reserve Univ, Sch Med, Div Hematol Oncol, Ireland Canc Ctr,Univ Hosp Cleveland, Wearn Bldg,Room 448,Mailstop WRN5061,10900 Euclid, Cleveland, OH 44106 USA. RI Damjanovich, Sandor/A-9284-2011 NR 33 TC 11 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JAN 21 PY 2002 VL 17 IS 2 BP 82 EP 90 DI 10.1006/cyto.2001.0978 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 535KK UT WOS:000174643500004 PM 11886175 ER PT J AU Sullivan, SL AF Sullivan, SL TI Mammalian chemosensory receptors SO NEUROREPORT LA English DT Review DE chemoreceptor; G-protein coupled receptor; gustatory; odorant; olfactory; pheromone; taste; vomeronasal ID PUTATIVE PHEROMONE RECEPTORS; CANDIDATE TASTE RECEPTORS; HUMAN OLFACTORY SUBGENOME; ODORANT RECEPTOR; VOMERONASAL SYSTEM; SWEET TASTE; SACCHARIN PREFERENCE; MULTIGENE FAMILY; SENSORY NEURONS; G-PROTEINS AB Chemosensory receptors are critical for the survival of many mammalian species, and their genes can comprise up to 1% of mammalian genomes. Odorant, taste, and vomeronasal receptors are being discovered and functionally characterized at a rapid pace which has been further accelerated by the availability of the human genome sequence. Five multigene families, consisting of >1000 genes in the mouse, have been proposed to encode functional chemoreceptors. Although all of the chemoreceptor gene families encode G-protein coupled receptors, they are largely unrelated and uniquely specialized for the processing of different chemosensory modalities. Using members of the families as molecular probes, great insights are being gained into the different organizational strategies used by these sensory systems to encode information in both the periphery and the brain. NeuroReport 13:A9-A17 (C) 2002 Lippincott Williams Wilkins. C1 Natl Inst Deafness & Other Commun Disorders, Mol Neurosci Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Sullivan, SL (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Neurosci Sect, Mol Biol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 110 TC 11 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JAN 21 PY 2002 VL 13 IS 1 BP A9 EP A17 DI 10.1097/00001756-200201210-00003 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 514NY UT WOS:000173449000005 PM 11924905 ER PT J AU Best, SM Wolfinbarger, JB Bloom, ME AF Best, SM Wolfinbarger, JB Bloom, ME TI Caspase activation is required for permissive replication of Aleutian mink disease parvovirus in vitro SO VIROLOGY LA English DT Article DE parvovirus; Aleutian mink disease parvovirus; caspase; apoptosis; persistent infection; replication; mink; mink enteritis virus; TUNEL ID PROGRAMMED CELL-DEATH; COMMITTED PROGENITOR CELLS; MINUTE VIRUS; NONSTRUCTURAL PROTEINS; ENTERITIS VIRUS; AUTONOMOUS PARVOVIRUS; NUCLEOCAPSID PROTEIN; NUCLEOTIDE-SEQUENCE; HEMATOPOIETIC STEM; ADULT MINK AB Aleutian mink disease parvovirus (ADV) is distinct among the parvoviruses as infection in vivo is persistent, restricted, and noncytopathic. In contrast, infections with other more prototypic parvoviruses, like mink enteritis virus (MEV), are acute, cytopathic, and characterized by permissive replication in vivo. Although apoptosis results in the death of cells acutely infected by parvoviruses, the role of apoptosis in ADV infections is unknown. Permissive infection of ADV resulted in apoptosis of Crandell feline kidney (CrFK) cells as indicated by TUNEL staining, Annexin-V staining, and characteristic changes in cell morphology Pretreatment of infected cells with caspase 3 or broad-spectrum caspase inhibitors prevented apoptosis. In addition, treatment of infected cells with these inhibitors caused a 2 log, reduction in the yield of infectious virus compared to untreated cultures. This block in replication preceded substantial viral DNA amplification and gene expression. However, inhibitors of caspases 1, 6, and 8 did not have this effect. MEV also induced caspase-dependent apoptosis following infection of CrFK cells, although production of infectious progeny was not affected by inhibition of apoptosis, Thus, permissive replication of ADV in vitro depended upon activation of specific caspases. If ADV infection of cells in vivo fails to initiate caspase activation, the requirement of caspase activity for replication may not be met, thus providing a possible mechanism for persistent, restricted infection. (C) 2002 Elsevier Science. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 55 TC 34 Z9 35 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2002 VL 292 IS 2 BP 224 EP 234 DI 10.1006/viro.2001.1238 PG 11 WC Virology SC Virology GA 520QG UT WOS:000173792100005 PM 11878925 ER PT J AU Straus, SE AF Straus, SE TI Caring for patients with chronic fatigue syndrome - Conclusions in CMO's report are shaped by anecdote not evidence SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID RANDOMIZED CONTROLLED TRIAL; COGNITIVE-BEHAVIOR THERAPY C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20854 USA. RP Straus, SE (reprint author), NIAID, Clin Invest Lab, NIH, Bethesda, MD 20854 USA. NR 11 TC 10 Z9 10 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 19 PY 2002 VL 324 IS 7330 BP 124 EP 125 DI 10.1136/bmj.324.7330.124 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 514ZH UT WOS:000173470600002 PM 11799015 ER PT J AU Montagnani, M Golovchenko, I Kim, I Koh, GY Goalstone, ML Mundhekar, AN Johansen, M Kucik, DF Quon, MJ Draznin, B AF Montagnani, M Golovchenko, I Kim, I Koh, GY Goalstone, ML Mundhekar, AN Johansen, M Kucik, DF Quon, MJ Draznin, B TI Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; NITRIC-OXIDE RELEASE; SMOOTH-MUSCLE CELLS; GROWTH-FACTOR; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; GENE-EXPRESSION; RESISTANCE; KINASE; HYPERINSULINEMIA AB The concept of "selective insulin resistance" has emerged as a unifying hypothesis in attempts to reconcile the influence of insulin resistance with that of hyper-insulinemia in the pathogenesis of macrovascular complications of diabetes. To explore this hypothesis in endothelial cells, we designed a set of experiments to mimic the "typical metabolic insulin resistance" by blocking the phosphatidylinositol 3-kinase pathway and exposing the cells to increasing concentrations of insulin ("compensatory hyperinsulinemia"). Inhibition of phosphatidylinositol 3-kinase with wortmannin blocked the ability of insulin to stimulate increased expression of endothelial nitric-oxide synthase, did not affect insulin-induced activation of MAP kinase, and increased the effects of insulin on prenylation of Ras and Rho proteins. At the same time, this experimental paradigm resulted in increased expression of vascular cellular adhesion molecules-1 and E-selectin, as well as increased rolling interactions of monocytes with endothelial cells. We conclude that inhibition of the metabolic branch of insulin signaling leads to an enhanced mitogenic action of insulin in endothelial cells. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Pohang Univ Sci & Technol, Natl Creat Res Ctr Endothelial Cells, Pohang 790784, South Korea. Univ Alabama, Sch Med, Vet Affairs Med Ctr, Res Serv, Birmingham, AL 35294 USA. Univ Alabama, Sch Med, Dept Pathol, Birmingham, AL 35294 USA. Univ Calif San Francisco, Program Host Pathogen Interact, San Francisco, CA 94143 USA. Univ Colorado, Sch Med, Vet Affairs Med Ctr, Res Serv, Denver, CO 80220 USA. Univ Colorado, Sch Med, Dept Med, Denver, CO 80220 USA. RP Draznin, B (reprint author), ACOS, Res & Dev, 1055 Clermont St,151, Denver, CO 80220 USA. RI Quon, Michael/B-1970-2008; Kim, Injune/C-1710-2011; Koh, Gou Young /C-1615-2011; OI Kim, Injune/0000-0001-9244-815X; Quon, Michael/0000-0002-9601-9915; montagnani, monica/0000-0002-5697-8185; Quon , Michael /0000-0002-5289-3707 NR 43 TC 200 Z9 220 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 18 PY 2002 VL 277 IS 3 BP 1794 EP 1799 DI 10.1074/jbc.M103728200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CW UT WOS:000173421300024 PM 11707433 ER PT J AU Ward, SDC Hamdan, FF Bloodworth, LM Wess, J AF Ward, SDC Hamdan, FF Bloodworth, LM Wess, J TI Conformational changes that occur during M-3 muscarinic acetylcholine receptor activation probed by the use of an in situ disulfide cross-linking strategy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA(2) ADRENERGIC-RECEPTOR; PROTEIN-COUPLED RECEPTORS; ALANINE-SCANNING MUTAGENESIS; TRANSMEMBRANE DOMAIN; AMINO-ACID; CONSTITUTIVE ACTIVATION; SENSORY RECEPTOR; CYTOPLASMIC SIDE; G ALPHA(Q); RHODOPSIN AB The structural changes involved in ligand-dependent activation of G protein-coupled receptors are not well understood at present. To address this issue, we developed an in situ disulfide cross-linking strategy using the rat M-3 muscarinic receptor, a prototypical G(q)-coupled receptor, as a model system. It is known that a tyrosine residue (Tyr(254)) located at the C terminus of transmembrane domain (TM) V and several primarily hydrophobic amino acids present within the cytoplasmic portion of TM VI play key roles in determining the G protein coupling selectivity of the M-3 receptor subtype. To examine whether M-3 receptor activation involves changes in the relative orientations of these functionally critical residues, pairs of cysteine residues were substituted into a modified version of the M. receptor that contained a factor Xa cleavage site within the third intracellular loop and lacked most endogenous cysteine residues. All analyzed mutant receptors contained a Y254C point mutation and a second cysteine substitution within the segment Lys(484)-Ser(493) at the intracellular end of TM VI. Following their transient expression in COS-7 cells, mutant receptors present in their native membrane environment (in situ) were subjected to mild oxidizing conditions, either in the absence or in the presence of the muscarinic agonist, carbachol. The successful formation of disulfide cross-links was monitored by studying changes in the electrophoretic mobility of oxidized, factor Xa-treated receptors on SDS gels. The observed cross-linking patterns indicated that M-3 receptor activation leads to structural changes that allow the cytoplasmic ends of TM V and TM VI to move closer to each other and that also appear to involve a major change in secondary structure at the cytoplasmic end of TM VI. This is the first study employing aninsitudisulfidecross-linkingstrategytoexamineagonistdependent dynamic structural changes in a G protein-coupled receptor. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-05, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov NR 58 TC 62 Z9 63 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 18 PY 2002 VL 277 IS 3 BP 2247 EP 2257 DI 10.1074/jbc.M107647200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CW UT WOS:000173421300085 PM 11698401 ER PT J AU Venkatesan, S Petrovic, A Van Ryk, DI Locati, M Weissman, D Murphy, PM AF Venkatesan, S Petrovic, A Van Ryk, DI Locati, M Weissman, D Murphy, PM TI Reduced cell surface expression of CCR5 in CCR5 Delta 32 heterozygotes is mediated by gene dosage, rather than by receptor sequestration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; IMMUNODEFICIENCY-VIRUS TYPE-1; MACROPHAGE-TROPIC HIV-1; CHEMOKINE RECEPTOR-5; MOLECULAR MECHANISMS; CD4(+) LYMPHOCYTES; BETA-CHEMOKINES; IN-VITRO; INFECTION; CORECEPTOR AB Macrophage tropic (M-tropic) human immunodeficiency virus (HIV) infection of primary human T cells and macrophages requires optimal cell surface expression of the chemokine receptor CCR5 in addition to CD4. Natural mutations of CCR5 that impair surface expression bestow in the homozygous state complete resistance to M-tropic HIV infection. ccr5Delta32 is the major prototype of such mutants. ccr5Delta32 heterozygosity is associated with delayed onset of AIDS and reduced risk of initial transmission, and this correlates with reduced levels of CCR5 and reduced infectability of CD4+ cells. In addition to gene dosage, sequestration of wild type (WT) CCR5 by mutant protein has been proposed as a mechanism to explain reduced surface expression of CCR5 in cells from ccr5Delta32 and CCR5-893(-) heterozygotes. However, here we demonstrate that a molar excess of ccr5Delta32 or related deletion mutants does not significantly impair the cell surface density of co-expressed WT receptor either in human epithelial cells or Jurkat T cells. Further, ligand-dependent signaling and M-tropic HIV usage of WT receptor are also unaffected. Nascent WT receptor does associate with ccr5Delta32 and related mutant proteins and with other unrelated CC and CXC chemokine receptors under transient labeling conditions. However, using confocal microscopy, we demonstrate that in the steady state, WT and truncated CCR5 proteins segregate into nonoverlapping subcellular compartments. These findings together with the observed and known variability in the cell surface density of CCR5 on quiescent PBLs lead us to conclude that reduced CCR5 gene dosage rather than receptor sequestration is the major determinant of reduced CCR5 expression in cells from ccr5Delta32 heterozygotes. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Ist Patol Gen, I-20133 Milan, Italy. Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. RP Venkatesan, S (reprint author), NIAID, LMM, NIH, Bldg 10,Rm 6A05, Bethesda, MD 20892 USA. RI Locati, Massimo/H-8404-2015 OI Locati, Massimo/0000-0003-3077-590X NR 69 TC 48 Z9 51 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 18 PY 2002 VL 277 IS 3 BP 2287 EP 2301 DI 10.1074/jbc.M108321200 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 514CW UT WOS:000173421300089 PM 11604406 ER PT J AU Yang, FQ Ito, Y AF Yang, FQ Ito, Y TI Preparative separation of lappaconitine, ranaconitine, N-deacetyllappaconitine and N-deacetylranaconitine from crude alkaloids of sample Aconitum sinomontanum Nakai by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Aconitum sinomontanum; counter-current chromatography; preparative chromatography; alkaloids; lappaconitine; ranaconitine; deacetyllappaconitine; deacetylranaconitine AB Analytical high-speed counter-current chromatography (HSCCC) was used for the systematic selection and optimization of the two-phase solvent system to separate alkaloids from Aconitum sinomontanum Nakai. The optimum solvent systems CHCl3-MeOH-0.3 M/0.2 M HCl (4:1.5:2, v/v) thus obtained led to the successful separation of lappaconitine, ranaconitine, N-deacetyllappaconitine and N-deacetylranaconitine from 60 to 500 mg of crude alkaloid sample by preparative HSCCC separation. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50,Room 3334, Bethesda, MD 20892 USA. NR 13 TC 39 Z9 46 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 18 PY 2002 VL 943 IS 2 BP 219 EP 225 DI 10.1016/S0021-9673(01)01464-9 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 510RV UT WOS:000173221800004 PM 11833641 ER PT J AU Zhou, M Horita, DA Waugh, DS Byrd, RA Morrison, DK AF Zhou, M Horita, DA Waugh, DS Byrd, RA Morrison, DK TI Solution structure and functional analysis of the cysteine-rich C1 domain of kinase suppressor of Ras (KSR) SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE KSR; cysteine-rich C1 domain; MAPK cascade; signal transduction; NMR structure ID ACTIVATED PROTEIN-KINASE; SIDE-CHAIN RESONANCES; BINDING DOMAIN; SIGNAL-TRANSDUCTION; C-13 MAGNETIZATION; ESCHERICHIA-COLI; LARGER PROTEINS; FUSION PROTEINS; BACKBONE AMIDE; RAF-1 ACTIVITY AB Kinase suppressor of Ras (KSR) is a conserved component of the Ras pathway that acts as a molecular scaffold to promote signal transmission from Raf-1 to MEK and MAPK. All KSR proteins contain a conserved cysteine-rich C1 domain, and studies have implicated this domain in the regulation of KSR1 subcellular localization and function. To further elucidate the biological role of the KSR1 C1 domain, we have determined its three-dimensional solution structure using nuclear magnetic resonance (NMR). We find that while the overall topology of the KSR1 C1 domain is similar to the C1 domains of Raf-1 and PKC-gamma, the predicted ligand-binding region and the surface charge distribution are unique. Moreover, by generating chimeric proteins in which these domains have been swapped, we find that the C1 domains of Raf-1, PKCgamma, and KSR1 are not functionally interchangeable. The KSR1 C1 domain does not bind with high affinity or respond biologically to phorbol esters or ceramide, and it does not interact directly with Ras, indicating that the putative ligand(s) for the KSR1 C1 domain are distinct from those that interact with PKCgamma and Raf-1. In addition, our analysis of the chimeric proteins supports the model that Raf-1 is a ceramide-activated kinase and that its C1 domain is involved in the ceramide-mediated response. Finally, our findings demonstrate an absolute requirement of the KSR1 C1 domain in mediating the membrane localization of KSR1, a crucial feature of its scaffolding activity. Together, these results underscore the functional specificity of these important regulatory domains and demonstrate that the structural features of the C1 domains can provide valuable insight into their ligand-binding properties. C1 NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Struct Biophys Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RI Byrd, R. Andrew/F-8042-2015; OI Byrd, R. Andrew/0000-0003-3625-4232; Horita, David/0000-0002-9563-107X NR 53 TC 63 Z9 65 U1 0 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 18 PY 2002 VL 315 IS 3 BP 435 EP 446 DI 10.1006/jmbi.2001.5263 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 516VL UT WOS:000173577400014 PM 11786023 ER PT J AU Anseth, KS Metters, AT Bryant, SJ Martens, PJ Elisseeff, JH Bowman, CN AF Anseth, KS Metters, AT Bryant, SJ Martens, PJ Elisseeff, JH Bowman, CN TI In situ forming degradable networks and their application in tissue engineering and drug delivery SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 10th International Symposium on Recent Advances in Drug Delivery Systems CY FEB 19-22, 2001 CL SALT LAKE CITY, UTAH DE photopolymerization; hydrogels; degradation; cartilage tissue engineering ID B-PLA HYDROGEL; PHOTOPOLYMERIZATION; POLYANHYDRIDES; PREVENTION; MACROMERS; BEHAVIOR; SYSTEMS AB Multi functional macromers based on poly(ethylene glycol) and poly(vinyl alcohol) were photopolymerized to form degradable hydrogel networks. The degradation behavior of the highly swollen gels was characterized by monitoring changes in their mass loss, degree of swelling, and compressive modulus. Experimental results show that the modulus decreases exponentially with time, while the volumetric swelling ratio increases exponentially. A degradation mechanism assuming pseudo first-order hydrolysis kinetics and accounting for the structure of the crosslinked networks successfully predicted the experimentally observed trends in these properties with degradation. Once verified, the proposed degradation mechanism was extended to correlate network degradation kinetics, and subsequent changes in network structure, with release behavior of bioactive molecules from these dynamic systems. A theoretical model utilizing a statistical approach to predict the cleavage of crosslinks within the network was used to predict the complex erosion profiles produced by these hydrogels. Finally, the application of these macromers as in situ forming hydrogel constructs for cartilage tissue engineering is demonstrated, (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Colorado, Dept Chem Engn, Ctr Engn, Boulder, CO 80309 USA. Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. NIH, Div Intramural Res, Bethesda, MD 20892 USA. RP Anseth, KS (reprint author), Univ Colorado, Dept Chem Engn, Ctr Engn, Room ECCH 111,Campus Box 424, Boulder, CO 80309 USA. RI Bowman, Christopher/B-1490-2008; Martens, Penny/B-4274-2011; OI Bowman, Christopher/0000-0001-8458-7723; Martens, Penny/0000-0003-3098-1420 FU NIDCR NIH HHS [DE-12998] NR 24 TC 287 Z9 292 U1 5 U2 76 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JAN 17 PY 2002 VL 78 IS 1-3 BP 199 EP 209 DI 10.1016/S0168-3659(01)00500-4 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 518HF UT WOS:000173661200019 PM 11772461 ER PT J AU Lifson, JD Martin, MA AF Lifson, JD Martin, MA TI AIDS vaccines - One step forwards, one step back SO NATURE LA English DT Editorial Material ID SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; RHESUS-MONKEYS; PROTECTION; INFECTION; MACAQUES; LIVE; ENV C1 NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Lifson, JD (reprint author), NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. NR 15 TC 31 Z9 31 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 17 PY 2002 VL 415 IS 6869 BP 272 EP 273 DI 10.1038/415272b PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 511YC UT WOS:000173293500026 PM 11796990 ER PT J AU Koch, CA Huang, SC Zhuang, ZP Stolle, C Azumi, N Chrousos, GP Vortmeyer, AO Pacak, K AF Koch, CA Huang, SC Zhuang, ZP Stolle, C Azumi, N Chrousos, GP Vortmeyer, AO Pacak, K TI Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma SO ONCOGENE LA English DT Article DE RET; MEN 2; VHL; pheochromocytoma; deletion ID HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR GENE; ENDOCRINE NEOPLASIA TYPE-2; RET PROTOONCOGENE; SPORADIC PHEOCHROMOCYTOMAS; FAMILIAL PHEOCHROMOCYTOMA; GERMLINE MUTATIONS; SHORT ARM; HETEROZYGOSITY; CHROMOSOME-3 AB Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these mechanisms. In the present study, we therefore searched for other possible mechanisms underlying the pathogenesis of MEN 2A-related pheochromocytoma. Hereditary pheochromocytoma also occurs in patients with von Hippel-Lindau (VHL) disease, a syndrome consisting of tumors caused by inactivation of the VHL tumor suppressor gene. A subset of sporadic pheochromocytomas have somatic mutations in RET or VHL, suggesting that both genes contribute to pheochromocytoma pathogenesis in a subset of tumors. It is unknown, however; whether VHL gene alterations would be associated with tumorigenesis in hereditary, MEN 2-related pheochromocytoma. We therefore investigated four pheochromocytomas from patients with MEN 2A and RET germline mutations for the presence of allelic deletion and/or somatic mutation of the VHL gene. LOH analysis using the polymorphic markers D3S1038 and D3S1110 that map to the VHL gene locus 3p25/26, revealed evidence for somatic VHL gene deletion in all four MEN 2A-related pheochromocytomas. Mutation analysis of the VHL gene showed frameshift mutations in two tumors and a splice acceptor mutation in one tumor. The remaining tumor did show LOH but not mutation of the VHL gene. These results suggest that somatic genetic alterations of the VHL gene may play a role in the tumorigenesis of some MEN 2A-related pheochromocytomas. C1 NICHHD, PREB, NIH, Bethesda, MD 20892 USA. NINCDS, Surg Neurol Branch, Mol Pathogenesis Unit, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Georgetown Univ, Washington, DC USA. RP Koch, CA (reprint author), NICHHD, PREB, NIH, Bldg 10,Rm 9D42, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 30 TC 25 Z9 25 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 17 PY 2002 VL 21 IS 3 BP 479 EP 482 DI 10.1038/sj.onc.1205133 PG 4 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 512FV UT WOS:000173311200016 PM 11821960 ER PT J AU Umemura, T Tanaka, Y Kiyosawa, K Alter, HJ Shih, JWK AF Umemura, T Tanaka, Y Kiyosawa, K Alter, HJ Shih, JWK TI Observation of positive selection within hypervariable regions of a newly identified DNA virus (SEN virus) SO FEBS LETTERS LA English DT Article DE evolutionary rate; hypervariable regions; phylogenetic analysis; positive selection; TT virus; Circoviridae ID HEPATITIS-C VIRUS; NUCLEOTIDE-SEQUENCES; EVOLUTION; INFECTION; PROTEIN; TTV; SUBSTITUTIONS; GENOME; SANBAN; HIV AB To elucidate the evolution of SEN virus (SEN-V), serial sequences of chronically SEN-V-infected patients were analyzed. In the hypervariable regions, non-synonymous substitutions significantly predominated. This could be attributed to positive selection in evading immune surveillance of the hosts and to establish a persistent infection. On the basis of the sequences in the two open reading frames of SEN-V DNA, the rate of synonymous substitutions was 7.32X10(-4) per site per year. Since this rate is close to RNA viruses and higher than other DNA viruses, the SEN-V might be replicated by machinery with poor or no proofreading function. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Shinshu Univ, Sch Med, Dept Internal Med 2, Matsumoto, Nagano 3908621, Japan. RP Shih, JWK (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NR 31 TC 28 Z9 33 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 16 PY 2002 VL 510 IS 3 BP 171 EP 174 DI 10.1016/S0014-5793(01)03258-6 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 512TZ UT WOS:000173340800012 PM 11801248 ER PT J AU Feller, SE Gawrisch, K MacKerell, AD AF Feller, SE Gawrisch, K MacKerell, AD TI Polyunsaturated fatty acids in lipid bilayers: Intrinsic and environmental contributions to their unique physical properties SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; DOCOSAHEXAENOIC ACID; COMPUTER-SIMULATION; WATER PERMEABILITY; COMPONENT VOLUMES; SURFACE-TENSION; ACYL-CHAIN; N-ALKANES; NMR; ENERGY AB Polyunsaturated lipids are an essential component of biological membranes, influencing order and dynamics of lipids, protein-lipid interaction, and membrane transport properties, To gain an atomic level picture of the impact of polyunsaturation on membrane properties, quantum mechanical (QM) and empirical force field based calculations have been undertaken. The QM calculations of the torsional energy surface for rotation about vinyl-methylene bonds reveal low barriers to rotation, indicating an intrinsic propensity toward flexibility. Based on QM and experimental data, empirical force field parameters were developed for polyunsaturated lipids and applied in a 16 ns molecular dynamics (MD) simulation of a 1-stearoyl-2-docosahexaenoyl-sn-glyerco-3-phosphocholine (SDPC) lipid bilayer. The simulation results are in good agreement with experimental data, suggesting an unusually high degree of conformational flexibility of polyunsaturated hydrocarbon chains in membranes. The detailed analysis of chain conformation and dynamics by simulations is aiding the interpretation of experimental data and is useful for understanding the unique role of polyunsaturated lipids in biological membranes. The complete force field is included as Supporting Information and is available from http://www.pharmacy.umaryland.edu/faculty/amackere/research.html. C1 Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Feller, SE (reprint author), Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. OI MacKerell, Alex/0000-0001-8287-6804 FU NIGMS NIH HHS [GM5150-01] NR 45 TC 280 Z9 285 U1 2 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JAN 16 PY 2002 VL 124 IS 2 BP 318 EP 326 DI 10.1021/ja0118340 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 510QH UT WOS:000173218400027 PM 11782184 ER PT J AU Sharma, Y Kwon, OY Brooks, B Tjandra, N AF Sharma, Y Kwon, OY Brooks, B Tjandra, N TI An ab initio study of amide proton shift tensor dependence on local protein structure SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL SHIELDING ANISOTROPY; HYDROGEN-BOND LENGTH; SECONDARY STRUCTURE; MOLECULAR-DYNAMICS; DIRECT REFINEMENT; NMR-SPECTROSCOPY; DIPOLAR; RELAXATION; CONFORMATION; BACKBONE AB Ab initio shielding tensor calculations were carried out on residues in human ubiquitin. Reported experimental data on isotropic and anisotropic components of the amide proton chemical shifts were used as benchmarks to test the validity of the chosen basis sets as well as methods in structure optimization and shielding calculations. The best agreement with the experimental values was observed when the 6-311**G and 6-311++G(2d,2p) basis sets were used to optimize the structure and to calculate the shielding tensor, respectively. The same method was employed in subsequent model calculations to characterize the dependence of amide proton shielding to the local structure. Both the isotropic and the anisotropic components of the symmetric tensor were found to depend very strongly on the hydrogen bond length, A weaker dependence can also be observed for the hydrogen bond angle. Antisymmetric tensor elements were found to be relatively small. This study permits separation of various local structure contributions to the amide proton shielding tensor that complements scarce experimental data. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 50, Bethesda, MD 20892 USA. NR 35 TC 24 Z9 24 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JAN 16 PY 2002 VL 124 IS 2 BP 327 EP 335 DI 10.1021/ja016859d PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 510QH UT WOS:000173218400028 PM 11782185 ER PT J AU Balis, FM AF Balis, FM TI Evolution of anticancer drug discovery and the role of cell-based screening SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ACUTE PROMYELOCYTIC LEUKEMIA; TRANS-RETINOIC ACID; CANCER; TARGETS C1 NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Balis, FM (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 13C102,10 Ctr Dr, Bethesda, MD 20892 USA. NR 19 TC 47 Z9 49 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 16 PY 2002 VL 94 IS 2 BP 78 EP 79 PG 2 WC Oncology SC Oncology GA 512GA UT WOS:000173311700001 PM 11792737 ER PT J AU Landi, MT Baccarelli, A Tarone, RE Pesatori, A Tucker, MA Hedayati, M Grossman, L AF Landi, MT Baccarelli, A Tarone, RE Pesatori, A Tucker, MA Hedayati, M Grossman, L TI DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BASAL-CELL CARCINOMA; SKIN-CANCER; MELANOCYTIC NEVI; SUN EXPOSURE; RISK FACTOR; EPIDEMIOLOGY; LYMPHOCYTES; CAPACITY; SURVEILLANCE; IRRADIATION AB Background: Exposure to UV radiation is associated with cutaneous malignant melanoma (CMM). In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. We designed this case-control study to determine whether DNA repair capacity (DRC) is associated with the risk of CMM and to identify risk factors that may interact biologically with DRC in the development of melanoma. Methods: Global DRC was measured in lymphocytes with the host-cell reactivation assay. Data were analyzed by use of multiple regression models. All statistical tests were two-sided. Results: DRC could be determined for 132 case patients with incident melanoma and for 145 age- and sex-matched control subjects. No statistically significant association between melanoma risk and DRC by itself was found (odds ratio [OR] = 1.0; 95% confidence interval [CI] = 0.6 to 1.7, adjusted for age, sex, lymphocyte viability, and sample storage time). DRC, however, strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. Individuals with a low tanning ability and a low DRC had a higher risk for CMM (OR = 8.6; 95% CI = 2.7 to 27.5) than individuals with a higher tanning ability and a high DRC. Likewise, individuals with dysplastic nevi and a low DRC had a higher relative risk (OR = 6.7; 95% CI = 2.4 to 18.6) than those lacking dysplastic nevi and having a high DRC. Subjects with dysplastic nevi and a high DRC had an intermediate risk. A likelihood-ratio test gave statistically significant interactions between DRC and tanning response (P =.001) and between DRC and dysplastic nevus status (P =.04), which were independently associated with CMM risk. Conclusions: DRC may modify the risk for melanoma in the presence of other strong risk factors, such as a low tanning ability and the presence of dysplastic nevi. The occurrence of melanoma in subjects without these risk factors appears to be independent of DRC. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Milan, Epidemiol Res Ctr, I-20122 Milan, Italy. Johns Hopkins Univ, Sch Publ Hlth, Dept Biochem, Baltimore, MD 21218 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015; OI pesatori, angela/0000-0002-0261-3252 FU NCI NIH HHS [CA65558-02]; NIGMS NIH HHS [GM22846] NR 50 TC 65 Z9 67 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 16 PY 2002 VL 94 IS 2 BP 94 EP 101 PG 8 WC Oncology SC Oncology GA 512GA UT WOS:000173311700009 PM 11792747 ER PT J AU Sherman, ME Schiffman, M Cox, JT AF Sherman, ME Schiffman, M Cox, JT TI Effects of age and human papilloma viral load on colposcopy triage: Data from the randomized atypical squamous cells of undetermined significance low-grade squamous intraepithelial lesion triage study (ALTS) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 23-31, 2000 CL NEW ORLEANS, LOUISIANA SP US & Canadian Acad Pathol ID NORMAL CERVICAL SMEARS; NESTED CASE-CONTROL; CARCINOMA IN-SITU; HIGH-RISK; WOMEN; NEOPLASIA; DNA; HPV; POPULATION; CANCER AB Background: Testing for oncogenic human papillomavirus (HPV) DNA at a 1.0-pg/mL threshold represents a promising approach for colposcopy triage of atypical squamous cells of undetermined significance (ASCUS), but not for low-grade squamous intraepithelial lesions (LSIL). Considering age or viral load could improve colposcopy triage. Methods: We determined the sensitivity for detecting Cervical Intraepithelial Neoplasia 3 (CIN3) and cancer and the percentage of referrals for colposcopy using HPV testing and repeat thin-layer cytopathology in 2198 women with ASCUS and in 848 women with LSIL enrolled in ALTS from November 1996 through December 1998. We analyzed results by age and at two thresholds for HPV load and repeat cytopathology. Results: For ASCUS, the overall sensitivity of HPV testing at 1.0 pg/mL was 96.1 % (95 % confidence interval [CI] = 92.8 to 99.5%) and varied minimally with age (range, 93.9% to 97.8%). HPV testing at this threshold would refer 31.2% (95% CI = 28.0% to 34.3%) of women aged 29 years or older as compared with more than 65% of younger women. Among women aged 29 years or older with ASCUS, referral for repeat cytopathology of ASCUS had a sensitivity of 90.9 % (95 % CI = 81.1 % to 100.0 %) and would refer 50.1 % (95% CI = 46.7 to 53.5%). Among all ASCUS, HPV testing using a 10.0-pg/mL threshold decreased sensitivity to 91.5% and referrals to 41.7%. More than 63% of LSIL would have been referred using any strategy achieving 90% sensitivity. Conclusion: For women with ASCUS, HPV testing was highly sensitive for detecting CIN3 and cancer with dramatically fewer referrals of older women. Neither a single HPV test nor repeat cytopathology provides useful triage for women with LSIL. C1 NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Calif Santa Barbara, Student Hlth Ctr, Santa Barbara, CA 93106 USA. RP Sherman, ME (reprint author), NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Rm 7080, Bethesda, MD 20892 USA. FU NCI NIH HHS [CN55157, CN55105, CN55153, CN55154, CN55155, CN55156, CN55158, CN55159] NR 29 TC 178 Z9 192 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 16 PY 2002 VL 94 IS 2 BP 102 EP 107 PG 6 WC Oncology SC Oncology GA 512GA UT WOS:000173311700010 PM 11792748 ER PT J AU Stefanek, M Hartmann, L Nelson, W AF Stefanek, M Hartmann, L Nelson, W TI Re: Risk-reduction mastectomy: Clinical issues and research needs - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Stefanek, M (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Rm 4066,Execut Plaza N,MSC 7363, Bethesda, MD 20892 USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 16 PY 2002 VL 94 IS 2 BP 143 EP 144 PG 2 WC Oncology SC Oncology GA 512GA UT WOS:000173311700015 ER PT J AU Zhu, JH Quyyumi, AA Muhlestein, JB Nieto, FJ Horne, BD Zalles-Ganley, A Anderson, JL Epstein, SE AF Zhu, JH Quyyumi, AA Muhlestein, JB Nieto, FJ Horne, BD Zalles-Ganley, A Anderson, JL Epstein, SE TI Lack of association of Helicobacter pylori infection with coronary artery disease and frequency of acute myocardial infarction or death SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ISCHEMIC-HEART-DISEASE; MIDDLE-AGED MEN; CHLAMYDIA-PNEUMONIAE; RISK-FACTORS; SEROPOSITIVITY; CYTOMEGALOVIRUS; STRAINS AB We investigated the association between Helicobacter pylori (H. pylori) infection and coronary artery disease (CAD) in 2 study populations: (1) a cross-sectional study to determine risk of having CAD, and (2) a longitudinal study to determine risk of acute myocardial infarction (AMI) or death over a mean follow-up period of 3 years in patients with angiographically documented CAD. Blood samples were tested for serum immunoglobulin G antibodies to H. pylori and C-reactive protein (CRP) levels. Study 1: Of 391 patients (62% men, mean age 57 years), 41% had antibodies to H. pylori. CAD prevalence was 70% in H. pylori seropositive patients and 59% in seronegative patients (p = 0.03). Elevated CRP levels (> 0.5 mg/dl) were significantly higher in patients with than without CAD (p = 0.02). By univariate analysis, CAD prevalence significantly increased stepwise depending on H. pylori seropositivity and elevated CRP levels (p = 0.008). Significance was lost after adjustment for traditional risk factors. Further analyses revealed that age was the critical confounder. Study 2: Of 929 patients (77% men, mean age 65 years), 56% had antibodies to H. pylori. By univariate analysis, the incidence of AMI or death was 22% in H. pylori seropositive patients and 18% in seronegative patients (p = 0.1). The adjusted hazard ratio of AMI or death for H. pylori seropositivity was 1.12 (95% confidence interval 0.81 to 1.54). Our data suggest that prior infection with H. pylori is not a major factor determining either risk of CAD, AMI, or death in patients with CAD. (C) 2002 by Excerpta Medica, Inc. C1 Washington Hosp Ctr, Inst Cardiovasc Res, MedStar Res Inst, Washington, DC 20010 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. LDS Hosp, Salt Lake City, UT USA. Univ Utah, Salt Lake City, UT USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Epstein, SE (reprint author), Washington Hosp Ctr, Inst Cardiovasc Res, MedStar Res Inst, 110 Irving St,NW,Suite 48-1, Washington, DC 20010 USA. NR 16 TC 35 Z9 39 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2002 VL 89 IS 2 BP 155 EP 158 DI 10.1016/S0002-9149(01)02192-0 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 512QG UT WOS:000173334600008 PM 11792334 ER PT J AU Calis, KA Daniels, CE AF Calis, KA Daniels, CE TI Secretin available under FDA treatment protocol SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Letter C1 NIH, Warren G Magnuson Clin Ctr, Drug Informat Serv, Dept Pharm, Bethesda, MD 20892 USA. RP Calis, KA (reprint author), NIH, Warren G Magnuson Clin Ctr, Drug Informat Serv, Dept Pharm, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD JAN 15 PY 2002 VL 59 IS 2 BP 198 EP 198 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 523CJ UT WOS:000173934000017 PM 11826574 ER PT J AU O'Leary, VB Parle-McDermott, A Molloy, AM Kirke, PN Johnson, Z Conley, M Scott, JM Mills, JL AF O'Leary, VB Parle-McDermott, A Molloy, AM Kirke, PN Johnson, Z Conley, M Scott, JM Mills, JL TI MTRR and MTHFR polymorphism: Link to Down syndrome? SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE methionine synthase reductase; methylenetetrahydrofolate reductase; Down syndrome; folate; MTRR A66G; MTHFR C677T mutation; trisomy 21 ID MATERNAL RISK-FACTORS; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; METHYLENETETRAHYDROFOLATE REDUCTASE; FOLATE METABOLISM; HOMOCYSTEINE; PLASMA; MUTATION; TRISOMY; VARIANT; HUMANS AB Polymorphisms in genes encoding the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase reductase (MTRR A66G) have been linked to the etiology of Down syndrome. We examined the prevalence of these variant genotypes in mothers who had given birth to a child with Down syndrome (n = 48) and in control mothers (n = 192), and investigated the biochemical factors influenced by the presence of MTRR A66G and MTHFR C677T. The frequency of the MTRR variant genotypes (AG, GG) was significantly higher in mothers of children with Down syndrome compared to controls (P = 0.0028). MTHFR C677T genotype frequencies were not significantly altered in mothers of children with Down syndrome (P = 0.74). However, mothers who had a MTHFR CT or TT genotype and a MTRR GG genotype had a 2.98-fold increased risk of having a child with Down syndrome (P = 0.02). The MTRR polymorphism did not increase plasma homocysteine. Higher homocysteine was found with the presence of the MTHFR T allele. In conclusion, MTRR A66G is significantly more common in mothers of children with Down syndrome but does not appear to increase the risk for Down syndrome by changing homocysteine metabolism. Women who have both the MTRR and MTHFR variant genotypes are also at increased risk of producing offspring with Down syndrome. (C) 2001 Wiley-Liss, Inc. C1 Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. Hlth Res Board, Dublin, Ireland. NICHHD, Bethesda, MD 20892 USA. Eastern Hlth Board, Hlth Informat Unit, Dublin, Ireland. RP Scott, JM (reprint author), Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. NR 14 TC 113 Z9 119 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JAN 15 PY 2002 VL 107 IS 2 BP 151 EP 155 DI 10.1002/ajmg.10121 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 508NZ UT WOS:000173096500012 PM 11807890 ER PT J AU Zeldin, DC AF Zeldin, DC TI The 5-lipoxygenase pathway - A new therapeutic target for the treatment of pulmonary fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID LUNG FIBROBLASTS; DEFICIENT MICE C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 12 TC 7 Z9 7 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2002 VL 165 IS 2 BP 146 EP 147 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 512XZ UT WOS:000173350000002 PM 11790644 ER PT J AU Parlato, R Rosica, A Cuccurullo, V Mansi, L Macchia, P Owens, JD Mushinski, JF De Felice, M Bonner, RF Di Lauro, R AF Parlato, R Rosica, A Cuccurullo, V Mansi, L Macchia, P Owens, JD Mushinski, JF De Felice, M Bonner, RF Di Lauro, R TI A preservation method that allows recovery of intact RNA from tissues dissected by laser capture microdissection SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID AMPLIFICATION; EXTRACTION; FIXATION; GENE; PCR AB We report a novel method for preparing samples for laser capture microdissection. The procedure described here permits extraction of intact RNA while preserving morphology, thus being suitable both for identification of specific cells and for analysis of their gene expression. The method is applicable to both mouse embryos and human tumors and may improve the preparation of cDNA libraries from specific cell types without interfering with histological diagnosis. (C) 2001 Elsevier Science. C1 Staz Zool Anton Dohrn, I-80121 Naples, Italy. Univ Naples Federico 2, Sch Med 2, Inst Radiol Sci & Nucl Med, I-80131 Naples, Italy. NCI, Genet Lab, Mol Genet Sect, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, Sect Med Biophys, Bethesda, MD 20892 USA. RP Parlato, R (reprint author), Staz Zool Anton Dohrn, Villa Comunale, I-80121 Naples, Italy. RI Macchia, Paolo Emidio/B-7391-2012; Di Lauro, Roberto/A-2746-2012; Bonner, Robert/C-6783-2015; Parlato, Rosanna/G-8768-2015; OI Macchia, Paolo Emidio/0000-0001-6503-6942; Di Lauro, Roberto/0000-0001-9493-3036; CUCCURULLO, Vincenzo/0000-0003-0474-7163; mansi, luigi/0000-0001-8258-5134; Parlato, Rosanna/0000-0001-6682-9645 NR 8 TC 27 Z9 40 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JAN 15 PY 2002 VL 300 IS 2 BP 139 EP 145 DI 10.1006/abio.2001.5463 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 513GZ UT WOS:000173371000005 PM 11779104 ER PT J AU Yang, FQ Ito, Y AF Yang, FQ Ito, Y TI Method for the fractionation of dextran by centrifugal precipitation chromatography SO ANALYTICAL CHEMISTRY LA English DT Article ID SIZE-EXCLUSION CHROMATOGRAPHY; AMMONIUM-SULFATE; SEPARATION MEDIUM; MONOLITHIC ROD; POLY(STYRENE-CO-DIVINYLBENZENE); PROTEINS; POLYMERS AB Recent advances in biotechnology and biochemistry have been facilitated by efficient separation methods for biopolymers, such as proteins and nucleic acids. On the other hand, research on polysaccharides is hindered by problems in their fractionation. For many decades, polysaccharides have been fractionated by stepwise ethanol precipitation, and even at the present time, almost all of their purification protocols include at least one such step, although it is tedious and inefficient. This paper describes a novel approach for chromatographic fractionation of polysaccharides by ethanol gradient precipitation using an open column under a centrifugal force field. Using a unique column design, chromatographic separation of polymers is achieved by subjecting the sample to a repetitive process of precipitation and dissolution along a long, spiral channel. In this article, we fully describe the principle, design of the prototype, and basic studies on various parameters for optimization of chromatographic conditions, using dextran as an example. C1 NHLBI, NIH, Biophys Chem Lab, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, NIH, Biophys Chem Lab, Room 3334,Bldg 50,50 S Dr MSC 8014, Bethesda, MD 20892 USA. NR 13 TC 12 Z9 12 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JAN 15 PY 2002 VL 74 IS 2 BP 440 EP 445 DI 10.1021/ac010948r PG 6 WC Chemistry, Analytical SC Chemistry GA 511XH UT WOS:000173290500018 PM 11811420 ER PT J AU Catlett, JP Alving, BM AF Catlett, JP Alving, BM TI Update in hematology SO ANNALS OF INTERNAL MEDICINE LA English DT Review C1 Washington Hosp Ctr, Hematol Oncol Sect, Washington, DC 20010 USA. NIH, Bethesda, MD USA. RP Catlett, JP (reprint author), Washington Hosp Ctr, Hematol Oncol Sect, 110 Irving St NW, Washington, DC 20010 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 15 PY 2002 VL 136 IS 2 BP 136 EP 143 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 512PZ UT WOS:000173333900006 PM 11790066 ER PT J AU Moss, J Vaughan, M AF Moss, J Vaughan, M TI Cytohesin-1 in 2001 SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review ID GUANINE-NUCLEOTIDE-EXCHANGE; ADP-RIBOSYLATION FACTOR; PLECKSTRIN-HOMOLOGY DOMAINS; YEAST GOLGI-APPARATUS; FACTOR SEC7 DOMAIN; BREFELDIN-A; PLASMA-MEMBRANE; PHOSPHATIDYLINOSITOL 3-KINASE; PH DOMAIN; PROTEIN C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Room 5N-307,Bldg 10,10 Ctr Dr MSC 1434, Bethesda, MD 20892 USA. NR 48 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 156 EP 161 DI 10.1006/abbi.2001.2661 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700004 PM 11795866 ER PT J AU Maurizi, MR Rasulova, F AF Maurizi, MR Rasulova, F TI Degradation of L-glutamate dehydrogenase from Escherichia coli: Allosteric regulation of enzyme stability SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE protein degradation; ATP-dependent protease; stationary phase; glutamate dehydrogenase; NADPH; allostery; ppGpp; stringent response ID SELF-COMPARTMENTALIZING PROTEASES; PROTEIN-DEGRADATION; GUANOSINE TETRAPHOSPHATE; TAGGING SYSTEM; IN-VIVO; PATHWAY; RECOGNITION; SPECIFICITY; MECHANISM; INSIGHTS AB L-glutamate dehydrogenase (GDH) is stable in exponentially growing Escherichia coli cells but is degraded at a rate of 20-30% per hour in cells starved for either nitrogen or carbon. GDH degradation is energy-dependent, and mutations in ATP-dependent proteases, ClpAP or Lon lead to partial stabilization. Degradation is inhibited by chloramphenicol and is completely blocked in relA mutant cells, suggesting that ribosome-mediated signaling may facilitate GDH degradation. Purified GDH has a single tight site for NADPH binding. Binding of NADPH in the absence of other ligands leads to destabilization of the enzyme. NADPH-induced instability and sensitivity to proteolysis is reversed by tri- and dicarboxylic acids or nucleoside di- and triphosphates. GTP and ppGpp bind to GDH at an allosteric site and reverse the destabilizing effects of NADPH. Native GDH is resistant to degradation by several purified ATP-dependent proteases: ClpAP, ClpXP, Lon, and ClpYQ, but denatured GDH is degraded by ClpAP. Our results suggest that, in vivo, GDH is sensitized to proteases by loss of a stabilizing ligand or interaction with an destabilizing metabolite that accumulates in starving cells, and that any of several ATP-dependent proteases degrade the sensitized protein. (C) 2002 Elsevier Science. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [1F32GM06442] NR 41 TC 26 Z9 26 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 206 EP 216 DI 10.1006/abbi.2001.2703 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700011 PM 11795873 ER PT J AU Petrovics, G Bird, T Lehel, C Oravecz, T Anderson, WB AF Petrovics, G Bird, T Lehel, C Oravecz, T Anderson, WB TI Protein kinase C epsilon mediates PMA-induced growth inhibition of low population density NIH 3T3 fibroblasts SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE protein kinase C epsilon; phorbol ester; phorbol 12-myristate-13 acetate; growth inhibition ID CELL-CYCLE ARREST; SIGNAL-TRANSDUCTION; SUBCELLULAR-LOCALIZATION; GENE-EXPRESSION; PKC-EPSILON; ACTIVATION; DELTA; DIFFERENTIATION; P21(CIP1); PHOSPHORYLATION AB Phorbol 12-myristate-13-acetate (PMA), a potent tumor promoter and activator of most protein kinase C (PKC) isotypes, was found to significantly inhibit the growth of low population density (1-5% confluency) NTH 3T3 cells. Higher cell population density (above 10% confluency) provided protection from this growth inhibitory effect of PMA. PMA-induced growth arrest is accompanied by an elevation in the level of p21(Clp1) protein, along with cell cycle arrest at the G1/S transition. Activation of PKC is required for this growth inhibitory response since the pan PKC inhibitor GF109203 blocked this effect of PMA. However, the classical PKC inhibitor G66976 had no effect, strongly suggesting the involvement of novel PKC isotypes (delta and/or epsilon). Overexpression of PKCepsilon, but not PKCdelta, was found to potentiate PMA-induced growth inhibition. Overexpression of a kinase-inactive dominant-negative mutant of PKCepsilon (K437R) decreased the growth inhibitory effect of PMA and also blocked the PMA-induced increase in the level of p21(Clp1) protein. Taken together, these results indicate that PMA has a cell population density-dependent effect on the growth of NIH 3T3 cells and that the PMA growth inhibitory effect at low cell population density is mediated through activation of PKCepsilon. (C) 2001 Elsevier Science. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Anderson, WB (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Room 3E08,37 Convent Dr, Bethesda, MD 20892 USA. NR 40 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 217 EP 223 DI 10.1006/abbi.2001.2640 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700012 PM 11795874 ER PT J AU Senturker, S Tschirret-Guth, R Morrow, J Levine, R Shacter, E AF Senturker, S Tschirret-Guth, R Morrow, J Levine, R Shacter, E TI Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE oxidants; apoptosis; cancer; chemotherapy ID MYELOBLASTIC-LEUKEMIA CELLS; AMINO-ACID-RESIDUES; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; CISPLATIN CYTOTOXICITY; SUPEROXIDE-DISMUTASE; THYMOCYTE APOPTOSIS; CANCER-CHEMOTHERAPY; LIPID-PEROXIDATION; CATALASE ACTIVITY AB Studies in a variety of cell types have suggested that cancer chemotherapy drugs induce tumor cell apoptosis in part by inducing formation of reactive oxygen species (ROS). Using human B lymphoma cells as the targets, we have found that apoptosis can be induced in the absence of any detectable oxidative stress. Apoptosis was induced with the chemotherapy drugs VP-16 and cisplatin. To determine whether oxidants are formed as part of the drug-induced apoptotic process, intracellular markers of oxidative stress were examined. These included measurement of (1) protein carbonyl groups by Western blot immunoassay, (2) protein methionine sulfoxide residues by amino acid analysis, (3) protein sulfhydryl oxidation by Western blot immunoassay, (4) F2-isoprostanes by GC/MS, and (5) intracellular ROS production using the oxidant-sensitive dyes DCFDA and dihydrorhodamine 123. Apoptosis was quantified using fluorescence microscopy to assess nuclear morphology. The results show that VP-16 and cisplatin induce extensive apoptosis in the absence of any detectable protein or lipid oxidation, measured in both the cytosolic and mitochondrial compartments of the cell. In contrast, 112021 which kills the cells by nonapoptotic pathways, caused increases in both protein and lipid oxidation. Three different antioxidant compounds (N-acetyl cysteine, Tempol, and MnTBAP) failed to inhibit VP-16-induced apoptosis, while inhibiting H2O2-induced cell death. Only N-acetyl cysteine inhibited cisplatin-induced cell death and this is attributed to its known ability to react directly with and inactivate cisplatin before it enters the cell. The results demonstrate that, at least in B lymphoma cells, chemotherapy-induced apoptosis occurs using a mechanism that does not involve oxidants. (C) 2002 Elsevier Science. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Immunol Lab, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20814 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA. RP Shacter, E (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Immunol Lab, Bethesda, MD 20892 USA. NR 59 TC 43 Z9 51 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 262 EP 272 DI 10.1006/abbi.2001.2681 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700019 PM 11795881 ER PT J AU Ginsburg, A Peterkofsky, A AF Ginsburg, A Peterkofsky, A TI Enzyme I: The gateway to the bacterial phosphoenolpyruvate: Sugar phosphotransferase system SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE enzyme I of the bacterial phosphoenol-pyruvate : sugar; phosphotransferase system (PTS); phosphorylation; dimerization; domain interactions; active-site mutations; thermal unfolding; stability; differential scanning calorimetry; isothermal titration calorimetry; sedimentation equilibrium; analytical ultracentrifugation; tryptophan fluorescence; circular dichroism ID ESCHERICHIA-COLI PHOSPHOENOLPYRUVATE; N-TERMINAL DOMAIN; RESTRAINED MOLECULAR-DYNAMICS; SALMONELLA-TYPHIMURIUM; PHOSPHORYL TRANSFER; TRANSPORT; HPR; COMPLEX; EXPRESSION; HISTIDINE AB Regulatory aspects of the bacterial phosphoenolpyruvate (PEP):sugar phosphotransferase system (PTS) are reviewed. The structure and conformational stability of the first protein (enzyme I) of the PTS, as well as the requirement for enzyme I to dimerize for autophosphorylation by PEP in the presence of MgCl2 are discussed. (C) 2001 Elsevier Science. C1 NHLBI, Biochem Lab, Sect Prot Chem, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ginsburg, A (reprint author), NHLBI, Biochem Lab, Sect Prot Chem, NIH, Bldg 50,Room 2339,MSC-8012, Bethesda, MD 20892 USA. NR 38 TC 28 Z9 29 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 273 EP 278 DI 10.1006/abbi.2001.2603 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700020 PM 11795882 ER PT J AU Colvis, C Garland, D AF Colvis, C Garland, D TI Posttranslational modification of human alpha A-crystallin: Correlation with electrophoretic migration SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE alpha crystallin; human; lens; posttranslational modification; mass spectrometry; 2D electrophoresis ID HUMAN LENS CRYSTALLINS; CLEAVAGE SITES; AMINO-ACID; DEGRADATION; DEAMIDATION; PROTEIN; AGE; IDENTIFICATION; METHIONINE; OXIDATION AB alphaA-crystallin is a major protein component of the human lens. It is known to undergo posttranslational modification. This study was done to further elucidate the temporal and spatial nature of these posttranslational modifications and to correlate the modified forms with electrophoretic migration. We dissected normal human lenses into concentric shells of fiber cells, separated the proteins by two-dimensional electrophoresis, and identified modified forms by mass spectrometry. We found that alphaA-crystallin migrated as a major spot and in over 20 additional protein spots. The extent of modification correlated with the age of the fiber cells and the depth within a lens. A correlation was also seen between these parameters and the concentration of modified forms that had full-length sequences but migrated at more acidic positions. These proteins were phosphorylated, acetylated, and/or deamidated. A few proteins migrated to a more basic position than the major form of aA-crystallin. The locations of several species that were truncated after C-terminal residues Ser172 and Ser162 were identified. Each of these species had intact N termini. The similarity of the C-terminal cleavage sites found in alphaA- and alphaB-crystallins was noted. (C) 2002 Elsevier Science. C1 NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. RP Garland, D (reprint author), NEI, Lab Mechanisms Ocular Dis, Bethesda, MD 20892 USA. NR 22 TC 32 Z9 34 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 319 EP 323 DI 10.1006/abbi.2001.2669 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700027 PM 11795889 ER PT J AU Moskovitz, J Yim, MB Chock, PB AF Moskovitz, J Yim, MB Chock, PB TI Free radicals and disease SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; METHIONINE SULFOXIDE REDUCTASE; CU,ZN SUPEROXIDE-DISMUTASE; METAL-CATALYZED OXIDATION; AGE-RELATED-CHANGES; HYDROGEN-PEROXIDE; PROTEIN OXIDATION; ALZHEIMERS-DISEASE; K-M; GENE AB Free radicals and reactive oxygen species (ROS) have been associated with the etiology and/or progression of a number of diseases and in aging. Many of the proteins oxidatively modified by free radicals contain side-chain carbonyl derivatives, which can be used as markers for protein oxidation. The protein carbonyl content has been quantitated as a function of age for human cultured dermal fibroblasts, lens, and brain tissue. These data were analyzed using a simple autocatalytic model with the assumption that free radicals randomly oxidize proteins or peptides to form carbonyl derivatives and lead to their inactivation. The carbonylated proteins and peptides are highly susceptible to proteolytic degradation. Implication of free radicals in aging and in age-dependent susceptibility to neurodegenerative diseases will be discussed in light of this simplified kinetic model. (C) 2002 Elsevier Science. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Chock, PB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. EM pbc@helix.nih.gov NR 57 TC 198 Z9 215 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 354 EP 359 DI 10.1006/abbi.2001.2692 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700032 PM 11795894 ER PT J AU Kim, JR Kwon, KS Yoon, HW Lee, SR Rhee, SG AF Kim, JR Kwon, KS Yoon, HW Lee, SR Rhee, SG TI Oxidation of proteinaceous cysteine residues by dopamine-derived H2O2 in PC12 cells SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE dopamine toxicity; hydrogen peroxide; cysteine oxidation; Parkinson's disease ID PHOSPHOLIPASE-C ISOZYMES; THIOREDOXIN REDUCTASE; PARKINSONS-DISEASE; HYDROGEN-PEROXIDE; SUBSTANTIA-NIGRA; MAMMALIAN THIOREDOXIN; DISULFIDE-ISOMERASE; ALPHA-SYNUCLEIN; GROWTH-FACTOR; LEWY BODIES AB Cellular metabolism of dopamine (DA) generates H2O2, which is further reduced to hydroxyl radicals in the presence of iron. Cellular damage inflicted by DA-derived hydroxyl radicals is thought to contribute to Parkinson's disease. We have previously developed procedures for detecting proteins that contain H2O2-sensitive cysteine (or selenocysteine) residues. Using these procedures, we identified ERP72 and ERP60, two members of the protein disulfide isomerase family, creatine kinase, glyceraldehyde-3-phosphate dehydrogenase, phospholipase C-gamma1, and thioredoxin reductase as the targets of DA-derived H2O2. Experiments with purified enzymes identified the essential Cys residues of creatine kinase and glyceraldehyde-3-phosphate dehydrogenase, that are specifically oxidized by H2O2. Although the identified proteins represent only a fraction of the targets of DA-derived H2O2, functional impairment of these proteins has previously been associated with cell death. The oxidation of proteins that contain reactive Cys residues by DA-derived H2O2 is therefore proposed both to be largely responsible for DA-induced apoptosis in neuronal cells and to play an important role in the pathogenesis of Parkinson's disease. (C) 2002 Elsevier Science. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Korea Res Inst Biosci & Biotechnol, Taejon 305606, South Korea. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 59 TC 28 Z9 31 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 414 EP 423 DI 10.1006/abbi.2001.2691 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700040 PM 11795902 ER PT J AU Richert, S Wehr, NB Stadtman, ER Levine, RL AF Richert, S Wehr, NB Stadtman, ER Levine, RL TI Assessment of skin carbonyl content as a noninvasive measure of biological age SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE aging; protein carbonyl; skin; protein oxidation ID OXIDATIVELY MODIFIED PROTEINS; QUANTITATION AB The oxidative modification of proteins by reactive species, especially reactive oxygen species, is implicated in the etiology or progression of a panoply of disorders and diseases. For the most part, oxidatively modified proteins are not repaired and must be removed by proteolytic degradation. The level of these modified molecules can be quantitated by measurement of the protein carbonyl content, which has been shown to increase in a variety of diseases and processes, most notably during aging. However, these studies have required invasive techniques to obtain cells for analysis. We examined the possibility that desquamating skin cells (corneocytes) would also show an age-related increase in protein carbonyl content, thus providing a noninvasive method for assessing biological age. This was not the case, as we found no age-dependent relationship in the protein carbonyl content of skin cells from volunteers aged 20 to 79 years. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 9 TC 24 Z9 27 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 430 EP 432 DI 10.1006/abbi.2001.2683 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700042 PM 11795904 ER PT J AU Horecker, BL AF Horecker, BL TI Personal notes - Earl R. Stadtman SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Biographical-Item C1 NCI, NIH, Bethesda, MD 20892 USA. RP Horecker, BL (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 448 EP 448 DI 10.1006/abbi.2001.2644 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700045 ER PT J AU Pastan, IH AF Pastan, IH TI Personal notes - Earl R. Stadtman SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Biographical-Item C1 NCI, NIH, Bethesda, MD 20892 USA. RP Pastan, IH (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 449 EP 450 DI 10.1006/abbi.2001.2645 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700048 ER PT J AU Lenfant, C AF Lenfant, C TI Personal notes - Earl R. Stadtman SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Biographical-Item C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2002 VL 397 IS 2 BP 450 EP 450 DI 10.1006/abbi.2001.2643 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 517LH UT WOS:000173611700049 ER PT J AU Liu, Y Graham, C Li, AQ Fisher, RJ Shaw, S AF Liu, Y Graham, C Li, AQ Fisher, RJ Shaw, S TI Phosphorylation of the protein kinase C-theta activation loop and hydrophobic motif regulates its kinase activity, but only activation loop phosphorylation is critical to in vivo nuclear-factor-kappa B induction SO BIOCHEMICAL JOURNAL LA English DT Article DE novel isoform; PKC; T-lymphocytes; turn motif ID ENZYMATIC-ACTIVITY; CATALYTIC SUBUNIT; AUTOPHOSPHORYLATION; DELTA; SITE; IDENTIFICATION; MEMBRANE; ALPHA; PKA AB Protein kinase C (PKC)-theta, a member of the 'novel' subfamily of PKC isoforms, is of singular importance in transducing signals in T-lymphocytes. Since understanding of regulatory phosphorylation of novel PKCs is fragmentary and inconsistent with findings for 'classical' PKC isoforms, we investigated three potential phosphorylation sites on PKC-theta; in the activation loop (Thr(538)), turn motif (Ser(676)) and hydrophobic motif (Ser(695)). Combined evidence from phospho-specific antisera and MS demonstrates phosphorylation at all three sites. Unlike its closest paralogue, PKC-delta, lack of negative charge in the activation loop of PKC-theta results in a profound catalytic defect (> 100-fold reduction in the T538A mutant); the high sequence similarity between PKC-theta and -delta assists in the formulation of structural hypotheses to account for this major difference. In contrast with mechanisms proposed for other PKC isoforms, phosphorylation at the other two sites does not reconstitute catalytic activity. Activation loop phosphorylation is critical in vivo, since the T538A mutant completely lost its capacity to mediate T-cell receptor-stimulation of nuclear factor kappaB (NF-kappaB) activation in Jurkat T-cells. Hydrophobic motif phosphorylation also substantially influences PKC-theta catalytic activity (5-fold reduction in the S695A mutant), but does not impair NF-kappaB activation in Jurkat T-cells. Its mechanism is independent of secondary effects on activation loop phosphorylation and cannot be explained by thermal instability. Turn motif phosphorylation has a limited effect on kinase activity, but negatively regulates other aspects of PKC-theta function, since the S676A mutant is more efficient than wild-type in inducing NF-kappaB activation in Jurkat T-cells. These findings expand our understanding of the roles of phosphorylation in novel PKCs, and indicate that PKC-theta is a constitutively competent kinase as a consequence of constitutive phosphorylation of its activation loop. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RI Fisher, Robert/B-1431-2009 NR 32 TC 86 Z9 90 U1 0 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2002 VL 361 BP 255 EP 265 PN 2 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 523XJ UT WOS:000173982600008 PM 11772397 ER PT J AU Keskin, O Bahar, I Flatow, D Covell, DG Jernigan, RL AF Keskin, O Bahar, I Flatow, D Covell, DG Jernigan, RL TI Molecular mechanisms of chaperonin GroEL-GroES function SO BIOCHEMISTRY LA English DT Article ID ALLOSTERIC MECHANISM; DOMAIN MOTIONS; SUBSTRATE-BINDING; PROTEIN DYNAMICS; CRYSTAL-STRUCTURE; INTERMEDIATE; MODEL; LYSOZYME; RELEASE; CAVITY AB The dynamics of the GroEL-GroES complex is investigated with a coarse-grained model. This model is one in which single-residue points are connected to other such points, which are nearby, by identical springs, forming a network of interactions. The nature of the most important (slowest) normal modes reveals a wide variety of motions uniquely dependent upon the central cavity of the structure, including opposed torsional rotation of the two GroEL rings accompanied by the alternating compression and expansion of the GroES cap binding region, bending, shear, opposed radial breathing of the cis and trans rings, and stretching and contraction along the protein assembly's long axis. The intermediate domains of the subunits are bifunctional due to the presence of two hinges, which are alternatively activated or frozen by an ATP-dependent mechanism. ATP binding stabilizes a relatively open conformation (with respect to the central cavity) and hinders the motion of the hinge site connecting the intermediate and equatorial domains, while enhancing the flexibility of the second hinge that sets in motion the apical domains. The relative flexibilities of the hinges are reversed in the nucleotide-free form. Cooperative cross-correlations between subunits provide information about the mechanism of action of the protein. The mechanical motions driven by the different modes provide variable binding surfaces and variable sized cavities in the interior to enable accommodation of a broad range of protein substrates. These modes of motion could be used to manipulate the substrate's conformations. C1 Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. NCI, Mol Struct Sect, Lab Expt & Computat Biol, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Computat Technol Lab, Screening Technol Branch, Dev Therapeut Program,NIH, Frederick, MD 21702 USA. RP Bahar, I (reprint author), Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Suite 601,L Kaufmann Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. RI Jernigan, Robert/A-5421-2012 NR 51 TC 109 Z9 115 U1 1 U2 10 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 15 PY 2002 VL 41 IS 2 BP 491 EP 501 DI 10.1021/bi011393x PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510PP UT WOS:000173216700007 PM 11781087 ER PT J AU Dunbar, C AF Dunbar, C TI Lentiviruses get specific SO BLOOD LA English DT Editorial Material C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dunbar, C (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 397 EP 397 DI 10.1182/blood.V99.2.397 PG 1 WC Hematology SC Hematology GA 510PF UT WOS:000173215900001 ER PT J AU Lyakh, LA Koski, GK Young, HA Spence, SE Cohen, PA Rice, NR AF Lyakh, LA Koski, GK Young, HA Spence, SE Cohen, PA Rice, NR TI Adenovirus type 5 vectors induce dendritic cell differentiation in human CD14(+) monocytes cultured under serum-free conditions SO BLOOD LA English DT Article ID NF-KAPPA-B; VIRAL GENE-EXPRESSION; NECROSIS-FACTOR-ALPHA; RECOMBINANT ADENOVIRUS; CALCIUM IONOPHORE; TRANSCRIPTION FACTORS; SIGNALING PATHWAYS; BLOOD MONOCYTES; IN-VITRO; MATURATION AB To determine whether Infection by a model virus Is capable of Initiating dendritic call (DC) differentiation, human CD14(+) peripheral blood monocytes were Infected with replication-defective type 5 adenovirus. Under serum-free conditions, this resulted In differentiation of a majority of cells toward a DC phenotype within 36 to 48 hours, without the need for cytokine-induced predifferentiation. Infection Induced DC morphology and altered the expression of surface markers, Including loss of CD14, de novo Induction of CD83 and CD25, and strongly augmented expression of CD86, CD80, CD40, and HLA-DR and HLA class I molecules. Differentiated cells maintained immunophanotype without loss of viability for at least 2 days after removal of the differentiation agent and cytokines. A greatly enhanced capacity to stimulate T-lymphocyte alloproliferation and increased expression of the DC-associated transcription factor RelB were observed. Virus without transgene was found to Induce changes similar to transgene-expressing viruses. RelB up-regulation and DC immunophenotype were sensitive to the antioxidant N-acetylcysteine, suggesting a critical role for nuclear factor kappaB. RNAse protection assays revealed elevated levels of messenger RNA for a number of chemokines and cytokines associated with DCs. Finally, during differentiation, adenovirus-infected monocytes were shown to secrete chemokines and cytokines, including tumor necrosis factor-alpha (TNF-alpha). Furthermore, a TNF-alpha-neutralizing antibody Inhibited the expression of some DC surface markers, Indicating a contributing role for this cytokine In the adenovirus-induced differentiation of DC from monocytes. These findings have Implications for the biology of monocytes as precursors to DCs and also for the use of recombinant adenovirus In vaccines or gene therapy. (Blood. 2002;99:600-608) (C) 2002 by The American Society of Hematology. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Cleveland Clin Fdn, Surg Res Ctr, Cleveland, OH USA. RP Rice, NR (reprint author), NCI, Regulat Cell Growth Lab, POB B, Frederick, MD 21702 USA. NR 54 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 600 EP 608 DI 10.1182/blood.V99.2.600 PG 9 WC Hematology SC Hematology GA 510PF UT WOS:000173215900028 PM 11781244 ER PT J AU Mow, BMF Chandra, J Svingen, PA Hallgren, CG Weisberg, E Kottke, TJ Narayanan, VL Litzow, MR Griffin, JD Sausville, EA Tefferi, A Kaufmann, SH AF Mow, BMF Chandra, J Svingen, PA Hallgren, CG Weisberg, E Kottke, TJ Narayanan, VL Litzow, MR Griffin, JD Sausville, EA Tefferi, A Kaufmann, SH TI Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro SO BLOOD LA English DT Article ID ABL TYROSINE KINASE; CHRONIC MYELOID-LEUKEMIA; DNA-BINDING ACTIVITY; BCR-ABL; SIGNAL-TRANSDUCTION; POSITIVE CELLS; IN-VITRO; C-KIT; APOPTOSIS; RESISTANCE AB The adenosine triphosphate binding-site-directed agent STI571 and the tyrphostin adaphostin are undergoing evaluation as bcr/abl kinase inhibitors. The current study compared the effects of these agents on the survival of K562 cells, bcr/abl-transduced FDC-P1 cells, and myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared with healthy donors. Treatment of K562 cells with 10 muM adaphostin resulted in decreased p210(bcr/abl) polypeptide levels in the first 6 hours, followed by caspase activation and accumulation of apoptotic cells in less than 12 hours. By 24 hours, 90% of the cells were apoptotic and unable to form colonies. In contrast, 20 muM STI571 caused rapid inhibition of bcr/abl autophosphorylation without p210(bcr/abl) degradation. Although this was followed by the inhibition of Stat5 phosphorylation and the down-regulation of BCI-x(L) and Mcl-1, only 7%+/-3% and 25%+/-9% of cells were apoptotic at 16 and 24 hours, respectively. Instead, the cytotoxic effects of STI571 became more pronounced with prolonged exposure, with IC90 values greater than 20 muM and 1.0+/-0.6 muM after 24 and 48 hours, respectively. Consistent with these results, 24-hour adaphostin exposure inhibited CML granulocyte colony-forming units (CFU-G) (median IC50,12 muM) but not normal CFU-G (median IC50, greater than 20 muM), whereas 24-hour STI571 treatment had no effect on CML or normal CFU-G. Additional experiments revealed that STI571-resistant K562 cells remained sensitive to adaphostin. Moreover, the combination of STI571 + adaphostin Induced more cytotoxicity In K562 cells and In CML CFU-G than either agent alone did. Collectively, these results Identify adaphostin as a mechanistically distinct CML-selective agent that retains activity In STI571-resistant cell lines. (Blood. 2002;99:664-671) (C) 2002 by The American Society of Hematology. C1 Mayo Clin, Dept Oncol, Div Oncol Res, Rochester, MN 55901 USA. Mayo Clin, Dept Internal Med, Div Hematol, Rochester, MN 55901 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kaufmann, SH (reprint author), Mayo Clin, Dept Oncol, Div Oncol Res, Guggenheim 1301,200 1st St SW, Rochester, MN 55901 USA. FU NCI NIH HHS [R01 CA85972, R01 CA69008, T32 CA09441] NR 57 TC 95 Z9 98 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 664 EP 671 DI 10.1182/blood.V99.2.664 PG 8 WC Hematology SC Hematology GA 510PF UT WOS:000173215900036 PM 11781252 ER PT J AU Harty, LC Lin, AY Goldstein, AM Jaffe, ES Carrington, M Tucker, MA Modi, WS AF Harty, LC Lin, AY Goldstein, AM Jaffe, ES Carrington, M Tucker, MA Modi, WS TI HLA-DR, HLA-DQ, and TAP genes in familial Hodgkin disease SO BLOOD LA English DT Article ID EPSTEIN-BARR-VIRUS; CLASS-II REGION; LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY; CONCORDANCE; SEQUENCE; ALLELES AB The HLA region has long been implicated in sporadic and familial Hodgkin disease (HD), with recent case-control studies suggesting that HLA class 11 loci predispose to sporadic nodular sclerosis HD (NSHD). To determine whether this predisposition extends to familial HD, HLA class II loci (DRB1, DQA1, DQB1, DRB3, DRB4, and DRB5) and transporter associated with antigen processing (TAP) loci (TAP1, TAP2) were investigated In 100 members of 16 families with at least 2 confirmed cases of HD. With the use of the transmission disequilibrium test, evidence for linkage disequilibrium with familial HD and, in particular, familial NSHD was obtained for the DRB1*15011-DQA1*0112-DQB1*0602 haplotype, the TAP1 allele encoding IIe at residue 333, and the DRB5-0101 allele. These 3 markers were In linkage disequilibrium and may not represent Independent susceptibility regions. Use of a family-based approach excludes population stratification as an explanation for these findings. (Blood. 2002; 99:690-693) (C) 2002 by The American Society of Hematology. C1 NCI, Genet Epidemiol Branch, DCEG, NIH,EPS MSC 7236, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21701 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Santa Clara Valley Med Ctr, Div Hematol Oncol, San Jose, CA 95128 USA. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, DCEG, NIH,EPS MSC 7236, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 FU NCI NIH HHS [N01-CO-56000] NR 23 TC 37 Z9 38 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 690 EP 693 DI 10.1182/blood.V99.2.690 PG 4 WC Hematology SC Hematology GA 510PF UT WOS:000173215900039 PM 11781255 ER PT J AU Kang, EM de Witte, M Malech, H Morgan, RA Phang, S Carter, C Leitman, SF Childs, R Barrett, AJ Little, R Tisdale, JF AF Kang, EM de Witte, M Malech, H Morgan, RA Phang, S Carter, C Leitman, SF Childs, R Barrett, AJ Little, R Tisdale, JF TI Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; CHRONIC MYELOGENOUS LEUKEMIA; FIBRONECTIN FRAGMENT CH-296; GRAFT-VERSUS-LEUKEMIA; NON-HODGKINS-LYMPHOMA; GENE-TRANSFER; REPOPULATING CELLS; HIV-INFECTION; ENGRAFTMENT; DISEASE AB To assess the safety and efficacy of nonmyeloablative allogeneic transplantation in patients with HIV infection, a clinical protocol was initiated in patients with refractory hematologic malignancies and concomitant HIV infection. The results from the first 2 patients are reported. The indications for transplantation were treatment-related acute myelogenous leukemia and primary refractory Hodgkin disease in patients 1 and 2, respectively. Only patient 1 received genetically modified cells. Both patients tolerated the procedure well with minimal toxicity, and complete remissions were achieved In both patients, but patient 2 died of relapsed Hodgkin disease 12 months after transplantation. Patient 1 continues in complete remission with undetectable HIV levels and rising CD4 counts, and with both the therapeutic and control gene transfer vectors remaining detectable at low levels more than 2 years after transplantation. These results suggest that nonmyeloablative allogeneic transplantation in the context of highly active antiretroviral therapy Is feasible In patients with treatment-sensitive HIV Infection. (Blood. 2002;99:698-701) (C) 2002 by The American Society of Hematology. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NIH, Dept Nursing, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Rm 9N116,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 29 TC 52 Z9 57 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2002 VL 99 IS 2 BP 698 EP 701 DI 10.1182/blood.V99.2.698 PG 4 WC Hematology SC Hematology GA 510PF UT WOS:000173215900041 PM 11781257 ER PT J AU Wu, WC Wang, Y Kao, LS Tang, FI Chai, CY AF Wu, WC Wang, Y Kao, LS Tang, FI Chai, CY TI Nitric oxide reduces blood pressure in the nucleus tractus solitarius: A real time electrochemical study SO BRAIN RESEARCH BULLETIN LA English DT Article DE nucleus tractus solitarius; nitric oxide; L-arginine; L-NAME; methylene blue; ODQ; hemoglobin ID SYMPATHETIC-NERVE ACTIVITY; BRAIN-STEM; L-ARGININE; VENTROLATERAL MEDULLA; CEREBRAL-CORTEX; NMDA RECEPTOR; RATS; SYNTHASE; NEURONS; SYSTEM AB Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N-G-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure. (C) 2002 Elsevier Science Inc. C1 Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan. Natl Yang Ming Univ, Taipei 112, Taiwan. NIDA, Baltimore, MD USA. RP Chai, CY (reprint author), Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan. NR 30 TC 27 Z9 31 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 15 PY 2002 VL 57 IS 2 BP 171 EP 177 AR PII S0361-9230(01)00737-7 DI 10.1016/S0361-9230(01)00737-7 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 522XY UT WOS:000173923300005 PM 11849823 ER PT J AU Bosetti, F Seemann, R Bell, JM Zahorchak, R Friedman, E Rapoport, SI Manickam, P AF Bosetti, F Seemann, R Bell, JM Zahorchak, R Friedman, E Rapoport, SI Manickam, P TI Analysis of gene expression with cDNA microarrays in rat brain after 7 and 42 days of oral lithium administration SO BRAIN RESEARCH BULLETIN LA English DT Article DE bipolar disorder; mood stabilizer; subacute; chronic ID INOSITOL-POLYPHOSPHATE 1-PHOSPHATASE; BIPOLAR AFFECTIVE-DISORDER; MANIC-DEPRESSIVE ILLNESS; CEREBRAL-CORTEX; ALPHA-SUBUNIT; G-PROTEINS; IN-VIVO; CELLS; ACTIVATION; MECHANISM AB The gene expression profile in rat brain was examined using microarrays in rats fed lithium chloride for 7 days (subacute) or 42 days (chronic). Brain lithium concentrations were 0.39 mM and 0.79 mM (therapeutically relevant), at 7 and 42 days, respectively. Of the 4132 genes represented in the microarrays, 25 genes were downregulated by at least twofold and none was upregulated after 7 days of treatment. Expression of 50 genes was downregulated by at least two-fold at 42 days, without any being upregulated. Lithium treatment for 7 days did not affect at a measurable extent expression of 37 of the 50 genes that were downregulated at 42 days. Genes whose expression was changed at 42 days coded for a number of receptors, protein kinases, transcription and translation factors, markers of energy metabolism, and signal transduction. Thus, chronic lithium at a therapeutically relevant concentration reduced expression of a large number of genes involved in multiple signaling and other pathways, without increasing expression at a comparable extent. (C) 2002 Elsevier Science. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Res Genet Inc, Huntsville, AL 35801 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 6N202, Bethesda, MD 20892 USA. NR 40 TC 57 Z9 57 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 15 PY 2002 VL 57 IS 2 BP 205 EP 209 AR PII S0361-9230(01)00744-4 DI 10.1016/S0361-9230(01)00744-4 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 522XY UT WOS:000173923300009 PM 11849827 ER PT J AU Jiang, Y Luo, YJ Parasuraman, R AF Jiang, Y Luo, YJ Parasuraman, R TI Neural correlates of perceptual priming of visual motion SO BRAIN RESEARCH BULLETIN LA English DT Article DE perceptual priming; visual motion; brain imaging; ERP; fMRI ID APPARENT MOTION; POTENTIALS; MECHANISMS; BRAIN; RESPONSES; INERTIA; SIGNALS; MEMORY; TIME; FMRI AB In two experiments, the temporal dynamics of neural activity underlying perceptual priming of visual motion was examined using event-related potentials (ERPs) during directional judgments of the apparent motion of two-dimensional sine-wave gratings. Compared to perceptually ambiguous motion, unambiguous left- or rightward motion was associated with enhanced ERP activity about 300 ms after the onset of apparent motion. In the second experiment, ERPs were recorded to two successive motion jumps in which an unambiguous motion jump served as a prime for a subsequent target motion that was ambiguous. The prime-target time interval was varied between 200, 400, and 1000 ms. In a control (motion reversal) condition, the two motion jumps were both unambiguous but in opposite directions. Compared to the motion reversal condition, motion priming was associated with an enhancement of ERP amplitudes at 100 ms and 350 ms following target stimulus onset. ERP enhancement was greatest at a short prime-target interval of 200 ms, which was also associated behaviorally with the strongest priming. The ERP enhancement and behavioral priming were both eliminated at the long 1000 ms prime-target interval. Functional magnetic resonance imaging (fMRI) data from a subset of subjects supported the view that motion priming involves modulation of neural responses both in early visual cortex and in later stages of visual processing. (C) 2002 Elsevier Science Inc. C1 Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Chinese Acad Sci, Inst Psychol, Beijing, Peoples R China. RP Jiang, Y (reprint author), Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. FU NIA NIH HHS [R01 AG007569, AG 00986, AG 07569, K01 AG000986] NR 28 TC 15 Z9 17 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 15 PY 2002 VL 57 IS 2 BP 211 EP 219 AR PII S0361-9230(01)00743-2 DI 10.1016/S0361-9230(01)00743-2 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 522XY UT WOS:000173923300010 PM 11849828 ER PT J AU Shojamanesh, H Gibril, F Louie, A Ojeaburu, JV Bashir, S Abou-Saif, A Jensen, RT AF Shojamanesh, H Gibril, F Louie, A Ojeaburu, JV Bashir, S Abou-Saif, A Jensen, RT TI Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma SO CANCER LA English DT Article DE pancreatic endocrine tumor; Zollinger-Ellison syndrome (ZES); somatostatin analogue; islet tumor; gastrinoma ID ZOLLINGER-ELLISON-SYNDROME; NEUROENDOCRINE GASTROINTESTINAL TUMORS; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; HEPATIC ARTERIAL CHEMOEMBOLIZATION; ISLET-CELL CARCINOMA; ANALOG SMS 201-995; ENDOCRINE TUMORS; LIVER METASTASES; GASTROENTEROPANCREATIC TUMORS; LANREOTIDE TREATMENT AB BACKGROUND. Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma. METHODS. Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 mug every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics. RESULTS. Tumors in 8 of the 15 patients studied (53%) responded at 3 months,with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0 +/- 6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide. CONCLUSIONS. Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival. (C) 2002 American Cancer Society. C1 NIDDK, DDB, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, DDB, NIH, Bldg 10,Rm 9C-103,10 Ctr Dr,MSC 1804, Bethesda, MD 20892 USA. NR 70 TC 119 Z9 124 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2002 VL 94 IS 2 BP 331 EP 343 DI 10.1002/cncr.10195 PG 13 WC Oncology SC Oncology GA 512CP UT WOS:000173303800007 PM 11900219 ER PT J AU Wood, BJ Ramkaransingh, JR Fojo, T Walther, MM Libutti, SK AF Wood, BJ Ramkaransingh, JR Fojo, T Walther, MM Libutti, SK TI Percutaneous tumor ablation with radiofrequency SO CANCER LA English DT Article DE radiofrequency thermal ablation; minimally invasive therapy; hyperthermia; tumor ablation ID RENAL-CELL CARCINOMA; TISSUE ABLATION; HEPATOCELLULAR-CARCINOMA; LIVER METASTASES; HEPATIC MALIGNANCIES; COAGULATION NECROSIS; COLORECTAL-CANCER; BLOOD-FLOW; EX-VIVO; IN-VIVO AB BACKGROUND. Radiofrequency thermal ablation (RFA) is a new minimally invasive treatment for localized cancer. Minimally invasive surgical options require less resources, time, recovery, and cost, and often offer reduced morbidity and mortality, compared with more invasive methods. To be useful, image-guided, minimally invasive, local treatments will have to meet those expectations without sacrificing efficacy. METHODS. Image-guided, local cancer treatment relies on the assumption that local disease control may improve survival. Recent developments in ablative techniques are being applied to patients with inoperable, small, or solitary liver tumors, recurrent metachronous hereditary renal cell carcinoma, and neoplasms in the bone, lung, breast, and adrenal gland. RESULTS. Recent refinements in ablation technology enable large tumor volumes to be treated with image-guided needle placement, either percutaneously, laparoscopically, or with open surgery. Local disease control potentially could result in improved survival, or enhanced operability. CONCLUSIONS. Consensus indications in oncology are ill-defined, despite widespread proliferation of the technology. A brief review is presented of the current status of image-guided tumor ablation therapy. More rigorous scientific review, long-term follow-up, and randomized prospective trials are needed to help define the role of RFA in oncology. Cancer 2002;94:443-51. Published 2002 by the American Cancer Society.* C1 NIH, Ctr Clin, Dept Diagnost Radiol, Special Procedures Div, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. Georgetown Univ, Med Ctr, Dept Radiol, Div Vasc & Intervent Radiol, Washington, DC 20007 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Clin, Dept Diagnost Radiol, Special Procedures Div, Bldg 10,Room 1C-660,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 62 TC 105 Z9 113 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2002 VL 94 IS 2 BP 443 EP 451 DI 10.1002/cncr.10234 PG 9 WC Oncology SC Oncology GA 512CP UT WOS:000173303800021 PM 11900230 ER PT J AU Nihei, N Kouprina, N Larionov, V Oshima, J Martin, GM Ichikawa, T Barrett, JC AF Nihei, N Kouprina, N Larionov, V Oshima, J Martin, GM Ichikawa, T Barrett, JC TI Functional evidence for a metastasis suppressor gene for rat prostate cancer within a 60-kilobase region on human chromosome 8p21-p12 SO CANCER RESEARCH LA English DT Article ID SHORT ARM; HUMAN GENOME; LONG ARM; LOCALIZATION; HETEROZYGOSITY; PROGRESSION; MAP; HUMAN-CHROMOSOME-8; EXPRESSION; DELETION AB We recently demonstrated that the human chromosome 8p21-p12 region encodes a metastasis suppressor gene for rat prostate cancer. The presence of this region suppresses the metastatic ability of rat prostate cancer cells (N. Nihei et al., Genes Chromosomes Cancer, 17: 260-268, 1996). To define further the region harboring the metastasis suppressor gene, a truncated human chromosome 8 containing this region was transferred into highly metastatic AT6.3 rat prostate cancer cells by microcell-mediated chromosome transfer. The region of human chromosome 8 retained in each microcell hybrid was determined by a PCR analysis with sequence-tagged site markers, and this analysis placed the metastasis suppressor gene in the interval between D8S2249 and D8S2244 on human chromosome 8p21-p12. One of the metastasis-suppressed microcell hybrids was used for construction of representative yeast/bacterial artificial chromosome (YAC/BAC) library covering the candidate region using a transformation-associated recombination technology (N. Kouprina et al, Genomics, 53: 21-28, 1998). The final contig corresponding to the candidate region was assembled by four YAC/BAC clones. Each clone was transfected into the AT6.3 cells, and the resultant transfectants were tested for their metastatic ability in athymic nude mice. Introduction of a 60-kb YAC/BAC clone resulted in significant suppression of the metastatic ability without suppression of the tumorigenicity. In contrast, other YAC/BAC clones in the contig had neither metastasis nor tumor suppressor activity. This demonstrates that the 60-kb fragment from the human chromosome 8p21-p12 region contains the metastasis suppressor gene for the AT6.3 cells. Frequent loss of heterozygosity of this region is detected in human prostate cancer, which suggests that our target metastasis suppressor gene may also play an important role in the progression of human prostate cancer. C1 NCI, Ctr Canc Res, Lab Biosys & Canc, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. Chiba Univ, Grad Sch Med, Dept Mol Oncol, Chiba 2608670, Japan. Chiba Univ, Grad Sch Med, Dept Urol, Chiba 2608670, Japan. RP Barrett, JC (reprint author), NCI, Ctr Canc Res, Lab Biosys & Canc, NIH, Bldg 31,Room 3A11,31 Ctr Dr, Bethesda, MD 20892 USA. NR 27 TC 24 Z9 27 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2002 VL 62 IS 2 BP 367 EP 370 PG 4 WC Oncology SC Oncology GA 515HE UT WOS:000173488700009 PM 11809681 ER PT J AU Shirakawa, K Kobayashi, H Heike, Y Kawamoto, S Brechbiel, MW Kasumi, F Iwanaga, T Konishi, F Terada, M Wakasugi, H AF Shirakawa, K Kobayashi, H Heike, Y Kawamoto, S Brechbiel, MW Kasumi, F Iwanaga, T Konishi, F Terada, M Wakasugi, H TI Hemodynamics in Vasculogenic mimicry and angiogenesis of inflammatory breast cancer xenograft SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL-CELL GROWTH; TUMOR ANGIOGENESIS; CARCINOMA; INTERLEUKIN-1; REGRESSION; RECEPTOR; MELANOMA AB In the present study, we examined hemodynamics in vasculogenic mimicry (VM) and angiogenesis of inflammatory breast cancer (IBC) xenografts (WIBC-9), having previously reported on the unique histological features and molecular basis of these processes (K. Shirakawa et al., Cancer Res., 61: 445-451, 2001). Histologically, the WIBC-9 xenografts exhibited invasive ductal carcinoma with a hypervascular structure (angiogenesis) in the tumor margin and VM without endothelial cells, central necrosis, or fibrosis in the tumor center. Results of molecular analysis indicated that WIBC-9 had a vasculogenic phenotype, including expression of Flt-1 and Tie-2. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-coursed dynamic micromagnetic resonance angiography analysis (with our newly developed intravascular macromolecular magnetic resonance imaging contrast agent), electromicroscopy, and immunohistochemistry, demonstrated blood now and a VM-angiogenesis junction in the central area of the WIBC-9 tumor. It has previously been considered impossible to prove a connection between VM and angiogenesis using angiography, because there are no intravascular macromolecular magnetic resonance imaging contrast agents that do not exhibit significant leakage through the vascular wall. In the present study, laser-captured microdissection was performed in regions of WIBC-9 tumors that exhibited VM without endothelial cells, central necrosis, or fibrosis, revealing expression of human-Flt-1 and human-Tie2 and the absence of human-CD31, human-endothelin B receptor, and human-thrombin receptor. These facts led us to hypothesize that the VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between VM and angiogenesis. C1 Natl Canc Ctr, Res Inst, Chuo Ku, Div Pharmacol, Tokyo 1040045, Japan. Natl Canc Ctr, Res Inst, Chuo Ku, Div Genet, Tokyo 1040045, Japan. Hitachi Med Co Chaired, Dept Diagnost & Intervent Imagiol, Kyoto 6068507, Japan. NCI, Radiat Oncol Branch, Radioimmune & Inorgan Chem Sect, NIH, Bethesda, MD 20892 USA. Japanese Fdn Canc Res, Dept Surg, Tokyo 1708455, Japan. Hokkaido Univ, Dept Vet Med, Sapporo, Hokkaido 0608638, Japan. Jichi Med Sch, Omiya Med Ctr, Dept Surg, Omiya, Saitama 3300834, Japan. RP Wakasugi, H (reprint author), Natl Canc Ctr, Res Inst, Chuo Ku, Div Pharmacol, Tsukiji 5-1-1, Tokyo 1040045, Japan. NR 26 TC 134 Z9 149 U1 1 U2 6 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 2002 VL 62 IS 2 BP 560 EP 566 PG 7 WC Oncology SC Oncology GA 515HE UT WOS:000173488700038 PM 11809710 ER PT J AU Piscitelli, SC Burstein, AH Welden, N Gallicano, KD Falloon, J AF Piscitelli, SC Burstein, AH Welden, N Gallicano, KD Falloon, J TI The effect of garlic supplements on the pharmacokinetics of saquinavir SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HIV PROTEASE INHIBITOR; INFECTED PATIENTS; BIOTRANSFORMATION; COMPLEMENTARY; THERAPIES; EXPOSURE AB Herbal therapies are widely used, but there are few data on their interactions with conventional medications. This study evaluated the effect of garlic supplements on the pharmacokinetics of saquinavir. Ten healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25, and 36-39, and they received a total of 41 doses of garlic caplets taken 2 times daily on study days 5-25. Blood samples were obtained on study days 4, 25, and 39 for determination of saquinavir plasma pharmacokinetic parameters. In the presence of garlic, the mean saquinavir area under the curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels at 8 h after dosing decreased by 49%, and the mean maximum concentrations (C-max) decreased by 54%. After the 10-day washout period, the AUC, trough, and C-max values returned to 60%-70% of their values at baseline. Patients should use caution when combining garlic supplements with saquinavir when it is used as a sole protease inhibitor. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Dept Pharm, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. Axelson Biopharma Res, Vancouver, BC, Canada. RP Falloon, J (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 11C103,10 Ctr Dr,MSC 1880, Bethesda, MD 20892 USA. EM Jfalloon@nih.gov NR 17 TC 222 Z9 233 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JAN 15 PY 2002 VL 34 IS 2 BP 234 EP 238 DI 10.1086/324351 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 502BC UT WOS:000172722900021 PM 11740713 ER PT J AU Ruangpanit, N Price, JT Holmbeck, K Birkedal-Hansen, H Guenzler, V Huang, XF Chan, D Bateman, JF Thompson, EW AF Ruangpanit, N Price, JT Holmbeck, K Birkedal-Hansen, H Guenzler, V Huang, XF Chan, D Bateman, JF Thompson, EW TI MT1-MMP-dependent and -independent regulation of gelatinase a activation in long-term, ascorbate-treated fibroblast cultures: Regulation by fibrillar collagen SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE ascorbic acid; collagen; fibril; MMP-2 activation; MT1-MMP; pC-procollagen ID MATRIX METALLOPROTEINASE-2 ACTIVATION; EMBRYONIC LETHAL MUTATION; PROCOLLAGEN C-PROTEINASE; HUMAN BREAST-CARCINOMA; CANCER CELL-LINES; EXTRACELLULAR-MATRIX; IV COLLAGENASE; ENDOTHELIAL-CELLS; METASTATIC PROGRESSION; MMP-2 ACTIVATION AB Human skin fibroblasts were cultured long-term in the presence of ascorbic acid to allow formation of a three-dimensional collagen matrix, and the effects of this on activation of secreted matrix metalloproteinase-2 (MMP-2) were examined. Accumulation of collagen over time correlated with increased levels of both mature MMP-2 and cell-associated membrane type 1-MMP (MT1-MMP), and subsequently increased mRNA levels for MT1-MMP, providing temporal resolution of the "nontranscriptional" and "transcriptional" effects of collagen on MT-1MMP functionality. MMP-2 activation by these cultures was blocked by inhibitors of prolyl-4-hydroxylase, or when fibroblasts derived from the collagen alpha1(I) gene-deficient Mov-13 mouse were used. MMP-2 activation by the Mov-13 fibroblasts was rescued by transfection of a full-length alpha1 (1) collagen cDNA, and to our surprise, also by transfection with an alpha1(l) collagen cDNA carrying a mutation at the C-proteinase cleavage, which almost abrogated fibrillogenesis. Although studies with ascorbate-cultured MT1-MMP-/- fibroblasts showed that MT1-MMP played a significant role in the collagen-induced MMP-2 activation, a residual MT1-MMP-independent activation of MMP-2 was seen which resembled the level of MMP-2 activation persisting when wild-type fibroblasts were cultured in the presence of both ascorbic acid and MMP inhibitors. We were also unable to block this residual activation with inhibitors specific for serinyl, aspartyl, or cysteinyl enzymes. (C) 2001 Elsevier Science. C1 St Vincents Inst Med Res, VBCRC Breast Canc Invas & Metastasis Unit, Melbourne, Vic, Australia. Univ Melbourne, Dept Pediat, Melbourne, Vic, Australia. Univ Melbourne, Dept Surg, Melbourne, Vic, Australia. Natl Inst Dent & Craniofacial Res, MMP Unit, NIH, Bethesda, MD USA. FibroGen Inc, San Francisco, CA USA. Chulalongkorn Univ, Fac Dent, Dept Anat, Bangkok, Thailand. RP Thompson, EW (reprint author), St Vincents Inst Med Res, VBCRC Invas & Metastasis Unit, 9 Princes St, Fitzroy, Vic 3065, Australia. RI Chan, Danny/C-4203-2009; Thompson, Erik/A-1425-2009; OI Thompson, Erik/0000-0002-9723-4924; Bateman, John/0000-0001-8542-0730; Price, John/0000-0002-8244-1023 NR 56 TC 22 Z9 22 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JAN 15 PY 2002 VL 272 IS 2 BP 109 EP 118 DI 10.1006/excr.2001.5403 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 510PR UT WOS:000173216900002 PM 11777335 ER PT J AU Caplen, NJ Taylor, JP Statham, VS Tanaka, F Fire, A Morgan, RA AF Caplen, NJ Taylor, JP Statham, VS Tanaka, F Fire, A Morgan, RA TI Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference SO HUMAN MOLECULAR GENETICS LA English DT Article ID EXPANDED ANDROGEN RECEPTOR; BULBAR MUSCULAR-ATROPHY; NEURONAL INTRANUCLEAR INCLUSIONS; IN-VITRO; MESSENGER-RNA; GENE-FUNCTION; CAENORHABDITIS-ELEGANS; HUNTINGTONS-DISEASE; CASPASE CLEAVAGE; CELL-DEATH AB RNA interference (RNAi) is a mechanism that appears to control unwanted gene expression in a wide range of species. In Drosophila, RNA! is most effectively induced by double-stranded RNAs (dsRNAs) of over similar to80 nucleotides (nt) and in mammalian cells an RNAi-like-inhibition of gene expression has been shown to be mediated by dsRNAs of similar to21-23 nt. To test if RNAi can be used to specifically down-regulate a human disease-related transcript we have used Drosophila and human tissue culture models of the dominant genetic disorder spinobulbar muscular atrophy (SBMA). A variety of different dsRNAs were assessed for the ability to inhibit expression of transcripts that included a truncated human androgen receptor (ar) gene containing different CAG repeat lengths (16-112 repeats). In Drosophila cells, dsRNAs corresponding to non-repetitive sequences mediated a high degree of sequence-specific inhibition, whereas RNA duplexes containing CAG repeat tracts only induced gene-specific inhibition when flanking ar sequences were included; dsRNAs containing various lengths of CAG repeats plus ar sequences were unable to induce allele-specific interference. In mammalian cells we tested sequence-specific small dsRNAs of 22 nt; these rescued the toxicity and caspase-3 activation induced by plasmids expressing a transcript encoding an expanded polyglutamine tract. This study demonstrates the feasibility of targeting a transcript associated with an important group of genetic diseases by RNAi. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NIND, Neurogenet Branch, NIH, Bethesda, MD USA. Carnegie Inst Washington, Dept Embryol, Baltimore, MD 21210 USA. RP Caplen, NJ (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,10C103, Bethesda, MD 20892 USA. RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 68 TC 89 Z9 99 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2002 VL 11 IS 2 BP 175 EP 184 DI 10.1093/hmg/11.2.175 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 521LP UT WOS:000173841700007 PM 11809726 ER PT J AU Schmidt, M Bowers, B Varma, A Roh, DH Cabib, E AF Schmidt, M Bowers, B Varma, A Roh, DH Cabib, E TI In budding yeast, contraction of the actomyosin ring and formation of the primary septum at cytokinesis depend on each other SO JOURNAL OF CELL SCIENCE LA English DT Article DE yeast; Saccharomyces cerevisiae; cytokinesis; primary septum; contractile ring; budding pattern ID SACCHAROMYCES-CEREVISIAE; SCHIZOSACCHAROMYCES-POMBE; CELL-CYCLE; CHITIN SYNTHASE-2; GENE; PROTEIN; WALL; MORPHOGENESIS; ARCHITECTURE; REQUIRES AB Saccharomyces cerevisiae chs2 mutants are unable to synthesize primary septum chitin, and myo1 mutants cannot construct a functional contractile ring. The morphology of the two mutants, as observed by electron microscopy, is very similar. In both cases, neither an invagination of the plasma membrane, which normally results from contraction of the actomyosin ring, nor generation of a chitin disc, the primary septum, is observed. Rather, both mutants are able to complete cytokinesis by an abnormal process in which lateral walls thicken gradually and finally meet over an extended region, giving rise to a thick septum lacking the normal trilaminar structure and often enclosing lacunae. Defects in chs2 or myo1 strains were not aggravated in a double mutant, an indication that the corresponding proteins participate in a common process. In contrast, in a chs3 background the chs2 mutation is lethal and the myo1 defect is greatly worsened, suggesting that the synthesis of chitin catalyzed by chitin synthase III is necessary for the functionality of the remedial septa. Both chs2 and myo1 mutants show abnormalities in budding pattern and a decrease in the level of certain proteins associated with budding, such as Bud3p, Bud4p and Spa2p. The possible reasons for these phenotypes and for the interdependence between actomyosin ring contraction and primary septum formation are discussed. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cabib, E (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 403, Bethesda, MD 20892 USA. NR 36 TC 123 Z9 124 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2002 VL 115 IS 2 BP 293 EP 302 PG 10 WC Cell Biology SC Cell Biology GA 520EZ UT WOS:000173768800007 PM 11839781 ER PT J AU Levine, JE Braun, T Penza, SL Beatty, P Cornetta, K Martino, R Drobyski, WR Barrett, AJ Porter, DL Giralt, S Leis, J Holmes, HE Johnson, M Horowitz, M Collins, RH AF Levine, JE Braun, T Penza, SL Beatty, P Cornetta, K Martino, R Drobyski, WR Barrett, AJ Porter, DL Giralt, S Leis, J Holmes, HE Johnson, M Horowitz, M Collins, RH TI Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; VERSUS-HOST DISEASE; COLONY-STIMULATING FACTOR; ACUTE-LEUKEMIA; DENDRITIC CELLS; GRAFT; THERAPY; TRANSFUSIONS; IMMUNOTHERAPY; FILGRASTIM AB Purpose: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy, was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)-primed DLIs. Patients and Methods: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF-primed DLIs. No prophylactic immunosuppression was provided. Results: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A post-transplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. Conclusion: Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem. (C) 2002 by American Society of Clinical Oncology. C1 Univ Michigan, Ann Arbor, MI 48109 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Utah, Salt Lake City, UT USA. Indiana Univ, Indianapolis, IN 46204 USA. Hosp Sant Pau, Barcelona, Spain. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Milwaukee, WI 53226 USA. NHLBI, Bethesda, MD 20892 USA. Univ Penn, MD Anderson Canc Ctr, Philadelphia, PA 19104 USA. Baylor Sammons Canc Ctr, Dallas, TX USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Levine, JE (reprint author), Blood & Marrow Stem Cell Transplantat Program, B1-207 CCGC,Box 0914,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. NR 31 TC 157 Z9 161 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 405 EP 412 DI 10.1200/JCO.20.2.405 PG 8 WC Oncology SC Oncology GA 513WR UT WOS:000173404000008 PM 11786567 ER PT J AU Brierley, JD Catton, PA O'Sullivan, B Dancey, JE Dowling, AJ Irish, JC McGowan, TS Sturgeon, JFG Swallow, CJ Rodrigues, GB Panzarella, T AF Brierley, JD Catton, PA O'Sullivan, B Dancey, JE Dowling, AJ Irish, JC McGowan, TS Sturgeon, JFG Swallow, CJ Rodrigues, GB Panzarella, T TI Accuracy of recorded tumor, node, and metastasis stage in a comprehensive cancer center SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article AB Purpose: The benefits of recording the tumor, node, and metastasis (TNM) stages of cancer patients are well accepted, but little is known about how accurately this is performed. An audit was performed to determine the accuracy of recorded stage and to act as a baseline before the implementation of an education program. Patients and Methods: All new patient referrals to Princess Margaret Hospital between July I and August 31, 1997, were reviewed. An audit panel composed of! five health record technicians (HRTs) and 10 doctors was assembled. Each auditor reviewed 10% of the health record. If there was a discrepancy between the stage in the health record and the auditor stage, then the final stage was determined by the audit committee. Analysis of the agreement between the health record, the physician auditor, the HRT auditor, and the final! stage was performed. Results: A total of 855 patients were referred with a new diagnosis of a malignancy for which there was a TNM stage system; 833 patients (97.4%) had a stage assigned. There was agreement between the health record stage and final stage in 80% (95% confidence interval [CI], 77% to 82%) of cases for clinical stage, compared with 90% (95% CI, 87% to 92%) for pathologic stage. Of the major site groups, lung was the least accurately recorded. The most common major discrepancies were due to the recording of X when a definite category could be assigned. Conclusion: This audit demonstrates the importance of staging and provides impetus to develop staging guidelines and education programs. (C) 2002 by American Society of Clinical Oncology. C1 Univ Toronto, Dept Radiat Oncol, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Surg Oncol, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Med Oncol, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Stat, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Canadian Radiol Oncol Serv Clin, Toronto, ON, Canada. NCI, Div Canc Treatment Diagnosis, Canc Therapy Evaluat Program, Investigat Drug Branch, Rockville, MD USA. St Vincents Hosp, Melbourne, Vic, Australia. RP Brierley, JD (reprint author), Univ Toronto, Dept Radiat Oncol, Princess Margaret Hosp, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. NR 11 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 413 EP 419 DI 10.1200/JCO.20.2.413 PG 7 WC Oncology SC Oncology GA 513WR UT WOS:000173404000009 PM 11786568 ER PT J AU Woods, WG Barnard, DR Alonzo, TA Buckley, JD Kobrinsky, N Arthur, DC Sanders, J Neudorf, S Gold, S Lange, BJ AF Woods, WG Barnard, DR Alonzo, TA Buckley, JD Kobrinsky, N Arthur, DC Sanders, J Neudorf, S Gold, S Lange, BJ TI Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: A report from the Children's Cancer Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BONE-MARROW TRANSPLANTATION; ACUTE NONLYMPHOCYTIC LEUKEMIA; DOSE CYTOSINE-ARABINOSIDE; THERAPY; CHEMOTHERAPY; CHILDHOOD; CLASSIFICATION; ADOLESCENTS AB Purpose: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer Group protocol 2891. Patients and Methods: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. Results: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and do novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. Conclusion: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown. (C) 2002 by American Society of Clinical Oncology. C1 Emory Univ Childrens Healthcare, AFLAC Canc Ctr, Atlanta, GA USA. Izaak Walton Killam Hosp Children, Halifax, NS B3J 3G9, Canada. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Roger Maris Canc Ctr, Fargo, ND USA. NCI, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. Univ N Carolina, Chapel Hill, NC USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Woods, WG (reprint author), Childrens Canc Grp, POB 60012, Arcadia, CA 91066 USA. NR 31 TC 62 Z9 69 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 434 EP 440 DI 10.1200/JCO.20.2.434 PG 7 WC Oncology SC Oncology GA 513WR UT WOS:000173404000012 PM 11786571 ER PT J AU Ben David, Y Chetrit, A Hirsh-Yechezkel, G Friedman, E Beck, BD Beller, U Ben-Baruch, G Fishman, A Levavi, H Lubin, F Menczer, J Piura, B Struewing, JP Modan, B AF Ben David, Y Chetrit, A Hirsh-Yechezkel, G Friedman, E Beck, BD Beller, U Ben-Baruch, G Fishman, A Levavi, H Lubin, F Menczer, J Piura, B Struewing, JP Modan, B CA Natl Israeli Study Ovarian Canc TI Effect of BRCA mutations on the length of survival in epithelial ovarian tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEREDITARY BREAST-CANCER; GERM-LINE MUTATIONS; HISTOPROGNOSTIC GRADE; WOMEN; FEATURES AB Purpose: To study the role of BRCA mutations in ovarian cancer survival. Patients and Methods: Blood samples and specimens of ovarian tumors (whenever blood samples were not available) at the time of the primary surgery were obtained in the course of a nationwide case-control study of women with ovarian cancer in Israel. The three common BRCA mutations in Israel (185delAG; 5382insC, and 6174delT) were analyzed with a multiplex polymerase chain reaction to amplify the exons containing the three mutations using fluor-labeled primers in a single reaction. Because each mutation is a small insertion or deletion, they can be detected as length polymorphisms. Patients were followed for up: to 5 years (range, 20 to 64 months). Statistical analysis was performed using the Kaplan-Meier method and the log-rank test. Stepwise Cox regression analysis was used for determination of independent prognostic factors. Results: This report is based on 896 blood or tumor specimens analyzed for the presence of the BRCA mutations. Of these, 234 women (26.1%) were found to be positive. A significant difference in survival pattern was found between BRCA1/BRCA2 carriers and non-carriers among the women with invasive ovarian cancer (median survival, 53.4 months v 37.8 months; 3-year survival, 65.8% v 51.9%, respectively). These differences were independent of age at diagnosis or stage of the disease. Conclusion: Our data indicate that the survival of patients with ovarian cancer is affected by BRCA germline mutation, at least in the early years after diagnosis. (C) 2002 by American Society of Clinical Oncology. C1 Haemek Med Ctr, Dept Gynecol, Afula, Israel. Chaim Sheba Med Ctr, Dept Clin Epidemiol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Oncogenet Unit, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Gynecol Oncol Unit, IL-52621 Tel Hashomer, Israel. Rambam Med Ctr, Dept Gynecol, Haifa, Israel. Shaare Zedek Med Ctr, Dept Gynecol, Jerusalem, Israel. Sapir Med Ctr, Dept Gynecol, Kefar Sava, Israel. Rabin Med Ctr, Dept Gynecol, Petah Tiqwa, Israel. E Wolfson Med Ctr, Dept Gynecol, Holon, Israel. Soroka Med Ctr, Dept Gynecol, IL-84101 Beer Sheva, Israel. Tel Aviv Univ, Sch Med, Stanley Steyer Inst, IL-69978 Tel Aviv, Israel. Ariel Coll, Tel Aviv, Israel. NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Chetrit, A (reprint author), Chaim Sheba Med Ctr, Canc Epidemiol Unit, Gertner Inst, Ramat Gan, Israel. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 FU NCI NIH HHS [CA 61126-03] NR 17 TC 107 Z9 109 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 463 EP 466 DI 10.1200/JCO.20.2.463 PG 4 WC Oncology SC Oncology GA 513WR UT WOS:000173404000016 PM 11786575 ER PT J AU Wei, JT Dunn, RL Sandler, HM McLaughlin, PW Montie, JE Litwin, MS Nyquist, L Sanda, MG AF Wei, JT Dunn, RL Sandler, HM McLaughlin, PW Montie, JE Litwin, MS Nyquist, L Sanda, MG TI Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BEAM RADIATION-THERAPY; OF-LIFE; RADICAL PROSTATECTOMY; FUNCTIONAL ASSESSMENT; OUTCOMES; MEN; BRACHYTHERAPY; RADIOTHERAPY; INCONTINENCE; CARCINOMA AB Purpose: Health-related quality-of-life (HRQOL) concerns are pivotal in choosing prostate cancer therapy. However, concurrent HRQOL comparison between brachytherapy, external radiation, radical prostatectomy, and controls is hitherto lacking. HRQOL effects of hormonal adjuvants and of cancer control after therapy also lack prior characterization. Patients and Methods: A cross-sectional survey was administered to patients who underwent brachytherapy, external-beam radiation, or radical prostatectomy during 4 years at an academic medical center and to age-matched controls. HRQOL among controls was compared with therapy groups. Comparison between therapy groups was performed using regression models to control covariates. HRQOL effects of cancer progression were evaluated. Results: One thousand fourteen subjects participated. Compared with controls, each therapy group: reported bothersome sexual dysfunction; radical prostatectomy was associated with adverse urinary HRQOL, external-beam radiation was associated with adverse bowel HRQOL; and brachytherapy was associated with adverse urinary, bowel, and sexual HRQOL (P less than or equal to .0002 for each). Hormonal adjuvant symptoms were associated with significant impairment (P < .002). More than I year after therapy, several HRQOL outcomes were less favorable among subjects after brachytherapy than after external radiation or radical prostatectomy. Progression-free subjects reported better sexual and hormonal HRQOL than subjects with increasing prostate-specific antigen (P <.0001). Conclusion: Long-term HRQOL after prostate brachytherapy showed no benefit relative to radical prostatectomy or external-beam radiation and may be less favorable in some domains. Hormonal adjuvants can be associated with significant impairment. Progression-free survival is associated with HRQOL benefits. These findings facilitate patient counseling regarding HRQOL expectations and highlight the need for prospective studies sensitive to urinary irritative and hormonal concerns in addition to incontinence, sexual, and bowel HRQOL domains. (C) 2002 by American Society of Clinical Oncology. C1 Ann Arbor Vet Affairs Med Ctr, Vet Affairs Ctr Practice Management & Outcomes Re, Ann Arbor, MI USA. Univ Michigan, Natl Canc Inst, Special Project Res Excellence Prostate Canc, Dept Radiat Oncol,Surg Urol Sect,Sch Publ Hlth, Ann Arbor, MI 48109 USA. Univ Michigan, Natl Canc Inst, Special Project Res Excellence Prostate Canc, Dept Radiat Oncol,Surg Urol Sect,Sch Nursing, Ann Arbor, MI 48109 USA. Univ Michigan, Canc Ctr Biostat Core, Ann Arbor, MI 48109 USA. Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA 90024 USA. RP Sanda, MG (reprint author), Univ Michigan, Taubman Ctr 2916, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; Wei, John/E-8967-2012 FU NCI NIH HHS [1P50CA69568, 5P30CA46598] NR 38 TC 277 Z9 281 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 557 EP 566 DI 10.1200/JCO.20.2.557 PG 10 WC Oncology SC Oncology GA 513WR UT WOS:000173404000027 PM 11786586 ER PT J AU Freidlin, B Dancey, J Korn, EL Zee, B Eisenhauer, E AF Freidlin, B Dancey, J Korn, EL Zee, B Eisenhauer, E TI Multinomial phase II trial designs SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. RP Freidlin, B (reprint author), NCI, Bethesda, MD 20892 USA. NR 2 TC 17 Z9 17 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2002 VL 20 IS 2 BP 599 EP 599 PG 1 WC Oncology SC Oncology GA 513WR UT WOS:000173404000032 PM 11786592 ER PT J AU Perera, L Darden, TA Pedersen, LG AF Perera, L Darden, TA Pedersen, LG TI Predicted solution structure of zymogen human coagulation FVII SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE structure predictions; molecular dynamics simulations; FVII; tissue factor; EGF-like domains; serine protease ID FACTOR-VII DEFICIENCY; TISSUE FACTOR-BINDING; FACTOR-LIKE DOMAIN; FACTOR-X ACTIVATION; MESH EWALD METHOD; EGF-LIKE DOMAIN; BLOOD-COAGULATION; ACTIVE-SITE; EXTRINSIC PATHWAY; CRYSTAL-STRUCTURE AB A model solution structure for the complete tissue factor-free calcium ion-bound human zymogen FVII (residues 1-406) (FVII) has been constructed to study possible conformational changes associated with the activation process and tissue factor (TF) binding. The initial structure for the present model was constructed using the X-ray crystallographic structure of human coagulation FVIIa/TF complex bound with calcium ions (Banner et al., Nature 1996, 380, 41-46). This model was subsequently subjected to lengthy molecular dynamics simulations. The Amber force field in conjunction with the PME electrostatic summation method was employed. The estimated TF free solution structure was then compared with the currently available X-ray crystal structures of FVIIa (with or without TF, variable inhibitor bound) to estimate the restructuring of FVII due to TF binding and activation. The solution structure of the zymogen FVII in the absence of TF is predicted to be an extended domain structure similar to that of the TF-bound X-ray crystal structure. An additional extension of the serine protease (SP) domain of the zymogen above a reference lipid surface by similar to7 Angstrom was in agreement with experiment, Significant Gla-EGF1 and EGF1-EGF2 interdomain motions in the zymogen were observed. Carbohydrate dimers attached to Ser-52 and Ser-60 did not cause restructuring in this domain. Minimal restructuring of the SP domain is found upon inference of the zymogen from the activated form. The catalytic triad residues maintain the H-bonded network while Lys-341 occupies the S1 specific site in the zymogen. (C) 2002 John Wiley & Sons, Inc. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU NHLBI NIH HHS [HL-06350] NR 82 TC 10 Z9 10 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 15 PY 2002 VL 23 IS 1 BP 35 EP 47 DI 10.1002/jcc.1155 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 505UW UT WOS:000172934800005 PM 11913388 ER PT J AU Doruker, P Jernigan, RL Bahar, I AF Doruker, P Jernigan, RL Bahar, I TI Dynamics of large proteins through hierarchical levels of coarse-grained structures SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE Gaussian network model; anisotropic fluctuations; vibration dynamics; collective motions; influenza virus hemagglutinin ID COLLECTIVE-COORDINATE SPACE; VIBRATIONAL DYNAMICS; SINGLE-PARAMETER; FOLDED PROTEINS; INFLUENZA-VIRUS; MOTIONS; HEMAGGLUTININ; FLUCTUATIONS; SIMULATIONS; SLOW AB Elastic network models have been successful in elucidating the largest scale collective motions of proteins. These models are based on a set of highly coupled springs, where only the close neighboring amino, acids interact, without any residue specificity. Our objective here is to determine whether the equivalent cooperative motions can be obtained upon further coarse-graining of the protein structure along the backbone. The influenza virus hemagglutinin A (HA), composed of N = 1509 residues, is utilized for this analysis. Elastic network model calculations are performed for coarse-grained HA structures containing only N/2, N/10, N/20, and N/40 residues along the backbone. High correlations (>0.95) between residue fluctuations are obtained for the first dominant (slowest) mode of motion between the original model and the coarse-grained models. In the case of coarse-graining by a factor of 1/40, the slowest mode shape for HA is reconstructed for all residues by successively selecting different subsets of residues, shifting one residue at a time. The correlation for this reconstructed first mode shape with the original all-residue case is 0.73, while the computational time is reduced by about three orders of magnitude. The reduction in computational time will be much more significant for larger targeted structures. Thus, the dominant motions of protein structures are robust enough to be captured at extremely high levels of coarse-graining. And more importantly, the dynamics of extremely large complexes are now accessible with this new methodology. (C) 2002 John Wiley & Sons, Inc. C1 NCI, Mol Struct Sect, Lab Expt & Computat Biol, Div Basic Sci,NIH, Bethesda, MD 20892 USA. Bogazici Univ, Dept Chem Engn, TR-80815 Bebek, Turkey. Bogazici Univ, Polymer Res Ctr, TR-80815 Bebek, Turkey. Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15213 USA. RP Jernigan, RL (reprint author), NCI, Mol Struct Sect, Lab Expt & Computat Biol, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RI Jernigan, Robert/A-5421-2012 NR 30 TC 163 Z9 171 U1 1 U2 15 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 15 PY 2002 VL 23 IS 1 BP 119 EP 127 DI 10.1002/jcc.1160 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 505UW UT WOS:000172934800013 PM 11913377 ER PT J AU Mazzoni, A Bronte, V Visintin, A Spitzer, JH Apolloni, E Serafini, P Zanovello, P Segal, DM AF Mazzoni, A Bronte, V Visintin, A Spitzer, JH Apolloni, E Serafini, P Zanovello, P Segal, DM TI Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TUMOR-INDUCED IMMUNOSUPPRESSION; COLONY-STIMULATING FACTOR; NITRIC-OXIDE PRODUCTION; IFN-GAMMA; SPLENIC MACROPHAGES; MICE; ANTIGEN; BEARING; PROLIFERATION AB CD11b(+)Gr-1(+) myeloid suppressor cells (MSC) accumulate in lymphoid organs under conditions of intense immune stress where they inhibit T and B cell function. We recently described the generation of immortalized MSC lines that provide a homogeneous source of suppressor cells for dissecting the mechanism of suppression. In this study we show that the DISC lines potently block in vitro proliferation of T cells stimulated with either mitogen or antigenic peptide, with as few as 3% of MSC cells causing complete suppression. Inhibition of mitogenic and peptide-specific responses is not associated with a loss in IL-2 production or inability to up-modulate the early activation markers, CD69 and CD25, but results in direct impairment of the three IL-2R signaling pathways, as demonstrated by the lack of Janus kinase 3, STAT5, extracellular signal-regulated kinase, and Akt phosphorylation in response to IL-2. Suppression is mediated by and requires NO, which is secreted by MSC in response to signals from activated T cells, including IFN-gamma and a contact-dependent stimulus. Experiments with inducible NO synthase knockout mice demonstrated that the inhibition of T cell proliferation by CD11b(+)Gr-1(+) cells in the spleens of immunosuppressed mice is also dependent upon NO, indicating that the MSC lines accurately represent their normal counterparts. The distinctive capacity of MSC to generate suppressive signals when encountering activated T cells defines a specialized subset of myeloid cells that most likely serve a regulatory function during times of heightened immune activity. C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. Azienda Ospedaliera, Dept Oncol & Surg Sci, Oncol Sect, Padua, Italy. RP Segal, DM (reprint author), NCI, NIH, Expt Immunol Branch, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. RI Serafini, Paolo/C-8195-2012; Bronte, Vincenzo/K-7902-2016 OI Serafini, Paolo/0000-0002-3651-9176; Bronte, Vincenzo/0000-0002-3741-5141 NR 39 TC 326 Z9 337 U1 2 U2 7 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 2002 VL 168 IS 2 BP 689 EP 695 PG 7 WC Immunology SC Immunology GA 510DP UT WOS:000173193700020 PM 11777962 ER PT J AU Michalec, L Choudhury, BK Postlethwait, E Wild, JS Alam, R Lett-Brown, M Sur, S AF Michalec, L Choudhury, BK Postlethwait, E Wild, JS Alam, R Lett-Brown, M Sur, S TI CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID OZONE-INDUCED INFLAMMATION; OBSTRUCTIVE PULMONARY-DISEASE; AIR-POLLUTION; ASTHMATIC SUBJECTS; CHEMOATTRACTANT CINC; GENE-EXPRESSION; INDUCED SPUTUM; IFN-GAMMA; CHEMOKINES; HYPERRESPONSIVENESS AB Oxidative stress from ozone (03) exposure augments airway neutrophil recruitment and chemokine production. We and others have shown that severe and sudden asthma is associated with airway neutrophilia, and that 03 oxidative stress is likely to augment neutrophilic airway inflammation in severe asthma. However, very little is known about chemokines that orchestrate oxidative stress-induced neutrophilic airway inflammation in vivo. To identify these chemokines, three groups of BALB/c mice were exposed to sham air, 0.2 ppm O-3, or 0.8 ppm O-3 for 6 h. Compared with sham air, 0.8 ppm O-3, but not 0.2 ppm O-3, induced pronounced neutrophilic airway inflammation that peaked at 18 h postexposure. The 0.8 ppm 03 up-regulated lung mRNA of CXCL1,2,3 (mouse growth-related oncogene-a and macrophage-inflammatory protein-2), CXCL10 (IFN-gamma-inducible protein-10), CCL3 (macrophage-inflammatory protein-1alpha), CCL7 (monocyte chemoattractant protein-3), and CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10, CCL3, and CCL7 mRNA was sustained 18 h postexposure. 03 increased lung protein levels of CXCL10, CCL7, and CCR3 (CCL7R). The airway epithelium was identified as a source of CCL7. The role of up-regulated chemokines was determined by administering control IgG or IgG Abs against six murine chemokines before 03 exposure. As expected, anti-mouse growth-related oncogene-a inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10 also decreased neutrophil recruitment by 63 and 72%, respectively. These findings indicate that CCL7 and CXCL10, two chemokines not previously reported to orchestrate neutrophilic inflammation, play a critical role in mediating oxidative stress-induced neutrophilic airway inflammation. These observations may have relevance in induction of neutrophilia in severe asthma. C1 NIH, Asthma & Allerg Dis Res Ctr, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Internal Med, Div Allergy & Immunol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. RP Sur, S (reprint author), NIH, Asthma & Allerg Dis Res Ctr, Galveston, TX 77555 USA. NR 37 TC 73 Z9 76 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 2002 VL 168 IS 2 BP 846 EP 852 PG 7 WC Immunology SC Immunology GA 510DP UT WOS:000173193700038 PM 11777981 ER PT J AU Fuss, IJ Boirivant, M Lacy, B Strober, W AF Fuss, IJ Boirivant, M Lacy, B Strober, W TI The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; CD4(+) T-CELLS; INTESTINAL INFLAMMATION; IFN-GAMMA; INDUCTION; INTERLEUKIN-10; SUPPRESSION; RESPONSES; DISEASE; MICE AB In the present study, we define the relation between TGF-beta and IL-10 in the regulation of the Th1-mediated inflammation occurring in trinitrobenzene sulfonic acid (TNBS)-colitis. In initial studies, we showed that the feeding of trinitrophenol-haptenated colonic protein to SJL/J mice induces CD4(+) regulatory T cells that transfer protection from induction of TNBS-colitis, and that such protection correlates with cells producing TGF-beta, not IL-10. Further studies in which SJL/J mice were fed haptenated colonic protein, and then administered either anti-TGF-beta or anti-IL-10 at the time of subsequent TNBS administration per rectum, showed that while both Abs abolished protection, anti-TGF-beta administration prevented TGF-beta secretion, but left IL-10 secretion intact; whereas anti-IL-10 administration prevented both TGF-beta secretion and IL-10 secretion. Thus, it appeared that the protective effect of IL-10 was an indirect consequence of its effect on TGF-beta secretion. To establish this point further, we conducted adoptive transfer studies and showed that anti-IL-10 administration had no effect on induction of TGF-beta producing T cells in donor mice. However, it did inhibit their subsequent expansion in recipient mice, probably by regulating the magnitude of the Th1 T cell response which would otherwise inhibit the TGF-beta response. Therefore, these studies suggest that TGF-beta production is a primary mechanism of counter-regulation of Th1 T cell-mediated mucosal inflammation, and that IL-10 is necessary as a secondary factor that facilitates TGF-beta production. C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Ist Super Sanita, Immunol Lab, I-00161 Rome, Italy. RP Fuss, IJ (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, 10 Ctr Dr,Bldg 10,Room 11N238, Bethesda, MD 20892 USA. RI BOIRIVANT, MONICA/B-9977-2016 NR 24 TC 198 Z9 210 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 2002 VL 168 IS 2 BP 900 EP 908 PG 9 WC Immunology SC Immunology GA 510DP UT WOS:000173193700045 PM 11777988 ER PT J AU Khong, HT Rosenberg, SA AF Khong, HT Rosenberg, SA TI Pre-existing immunity to tyrosinase-related protein (TRIP)-2, a new TRP-2 isoform, and the NY-ESO-1 melanoma antigen in a patient with a dramatic response to immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; CYTOLYTIC T-LYMPHOCYTES; HLA-A2 MELANOMAS; CELL EPITOPE; GENE; IDENTIFICATION; EXPRESSION; SEQUENCE; CLONING; INTRON AB We have performed a detailed analysis of the recognition of melanoma Ags by the tumor-infiltrating lymphocytes (TIL) 1790, isolated from a patient who experienced a dramatic tumor regression following immunization with peptides from the gp100, MART-1, and tyrosinase Ags. This TIL was found to recognize HLA-A2-restricted CTL epitopes in tyrosinase-related protein (TRP)-2 (clone MR7) and NY-ESO-1 (clone M8). These epitopes were the same as the previously identified nonapeptide TRP-2: 180-188, and the overlapping NY-ESO-1 peptides, obtained by using lymphocytes from in vitro stimulation. We also cloned a previously unknown TRP-2 mRNA isoform (TRP-2-6b) that contained two novel exons alternatively spliced from the sixth intron between exons 6 and 7 of TRP-2 mRNA. The isoform encoded an HLA-A2-restricted antigenic epitope recognized by TIL clone MB4. An immunologic analysis of the patient's PBMC obtained before treatment showed the presence of high reactivity against NY-ESO-1 and both TRP-2 Ags, but not the Ags used for immunization. Because immune response against these Ags was less pronounced, it is possible that NY-ESO-1, TRP-2, and TRP-2-6b may be of importance in the generation of CTL-mediated tumor destruction and may have played a role in the dramatic tumor regression seen in this patient. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,10 Ctr Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 SC003811-33] NR 32 TC 51 Z9 53 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2002 VL 168 IS 2 BP 951 EP 956 PG 6 WC Immunology SC Immunology GA 510DP UT WOS:000173193700051 PM 11777994 ER PT J AU Green, KY Belliot, G Taylor, JL Valdesuso, J Lew, JF Kapikian, AZ Lin, FYC AF Green, KY Belliot, G Taylor, JL Valdesuso, J Lew, JF Kapikian, AZ Lin, FYC TI A predominant role for Norwalk-like viruses as agents of epidemic gastroenteritis in Maryland nursing homes for the elderly SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ROUND-STRUCTURED VIRUSES; ACUTE NONBACTERIAL GASTROENTERITIS; HUMAN CALICIVIRUS; VIRAL GASTROENTERITIS; UNITED-STATES; MOLECULAR CHARACTERIZATION; ROTAVIRUS INFECTION; SEQUENCE DIVERSITY; HOSPITAL OUTBREAK; ASTROVIRUS TYPE-1 AB Stool specimens from 156 Maryland nursing home residents, who became ill during 20 outbreaks of gastroenteritis from November 1987 through February 1988, were analyzed. All tested negative for astroviruses, enteroviruses, Group A rotaviruses, Sapporo-like caliciviruses, and enteric bacteria (i.e., Salmonella, Clostridium, and Shigella species). Eighty-two (52%) were positive for Norwalk-like viruses (NLVs), members of the family Caliciviridae. Six distinct genetic clusters within genogroups I and II of the NLVs were detected; a genogroup II (GII) virus closely related to the Camberwell virus in the NLV GII/4 genetic cluster was the predominant strain. Serologic evidence of infection with greater than or equal to1 NLV was detected in 61 (56%) of 109 patients tested against 3 NLV antigens (i.e., Norwalk, Hawaii, and Toronto viruses). Sixteen (80%) outbreaks met the definition for an NLV outbreak. Taken together with a retrospective analysis of bacterial gastroenteritis in this same setting, these data support a major role for NLVs as etiologic agents of gastroenteritis in elderly persons. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Maryland Dept Hlth & Mental Hyg, Epidemiol & Dis Control Program, Baltimore, MD USA. RP Green, KY (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike,Bldg 7,Rm 137, Bethesda, MD 20892 USA. EM kgreen@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000897-07] NR 89 TC 117 Z9 126 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2002 VL 185 IS 2 BP 133 EP 146 DI 10.1086/338365 PG 14 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 508LX UT WOS:000173091300001 PM 11807686 ER PT J AU Thio, CL O'Brien, SJ Carrington, M AF Thio, CL O'Brien, SJ Carrington, M TI The importance of assessing effect modification when asserting racial differences in associations between human leukocyte antigen class II alleles and hepatitis C virus outcomes - Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID ADMIXTURE; INFECTION C1 Johns Hopkins Univ, Dept Med, Baltimore, MD 21231 USA. NCI, Frederick, MD 21701 USA. RP Thio, CL (reprint author), Johns Hopkins Univ, Dept Med, 424 N Bond St, Baltimore, MD 21231 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2002 VL 185 IS 2 BP 267 EP 268 DI 10.1086/338199 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 508LX UT WOS:000173091300019 ER PT J AU Banwart, B Splaingard, ML Farrell, PM Rock, MJ Havens, PL Moss, J Ehrmantraut, ME Frank, DW Barbieri, JT AF Banwart, B Splaingard, ML Farrell, PM Rock, MJ Havens, PL Moss, J Ehrmantraut, ME Frank, DW Barbieri, JT TI Children with cystic fibrosis produce an immune response against exoenzyme S, a type III cytotoxin of Pseudomonas aeruginosa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID ANTIBODIES C1 Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. Childrens Hosp Wisconsin, Dept Pediat, Milwaukee, WI 53201 USA. Univ Wisconsin, Sch Med, Madison, WI USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Barbieri, JT (reprint author), Med Coll Wisconsin, Dept Microbiol & Mol Genet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. RI Splaingard, Mark/D-9206-2012 FU NIAID NIH HHS [AI31665, AI01289, AI30162] NR 9 TC 17 Z9 17 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2002 VL 185 IS 2 BP 269 EP 270 DI 10.1086/338197 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 508LX UT WOS:000173091300021 PM 11807706 ER PT J AU Moron, JA Brockington, A Wise, RA Rocha, BA Hope, BT AF Moron, JA Brockington, A Wise, RA Rocha, BA Hope, BT TI Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nucleus accumbens; caudate; frontal cortex; synaptosomes; nisoxetine; GBR 12909; cocaine ID RAT PREFRONTAL CORTEX; INCREASES EXTRACELLULAR DOPAMINE; NUCLEUS-ACCUMBENS; MICE LACKING; SUBCELLULAR-LOCALIZATION; MONOAMINE TRANSMITTERS; NORADRENALINE CARRIER; COCAINE; SEROTONIN; STRIATUM AB Selective blockers of the norepinephrine transporter (NET) inhibit dopamine uptake in the prefrontal cortex. This suggests that dopamine in this region is normally cleared by the somewhat promiscuous NET We have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of H-3-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice. At transporter-specific concentrations, nisoxetine and GBR12909 failed to block dopamine uptake into frontal cortex synaptosomes from NET knock-out mice. The efficacy of cocaine at the highest dose (1 mm) was normal in DAT knock-out mice but reduced by 70% in NET knock-out mice. Nisoxetine inhibited dopamine uptake by 20% in caudate and nucleus accumbens synaptosomes from wild-type and DAT knock-out mice but had no effect in those from NET knock-out mice. Cocaine failed to block dopamine uptake into caudate or nucleus accumbens synaptosomes from DAT knock-out mice. Cocaine and GBR12909 each inhibited dopamine uptake into caudate synaptosomes from NET knock-out mice, but cocaine effectiveness was reduced in the case of nucleus accumbens synaptosomes. Thus, whereas dopamine uptake in caudate and nucleus accumbens depends primarily on the DAT, dopamine uptake in frontal cortex depends primarily on the NET. These data underscore the fact that which transporter clears dopamine from a given region depends on both the affinities and the local densities of the transporters. C1 NIDA, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, NIH, 5500 Nathan Schock Dr, Baltimore, MD 21224 USA. RI Wise, Roy/A-6465-2012; Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 NR 50 TC 353 Z9 362 U1 4 U2 15 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 2002 VL 22 IS 2 BP 389 EP 395 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 510JK UT WOS:000173204800009 PM 11784783 ER PT J AU Pedersen, WA Wan, RQ Zhang, PS Mattson, MP AF Pedersen, WA Wan, RQ Zhang, PS Mattson, MP TI Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I SO JOURNAL OF NEUROSCIENCE LA English DT Article DE antalarmin; cAMP; excitotoxicity; lipid peroxidation; sauvagine; stress ID IMPAIRED STRESS-RESPONSE; FOCAL CEREBRAL-ISCHEMIA; CRH MESSENGER-RNA; RAT-BRAIN; KINASE-C; LIPID-PEROXIDATION; ALZHEIMER-DISEASE; PRECURSOR PROTEIN; CARDIAC MYOCYTES; CORTICAL-NEURONS AB Urocortin and urocortin II are members of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. Two high-affinity G-protein-coupled receptors have been identified that bind CRH and/or urocortin I and II, designated CRHR1 and CRHR2, both of which are present in hippocampal regions of mammalian brain. The hippocampus plays an important role in regulating stress responses and is a brain region in which neurons are vulnerable during disease and stress conditions, including cerebral ischemia, Alzheimer's disease, and anxiety disorders. Here we report that urocortin exerts a potent protective action in cultured rat hippocampal neurons with concentrations in the range of 0.5-5.0 pM, increasing the resistance of the cells to oxidative (amyloid beta-peptide, 4-hydroxynonenal, ferrous sulfate) and excitotoxic (glutamate) insults. We observed that urocortin is 10-fold more potent than CRH in protecting hippocampal neurons from insult, whereas urocortin II is ineffective. RT-PCR and sequencing analyses revealed the presence of both CRHR1 and CRHR2 in the hippocampal cultures, with CRHR1 being expressed at much higher levels than CRHR2. Using subtype-selective CRH receptor antagonists, we provide evidence that the neuroprotective effect of exogenously added urocortin is mediated by CRHR1. Furthermore, we provide evidence that the signaling pathway that mediates the neuroprotective effect of urocortin involves cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinase. This is the first demonstration of a biological activity of urocortin in hippocampal neurons, suggesting a role for the peptide in adaptive responses of hippocampal neurons to potentially lethal oxidative and excitotoxic insults. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr,4F 02, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 71 TC 92 Z9 95 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 15 PY 2002 VL 22 IS 2 BP 404 EP 412 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 510JK UT WOS:000173204800011 PM 11784785 ER PT J AU Senatorov, VV AF Senatorov, VV TI Dark-field microscopy visualization of unstained axonal pathways using oil of wintergreen SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE dark-field microscopy; oil of wintergreen; axonal bundles; brain slices ID PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; NEURONS; RAT; PROTEIN; TISSUE; CORTEX; GOLD AB Despite enormous progress in the development of new morphological techniques, there is still not a simple technique for visualization of the fiber architecture in the mammalian brain. To develop such a technique, thick (400-600 mum) sections of the rat, mice, calf or postmortal human brain were fixed in paraformaldehyde, dehydrated in a series of ethanol and finally immersed in methyl salicylate. The major principle of this newly developed method was to make the neural tissue transparent, and then utilize the ability of neuronal fibers to deflect and deviate light directed from the side to render them visible. Dark-field illumination was used to create illuminating rays of light arriving at an angle exceeding the collecting angle of the objective lens, thus causing only the axonal pathways to be visible as a bright silver silhouette against a dark background. As a result, a three-dimensional structure of the whole white matter of the brain slice became clearly viewable. This technique worked equally well for mammalian brain frontal, sagittal and horizontal sections, as well as for the spinal cord sections. The method was appropriate for verification of axonal fiber courses in brain slice preparations used in electrophysiological experiments, including special applications, such as visualization of axonal bundles within neural transplants. Due to its simplicity, the technique can be successfully used even in an amateur laboratory having basic microscopy equipment and reagents. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Inst Expt Med, Pavlov Physiol Dept, St Petersburg, Russia. RP Senatorov, VV (reprint author), NIMH, Natl Inst Hlth, Bldg 10,Room 4C206 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. NR 23 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 15 PY 2002 VL 113 IS 1 BP 59 EP 62 DI 10.1016/S0165-0270(01)00474-5 PG 4 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 518VL UT WOS:000173688500007 PM 11741722 ER PT J AU Fried, KM Young, AE Yasuda, SU Wainer, IW AF Fried, KM Young, AE Yasuda, SU Wainer, IW TI The enantioselective determination of chlorpheniramine and its major metabolites in human plasma using chiral chromatography on a beta-cyclodextrin chiral stationary phase and mass spectrometric detection SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE chlorpheniramine; chiral chromatography; chiral stationary phase; beta-cyclodextrin; LC-MS ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CAPILLARY-ELECTROPHORESIS; ELECTROCHEMICAL DETECTION; ENANTIOMERS; RECOGNITION; SEPARATION; URINE AB A sensitive enantioselective high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of plasma concentrations of (-)(R)- and (+)(S)-chlorpheniramine (CP) and their metabolites, desmethyl-chlorpheniramine (DCP), didesmethyl-chorpheniramine (DDCP) and chlorpheniramine N-oxide (CPNO). Enantioselective separations were achieved on a beta-cyclodextrin chiral stationary phase (CYCLOBOND I 2000(TM)) with a mobile phase consisting of diethylamine acetate (0.25%, pH 4.4):methanol:acetonitrile {85:7.5:7.5, (v/v/v)} and a flow-rate of 0.5 ml/min. For CP, the enantioselectivity (alpha) of the separation was 1.12 with a resolution factor (R-s) of 1.17. The method was validated for CP by using mass spectroscopy detection (MSD). Concentrations of each enantiomer could be measured down to 125 pg/ml from a 1-ml plasma sample. Extracted calibration curves were linear from 0.13 to 50.00 ng/ml for each enantiomer. The method was applied to samples from two clinical studies. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Georgetown Univ, Dept Pharmacol, Washington, DC USA. Georgetown Univ, Clin Res Ctr, Bioanalyt Ctr, Washington, DC USA. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 13 TC 21 Z9 23 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 15 PY 2002 VL 27 IS 3-4 BP 479 EP 488 DI 10.1016/S0731-7085(01)00570-2 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 514GK UT WOS:000173430500012 PM 11755749 ER PT J AU Chen, S Zheng, X Schulze, KL Morris, T Bellen, H Stanley, EF AF Chen, S Zheng, X Schulze, KL Morris, T Bellen, H Stanley, EF TI Enhancement of presynaptic calcium current by cysteine string protein SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID N-TYPE; TRANSMITTER RELEASE; FUNCTIONAL INTERACTION; MUTANT DROSOPHILA; CA2+ CHANNELS; SYNTAXIN; CSP; MODULATION; FACE AB The isolated chick ciliary neuron calyx synapse preparation was used to test cysteine string protein (CSP) action on presynaptic N-type Ca2+ channels. Endogenous CSP was localized primarily to secretory vesicle clusters in the presynaptic nerve terminal. Introduction of recombinant CSP into the voltage clamped terminal resulted in a prominent increase in Ca2+ current amplitude. However, this increase could not be attributed to a change in Ca2+ channel kinetics, voltage dependence, prepulseinactivation, or G protein inhibition but was attributed to the recruitment of dormant channels. Secretory vesicle associated endogenous CSP may play an important role in enhancing Ca2+ channel activity at the transmitter release site. C1 Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. NINCDS, Synapt Mechanisms Sect, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Howard Hughes Med Inst, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Stanley, EF (reprint author), Toronto Western Res Inst, MP14-320,399 Bathurst St, Toronto, ON M5T 2S8, Canada. OI Bellen, Hugo/0000-0001-5992-5989 NR 29 TC 41 Z9 41 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JAN 15 PY 2002 VL 538 IS 2 BP 383 EP 389 DI 10.1113/jphysiol.2001.013397 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 522DW UT WOS:000173881300005 PM 11790807 ER PT J AU Rusnak, M House, SB Arima, H Gainer, H AF Rusnak, M House, SB Arima, H Gainer, H TI Ciliary neurotrophic factor increases the survival of magnocellular vasopressin and oxytocin neurons in rat supraoptic nucleus in organotypic cultures SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE neurodegeneration; axotomy; apoptosis; mRNA; hypothalamus; organotypic slices; c-Fos ID HYPOTHALAMO-NEUROHYPOPHYSEAL SYSTEM; CENTRAL-NERVOUS-SYSTEM; CYTOARCHITECTONIC SUBDIVISIONS; SUPRACHIASMATIC NUCLEUS; PARAVENTRICULAR NUCLEUS; EXPLANT CULTURES; CELL-DEATH; EXPRESSION; TISSUE; DEGENERATION AB Organotypic cultures of the rat hypothalamus are very useful models for the long-term study of parvocellular vasopressin (VP) neurons in the paraventricular (PVN) and suprachiasmatic (SCN) nuclei. However, they do not preserve significant numbers of V-P magnocellular neurons (VP-MCNs) in either the PVN or the supraoptic nucleus (SON). Vutskits et al. [(1998) Neuroscience 87:571-582] reported that ciliary neurotrophic factor (CNTF) was a selective survival factor for rat VP-MCNs in organotypic cultures of the rat hypothalamic paraventricular nucleus (PVN). We examined the effects of CNTF on the survival of these neurons in rat and mouse SONs. CNTF (10 ng/ml) in the culture media increased the survival of VP-MCNs by 6-fold and OT-MCNs by 3-fold. In the mouse, both OT- and VP-MCNs survive very well in organotypic cultures under standard culture conditions and the addition of CNTF had no further effect. Consistent with these results, in situ hybridization showed substantially higher levels of VP- and OT-mRNA in rat PVNs and SONS in the presence of CNTF, but produced no changes in these nuclei in the mouse. The optimum period for the survival effect of CNTF on MCNs in the rat hypothalamic cultures was in the first 7-10 days of culture and this effect is maintained for at least 5 additional days if CNTF is then removed from the medium. Therefore, using CNTF in the culture media can provide an opportunity for long-term studies of rat VP- and OT-MCNs in SONS in organotypic cultures. Microsc. Res. Tech. 56:101-112, 2002. Published 2002 Wiley-Liss, Inc.dagger. C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Sch Med, Dept Internal Med 1, Nagoya, Aichi 4668550, Japan. RP Gainer, H (reprint author), NINCDS, Neurochem Lab, NIH, Bldg 36,Room 4D-18, Bethesda, MD 20892 USA. RI Arima, Hiroshi/I-7383-2014 OI Arima, Hiroshi/0000-0003-3746-1997 NR 37 TC 20 Z9 21 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 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD JAN 15 PY 2002 VL 56 IS 2 BP 101 EP 112 DI 10.1002/jemt.10015 PG 12 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 513QM UT WOS:000173389900004 PM 11810713 ER PT J AU Makarova, KS Aravind, L Grishin, NV Rogozin, IB Koonin, EV AF Makarova, KS Aravind, L Grishin, NV Rogozin, IB Koonin, EV TI A DNA repair system specific for thermophilic Archaea and bacteria predicted by genomic context analysis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; HYPERTHERMOPHILIC ARCHAEON; EVOLUTIONARY INFORMATION; THERMOTOGA-MARITIMA; SECONDARY STRUCTURE; CONSERVED DOMAINS; ACTIVE-SITE; PSI-BLAST; SEQUENCE; PROTEIN AB During a systematic analysis of conserved gene context in prokaryotic genomes, a previously undetected, complex, partially conserved neighborhood consisting of more than 20 genes was discovered in most Archaea. (with the exception of Thermoplasma acidophilum and Halobacterium NRC-1) and some bacteria, including the hyperthermophiles, Thermotoga maritima and. Aquifex aeolicus. The gene composition and gene order in this neighborhood vary greatly between species, but all versions have a stable, conserved core that consists of five genes. One of the core genes encodes a predicted DNA helicase, often fused to a predicted HD-superfamily hydrolase, and another encodes a RecB family exonuclease; three core genes remain uncharacterized, but one of these might encode a nuclease of a new family. Two more genes that belong to this neighborhood and are present in most of the genomes in which the neighborhood was detected encode, respectively, a predicted HD-superfamily hydrolase (possibly a nuclease) of a distinct family and a predicted, novel DNA polymerase. Another characteristic feature of this neighborhood is the expansion of a superfamily of paralogous, uncharacterized proteins, which are encoded by at least 20-30% of the genes in the neighborhood. The functional features of the proteins encoded in this neighborhood suggest that they comprise a previously undetected DNA repair system, which, to our knowledge, is the first repair system largely specific for thermophiles to be identified. This hypothetical repair system might be functionally analogous to the bacterial-eukaryotic system of translesion, mutagenic repair whose central components are DNA polymerases of the UmuC-DinB-Rad30-Rev1 superfamily, which typically are missing in thermophiles. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 380, Bethesda, MD 20894 USA. NR 77 TC 156 Z9 178 U1 5 U2 29 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 2002 VL 30 IS 2 BP 482 EP 496 DI 10.1093/nar/30.2.482 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 516JY UT WOS:000173551200009 PM 11788711 ER PT J AU Park, GT Morasso, MI AF Park, GT Morasso, MI TI Bone morphogenetic protein-2 (BMP-2) transactivates Dlx3 through Smad1 and Smad4: alternative mode for Dlx3 induction in mouse keratinocytes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-BINDING PROTEINS; TGF-BETA; OSTEOBLAST DIFFERENTIATION; EPIDERMAL DIFFERENTIATION; VERTEBRATE DEVELOPMENT; HOMEODOMAIN GENE; TRANSGENIC MICE; HOMEOBOX GENE; TRANSCRIPTION; EXPRESSION AB Expression of the Dlx3 homeodomain gene is induced in terminally differentiated epidermal cells. Dlx3 regulates gene expression in skin and plays important roles in patterning of the embryonic ectoderm through differential sensitivity to bone morphogenetic protein (BMP) signaling. We analyzed the expression of BMP family members in murine keratinocytes; BMP-2 is expressed in proliferative basal and differentiated suprabasal keratinocytes. BMP-2 induced transcription of Dlx3 within 12 h of treatment of keratinocytes cultured in vitro. We proceeded to delineate the BMP-2-responsive region to an area between -1917 and -1747 in the Dlx3 promoter. Gel shift assays with recombinant Smad1 and Smad4 demonstrated that this DNA fragment (-1917 to -1747) was competent in the formation of protein-DNA complexes. By deletion and mutational analyses we localized a Smad1/Smad4-binding site containing a GCAT motif, which showed similarity to other TGF-beta family responsive elements. Supershift assays with keratinocyte nuclear extracts and antibodies against members of the Smad family showed that this motif was able to form a complex with Smad1. Mutation of the Smad1/Smad4-binding site inhibited transcriptional activation of the Dlx3 gene by BMP-2. In the hair follicle, where Dlx3 is expressed in the hair matrix cells, BMP-2 also activates Dlx3 transcription. These results provide a possible mechanism of action for the BMP signaling pathway on the regulation of Dl x3. C1 NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [Z01 AR041124-06] NR 42 TC 51 Z9 59 U1 0 U2 5 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 2002 VL 30 IS 2 BP 515 EP 522 DI 10.1093/nar/30.2.515 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 516JY UT WOS:000173551200012 PM 11788714 ER PT J AU Dolle, MET Snyder, WK Dunson, DB Vijg, J AF Dolle, MET Snyder, WK Dunson, DB Vijg, J TI Mutational fingerprints of aging SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SOMATIC MUTATIONS; TRANSGENIC MICE; MISMATCH REPAIR; AGE; SPECTRA; CANCER; GENOME AB Using a lacZ plasmid transgenic mouse model, spectra of spontaneous point mutations were determined in brain, heart, liver, spleen and small intestine in young and old mice. While similar at a young age, the mutation spectra among these organs were significantly different in old age. In brain and heart G:C-->A:T transitions at CpG sites were the predominant mutation, suggesting that oxidative damage is not a major mutagenic event in these tissues. Other base changes, especially those affecting A:T base pairs, positively correlated with increasing proliferative activity of the different tissues. A relatively high percentage of base changes at A:T base pairs and compound mutants were found in both spleen and spontaneous lymphoma, suggesting a possible role of the hypermutation process in splenocytes in carcinogenesis. The similar mutant spectra observed at a young age may reflect a common mutation mechanism for all tissues that could be driven by the rapid cell division that takes place during development. However, the spectra of the young tissues did not resemble that of the most proliferative aged tissue, implying that replicative history per se is not the underlying causal factor of age-related organ-specific differences in mutation spectra. Rather, differences in organ function, possibly in association with replicative history, may explain the divergence in mutation spectra during aging. C1 Univ Texas, Hlth Sci Ctr, Sam & Ann Barshop Ctr Longev & Aging Studies, San Antonio, TX 78245 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dolle, MET (reprint author), Univ Texas, Hlth Sci Ctr, Sam & Ann Barshop Ctr Longev & Aging Studies, 15355 Lambda Dr,STCBM 2-200, San Antonio, TX 78245 USA. FU NCI NIH HHS [1R01CA75653-03]; NIA NIH HHS [1PO1AG17242-01, AG13319-05, P01 AG017242, P30 AG013319] NR 26 TC 49 Z9 54 U1 0 U2 2 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 2002 VL 30 IS 2 BP 545 EP 549 DI 10.1093/nar/30.2.545 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 516JY UT WOS:000173551200015 PM 11788717 ER PT J AU Noskov, V Kouprina, N Leem, SH Koriabine, M Barrett, JC Larionov, V AF Noskov, V Kouprina, N Leem, SH Koriabine, M Barrett, JC Larionov, V TI A genetic system for direct selection of gene-positive clones during recombinational cloning in yeast SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSFORMATION-ASSOCIATED RECOMBINATION; SACCHAROMYCES-CEREVISIAE; ARTIFICIAL CHROMOSOMES; HUMAN DNA; FRAGMENTS; SEGMENTS; SEQUENCE; VECTOR AB Transformation-associated recombination (TAR) Is a cloning technique that allows specific chromosomal regions or genes to be isolated directly from genomic DNA without prior construction of a genomic library. This technique Involves homologous recombination during spheroplast transformation between genomic DNA and a. TAR vector that has 5' and 3' gene targeting sequences (hooks). Typically, TAR cloning produces positive YAC recombinants at a frequency of similar to0.5%; the positive clones are identified by PCR or colony hybridization. This paper describes a novel TAR cloning procedure that selects positive clones by positive and negative genetic selection. This system utilizes a TAR vector with two targeting hooks, HISS as a positive selectable marker, URA3 as a negative selectable marker and a gene-specific sequence called a loop sequence. The loop sequence lies distal to a targeting hook sequence in the chromosomal target, but proximal to the targeting hook and URA3 in the TAR vector. When this vector recombines with chromosomal DNA at the gene-specific targeting hook, the recombinant YAC product carries two copies of the loop sequence, therefore, the URA3 negative selectable marker becomes mitotically unstable and is, lost at high frequency by direct repeat recombination Involving the loop sequence. Positive clones are identified by selecting against URA3. This method produces positive YAC recombinants at a frequency of similar to40%. This novel TAR cloning method provides a powerful tool for structural and functional analysis of complex genomes. C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. Dong A Univ, Dept Biol, Pusan 604714, South Korea. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, NIH, Bldg 37,Room 5032, Bethesda, MD 20892 USA. NR 23 TC 14 Z9 18 U1 0 U2 6 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 2002 VL 30 IS 2 AR e8 DI 10.1093/nar/30.2.e8 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 516JY UT WOS:000173551200032 PM 11788734 ER PT J AU Raedler, TJ Knable, MB Jones, DW Urbina, RA Gorey, JG Lee, KS Egan, M Weinberger, DR AF Raedler, TJ Knable, MB Jones, DW Urbina, RA Gorey, JG Lee, KS Egan, M Weinberger, DR TI Reduced central muscarinic acetylcholine receptor availability in vivo in schizophrenic patients SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Univ Hamburg, Dept Psychiat, D-20246 Hamburg, Germany. Stanley Fdn Res Programs, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JAN 15 PY 2002 VL 53 IS 3 SU S SI SI BP 116 EP 116 PG 1 WC Psychiatry SC Psychiatry GA 520VJ UT WOS:000173802600295 ER PT J AU Elvevag, B Weickert, T Wechsler, M Coppola, R Weinberger, DR Goldberg, TE AF Elvevag, B Weickert, T Wechsler, M Coppola, R Weinberger, DR Goldberg, TE TI An investigation of the integrity of semantic boundaries in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE semantic boundaries; schizophrenia ID VERBAL FLUENCY; THOUGHT-DISORDER; MEMORY AB Organizing information and knowledge, and hence categorization, requires specifying boundaries between items, concepts and words. Over-inclusiveness in categorization may be seen as looseness of association; over-inclusive thinking was an early description of schizophrenic thinking. Recent studies suggest semantic memory problems in schizophrenia, and that thought disorder is associated with a disorganized semantic network. One such study [Psychol. Med. 24 (1994) 193], using a word categorization task, found patients slowest to respond to items semantically related to, but outside the category, whereas controls were slower responding to items sharing less features of the category (i.e. borderline). The authors suggested that there is an outward shift of semantic category boundaries in schizophrenia. In Experiment 1, we replicated Chen et al.'s (1994) methods, but did not find this qualitative difference in patients (28 patients, 26 controls). We extended this question in Experiment 2 to a more visual domain using pictures that 'morphed' from one entity into another and asked participants to decide when they no longer considered an item to be that item (20 patients, 25 controls). We did not find a difference between patients and controls in their sensitivity to detect boundaries of representations. These two experiments do not support the notion that thought disorder with postulated looseness of association or over-inclusive thinking is related to reduced awareness of boundaries of semantic category membership or entities, and inferentially their featural network. Despite anomalies in the semantic system in schizophrenia, we found aspects to be intact. This specificity of semantic processing is promising, suggesting that research will be informative as to how semantic memory is constructed, and thus how it can selectively break down. Moreover, this study indicates that patients do not 'fail' semantic tasks (e.g. priming) because of globally disorganized decision-making: here their capability to make precise distinctions between representations was intact. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Room 4S235,MSC 1379,Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 17 Z9 17 U1 1 U2 2 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 15 PY 2002 VL 53 IS 3 BP 187 EP 198 DI 10.1016/S0920-9964(01)00202-X PG 12 WC Psychiatry SC Psychiatry GA 511KV UT WOS:000173263800003 PM 11738532 ER PT J AU Freidlin, B Korn, EL AF Freidlin, B Korn, EL TI A testing procedure for survival data with few responders SO STATISTICS IN MEDICINE LA English DT Article DE survival data; trials with few responders ID RANK-TESTS; NONRESPONDERS AB In the course of designing a clinical trial, investigators are often faced with the possibility that only a fraction of the patients will benefit from the experimental treatment. A proper clinical trial design requires prospective specification of the testing procedures to be used in the analysis. In the absence of reliable prognostic factors capable of identifying the appropriate subset of patients, there is a need for a test procedure that will be sensitive to a range of possible fractions of responders. Focusing on survival data, we propose guidelines for selecting a proper test procedure based on the anticipated proportion of responding patients. These guidelines suggest that the logrank test should be used when the fraction of responders is expected to be greater than 0.5, otherwise procedures based on weighted linear rank tests are preferable. Overall this approach provides good power properties when the treatment affects only a small proportion of patients while protecting against Substantial loss of power when all patients are affected. Use of the procedure is illustrated with data from two published randomized studies. C1 NCI, BRB, DCTD, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, BRB, DCTD, 6130 Execut Blvd EPN 8122,MSC 7434, Bethesda, MD 20892 USA. NR 19 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2002 VL 21 IS 1 BP 65 EP 78 DI 10.1002/sim.983 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 509YF UT WOS:000173177300006 PM 11782051 ER PT J AU Park, T Lee, YJ AF Park, T Lee, YJ TI Covariance models for nested repeated measures data: analysis of ovarian steroid secretion data SO STATISTICS IN MEDICINE LA English DT Article DE composite covariance; covariance structures; random effect models ID LONGITUDINAL DATA-ANALYSIS AB We consider several covariance models for analysing repeated measures data from a study of ovarian steroid secretion in reproductive-aged women. Urinary oestradiol and serum oestrogen were repeatedly observed over three or four menstrual periods, each period separated by one year. For each menstrual period, daily first morning urine specimens were collected 8 to 18 times, and serum specimens 2 to 5 times. Thus, measurements were repeatedly observed over menstrual cycle days within menstrual periods. Owing to missing observations, the number of observations differed from subject to subject. In this study, there were two repeat factors: menstrual cycle day and menstrual period. The first repeat factor, cycle day, is nested within the second repeat factor, menstrual period. In analysing these nested repeated measures data, the correlation structure should be modelled that will account for both repeat factors. We present several covariance models for defining appropriate covariance structures for these data. C1 Seoul Natl Univ, Dept Stat, Seoul 151742, South Korea. NICHHD, Biometry & Math Stat Branch, Bethesda, MD 20892 USA. Hanyang Univ, Seoul 133791, South Korea. RP Park, T (reprint author), Seoul Natl Univ, Dept Stat, San 56-1 Shillim Dong, Seoul 151742, South Korea. NR 14 TC 20 Z9 20 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2002 VL 21 IS 1 BP 143 EP 164 DI 10.1002/sim.949 PG 22 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 509YF UT WOS:000173177300011 PM 11782056 ER PT J AU Krishnamurti, C Stewart, MW Cutting, MA Rothwell, SW AF Krishnamurti, C Stewart, MW Cutting, MA Rothwell, SW TI Assessment of omega-fatty-acid-supplemented human platelets for potential improvement in long-term storage SO THROMBOSIS RESEARCH LA English DT Article; Proceedings Paper CT 18th Congress of the International-Society-on-Thrombosis-and-Haemostasis CY JUL 06-12, 2001 CL PARIS, FRANCE SP Int Soc Thrombosis & Haemostasis DE platelet function; omega-fatty acids; hemostatic efficacy; rabbit model ID FISH-OIL; DIETARY SUPPLEMENTATION; FLOW-CYTOMETRY; DOUBLE-BLIND; IN-VIVO; OMEGA-3-FATTY-ACIDS; RABBIT; MODEL; ACTIVATION; PLASMA AB Uptake of omega (omega) - 3 fatty acids can influence membrane stability and cell mobility. We investigated the effects of omega - 3 and - 6 fatty acids on the hemostatic efficacy of human platelets using an in vivo rabbit bleeding model. In vitro assays such as platelet aggregation, vWF bead-mediated ATP release and platelet adhesion to beads {measured by the residual platelet count [RPC],free platelet count after reacting with the beads}/{baseline platelet count} x 100=%RPC; a high %RPC indicates reduced platelet function) were conducted on platelets treated with 1% fish oil (omega - 3); 2% fish oil emulsion or 1% soy oil (omega - 6). Oil treatment of platelets reduced the vWF bead-induced ATP release insignificantly. Addition of omega-3 agents reduced physical reactivity (%RPC) with the vWF beads by a factor of 1.2 (oil) and 1.9 (emulsion). The omega - 6 oil enhanced reactivity by a factor of 1.7. After washing to remove excess reagent, platelet resuspension was most efficient with the omega - 3 emulsion. Platelet function was higher with the omega - 3-treated platelets (%RPC=52.3%, omega - 3 oil; 63.3%, omega - 3 emulsion vs. 85%, omega - 6 oil; 82% untreated platelets). Ethyl-palmitate-treated thrombocytopenic rabbits were infused with human platelets. Survival times of the treated platelets, as monitored by flow cytometry (6.2 - 8.2 h) were comparable to untreated platelets (8.6 h). In the rabbit kidney injury model, blood loss after infusion of the treated platelets was similar to that of saline-infused rabbits (75.3 +/- 3.4 g). However, platelets washed prior to infusion reduced blood loss to a value comparable to that of fresh platelets (48.3 +/- 5 g). Furthermore, the presence of the infused platelets at the injury site was clearly visualized using FITC-tagged anti CD42a antibody. Thus, the omega - 3-based agents protect the platelets from damage during the washing procedure as demonstrated in vitro by improved platelet resuspension, low %RPC, high stimulus-responsive ATP secretion and a reduction in blood loss in vivo. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Walter Reed Army Inst Res, Dept Blood Res, Silver Spring, MD 20910 USA. Thrombotics Inc, Edmonton, AB, Canada. RP Krishnamurti, C (reprint author), NHLBI, NIH, DEA, Review Branch,Rockledge Ctr 2, Room No 7206,6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 31 TC 4 Z9 4 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD JAN 15 PY 2002 VL 105 IS 2 BP 139 EP 145 AR PII S0049-3848(02)00009-9 DI 10.1016/S0049-3848(02)00009-9 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 534JQ UT WOS:000174582600006 PM 11958804 ER PT J AU Liu, J Liu, YP Powell, DA Waalkes, MP Klaassen, CD AF Liu, J Liu, YP Powell, DA Waalkes, MP Klaassen, CD TI Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues SO TOXICOLOGY LA English DT Article DE arsenic; acute toxicity; mdr1a/1b(-/-) mice; tissue arsenic accumulation ID HEAVY-METAL RESISTANCE; BARRIER P-GLYCOPROTEIN; BILIARY-EXCRETION; CARCINOMA-CELLS; DRUG; GLUTATHIONE; TRANSPORTERS; CONTRIBUTE; EXPRESSION; GENES AB Arsenic is an environmental toxicant. Active extrusion via the ArsAB pump is a mechanism for arsenic detoxication in bacteria. However, how arsenic is effluxed from mammalian cells is not completely known. Our recent work shows that acquired arsenic resistance is associated with overexpression of P-glycoprotein and can be reversed by PSC833, an inhibitor for P-glycoprotein. This study utilized the mdrla/l b( -/- ) mice, which lack mdrla-type P-glycoproteins. to examine whether these mice are sensitive to arsenic toxicity and have higher arsenic accumulation in their tissues. The mdrl a/l b(- / - ) and wild-type FVB mice were given arsenic as sodium arsenite (12-19 mg/kg, sc) and toxicity was examined 24 h later. The mdrla/lb( - / -) mice were more sensitive than wild-type mice to arsenite-induced lethality, with LD50 of 14.5 and 17 mg/kg, respectively. Histologically, arsenite produced more frequent and more severe lesions in the liver and kidney of the mdrla/lb(-/-) mice than in wild-type mice. Serum alanine amino transferase activity and blood urea nitrogen levels, indicative of hepatic and renal damage respectively, were increased 4 to 6-fold in the mdrla/lb(-/-) mice as compared with 1-2-fold increases in wild-type mice. The mdrla/lb(-/-) mice accumulated more arsenic in the liver (15.3 vs. 5.2 mug/g), kidney (7.23 vs. 3.22 mug/g), small intestine (3.98 vs 1.57 mug/g) and brain (0.45 vs. 0.17 mug/g), as compared with wild-type mice 24 h after sodium arsenite (14 mg/kg, s.c.) administration. In summary, this study demonstrated that the mdrla/lb( - / -) mice were more sensitive to acute arsenic toxicity and accumulated more arsenic than wild-type mice, suggesting that P-glycoproteins are involved, at least in part, in arsenic efflux in mammalians. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, NCI, NIEHS, Res Triangle Pk, NC 27709 USA. Univ Kansas, Med Ctr, Dept Pharmacol, Kansas City, KS 66103 USA. Data Management Serv Inc, NCI, Frederick, MD 21701 USA. RP Liu, J (reprint author), Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, NCI, NIEHS, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [ES-09716] NR 27 TC 54 Z9 56 U1 0 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JAN 15 PY 2002 VL 170 IS 1-2 BP 55 EP 62 DI 10.1016/S0300-483X(01)00532-7 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 511JU UT WOS:000173261500006 PM 11750083 ER PT J AU Treanor, J Keitel, W Belshe, R Campbell, J Schiff, G Zangwill, K Wolff, M Klimov, A Levandowski, R Lambert, L AF Treanor, J Keitel, W Belshe, R Campbell, J Schiff, G Zangwill, K Wolff, M Klimov, A Levandowski, R Lambert, L TI Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults SO VACCINE LA English DT Article DE influenza vaccine; healthy adults; dose response ID ANTIBODY-RESPONSE; VIRUS-VACCINE; REACTOGENICITY; A/USSR/77; SERUM AB Because of delays in the manufacturing of the 2000-2001, trivalent inactivated influenza vaccine in the US, there were concerns that there might be shortages of vaccine supply in the US, Therefore, we conducted a prospective, randomized, open-label, multicenter trial at six C academic medical centers in the US, to evaluate the immunogenicity of a half dose of inactivated vaccine in healthy adults. Healthy adults between the ages of 18 and 49 were randomized to receive either a full 0.5 ml (15.5 mug of each HA antigen) dose or a 0.25 ml (7.75 mug of each HA antigen) dose of the 2000-2001 trivalent inactivated influenza vaccine by intramuscular injection. Sera were obtained for assessment of hemagglutination-inhibiting antibody to each of the three strains contained in the vaccine before and 21 days after vaccination. The proportions of individuals achieving a post-vaccination titer of greater than or equal to1:40, the geometric mean titers (GMTs) of post-vaccination antibody, and the proportions of individuals with a four-fold or greater increase in antibody were lower for all three strains in those receiving 0.25 ml of vaccine compared to those receiving 0.5 ml. However, the differences were small for all three antigens. The upper 95% confidence limits for differences between 0.25 and 0.5 ml doses were less than 20% for rates of achieving a titer of greater than or equal to1:40 and four-fold response, and less than 1.5 for the ratios of GMTs between dose groups, for all three vaccine antigens. These results suggest that when vaccine is in short supply, a strategy using a half dose in healthy adults could increase the number of people vaccinated with relatively little adverse impact on vaccine immunogenicity. (C) 2002 Published by Elsevier Science Ltd. C1 Univ Rochester, Infect Dis Unit, Rochester, NY 14642 USA. Baylor Coll Med, Houston, TX 77030 USA. St Louis Univ, St Louis, MO 63103 USA. Univ Maryland, Baltimore, MD 21201 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Univ Calif Los Angeles, Ctr Vaccine Res, Los Angeles, CA 90024 USA. EMMES Corp, Rockville, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. US FDA, Bethesda, MD 20014 USA. NIAID, Bethesda, MD 20892 USA. RP Treanor, J (reprint author), Univ Rochester, Infect Dis Unit, 601 Elmwood Ave, Rochester, NY 14642 USA. FU NCRR NIH HHS [M01 RR 00425, M01 RR0044-40]; NIAID NIH HHS [N01 AI 45250, N01 AI 45249, N01 AI 45252, N01 AI 65313, T32 AI 07524, N01 AI 45251, N01 AI 45248, N01 AI 65316]; PHS HHS [N01 45250] NR 15 TC 55 Z9 56 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 15 PY 2002 VL 20 IS 7-8 BP 1099 EP 1105 AR PII S0264-410X(01)00440-6 DI 10.1016/S0264-410X(01)00440-6 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 521TV UT WOS:000173858200016 PM 11803070 ER PT J AU Dabdoub, A Payne, R Jinks, RN AF Dabdoub, A Payne, R Jinks, RN TI Protein kinase C-induced disorganization and endocytosis of photosensitive membrane in Limulus ventral photoreceptors SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE PKC; rhodopsin; endocytosis; phototransduction; rhabdom; G protein-coupled receptor; membrane turnover ID ROD OUTER SEGMENTS; PHOTOTRANSDUCTIVE MEMBRANE; BETA(2)-ADRENERGIC RECEPTOR; DROSOPHILA PHOTORECEPTORS; INOSITOL-TRISPHOSPHATE; PHOTOEXCITED RHODOPSIN; INTRACELLULAR CALCIUM; SIGNAL-TRANSDUCTION; VISUAL EXCITATION; RHABDOM TURNOVER AB Protein kinase C (PKC) desensitizes the light response in photoreceptors from the ventral optic nerve of the horseshoe crab Limulus. Photoisomerization of Limulus rhodopsin leads to phosphoinositide hydrolysis, resulting in the production of inositol trisphosphate and diacylglycerol (DAG). Inositol trisphosphate mobilizes intracellular stores of Ca2+, resulting in photoreceptor excitation in Limulus, while DAG may activate PKC. We investigated whether PKC-mediated desensitization of the photoresponse is accompanied by ultrastructural changes in the rhodopsin-bearing photosensitive membrane (rhabdom) in Limulus ventral photoreceptors. PKC activation by (-)-indolactam V in darkness induces disorganization and swelling of the rhodopsin-containing microvilli and endocytosis of rhabdomeral membrane. The effects of (-)-indolactam V on dark-adapted photoreceptor ultrastructure are reversible, are stereospecific, are blocked by coapplication of PKC inhibitors, and closely match those induced by continuous, bright light. Rhabdom disorganization and endocytosis via PKC activation may, therefore, contribute to desensitization of the light-adapted photoreceptor. J. Comp. Neurol. 442:217-225, 2002. (C) 2001 Wiley-Liss, Inc. C1 Franklin & Marshall Coll, Dept Biol, Lancaster, PA 17604 USA. NIDCD, NIH, Rockville, MD 20850 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. RP Jinks, RN (reprint author), Franklin & Marshall Coll, Dept Biol, Lancaster, PA 17604 USA. FU NEI NIH HHS [EY-13196, EY-07743, R15 EY013196] NR 60 TC 9 Z9 9 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 14 PY 2002 VL 442 IS 3 BP 217 EP 225 DI 10.1002/cne.10091 PG 9 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 507CP UT WOS:000173009600003 PM 11774337 ER PT J AU Moskovitz, J Singh, VK Requena, J Wilkinson, BJ Jayaswal, RK Stadtman, ER AF Moskovitz, J Singh, VK Requena, J Wilkinson, BJ Jayaswal, RK Stadtman, ER TI Purification and characterization of methionine sulfoxide reductases from mouse and Staphylococcus aureus and their substrate stereospecificity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE methionine sulfoxide; oxidative stress; methionine sulfoxide reductase; free radicals; methionine oxidation; selenoprotein; stereospecificity ID OXIDATIVE STRESS; EXPRESSION; PROTEINS; GENE; REDUCTION; RESIDUES; MSRA AB Many organisms have been shown to possess a methionine sulfoxide reductase (MsrA), exhibiting high specificity for reduction the S form of free and protein-bound methionine sulfoxide to methionine. Recently, a different form of the reductase (referred to as MsrB) has been detected in several organisms. We show here that MsrB is a selenoprotein that exhibits high specificity for reduction of the R forms of free and protein-bound methionine sulfoxide. The enzyme was partially purified from mouse liver and a derivative of the mouse MsrB gene, in which the codon specifying selenocystein incorporation was replaced by the cystein codon, was prepared, cloned, and overexpressed in Escherichia coli. The properties of the modified MsrB protein were compared directly with those of MsrA. Also, we have shown that in Staphylococcus aureus there are two MsrA and one nonselenoprotein MsrB, which demonstrates the same substrate stereospecificity as the mouse MsrB. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Illinois State Univ, Dept Biol Sci, Microbiol Grp, Normal, IL 61790 USA. RP Moskovitz, J (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. FU NIAID NIH HHS [1R21-AI43970-01A2] NR 17 TC 101 Z9 108 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 11 PY 2002 VL 290 IS 1 BP 62 EP 65 DI 10.1006/bbrc.2001.6171 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 515DV UT WOS:000173480900010 PM 11779133 ER PT J AU Vinogradova, TM Bogdanov, KY Lakatta, EG AF Vinogradova, TM Bogdanov, KY Lakatta, EG TI beta-Adrenergic stimulation modulates ryanodine receptor Ca2+ release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells SO CIRCULATION RESEARCH LA English DT Article DE sinoatrial node; beta-adrenergic stimulation; ryanodine receptor; local Ca2+ release ID RAT VENTRICULAR MYOCYTES; SARCOPLASMIC-RETICULUM; CALCIUM SPARKS; PROTEIN-KINASE; HEART; CHANNELS; CONTRACTION; CURRENTS; MUSCLE; AUTOMATICITY AB It has long been recognized that activation of sympathetic beta-adrenoceptors (beta-ARs) increases the spontaneous beating rate of sinoatrial nodal cells (SANCs); however, the specific links between stimulation of beta-ARs and the resultant increase in firing rate remain an enigma. In the present study, we show that the positive chronotropic effect of beta-AR stimulation is critically dependent on localized subsarcolemmal ryanodine receptor (RyR) Ca2+ releases during diastolic depolarization (CRDD). Specifically, isoproterenol (ISO: 0.1 mumol/L) induces a 3-fold increase in the number of CRDDs per cycle; a shift to higher CRDD amplitudes (from 2.00+/-0.04 to 2.17+/-0.03 F/F-0; P<0.05 [F and F-0 refer to peak and minimal fluorescence]); and an increase in spatial width (from 3.80+/-0.44 to 5.45+/-0.47 μm; P<0.05). The net effect results in an augmentation of the amplitude of the local preaction potential subsarcolemmal Ca2+ transient that, in turn, accelerates the diastolic depolarization rate, leading to an increase in SANC firing rate. When RyRs are disabled by ryanodine, beta-AR stimulation fails to amplify subsarcolemmal Ca2+ releases, fails to augment the diastolic depolarization rate, and fails to increase the SANC firing rate, despite preserved beta-AR stimulation-induced augmentation of L-type Ca2+ current amplitude. Thus, the RyR Ca2+ release acts as a switchboard to link beta-AR stimulation to an increase in SANC firing rate: recruitment of additional localized CRDDs and partial synchronization of their occurrence by beta-AR stimulation lead to an increase in the heart rate. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Vinogradova, TM (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 116 Z9 118 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 11 PY 2002 VL 90 IS 1 BP 73 EP 79 DI 10.1161/hh0102.102271 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 513PJ UT WOS:000173386700015 PM 11786521 ER PT J AU Chipuk, JE Cornelius, SC Pultz, NJ Jorgensen, JS Bonham, MJ Kim, SJ Danielpour, D AF Chipuk, JE Cornelius, SC Pultz, NJ Jorgensen, JS Bonham, MJ Kim, SJ Danielpour, D TI The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT VENTRAL PROSTATE; STEROID BINDING CHARACTERISTICS; BASAL EPITHELIAL-CELLS; GROWTH-FACTOR-BETA-1 GENE; AP-1 COMPLEX; CANCER; EXPRESSION; PROTEIN; COACTIVATOR; DOMAIN AB In the prostate, androgens negatively regulate the expression of transforming growth factor-beta (TGF-beta) ligands and receptors and Smad activation through unknown mechanisms. We show that androgens (dihydrotestosterone and R1881) down-regulate TGF-beta1-induced expression of TGF-beta1, c-Fos, and Egr-1 in the human prostate adenocarcinoma cell line, LNCaP. Moreover, 5alpha-dihydrotestosterone (DHT) inhibits TGF-beta1 activation of three TGF-beta1-responsive promoter constructs, 3TP-luciferase, AP-1-luciferase, and SBE4(BV)-luciferase, in LNCaP cells either with or without enforced expression of TGF-beta receptors (TbetaRI and TbetaRII). Similarly, DHT inhibits the activation of Smad-binding element (SBE)4(BV)-luciferase by either constitutively activated TbetaRI (T204D) or constitutively activated Smad3 (S3*). Activation of SBE4(BV)-luciferase by S3* in the NRP-154 prostatic cell line, which is androgen receptor (AR)-negative but highly responsive to TGF-beta1, is blocked by co-transfection with either full-length AR or AR missing the DNA binding domain. Immunoprecipitation and GST pull-down assays show that AR directly associates with Smad3 but not Smad2 or Smad4. Electrophoretic mobility shift assays indicate that the AR ligand binding domain directly inhibits the association of Smad3 to the Smad-binding element. In conclusion, our data demonstrate for the first time that ligand-bound AR inhibits TGF-beta transcriptional responses through selectively repressing the binding of Smad3 to SBE. C1 Case Western Reserve Univ, Univ Hosp Cleveland, Ireland Canc Ctr, Res Labs, Cleveland, OH 44106 USA. Case Western Reserve Univ, Univ Hosp Cleveland, Dept Pharmacol, Cleveland, OH 44106 USA. NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Danielpour, D (reprint author), Case Western Reserve Univ, Ireland Canc Ctr, Res Labs, Samuel Gerber Bldg,Ste 200,Lab 3,11001 Cedar Rd, Cleveland, OH 44106 USA. OI Chipuk, Jerry Edward/0000-0002-1337-842X FU NCI NIH HHS [P30CA43703, 1R01-CA3069-01] NR 81 TC 118 Z9 128 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1240 EP 1248 DI 10.1074/jbc.M108855200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800049 PM 11707452 ER PT J AU Parent, CA Borleis, J Devreotes, PN AF Parent, CA Borleis, J Devreotes, PN TI Regulation of adenylyl cyclases by a region outside the minimally functional cytoplasmic domains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID G-PROTEINS; DICTYOSTELIUM DEVELOPMENT; CATALYTIC MECHANISM; BETA-GAMMA; STIMULATION; MUTANTS; IDENTIFICATION; EXPRESSION; ACTIVATION; G(S-ALPHA) AB The highly conserved topological structure of G protein-activated adenylyl cyclases seems unnecessary because the soluble cytoplasmic domains retain regulatory and catalytic properties. Yet, we previously isolated a constitutively active mutant of the Dictyostelium discoideum adenylyl cyclase harboring a single point mutation in the region linking the cytoplasmic and membrane domains (Leu-394). We show here that multiple amino acid substitutions at Leu-394 also display constitutive activity. The constitutive activity of these mutants is not dependent on G proteins or cytosolic regulators, although some of the mutants can be activated to higher levels than wild type. Combining a constitutive mutation such as L394T with K482N, a point mutation that renders the enzyme insensitive to regulators, restores an enzyme with wild type properties of low basal activity and the capacity to be activated by G proteins. Thus regions located outside the cytoplasmic loops of adenylyl cyclases are not only important in the acquisition of an activated conformation, they also have impact on other regions within the catalytic core of the enzyme. C1 Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, NIH, 37 Convent Dr,Bldg 37,Rm 1E24, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM57874] NR 36 TC 7 Z9 7 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1354 EP 1360 DI 10.1074/jbc.M106430200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800064 PM 11694527 ER PT J AU Hofmann, A Grella, M Botos, I Filipowicz, W Wlodawer, A AF Hofmann, A Grella, M Botos, I Filipowicz, W Wlodawer, A TI Crystal structures of the semireduced and inhibitor-bound forms of cyclic nucleotide phosphodiesterase from Arabidopsis thaliana SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RIBOSE 1'',2''-CYCLIC PHOSPHATE; ELECTRON-DENSITY MAPS; DISULFIDE BONDS; RIBONUCLEASE-A; WHEAT-GERM; PROTEIN; PURIFICATION; DIFFRACTION; METABOLISM; MOLSCRIPT AB The crystal structure of the semireduced form of cyclic nucleotide phosphodiesterase (CPDase) from Arabidopsis thaliana has been solved by molecular replacement and refined at the resolution of 1.8 Angstrom. We have previously reported the crystal structure of the native form of this enzyme, whose main target is ADP-ribose 1",2"-cyclic phosphate, a product of the tRNA splicing reaction. CPDase possesses six cysteine residues, four of which are involved in forming two intra-molecular disulfide bridges. One of these bridges, between Cys-104 and Cys-110, is opened in the semireduced CPDase, whereas the other remains intact. This change of the redox state leads to a conformational rearrangement in the loop covering the active site of the protein. While the native structure shows this partially disordered loop in a coil conformation, in the semireduced enzyme the N-terminal lobe of this loop winds up and elongates the preceding alpha-helix. The semireduced state of CPDase also enabled co-crystallization with a putative inhibitor of its enzymatic activity, 2',3'-cyclic uridine vanadate. The ligand is bound within the active site, and the mode of binding is in agreement with the previously proposed enzymatic mechanism. Selected biophysical properties of the oxidized and the semireduced CPDase are also discussed. C1 NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. Friedrich Miescher Inst, CH-4002 Basel, Switzerland. RP Hofmann, A (reprint author), NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. RI Hofmann, Andreas/B-9515-2008 OI Hofmann, Andreas/0000-0003-4408-5467 NR 33 TC 22 Z9 24 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1419 EP 1425 DI 10.1074/jbc.M107889200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800072 PM 11694509 ER PT J AU Wang, J Whitman, MC Natarajan, K Tormo, J Mariuzza, RA Margulies, DH AF Wang, J Whitman, MC Natarajan, K Tormo, J Mariuzza, RA Margulies, DH TI Binding of the natural killer cell inhibitory receptor Ly49A to its major histocompatibility complex class I ligand - Crucial contacts include both H-2D(d) and beta(2)-microglobulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 3-DIMENSIONAL STRUCTURE; MONOCLONAL-ANTIBODIES; LY-49A RECOGNIZES; HYDROGEN-BOND; MHC; PEPTIDE; NK; MOLECULES; MURINE; SPECIFICITY AB Ly49A, an inhibitory C-type lectin-like mouse natural killer cell receptor, functions through interaction with the major histocompatibility complex class I molecule, H-2D(d). The x-ray crystal structure of the Ly49A(.)H-2D(d) complex revealed that homodimeric Ly49A interacts at two distinct sites of H-2Dd: Site 1, spanning one side of the alpha1 and alpha2 helices, and Site 2, involving the alpha1, alpha2, alpha3, and beta(2)m domains. Mutants of Ly49A, H-2D(d), and beta(2)-microglobulin at intermolecular contacts and the Ly49A dimer interface were examined for binding affinity and kinetics. Although mutations at Site 1 had little affect, several at Site 2 and at the dimer interface hampered the Ly49A(.)H-2D(d) interaction, with no effect on gross structure or T cell receptor interaction. The region surrounding the most critical residues (in H-2D(d), Asp(122); in Ly49A, Asp(229), Ser(236), Thr(238), Arg(231), and Asp(241); and in beta(2)-microglobulin, Gln(29) and Lys(58)) of the Ly49A(.)H-2D(d) interface at Site 2 includes a network of water molecules, suggesting a molecular basis for allelic specificity in natural killer cell recognition. C1 NIH, LI NIAID, Mol Biol Sect, Bethesda, MD 20892 USA. Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Margulies, DH (reprint author), NIH, LI NIAID, Mol Biol Sect, Bldg 10,Rm 11N311, Bethesda, MD 20892 USA. RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 FU NIAID NIH HHS [AI47900]; NIGMS NIH HHS [GM52801] NR 56 TC 58 Z9 58 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1433 EP 1442 DI 10.1074/jbc.M110316200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800074 PM 11696552 ER PT J AU Skorvaga, M Theis, K Mandavilli, BS Kisker, C Van Houten, B AF Skorvaga, M Theis, K Mandavilli, BS Kisker, C Van Houten, B TI The beta-hairpin motif of UvrB is essential for DNA binding, damage processing, and UvrC-mediated incisions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; ESCHERICHIA-COLI UVRAB; CRYSTAL-STRUCTURE; PROTEIN COMPLEX; PREINCISION COMPLEX; POLYMERASE-I; HELICASE-II; THERMUS-THERMOPHILUS; (A)BC EXCINUCLEASE; NUCLEASE AB UvrB plays a major role in recognition and processing of DNA lesions during nucleotide excision repair. The crystal structure of UvrB revealed a similar fold as found in monomeric DNA helicases. Homology modeling suggested that the beta-hairpin motif of UvrB might be involved in DNA binding (Theis, K., Chen, P. J., Skorvaga, M., Van Houten, B., and Kisker, C. (1999) EMBO J. 18, 6899-6907). To determine a role of the beta-hairpin of Bacillus caldotenax UvrB, we have constructed a deletion mutant, Deltabetah UvrB, which lacks residues Gln-97-Asp-112 of the beta-hairpin. Deltabetah UvrB does not form a stable UvrB-DNA pre-incision complex and is inactive in UvrABC-mediated incision. However, Deltabetah UvrB is able to bind to UvrA and form a complex with UvrA and damaged DNA, competing with wild type UvrB. In addition, Deltabetah UvrB shows wild type-like ATPase activity in complex with UvrA that is stimulated by damaged DNA. In contrast to wild type UvrB, the ATPase activity of mutant UvrB does not lead to a destabilization of the damaged duplex. These results indicate that the conserved beta-hairpin motif is a major factor in DNA binding. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Slovak Acad Sci, Canc Res Inst, Dept Mol Genet, Bratislava 83391, Slovakia. SUNY Stony Brook, Dept Pharmacol Sci, Ctr Struct Biol, Stony Brook, NY 11794 USA. RP Van Houten, B (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233,MD D3-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 38 TC 76 Z9 77 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1553 EP 1559 DI 10.1074/jbc.M108847200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800089 PM 11687584 ER PT J AU Volodin, AA Camerini-Otero, RD AF Volodin, AA Camerini-Otero, RD TI Influence of DNA sequence on the positioning of RecA monomers in RecA-DNA cofilaments SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI GENOME; PAIRING SEQUENCES; LOW FIDELITY; CHI-SITES; PROTEIN; RECOMBINATION; COMPLEXES; ISLANDS; RECOGNITION; SELECTION AB We show that certain DNA sequences have the ability to influence the positioning of RecA monomers in RecA-DNA complexes. A tendency for RecA monomers to be phased was observed in RecA protein complexes with several oligonucleotides containing a recombinational hotspot sequence, the chi-site from Escherichia coli. This influence was observed in both the 5' to 3' and 3' to 5' directions with respect to chi. A 5'-end phosphate group and probably some other features in DNA also influence the phasing of RecA monomers. We conclude that natural DNAs contain a number of features that influence the positioning of RecA monomers. The ability of specific DNA sequences to influence the positioning of RecA monomers demonstrates some specificity in the binding of individual bases at different sites within a RecA monomer and, most likely, reflects the stereochemical non-equivalence of these sites. The possible biological implications of the phasing of RecA monomers in presynaptic DNA-protein cofilaments are discussed. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RI Volodin, Alexander/B-9656-2012 NR 19 TC 9 Z9 10 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 11 PY 2002 VL 277 IS 2 BP 1614 EP 1618 DI 10.1074/jbc.M108871200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 509TY UT WOS:000173166800097 PM 11700314 ER PT J AU Hasegawa, RP Blitz, AM Geller, NL Goldberg, ME AF Hasegawa, RP Blitz, AM Geller, NL Goldberg, ME TI Do neurons predict the future? Response SO SCIENCE LA English DT Editorial Material C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Hlth Res, Howard Hughes Med Inst, Scholars Program, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20007 USA. RP Hasegawa, RP (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NR 1 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 11 PY 2002 VL 295 IS 5553 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 511RD UT WOS:000173278600002 ER PT J AU Song, YS Park, EH Hur, GM Ryu, YS Lee, YS Lee, JY Kim, YM Jin, CB AF Song, YS Park, EH Hur, GM Ryu, YS Lee, YS Lee, JY Kim, YM Jin, CB TI Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity SO CANCER LETTERS LA English DT Article DE caffeic acid phenethyl ester; inducible nitric oxide synthase; promoter activity; NF-kappa B; iNOS activity ID NF-KAPPA-B; INTERFERON-GAMMA; KINASE COMPLEX; ANTIOXIDANT PROPERTIES; IKK-ALPHA; ACTIVATION; CELLS; INFLAMMATION; LIPOPOLYSACCHARIDE; PROPOLIS AB Since nitric oxide (NO) synthesized by inducible nitric oxide synthase (iNOS) has been known to be involved in inflammatory and autoimmune-mediated tissue destruction, modulation of NO synthesis or action represents a new approach to the treatment of inflammatory and autoimmune diseases. Caffeic acid phenethyl ester (CAPE), an active component of honeybee propolis, has been identified to show anti-inflammatory, anti-viral and anti-cancer activities. The present study, therefore, examined effects of CAPE on iNOS expression and activity of iNOS enzyme itself. Treatment of RAW 264.7 cells with CAPE significantly inhibited NO production and iNOS protein expression induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). CAPE also inhibited iNOS rnRNA expression and nuclear factor-kappa B (NF-kappaB) binding activity in a concentration-dependent manner. Furthermore, transfection of RAW 264.7 cells with iNOS promoter linked to a chloramphenicol acetyltransferase reporter gene, revealed that CAPE inhibited the iNOS promoter activity induced by LPS plus IFN-gamma through the NF-kappaB sites of the iNOS promoter. In addition, CAPE directly interfered with the catalytic activity of murine recombinant iNOS enzyme. These results suggest that CAPE may exert its anti-inflammatory effect by inhibiting the iNOS gene expression at the transcriptional level through the suppression of NF-kappaB activation, and by directly inhibiting the catalytic activity of iNOS. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Korea Inst Sci & Technol, Bioanal & Biotransformat Res Ctr, Seoul 130650, South Korea. Sookmyung Womens Univ, Coll Pharm, Seoul 140742, South Korea. Chungnam Natl Univ, Coll Med, Dept Pharmacol, Taejon 301131, South Korea. Korea Inst Sci & Technol, Med Chem Res Ctr, Seoul 130650, South Korea. NINCDS, Genet Pharmacol Unit, NIH, Bethesda, MD 20892 USA. RP Jin, CB (reprint author), Korea Inst Sci & Technol, Bioanal & Biotransformat Res Ctr, POB 131, Seoul 130650, South Korea. OI Lee, Jae Yeol/0000-0001-6622-6692 NR 39 TC 99 Z9 104 U1 1 U2 10 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 10 PY 2002 VL 175 IS 1 BP 53 EP 61 DI 10.1016/S0304-3835(01)00787-X PG 9 WC Oncology SC Oncology GA 511DV UT WOS:000173250100007 PM 11734336 ER PT J AU de Koning, HJ Auvinen, A Sanchez, AB da Silva, FC Ciatto, S Denis, L Gohagan, JK Hakama, M Hugosson, J Kranse, R Nelen, V Prorok, PC Schroder, FH AF de Koning, HJ Auvinen, A Sanchez, AB da Silva, FC Ciatto, S Denis, L Gohagan, JK Hakama, M Hugosson, J Kranse, R Nelen, V Prorok, PC Schroder, FH CA ERSPC PLCO Trials TI Large-scale randomized prostate cancer screening trials: Program performances in the European randomized screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer screening trials; randomized; controlled trial; PSA ID DIGITAL RECTAL EXAMINATION; ANTIGEN; DIAGNOSIS; MEN AB Two large-scale randomized screening trials, the Prostate, Lung, Colorectal and Ovary (PLCO) cancer trial in the USA and the European Randomized Screening for Prostate Cancer (ERSPC) trial in Europe are currently under way, aimed at assessing whether screening reduces prostate cancer mortality. Up to the end of 1998, 102,691 men have been randomized to the intervention arm and 115,322 to the control arm (which represents 83% of the target sample size) from 7 European countries and 10 screening centers in the USA. The principal screening method at all centers is determination of serum prostate-specific antigen (PSA). The PLCO trial and some European centers use also digital rectal examination (DRE) as an ancillary screening test. In the core age group (55-69 years), 3,362 of 32,486 men screened (10%) had a serum PSA concentration of 4 ng/ml or greater, which is 1 cut-off for biopsy (performed in 84%). An additional 6% was referred for further assessment based on other criteria, with much less efficiency. Differences in PSA by country are largely attributable to the age structure of the study population. The mean age-specific PSA levels are lower in the PLCO trial (1.64 ng/ml [in the age group 55-59 years], 1.80 [60-64 years] and 2.18 [65-69 years) than in the ERSPC trial (1.28-1.71 [55-59], 1.75-2.87 [60-64] and 2.48-3.06 [65-69 years]). Detection rates at the first screen in the ERSPC trial range from 11 to 42/1,000 men screened and reflect underlying differences in incidence rates and screening procedures. In centers with consent to randomization design, adherence in the screening arm is 91%, but less than half of the men in the target population are enrolled in the trial. In population-based centers in which men were randomized prior to consent, all eligible subjects are enrolled, but only about two-thirds of the men in the intervention arm undergo screening. Considerable progress has been made in both trials. Enrollment will be completed in 2001. A substantial number of early prostate cancers have been detected. The differences between countries seem to reflect both underlying prostate cancer incidence and screening policy. The trials have the power to show definitive results in 2005-2008. (C) 2002 Wiley-Liss, Inc. C1 Erasmus Univ, Dept Publ Hlth, NL-3000 DR Rotterdam, Netherlands. Inst Stat Canc Res, Finnish Canc Registry, Helsinki, Finland. Hosp Univ Getafe, Madrid, Spain. Hosp Desterro, Lisbon, Portugal. Ctr Studio & Prevenz Oncol, Dept Diagnost Med Imaging, I-50131 Florence, Italy. Oncol Ctr Antwerp, Antwerp, Belgium. NCI, Early Detect Branch, NIH, Bethesda, MD 20892 USA. Univ Tampere, Dept Publ Hlth, FIN-33101 Tampere, Finland. Sahlgrenska Univ Hosp Ostra, Dept Urol, Gothenburg, Sweden. Rotterdam Canc Registry, Rotterdam, Netherlands. Prov Inst Hyg, Antwerp, Belgium. NCI, Screening Sect, Biometry Branch, NIH, Bethesda, MD 20892 USA. Erasmus Univ, Dept Urol, NL-3000 DR Rotterdam, Netherlands. Acad Hosp Rotterdam, Rotterdam, Netherlands. RP de Koning, HJ (reprint author), Erasmus Univ, Dept Publ Hlth, POB 1738, NL-3000 DR Rotterdam, Netherlands. OI Auvinen, Anssi/0000-0003-1125-4818 NR 24 TC 215 Z9 219 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 10 PY 2002 VL 97 IS 2 BP 237 EP 244 DI 10.1002/ijc.1588 PG 8 WC Oncology SC Oncology GA 504WB UT WOS:000172877900016 PM 11774270 ER PT J AU Nutman, TB Kradin, RL Scully, RE Ryan, ET AF Nutman, TB Kradin, RL Scully, RE Ryan, ET TI A 24-year-old woman with paresthesias and muscle cramps after a stay in Africa - Infection with Loa loa. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID EOSINOPHILIA-MYALGIA-SYNDROME; HYPEREOSINOPHILIC SYNDROME; BANCROFTIAN FILARIASIS; NONENDEMIC POPULATIONS; CLINICAL PRESENTATION; ANGIOEDEMA; DIETHYLCARBAMAZINE; ONCHOCERCIASIS; LOIASIS; MANIFESTATIONS C1 NIAID, Parasit Dis Lab, Helminth Immunol Sect, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, Helminth Immunol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 39 TC 13 Z9 13 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 10 PY 2002 VL 346 IS 2 BP 115 EP 122 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 509EM UT WOS:000173133400008 PM 11784879 ER PT J AU Murga, C Zohar, M Teramoto, H Gutkind, JS AF Murga, C Zohar, M Teramoto, H Gutkind, JS TI Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappa B SO ONCOGENE LA English DT Article DE RhoG; PI3K; Akt; cell survival ID PROTEIN-KINASE B; PHOSPHATIDYLINOSITOL 3-KINASE; PC12 CELLS; SIGNAL-TRANSDUCTION; COUPLED RECEPTORS; PATHWAY; APOPTOSIS; RAS; GTPASES; TARGET AB Small GTPases of the Rho family play a central role in cellular processes that involve the reorganization of the actin-based cytoskeleton. Rho-related GTPases, which include Rac and Cdc42, can also regulate gene expression often through the activation of kinase cascades leading to enhanced activity of stress activated protein kinases (SAPKs), including JNK and p38 MAP kinases. As SAPKs are implicated in programmed cell death, these observations suggest that Rho GTPases may promote the initiation of the apoptotic process. However, recent reports suggest that Rho GTPases can have either a protective or a proapoptotic role, depending on the particular cellular context. In an effort to explore the molecular mechanisms underlying these divergent biological activities, we asked whether there was indeed a correlation between the ability to induce SAPKs and apoptosis by Rho family members. We found that although constitutively activated (Q61L) mutants of Rac1, Cdc42, and RhoG, a Rac1 related GTPase of unknown function, potently induce JNK in COS 7 cells, none of these GTPases could induce apoptosis, nor enhance uv-induced cell death. In contrast, Rac1 and RhoG efficiently protected cells from uv-induced apoptosis. Furthermore, we provide evidence that Rac1 and RhoG can activate both apoptotic and anti-apoptotic pathways. Whereas the former is mediated through JNK, the latter is independent on the transcriptional activation of NF-KB, a pro-survival pathway, but results from the direct interaction of these GTPases with phosphatidylinositol 3-kinase (PI3K) and the stimulation of Akt. Together, these findings indicate that members of the Rho family of small GTP-binding proteins can provoke the concomitant stimulation of two counteracting signaling pathways, and that their balance ultimately determines the ability of these GTPases to promote cell survival or death. C1 NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Teramoto, H (reprint author), NIDR, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; Murga, Cristina/E-1965-2014 OI Murga, Cristina/0000-0002-8964-4077 NR 50 TC 99 Z9 103 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 10 PY 2002 VL 21 IS 2 BP 207 EP 216 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 507KG UT WOS:000173026200005 PM 11803464 ER PT J AU Kreslova, J Holland, LZ Schubert, M Burgtorf, C Benes, V Kozmik, Z AF Kreslova, J Holland, LZ Schubert, M Burgtorf, C Benes, V Kozmik, Z TI Functional equivalency of amphioxus and vertebrate Pax258 transcription factors suggests that the activation of mid-hindbrain specific genes in vertebrates occurs via the recruitment of Pax regulatory elements SO GENE LA English DT Article DE gene evolution; development; alternative splicing; paired box ID PAIRED DOMAIN; DNA-BINDING; TRANSACTIVATION PROPERTIES; DEVELOPMENTAL EXPRESSION; FACTOR BSAP; SEA-URCHIN; MIDBRAIN; DROSOPHILA; SEQUENCE; BOUNDARY AB Pax genes encode transcription factors that control key developmental decisions in various animal phyla. The Pax2/5/8 subfamily plays a key role in specification and/or maintenance of vertebrate mid-hindbrain boundary (MHB) region by directly regulating expression of other genes, most notably En2. In the invertebrate chordate amphioxus, expression of AmphiPax2/5/8 is found in many sites that are homologous to the regions of the vertebrate embryo expressing orthologous genes Pax2, Pax5 or Pax8. However, no co-expression of AmphiPax2/5/8 and AmphiEn is detected in the region of the neural tube that might correspond to the vertebrate MHB. Based on this observation and the absence of AmphiWnt expression in this region it appears that amphioxus does not have a MHB. Here we investigated the possibility that the AmphiPax2/5/8, as a key component of MHB development, has lost some of the properties of its vertebrate counterparts. We have analyzed both the DNA-binding and transactivation properties of AmphiPax2/5/8 as well as its ability to interact with the groucho co-repressor. In all these assays AmphiPax2/5/8 is indistinguishable from the human Pax5. In addition, we found two alternatively spliced AmphiPax2/5/8 isoforms that function similarly to the alternatively spliced isoforms of human Pax8. Analysis of the AmphiEn regulatory region provided no evidence for AmphiPax2/5/8 binding and transactivation. Therefore, in amphioxus, AmphiPax2/5/8, although capable of performing all the necessary functions has not been recruited for a developmental mechanism which usually sets up MHB development in vertebrates. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Inst Mol Genet, Ctr Integrated Genom, Prague 16637 6, Czech Republic. Scripps Inst Oceanog, Div Marine Biol Res, La Jolla, CA USA. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. EMBL, D-69117 Heidelberg, Germany. RP Kozmik, Z (reprint author), Natl Inst Hlth, Mol & Dev Biol Lab, Bldg 6,Room 203, Bethesda, MD 20892 USA. RI Kozmik, Zbynek/G-3581-2014; Kozmik, Zbynek/I-8807-2014 NR 32 TC 11 Z9 11 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 9 PY 2002 VL 282 IS 1-2 BP 143 EP 150 DI 10.1016/S0378-1119(01)00840-X PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 521GA UT WOS:000173829800014 ER PT J AU Jenkins, TM Wapner, RJ Thom, EA Das, AF Spong, CY AF Jenkins, TM Wapner, RJ Thom, EA Das, AF Spong, CY TI Are weekly courses of antenatal steroids beneficial or dangerous? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. MCP Hahnemann Univ, Dept Obstet & Gynecol, Philadelphia, PA USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NICHHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Jenkins, TM (reprint author), Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. NR 4 TC 5 Z9 5 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 9 PY 2002 VL 287 IS 2 BP 187 EP 188 DI 10.1001/jama.287.2.187 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 508XK UT WOS:000173114900013 PM 11779253 ER PT J AU Dhanvantari, S Arnaoutova, I Snell, CR Steinbach, PJ Hammond, K Caputo, GA London, E Loh, YP AF Dhanvantari, S Arnaoutova, I Snell, CR Steinbach, PJ Hammond, K Caputo, GA London, E Loh, YP TI Carboxypeptidase E, a prohormone sorting receptor, is anchored to secretory granules via a C-terminal transmembrane insertion SO BIOCHEMISTRY LA English DT Article ID PROCESSING ENZYME; BILAYER THICKNESS; MEMBRANE-BINDING; CPE(FAT) MICE; ATT-20 CELLS; PH; PATHWAY; CHOLESTEROL; VESICLES; PEPTIDES AB Carboxypeptidase E (CPE) is a sorting receptor that directs the prohormone pro-opiometanocortin (POMC) to the regulated secretory pathway, and is also a prohormone processing enzyme in neuro/endocrine cells. It has been suggested that the 25 C-terminal amino acids are necessary for the binding of CPE to secretory granule membranes, but its orientation in the membrane is not known. In this study, we examined the structure and orientation of the membrane-binding domain at the C-terminus of CPE. In vitro experiments using model membranes demonstrated that the last 22 amino acids of CPE (CP peptide) insert in a shallow orientation into lipid bilayers at low pH. Circular dichroism analysis indicated that the CP peptide adopts a partial alpha-helical configuration at low pH, and helix content increases when it is bound to lipid. Protease protection experiments, immunolabeling, and immunoisolation of intact secretory granules with a C-terminal antibody revealed a cytoplasmic domain in CPE, consistent with a transmembrane orientation of this protein. We conclude that the membrane-binding domain of CPE must adopt an alpha-helical configuration to bind to lipids, and that CPE may require another integral membrane "chaperone" protein to insert through the lipid bilayer in a trails membrane fashion. C1 NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Novartis Inst Med Sci, London WC1E 6BN, England. NIH, Ctr Mol Modelling, Ctr Informat Technol, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. RP Loh, YP (reprint author), NICHHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bldg 49,Room 5A38,MSC 4480, Bethesda, MD 20892 USA. RI Dhanvantari, Savita/B-5362-2015; OI Caputo, Gregory/0000-0002-4510-2815 FU NIGMS NIH HHS [GM 31986] NR 39 TC 50 Z9 51 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 8 PY 2002 VL 41 IS 1 BP 52 EP 60 DI 10.1021/bi015698n PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510PM UT WOS:000173216500007 PM 11772002 ER PT J AU DeRose, EF Li, DW Darden, T Harvey, S Perrino, FW Schaaper, RM London, RE AF DeRose, EF Li, DW Darden, T Harvey, S Perrino, FW Schaaper, RM London, RE TI Model for the catalytic domain of the proofreading epsilon subunit of Escherichia coli DNA polymerase III based on NMR structural data SO BIOCHEMISTRY LA English DT Article ID TRIPLE-RESONANCE NMR; SINGLE-STRANDED-DNA; GLOBAL FOLDS; PERDEUTERATED PROTEINS; SEQUENTIAL ASSIGNMENT; BACKBONE ASSIGNMENT; MOLECULAR-DYNAMICS; CHEMICAL-SHIFT; PULSE SCHEME; EXONUCLEASE AB The DNA polymerase III holoenzyme (HE) is the primary replicative polymerase of Escherichia coli. The epsilon subunit of the HE complex provides the 3'-exonucleolytic proofreading activity for this enzyme complex. epsilon consists of two domains: an N-terminal domain containing the proofreading exonuclease activity (residues 1-186) and a C-terminal domain required for binding to the polymerase (alpha) subunit (residues 187-243). Multidimensional NMR studies of H-2-, C-13-, and N-15-labeled N-terminal domains (epsilon186) were performed to assign the backbone resonances and measure H-N-H-N nuclear Overhauser effects (NOEs). NMR studies were also performed on triple-lableled [U-H-2,C-13,N-15]epsilon186 containing Val, Leu, and Ile residues with protonated methyl groups, which allowed for the assignment of H-N-CH3 and CH3-CH3 NOES. Analysis of the C-13(alpha), C-13(beta), and (CO)-C-13 shifts, using chemical shift indexing and the TALOS program, allowed for the identification of regions of the secondary structure. H-N-H-N NOEs provided information on the assembly of the extended strands into a beta-sheet structure and confirmed the assignment of the alpha helices. Measurement of H-N-CH3 and CH3-CH3 NOEs confirmed the beta-sheet structure and assisted in the positioning of the alpha helices. The resulting preliminary characterization of the three-dimensional structure of the protein indicated that significant structural homology exists with the active site of the Klenow proofreading exonuclease domain, despite the extremely limited sequence homology. On the basis of this analogy, molecular modeling studies of epsilon186 were performed using as templates the crystal structures of the exonuclease domains of the Klenow fragment and the T4 DNA polymerase and the recently determined structure of the E. coli Exonuclease I. A multiple sequence alignment was constructed, with the initial alignment taken from the previously published hidden Markov model and NMR constraints. Because several of the published structures included complexed ssDNA, we were also able to incorporate an A-C-G trinucleotide into the epsilon186 structure. Nearly all of the residues which have been identified as mutators are located in the portion of the molecule which binds the DNA. with most of these playing either a catalytic or structural role. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. Wake Forest Univ, Med Ctr, Dept Biochem, Winston Salem, NC 27157 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, Box 12233, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA75350] NR 51 TC 27 Z9 27 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 8 PY 2002 VL 41 IS 1 BP 94 EP 110 DI 10.1021/bi0114170 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510PM UT WOS:000173216500012 PM 11772007 ER PT J AU Storey, NM O'Bryan, JP Armstrong, DL AF Storey, NM O'Bryan, JP Armstrong, DL TI Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel SO CURRENT BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; PITUITARY-TUMOR CELLS; SIGNAL-TRANSDUCTION; ARACHIDONIC-ACID; THYROID-HORMONE; KINASE-C; INHIBITION; ACTIVATION; GTPASES; PHOSPHATASE AB Background: Previous studies of ion channel regulation by G proteins have focused on the larger, heterotrimeric GTPases, which are activated by heptahelical membrane receptors. In contrast, studies of the Rho family of smaller, monomeric, Ras-related GTPases, which are activated by cytoplasmic guanine nucleotide exchange factors, have focused on their role in cytoskeletal regulation. Results: Here we demonstrate novel functions for the Rho family GTPases Rac and Rho in the opposing hormonal regulation of voltage-activated, ether-a-go-go-related potassium channels (ERG) in a rat pituitary cell line, GH(4)C(1). The hypothalamic neuropeptide, thyrotropin-releasing hormone (TRH) inhibits ERG channel activity through a PKC-independent process that is blocked by RhoA(19N) and the Clostridium botulinum C3 toxin, which inhibit Rho signaling. The constitutively active, GTPase-deficient mutant of RhoA(63L) rapidly inhibits the channels when the protein is dialysed directly into the cell through the patch pipette, and inhibition persists when the protein is overexpressed. In contrast, GTPase-deficient Rac1(61L) stimulates ERG channel activity. The thyroid hormone triiodothyronine (T3), which antagonizes TRH action in the pituitary, also stimulates ERG channel activity through a rapid process that is blocked by Rac1(17N) and wortmannin but not by RhoA(19N). Conclusions: Rho stimulation by G(13)-coupled receptors and Rac stimulation by nuclear hormones through P-13-kinase may be general mechanisms for regulating ion channel activity in many cell types. Disruption of these novel signaling cascades is predicted to contribute to several specific human neurological diseases, including epilepsy and deafness. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Armstrong, DL (reprint author), NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NR 41 TC 54 Z9 55 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 8 PY 2002 VL 12 IS 1 BP 27 EP 33 DI 10.1016/S0960-9822(01)00625-X PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 510YE UT WOS:000173234500018 PM 11790300 ER PT J AU Berger, JR Oral, EA Taylor, SL AF Berger, JR Oral, EA Taylor, SL TI Familial lipodystrophy associated with neurodegeneration and congenital cataracts SO NEUROLOGY LA English DT Article; Proceedings Paper CT 53rd Annual Meeting of the American-Academy-of-Neurology CY MAY 05-11, 2001 CL PHILADELPHIA, PENNSYLVANIA SP Amer Acad Neurol ID CHROMOSOME 1Q21-22; LAMIN A/C; GENE; DISORDERS AB Background: The lipodystrophies are characterized by loss of body fat and metabolic disturbances, but the CNS is seldom affected. Methods: An investigation of a family with partial lipodystrophy and neurologic abnormalities included lipid analysis, dual-energy x-ray absorbtiometry (DEXA) for adiposity, insulin resistance, karyotype and other genetic analyses, peroxisomal function, glycosylation pattern of transferrin and thyroglobulin, and muscle biopsy. Results: The propositus, a 28-year-old woman with congenital partial lipodystrophy and cataracts, presented with a spastic-ataxic gait and lower extremity paresthesiae at age 18. Laboratory investigation revealed a type V hyperlipidemia pattern, insulin resistance, and high alpha-tocopherol levels. A similar syndrome in other family members suggested an autosomal dominant pattern of inheritance. Discussion: The progressive neurologic degenerative condition associated with this autosomal dominant, partial lipodystrophy may be misdiagnosed as MS or spinocerebellar degeneration. Search for a few relevant candidate genes was unrevealing. A genome-wide search to determine the molecular etiology can be undertaken if other similar cases are identified. C1 Univ Kentucky, Dept Neurol, Kentucky Clin L445, Coll Med, Lexington, KY 40536 USA. Univ Kentucky, Dept Internal Med, Coll Med, Lexington, KY 40536 USA. NIDDKD, NIH, Diabet Branch, Bethesda, MD 20892 USA. RP Berger, JR (reprint author), Univ Kentucky, Dept Neurol, Kentucky Clin L445, Coll Med, Lexington, KY 40536 USA. OI Oral, Elif/0000-0002-9171-1144 NR 24 TC 6 Z9 6 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 8 PY 2002 VL 58 IS 1 BP 43 EP 47 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 509CR UT WOS:000173127800011 PM 11781404 ER PT J AU Shao, XP Koizumi, K Nosworthy, N Tan, DP Odenwald, W Nirenberg, M AF Shao, XP Koizumi, K Nosworthy, N Tan, DP Odenwald, W Nirenberg, M TI Regulatory DNA required for vnd/NK-2 homeobox gene expression pattern in neuroblasts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE homeobox; Drosophila ID CENTRAL-NERVOUS-SYSTEM; DROSOPHILA EGF RECEPTOR; DORSOVENTRAL AXIS; VENTRAL ECTODERM; COLUMN IDENTITY; SPECIFICATION; NEUROECTODERM; CNS; NEUROGENESIS; VND AB Vnd/NK-2 protein was detected in 11 neuroblasts per hemisegment in Drosophila embryos, 9 medial and 2 intermediate neuroblasts. Fragments of DNA from the 5'-flanking region of the vnd/NK-2 gene were inserted upstream of an enhancerless beta-galactosidase gene in a P-element and used to generate transgenic fly lines. Antibodies directed against Vnd/NK-2 and beta-galactosidase proteins then were used in double-label experiments to correlate the expression of beta-galactosidase and Vnd/NK-2 proteins in identified neuroblasts. DNA region A, which corresponds to the -4.0 to -2.8-kb fragment of DNA from the 5'-flanking region of the vnd/NK-2 gene was shown to contain one or more strong enhancers required for expression of the vnd/NK-2 gene in ten neuroblasts. DNA region B (-5.3 to -4.0 kb) contains moderately strong enhancers for vnd/NK-2 gene expression in four neuroblasts. Hypothesized DNA region C, whose location was not identified, contains one or more enhancers that activate vnd/NK-2 gene expression only in one neuroblast. These results show that nucleotide sequences in at least three regions of DNA regulate the expression of the vnd/NK-2 gene, that the vnd/NK-2 gene can be activated in different ways in different neuroblasts, and that the pattern of vnd/NK-2 gene expression in neuroblasts of the ventral nerve cord is the sum of partial patterns. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 32 TC 17 Z9 17 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 8 PY 2002 VL 99 IS 1 BP 113 EP 117 DI 10.1073/pnas.012584599 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300023 PM 11752402 ER PT J AU Melek, M Jones, JM O'Dea, MH Pais, G Burke, TR Pommier, Y Neamati, N Gellert, M AF Melek, M Jones, JM O'Dea, MH Pais, G Burke, TR Pommier, Y Neamati, N Gellert, M TI Effect of HIV integrase inhibitors on the RAG1/2 recombinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE V(D)J recombination; transposition; immune development ID V(D)J RECOMBINATION; RAG2 PROTEINS; DNA; TRANSPOSITION; RESOLUTION; CLEAVAGE; COMPLEX; STEPS AB Assembly of functional Ig and T cell receptor genes by V(D)J recombination depends on site-specific cleavage of chromosomal DNA by the RAG1/2 recombinase. As RAG1/2 action has mechanistic similarities to DNA transposases and integrases such as HIV-1 integrase, we sought to determine how integrase inhibitors of the diketo acid type would affect the various activities of RAG1/2. Both of the inhibitors we tested interfered with DNA cleavage and disintegration activities of RAG1/2, apparently by disrupting interaction with the DNA motifs bound specifically by the recombinase. The inhibitors did not ablate RAG1/2's transposition activity or capture of nonspecific transpositional target DNA, suggesting this DNA occupies a site on the recombinase different from that used for specific binding. These results further underscore the similarities between RAG1/2 and integrase and suggest that certain integrase inhibitors may have the potential to interfere with aspects of B and T cell development. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Med Chem Lab, Frederick, MD 21702 USA. NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 241, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014 NR 21 TC 37 Z9 38 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 JAN 8 PY 2002 VL 99 IS 1 BP 134 EP 137 DI 10.1073/pnas.012610699 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300027 PM 11756686 ER PT J AU Dmitrieva, NI Bulavin, DV Fornace, AJ Burg, MB AF Dmitrieva, NI Bulavin, DV Fornace, AJ Burg, MB TI Rapid activation of G(2)/M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; OSMOTIC RESPONSE ELEMENT; DNA-DAMAGE CHECKPOINT; PROTEIN-KINASE; KIDNEY-CELLS; HEAT-SHOCK; PHOSPHORYLATION; CYCLE; INDUCTION; MECHANISMS AB Cells in the kidney medulla are subject to variable and often extreme osmotic stress during concentration of the urine. Previous studies showed that renal inner medullary epithelial (IME) cells respond to hypertonicity by G(2) arrest. The purpose of the present study was to investigate the mechanisms involved in initiation and maintenance of G(2) arrest. Rapid initiation of G(2) arrest after UV radiation is mediated by p38 kinase. Here we find that p38 kinase is responsible for rapid initiation of the G(2) delay in IME cells after the hypertonic stress created by adding NaCl. High NaCl, but not high urea, rapidly initiates G(2) arrest. Inhibition of p38 kinase by SB202190 (10 muM) blocks the rapid initiation of this checkpoint both in an immortalized cell line (mIMCD3) and in second-passage IME cells from mouse renal inner medulla. p38 inhibition does not affect exit from G(2) arrest. The rapid initiation of G(2) arrest is followed by inhibition of cdc2 kinase, which is also prevented by SB202190. To assess the possible protective role of G(2) arrest, we measured DNA strand breaks as reflected by immunostaining against phospho-histone H2AX, which becomes phosphorylated on Ser-139 associated with DNA breaks. Abrogation of rapid G(2)/M checkpoint activation by SB202190 increases the histone H2AX phosphorylation in G(2)/M cells. We propose that the rapid initiation of G(2) delay by p38 kinase after hypertonicity protects the cells by decreasing the level of DNA breaks caused by aberrant mitosis entry. C1 NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. NCI, Gene Response Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, Bldg 10, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008; Dmitrieva, Natalia/A-2924-2013 OI Fornace, Albert/0000-0001-9695-085X; Dmitrieva, Natalia/0000-0001-8074-6950 NR 44 TC 66 Z9 69 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 8 PY 2002 VL 99 IS 1 BP 184 EP 189 DI 10.1073/pnas.231623498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300036 PM 11756692 ER PT J AU Zhu, SY Yoon, K Sterneck, E Johnson, PF Smart, RC AF Zhu, SY Yoon, K Sterneck, E Johnson, PF Smart, RC TI CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NECROSIS-FACTOR-ALPHA; V-HA-RAS; C/EBP-BETA; TRANSCRIPTION FACTORS; MOUSE SKIN; MAMMARY-GLAND; DNA-BINDING; IN-VIVO; NF-M; EXPRESSION AB The basic leucine zipper transcription factor CCAAT/enhancer binding protein-beta (C/EBPbeta) is expressed in many cell types, including keratinocytes. C/EBPbeta activity can be increased by phosphorylation through pathways stimulated by oncogenic Ras, although the biological implications of Ras-C/EBPbeta signaling are not currently understood. We report here that C/EBPbeta-nullizygous mice are completely refractory to skin tumor development induced by a variety of carcinogens and carcinogenesis protocols, including 7,12-dimethylbenz[a]anthracene-initiation/12-O-tetradecanoylphorbol 13-acetate promotion, that produce tumors containing oncogenic Ras mutations. No significant differences in TPA-induced epidermal keratinocyte proliferation were observed in C/EBPbeta-null versus wild-type mice. However, apoptosis was significantly elevated (17-fold) in the epidermal keratinocytes of 7,12-dimethylbenz[a]anthracene-treated C/EBPbeta-null mice compared with wild-type mice. In v-Ha-ras transgenic mice, C/EBPbeta deficiency also led to greatly reduced skin tumor multiplicity and size, providing additional evidence for a tumorigenesis pathway linking Ras and C/EBPbeta. Oncogenic Ras potently stimulated C/EBPbeta to activate a C/EBP-responsive promoter-reporter in keratinocytes and mutating an ERK1/2 phosphorylation site (T188) in C/EBPbeta abolished this Ras effect. Finally, we observed that C/EBPbeta participates in oncogenic Ras-induced transformation of NIH 3T3 cells. These findings indicate that C/EBPbeta has a critical role in Ras-mediated tumorigenesis and cell survival and implicate C/ECPbeta as a target for tumor inhibition. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Raleigh, NC 27695 USA. NCI, Eukaryot Transcript Regulat Sect, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Smart, RC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Raleigh, NC 27695 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NCI NIH HHS [CA46637, R01 CA046637] NR 54 TC 154 Z9 155 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 8 PY 2002 VL 99 IS 1 BP 207 EP 212 DI 10.1073/pnas.012437299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300040 PM 11756662 ER PT J AU Miyoshi, K Shillingford, JM Le Provost, F Gounari, F Bronson, R von Boehmer, H Taketo, MM Cardiff, RD Hennighausen, L Khazaie, K AF Miyoshi, K Shillingford, JM Le Provost, F Gounari, F Bronson, R von Boehmer, H Taketo, MM Cardiff, RD Hennighausen, L Khazaie, K TI Activation of beta-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mammary gland; cell identity; Wnt-signaling; Cre; differentiation ID TRANSGENIC MICE; GENE; PROTEIN; GLAND AB Mammary anlagen are formed in the embryo as a derivative of the epidermis, a process that is controlled by Lef-1 and therefore possibly by beta-catenin. To investigate the role of beta-catenin signaling in mammary alveolar epithelium, we have stabilized endogenous beta-catenin in differentiating alveolar epithelium through the deletion of exon 3 (amino acids 5-80) of the beta-catenin gene. This task was accomplished in mice carrying a floxed beta-catenin gene and a Cre transgene under control of the mammary-specific whey acidic protein (WAP) gene promoter or the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Stabilized beta-catenin was obtained during the first pregnancy, and its presence resulted in the dedifferentiation of alveolar epithelium followed by a transdifferentiation into epidermal and pilar structures. Extensive squamous metaplasia, but no adenocarcinomas, developed upon beta-catenin activation during pregnancy and persisted throughout involution. These data demonstrate that the activation of beta-catenin signaling induces a program that results in loss of mammary epithelial cell differentiation and induction of epidermal structures. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. INRA, Lab Genet Biochim 7 Cytogenet, F-78352 Jouy En Josas, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. RP Khazaie, K (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NR 20 TC 96 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 JAN 8 PY 2002 VL 99 IS 1 BP 219 EP 224 DI 10.1073/pnas.012414099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300042 PM 11773619 ER PT J AU Limoli, CL Giedzinski, E Bonner, WM Cleaver, JE AF Limoli, CL Giedzinski, E Bonner, WM Cleaver, JE TI UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, gamma-H2AX formation, and Mre11 relocalization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA damage; X-ray; S-phase; checkpoints; recombination ID S-PHASE CHECKPOINT; SYNDROME GENE-PRODUCT; MAMMALIAN-CELLS; ULTRAVIOLET-LIGHT; HOMOLOGOUS RECOMBINATION; INDUCED PHOSPHORYLATION; HOLLIDAY JUNCTIONS; HUMAN-FIBROBLASTS; PYRIMIDINE DIMER; VERTEBRATE CELLS AB UV-induced replication arrest in the xeroderma pigmentosum variant (XPV) but not in normal cells leads to an accumulation of the Mre11/Rad50/Nbs1 complex and phosphorylated histone H2AX (gamma-H2AX) in large nuclear foci at sites of stalled replication forks. These complexes have been shown to signal the presence of DNA damage, in particular, double-strand breaks (DSBs). This finding suggests that UV damage leads to the formation of DSBs during the course of replication arrest. After UV irradiation, XPV cells showed a fluence-dependent increase in the yield of gamma-H2AX foci that paralleled the production of Mre11 foci. The percentage of foci-positive cells increased rapidly (10-15%) up to fluences of 10 J(.)m(-2) before saturating at higher fluences. Frequencies of gamma-H2AX and Mre11 foci both reached maxima at 4 h after UV irradiation. This pattern contrasts sharply to the situation observed after x-irradiation, where peak levels of gamma-H2AX foci were found to precede the formation of Well foci by several hours. The nuclear distributions of gamma-H2AX and Well were found to colocalize spatially after UV- but not x-irradiation. UV-irradiated XPV cells showed a one-to-one correspondence between Mre11 and gamma-H2AX foci-positive cells. These results show that XPV cells develop DNA DSBs during the course of UV-induced replication arrest. These UV-induced foci occur in cells that are unable to carry out efficient bypass replication of UV damage and may contribute to further genetic variation. C1 Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94103 USA. NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Univ Calif San Francisco, Ctr Canc, Dept Dermatol, San Francisco, CA 94143 USA. RP Limoli, CL (reprint author), Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94103 USA. FU NIEHS NIH HHS [1 R01 ES80601, R01 ES008061] NR 67 TC 153 Z9 156 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 JAN 8 PY 2002 VL 99 IS 1 BP 233 EP 238 DI 10.1073/pnas.231611798 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300044 PM 11756691 ER PT J AU Stowers, AW Chen, LH Zhang, YL Kennedy, MC Zou, LL Lambert, L Rice, TJ Kaslow, DC Saul, A Long, CA Meade, H Miller, LH AF Stowers, AW Chen, LH Zhang, YL Kennedy, MC Zou, LL Lambert, L Rice, TJ Kaslow, DC Saul, A Long, CA Meade, H Miller, LH TI A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; MALARIA PARASITES; ANTIBODIES; GENERATION AB Two strains of transgenic mice have been generated that secrete into their milk a malaria vaccine candidate, the 42-kDa C-terminal portion of Plasmodium falciparum merozoite surface protein 1 (MSP1(42)). One strain secretes an MSP1(42) with an amino acid sequence homologous to that of the FVO parasite line, the other an MSP1(42) where two putative N-linked glycosylation sites in the FVO sequence have been removed. Both forms of MSP1(42) were purified from whole milk to greater than 91% homogeneity at high yields. Both proteins are recognized by a panel of monoclonal antibodies and have identical N termini, but are clearly distinguishable by some biochemical properties. These two antigens were each emulsified with Freund's adjuvant and used to vaccinate Aotus nancymai monkeys, before challenge with the homologous A falciparum FVO parasite line. Vaccination with a positive control molecule, a glycosylated form Of MSP1(42) produced in the baculovirus expression system, successfully protected five of six monkeys. By contrast, vaccination with the glycosylated version of milk-derived MSP1(42) conferred no protection compared with an adjuvant control. Vaccination with the nonglycosylated, milk-derived MSP1(42) successfully protected the monkeys, with 4/5 animals able to control an otherwise lethal infection with P. falciparum compared with 1/7 control animals. Analysis of the different vaccines used suggested that the differing nature of the glycosylation patterns may have played a critical role in determining efficacy. This study demonstrates the potential for producing efficacious malarial vaccines in transgenic animals. C1 NIAID, Lab Parasit Dis, Malaria Vaccine Dev Unit, Rockville, MD 20852 USA. Genzyme Transgen Corp, Framingham, MA 01701 USA. RP Stowers, AW (reprint author), NIAID, Lab Parasit Dis, Malaria Vaccine Dev Unit, 5640 Fishers Lane, Rockville, MD 20852 USA. RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 21 TC 69 Z9 72 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 8 PY 2002 VL 99 IS 1 BP 339 EP 344 DI 10.1073/pnas.012590199 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300062 PM 11752405 ER PT J AU Joyce, CW Amar, MJA Lambert, G Vaisman, BL Paigen, B Najib-Fruchart, J Hoyt, RF Neufeld, ED Remaley, AT Fredrickson, DS Brewer, HB Santamarina-Fojo, S AF Joyce, CW Amar, MJA Lambert, G Vaisman, BL Paigen, B Najib-Fruchart, J Hoyt, RF Neufeld, ED Remaley, AT Fredrickson, DS Brewer, HB Santamarina-Fojo, S TI The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CELLULAR CHOLESTEROL EFFLUX; APOLIPOPROTEIN-E; TANGIER-DISEASE; TRANSGENIC MICE; GENE; MACROPHAGES; MUTATIONS; RECEPTOR; DEFICIENCY AB identification of mutations in the ABCA1 transporter (ABCA1) as the genetic defect in Tangier disease has generated interest in modulating atherogenic risk by enhancing ABCA1 gene expression. To investigate the role of ABCA1 in atherogenesis, we analyzed diet-induced atherosclerosis in transgenic mice overexpressing human ABCA1 (hABCA1-Tg) and spontaneous lesion formation in hABCA1-Tg X apoE-knockout (KO) mice. Overexpression of hABCA1 in C57BL/6 mice resulted in a unique anti-atherogenic profile characterized by decreased plasma cholesterol (63%), cholesteryl ester (63%), free cholesterol (67%), non-high density lipoprotein (HDL)-cholesterol (53%), and apolipoprotein (apo) B (64%) but markedly increased HDL-cholesterol (2.8-fold), apoA-1 (2.2-fold), and apoE (2.8-fold) levels. These beneficial changes in the lipid profile led to significantly lower (65%) aortic atherosclerosis in hABCA1-Tg mice. In marked contrast, ABCA1 overexpression had a minimal effect on the plasma lipid profile of apoE-KO mice and resulted in a 2- to 2.6-fold increase in aortic lesion area. These combined results indicate that overexpression of ABCA1 in C57BL/6 mice on a high cholesterol diet results in an atheroprotective lipoprotein profile and decreased atherosclerosis, and thus provide previously undocumented in vivo evidence of an anti-atherogenic role for the ABCA1 transporter. In contrast, overexpression of ABCA1 in an apoE-KO background led to increased atherosclerosis, further substantiating the important role of apoE in macrophage cholesterol metabolism and atherogenesis. In summary, these results establish that, in the presence of apoE, overexpression of ABCA1 modulates HDL as well as apoB-containing lipoprotein metabolism and reduces atherosclerosis in vivo, and indicate that pharmacological agents that will increase ABCA1 expression may reduce atherogenic risk in humans. C1 Natl Heart Lung & Blood Inst, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Inst Pasteur, Dept Atherosclerosis, F-59019 Lille, France. Jackson Lab, Bar Harbor, ME 04609 USA. RP Joyce, CW (reprint author), Natl Heart Lung & Blood Inst, Mol Dis Branch, NIH, Bldg 10,Rm 7N1115 10 Ctr Dr, Bethesda, MD 20892 USA. RI 应, 宁宁/G-9472-2011 NR 45 TC 187 Z9 206 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 8 PY 2002 VL 99 IS 1 BP 407 EP 412 DI 10.1073/pnas.012587699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300073 PM 11752403 ER PT J AU Hamelink, C Tjurmina, O Damadzic, R Young, WS Weihe, E Lee, HW Eiden, LE AF Hamelink, C Tjurmina, O Damadzic, R Young, WS Weihe, E Lee, HW Eiden, LE TI Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT ADRENAL-MEDULLA; CHROMAFFIN CELLS; TYROSINE-HYDROXYLASE; SECRETION; PACAP; EXPRESSION; RECEPTOR; PEPTIDE; ASSAY; ACETYLCHOLINE AB The adrenal gland is important for homeostatic responses to metabolic stress: hypoglycemia stimulates the splanchnic nerve, epinephrine is released from adrenomedullary chromaffin cells, and compensatory glucogenesis ensues. Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla. Accumulating evidence suggests that a secretin-related neuropeptide also may function as a transmitter at the adrenomedullary synapse. Costaining with highly specific antibodies against the secretin-related neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) and the vesicular acetylcholine transporter (VAChT) revealed that PACAP is found in nerve terminals at all mouse adrenomedullary cholinergic synapses. Mice with a targeted deletion of the PACAP gene had otherwise normal cholinergic innervation and morphology of the adrenal medulla, normal adrenal catecholamine and blood glucose levels, and an intact initial catecholamine secretory response to insulin-induced hypoglycemia. However, insulin-induced hypoglycemia was more profound and longer-lasting in PACAP knock-outs, and was associated with a dose-related lethality absent in wildtype mice. Failure of PACAP-deficient mice to adequately counter-regulate plasma glucose levels could be accounted for by impaired long-term secretion of epinephrine, secondary to a lack of induction of tyrosine hydroxylase, normally occurring after insulin hypoglycemia in wild-type mice, and a consequent depletion of adrenomedullary epinephrine stores. Thus, PACAP is needed to couple epinephrine biosynthesis to secretion during metabolic stress. PACAP appears to function as an "emergency response" cotransmitter in the sympathoadrenal axis, where the primary secretory response is controlled by a classical neurotransmitter but sustained under paraphysiological conditions by a neuropeptide. C1 NIMH, Lab Cellular & Mol Regulat, Sect Mol Neurosci, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, Sect Neural Gene Express, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Univ Marburg, Dept Anat & Cell Biol, D-35037 Marburg, Germany. RP Eiden, LE (reprint author), NIMH, Lab Cellular & Mol Regulat, Sect Mol Neurosci, Bethesda, MD 20892 USA. RI Young, W Scott/A-9333-2009; OI Young, W Scott/0000-0001-6614-5112; Eiden, Lee/0000-0001-7524-944X NR 36 TC 149 Z9 150 U1 3 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 8 PY 2002 VL 99 IS 1 BP 461 EP 466 DI 10.1073/pnas.012608999 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 510XV UT WOS:000173233300082 PM 11756684 ER PT J AU Norman, A Moradi, T Gridley, G Dosemeci, M Rydh, B Nyren, O Wolk, A AF Norman, A Moradi, T Gridley, G Dosemeci, M Rydh, B Nyren, O Wolk, A TI Occupational physical activity and risk for prostate cancer in a nationwide cohort study in Sweden SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostatic neoplasms; occupational physical activity; exercise; cohort studies; risk factors ID GROWTH-FACTOR-I; HORMONE-BINDING GLOBULIN; LIFE-STYLE; INSULIN; MEN; POPULATION; EXERCISE; HEALTH; TESTOSTERONE; ASSOCIATIONS AB We investigated effects of occupational physical activity on relative risk for prostate cancer. From Swedish nationwide censuses in 1960 and 1970, we defined two cohorts of men whose occupational titles allowed classification of physical activity levels at work in 1960 (n=1 348 971) and in 1970 (n=1 377 629) A third cohort included only men whose jobs required a similar level of physical activity in both 1960 and 19 70 (n=673 443). The incidence of prostate cancer between 1971 and 1989 was ascertained through record linkage to the Swedish Cancer Register. A total of 43 836, 28 702, and 19 670 prostate cancers, respectively, occurred in the three cohorts. In all three cohorts, the relative risk for, prostate cancer increased with decreasing level of occupational physical activity (P < 0.001), using Poisson regression. Among men with the same physical activity levels in 1960 and 1970, the rate ratio was 1.11 for men with sedentary jobs as compared with those whose jobs had very high/high activity levels after adjustment for age at follow-up, calendar year of follow-up and place of residence (95% CI 1.05-1.17; P for trend < 0.001). There was no association between occupational activity and prostate cancer mortality, Since we had no data on other potential risk factors the observed associations for both incidence and mortality might have been confounded. Further studies are needed to better understand the potential role of physical activity for prostate cancer. C1 Karolinska Inst, Dept Med Epidemiol, SE-17177 Stockholm, Sweden. Karolinska Inst, Family Med Stockholm, Dept Clin Sci, S-14157 Huddinge, Sweden. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Norman, A (reprint author), Karolinska Inst, Dept Med Epidemiol, POB 281, SE-17177 Stockholm, Sweden. NR 48 TC 32 Z9 35 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 7 PY 2002 VL 86 IS 1 BP 70 EP 75 DI 10.1038/sj/bjc/6600023 PG 6 WC Oncology SC Oncology GA 526VK UT WOS:000174150200014 PM 11857014 ER PT J AU Goletti, D Kinter, AL Coccia, EM Battistini, A Petrosillo, N Ippolito, G Poli, G AF Goletti, D Kinter, AL Coccia, EM Battistini, A Petrosillo, N Ippolito, G Poli, G TI Interleukin (IL)-4 inhibits phorbol-ester induced HIV-1 expression in chronically infected U1 cells independently from the autocrine effect of endogenous tumour necrosis factor-alpha, IL-1 beta, and IL-1 receptor antagonist SO CYTOKINE LA English DT Article DE latency; monocytic cells; Th-2 cytokines ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOKINE-INDUCED EXPRESSION; NF-KAPPA-B; PROMONOCYTIC CELLS; BETA-CHEMOKINES; GENE-EXPRESSION; T-LYMPHOCYTES; MACROPHAGES; REPLICATION; MONOCYTES AB The anti-inflammatory cytokine interleukin 4 (IL-4) has shown both inductive and inhibitory effects on the replication 4 the human immunodeficiency virus type I (HIV-1) in primary CD4(+) T cells and mononuelear phagocytes. In this study, IL-4 did not induce virus production, but inhibited phorbol esters (PMA)-stimulated HIV expression in chronically infected promonocytic U1 cells. This effect, however, was not accounted for by a decreased secretion of endogenous TNF-alpha induced by phorbol myristate acetate (PMA). We also observed that PMA upregulated the production of both IL-1beta and of IL-1 receptor antagonist (IL-1ra). IL-4 inhibited the secretion of IL-1beta and strongly increased that of IL-1ra; however, these effects were not responsible of IL-4-mediated inhibition of PMA-induced HIV expression since anti-IL-1ra antibodies did not revert IL-4 mediated suppression. U1 cells were transiently transfected with both wild-type (WT) long terminal repeat (LTR) constructs, or with LTR plasmids containing deletions of either the NF-kappaB or the Sp-1 binding sites. IL-4 inhibited LTR-driven transcription triggered by PMA stimulation of U1 cells, and this effect was dependent upon intact NF-kappaB but not Sp-1 binding sites. Thus, IL-4 may favour a state of microbiological quiescence in infected monocytic cells bypassing the induction of HIV expression mediated by pro-inflammatory cytokines. (C) 2002 Elsevier Science Ltd. C1 Italian Natl Inst Infect Dis Lazzaro Spallanzani, Rome, Italy. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Ist Super Sanita, Lab Immunol & Virol, I-00161 Rome, Italy. San Raffaele Sci Inst, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. RP Goletti, D (reprint author), IRCCS L Spallanzani, Lab Clin Immunol, Via Portuense 292, I-00149 Rome, Italy. RI Coccia, Eliana/B-4752-2013; BATTISTINI, ANGELA/C-2944-2016; OI Coccia, Eliana/0000-0002-1606-2949; Ippolito, Giuseppe/0000-0002-1076-2979; Goletti, Delia/0000-0001-8360-4376 NR 50 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JAN 7 PY 2002 VL 17 IS 1 BP 28 EP 35 DI 10.1006/cyto.2001.0989 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 534TL UT WOS:000174602800003 PM 11886168 ER PT J AU Kaufman, HL Swartout, BG Horig, H Lubensky, I AF Kaufman, HL Swartout, BG Horig, H Lubensky, I TI Combination interleukin-2 and interleukin-12 induces severe gastrointestinal toxicity and epithelial cell apoptosis in mice SO CYTOKINE LA English DT Article DE apoptosis; cytokines; gastrointestinal; interleukin-2; interleukin-12 ID DOSE RECOMBINANT INTERLEUKIN-2; ESTABLISHED PULMONARY METASTASES; INTRAEPITHELIAL LYMPHOCYTES; INTERFERON-GAMMA; IFN-GAMMA; CROHNS-DISEASE; GENE-THERAPY; TUMOR-CELLS; IL-12; EXPRESSION AB Interleukin 2 (IL-2) and interleukin 12 (IL-12) have potent anti-tumour activity as single agent therapy against several different murine and human tumours. Combining these cytokines may result in improved therapeutic effectiveness, however, the toxicity associated with simultaneous administration is prohibitive. This study was designed to determine the specific histopathologic changes associated with combination therapy. Mice were treated with 5 days of interleukin-2, interleukin-12, or both using standard doses and schedules. Histologic specimens were prepared from all internal organs on a daily basis to identify specific pathologic abnormalities. Treatment with interleukin-2, interleukin-12, or both resulted in pathologic insult to the liver and gastrointestinal tract. Mild lymphoplasmacytic infiltrates were seen in the liver. The most significant pathology was seen in the large bowel and consisted of apoptosis of colonic epithelial cells. While recovery of injured gastrointestinal mucosa occurred in mice treated with interleukin-2 or interleukin-12 alone, combination therapy resulted in death before recovery was possible. Combination interleukin-2 and interleukin-12 therapy results in irreversible injury of the colon as manifested by increased epithelial cell apoptosis and death in mice. Understanding the pathologic changes associated with combination cytokine therapy may lead to strategies that prevent toxicity while maintaining therapeutic effects. (C) 2002 Elsevier Science Ltd. C1 Albert Einstein Coll Med, Dept Surg, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Immunol & Microbiol, Bronx, NY 10461 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Kaufman, HL (reprint author), Albert Einstein Coll Med, Dept Surg, 1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NCI NIH HHS [K08 CA79881-01] NR 35 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JAN 7 PY 2002 VL 17 IS 1 BP 43 EP 52 DI 10.1006/cyto.2001.0986 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 534TL UT WOS:000174602800005 PM 11886170 ER PT J AU Devadas, S Zaritskaya, L Rhee, SG Oberley, L Williams, MS AF Devadas, S Zaritskaya, L Rhee, SG Oberley, L Williams, MS TI Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: Selective regulation of mitogen-activated protein kinase activation and Fas ligand expression SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T lymphocytes; reactive oxygen species; signal transduction; genes, reporter; oxidoreductases ID SIGNAL-TRANSDUCTION; TYROSINE PHOSPHORYLATION; KAPPA-B; APOPTOTIC DEATH; OXYGEN RADICALS; NAD(P)H OXIDASE; LYMPHOCYTES; PROMOTER; TRANSCRIPTION; INDUCTION AB Receptor-stimulated generation of reactive oxygen species (ROS) has been shown to regulate signal transduction, and previous studies have suggested that T cell receptor (TCR ) signals may involve or be sensitive to ROS. In this study, we have shown for the first time that TCR cross-linking induced rapid (within 15 min) generation of both hydrogen peroxide and superoxide anion, as defined with oxidation-sensitive dyes, selective pharmacologic antioxidants, and overexpression of specific antioxidant enzymes. Furthermore, the data suggest the novel observation that superoxide anion and hydrogen peroxide are produced separately by distinct TCR-stimulated pathways. Unexpectedly, TCR-stimulated activation of the Fas ligand (FasL) promoter and subsequent cell death was dependent upon superoxide anion, but independent of hydrogen peroxide, while nuclear factor of activated T cells (NFAT) activation or interleukin 2 transcription was independent of A ROS. Anti-CD3 induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 required hydrogen peroxide generation but was unaffected by superoxide anion. Thus, antigen receptor signaling induces generation of discrete species of oxidants that selectively regulate two distinct redox sensitive pathways, a proapoptotic (FasL) and a proliferative pathway (ERK). C1 Amer Red Cross, Holland Lab, Dept Immunol, Rockville, MD 20855 USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Univ Iowa, Free Radical & Radiat Biol Program, Iowa City, IA 52242 USA. RP Williams, MS (reprint author), Amer Red Cross, Holland Lab, Dept Immunol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. EM willmark@usa.redcross.org NR 56 TC 244 Z9 248 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN 7 PY 2002 VL 195 IS 1 BP 59 EP 70 DI 10.1084/jem.20010659 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 512DJ UT WOS:000173305600008 PM 11781366 ER PT J AU Houle, D Kondrashov, AS AF Houle, D Kondrashov, AS TI Coevolution of costly mate choice and condition-dependent display of good genes SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE good gene; mate choice; sexual selection; deleterious mutation; condition dependence ID MATING PREFERENCES; SEXUAL SELECTION; LEK PARADOX; HANDICAP PRINCIPLE; EVOLUTION; PERSPECTIVE; ORNAMENTS; MUTATIONS; FITNESS; TRAITS AB Females often choose their mates, instead of mating at random, even when a father contributes nothing but genes to his offspring. Costly female preferences for males with exaggerated traits that reduce viability, such as die peacock's tail, are particularly puzzling. Such preferences can evolve if directly favoured by natural selection or when the exaggerated trait, although maladaptive per se, indicates high overall quality of the male's genotype. Two recent analyses suggested that the advantage to mate choice based on genetic quality is too weak to explain extreme cases of exaggeration of display traits and the corresponding preferences. We studied coevolution of a female mate-preference function and a genotype-dependent male display function where mutation supplies variation in genotype quality and mate preference is costly. Preference readily evolves, often causing extreme exaggeration of the display. Mate choice and trait expression can approach an equilibrium, or a limit cycle, or exaggeration can proceed forever, eventually causing extinction. C1 Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Houle, D (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. EM dhoule@bio.fsu.edu; kondrash@ray.nlm.nih.gov NR 40 TC 138 Z9 140 U1 5 U2 77 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JAN 7 PY 2002 VL 269 IS 1486 BP 97 EP 104 DI 10.1098/rspb.2001.1823 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 515AP UT WOS:000173473500014 PM 11788042 ER PT J AU Ullrich, T Binder, D Pyerin, M AF Ullrich, T Binder, D Pyerin, M TI Asymmetric synthesis of (+)- and (-)-7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane as conformationally restricted analogues of nicotine SO TETRAHEDRON LETTERS LA English DT Article DE nicotine; conformational restriction; Stille coupling; diastereoselective reduction ID ACETYLCHOLINE-RECEPTORS AB Both enantiomers of the conformationally restricted nicotine analogue 7-(3-pyridyl)-1-azabicyclo[2.2.1]heptane were prepared in a convenient, asymmetric synthetic route. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Vienna Univ Technol, Inst Organ Chem, Med Chem Lab, A-1060 Vienna, Austria. RP Ullrich, T (reprint author), NIDDK, Med Chem Lab, NIH, Bethesda, MD 20817 USA. NR 14 TC 21 Z9 21 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 7 PY 2002 VL 43 IS 2 BP 177 EP 179 DI 10.1016/S0040-4039(01)01985-2 PG 3 WC Chemistry, Organic SC Chemistry GA 511JZ UT WOS:000173261900001 ER PT J AU Markoglou, N Wainer, IW AF Markoglou, N Wainer, IW TI On-line synthesis utilizing immobilized enzyme reactors based upon immobilized dopamine beta-hydroxylase SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE immobilized enzyme reactors; enzymes; dopamine beta-hydroxylase ID MEMBRANE AB Inunobilized enzyme reactors (IMERS) based upon dopamine beta-hydroxylase (DBH) have been developed. Immobilized artificial membrane (IAM) and glutaraldehyde-P (Glut-P) stationary phases have been used to immobilize DBH. When DBH is immobilized on the Glut-P interphase the enzyme is outside the stationary phase whereas with the LAM interphase the enzyme is embedded within the interphase surroundings. The activity of each IMER and their ability for on-line hydroxylation has been investigated. The resulting IMERs are enzymatically active and reproducible. The IMERs can be utilized through the use of coupled chromatography to characterize the cytosolic (DBH-Glut-P-IMER) and membrane-bound (DBH-IAM-IMER) forms of the enzyme. The substrate is injected onto the individual IMERs and the reactants and products are eluted onto a phenylboronic acid column for on-line extraction. The substrates and products are then transported via a switching valve to coupled analytical columns. The results demonstrate that enzyme-substrate and enzyme-inhibitor interactions can be investigated with the on-line system. These IMERs can be utilized for the discovery and characterization of new drug candidates specific for the soluble form and membrane-bound form of DBH. The effects of flow-rate, contact time, pH and temperature have also been investigated. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIA, Gerontol Res Ctr, Bioanalyt & Drug Discovery Unit, NIH, Baltimore, MD 21224 USA. McGill Univ, Dept Med, Div Expt Med, Montreal, PQ, Canada. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, Bioanalyt & Drug Discovery Unit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 9 TC 14 Z9 15 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 5 PY 2002 VL 766 IS 1 BP 145 EP 151 DI 10.1016/S0378-4347(01)00458-3 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 508NC UT WOS:000173094500016 PM 11820290 ER PT J AU Arthos, J Cicala, C Selig, SM White, AA Ravindranath, HM Van Ryk, D Steenbeke, TD Machado, E Khazanie, P Hanback, MS Hanback, DB Rabin, RL Fauci, AS AF Arthos, J Cicala, C Selig, SM White, AA Ravindranath, HM Van Ryk, D Steenbeke, TD Machado, E Khazanie, P Hanback, MS Hanback, DB Rabin, RL Fauci, AS TI The role of the CD4 receptor versus HIV coreceptors in envelope-mediated apoptosis in peripheral blood mononuclear cells SO VIROLOGY LA English DT Article DE CCR5; CXCR4; retrovirus; gp120; TUNEL; annexin-V; T cell ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LYMPHOID-TISSUE; FOCAL ADHESION KINASE; MACROPHAGE-TROPIC HIV; NECROSIS-FACTOR-ALPHA; CD8(+) T-CELLS; CHEMOKINE RECEPTOR; SIGNAL-TRANSDUCTION; NEURONAL APOPTOSIS; TYPE-1 AB We examined the role of CD4, CXCR4, and CCR5 in HIV envelope-mediated apoptosis by measuring the response of activated PBMCs to recombinant envelope proteins derived from CXCR4- and CCR5-utilizing viruses. Apoptosis of T cells was assessed by annexin-V staining and TdT-mediated dUTP-biotin nick-end labeling. Treatment of CCR5Delta32 homozygote PBMCs with a CCR5-specific envelope induced apoptosis in T cells, demonstrating that envelope-CD4 interactions are sufficient to induce apoptosis. However, a CXCR4-specific envelope induced higher levels of apoptosis than a CCR5-specific envelope, suggesting that envelope-mediated apoptosis can be enhanced by envelope-CXCR4 interactions. We conclude that envelope can induce apoptosis in T cells independently of the coreceptor specificity of a given envelope, or the expression profile of CXCR4 or CCR5 on a target cell. However, envelope-coreceptor interactions, and in particular, envelope-CXCR4 interactions, can contribute to this process. (C) 2002 Elsevier Science. C1 Natl Inst Hlth, NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Arthos, J (reprint author), 10 Ctr Dr,MSC 1576,Bldg 10,Room 6A08, Bethesda, MD 20892 USA. OI White, Andrew/0000-0002-9859-0947 NR 53 TC 27 Z9 30 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2002 VL 292 IS 1 BP 98 EP 106 DI 10.1006/viro.2001.1266 PG 9 WC Virology SC Virology GA 517QU UT WOS:000173622000011 PM 11878912 ER PT J AU Patterson, LJ Prince, GA Richardson, E Alvord, WG Kalyan, N Robert-Guroff, M AF Patterson, LJ Prince, GA Richardson, E Alvord, WG Kalyan, N Robert-Guroff, M TI Insertion of HIV-1 genes into Ad4 Delta E3 vector abrogates increased pathogenesis in cotton rats due to E3 deletion SO VIROLOGY LA English DT Article DE adenovirus; HIV-1; vaccines ID HUMAN-IMMUNODEFICIENCY-VIRUS; ADENOVIRUS; PROTEIN; INHIBITION; EXPRESSION; PROTECTION; TYPE-1; P24 AB Adenovirus type 5 (Ad5) E3 region proteins abrogate Ad pathogenicity in the lungs of cotton rats. Our use of Ad4-HIV E3-deleted (DeltaE3) recombinants as vaccines necessitates further examination of these viruses for enhanced pathogenesis, Equivalent infectious doses of Ad4 wild-type (Ad4WT), Ad4AE3, and two recombinants: Ad4DeltaE3HIVenv and Ad4DeltaE3HIVgag, were inoculated intranasally into cotton rats. Ad4 viruses did not replicate in the lungs, but caused mild pathologic effects, including peribronchiolitis, bronchitis, alveolitis, and interstitial pneumonia. As found previously for Ad5, deletion of Ad4 E3 genes resulted in increased lung pathology Surprisingly, insertion of HIV genes into this region significantly restored protection attributed to E3 gene products, diminishing overall pathologic effects to Ad4WT levels (P < 0.0001). Similarly, following administration of equivalent particle numbers of the four viruses, only Ad4AE3 caused increased overall pathology, while the two HIV recombinant viruses showed effects comparable to Ad4WT (P < 0.01). Our observation that Ad4DeltaE3HIV recombinants areas safe in cotton rats as Ad4WT encourages their continued development as AIDS vaccines. (C) 2002 Elsevier Science. C1 NCI, Basic Res Labs, Bethesda, MD 20892 USA. Virion Syst Inc, Rockville, MD USA. Frederick Canc Res & Dev Ctr, Natl Canc Inst, Data Management Serv, Frederick, MD USA. RP Robert-Guroff, M (reprint author), NCI, Basic Res Labs, 41 Lib Dr MSC 5055,Bldg 41,Room D804, Bethesda, MD 20892 USA. NR 15 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2002 VL 292 IS 1 BP 107 EP 113 DI 10.1006/viro.2001.1248 PG 7 WC Virology SC Virology GA 517QU UT WOS:000173622000012 PM 11878913 ER PT J AU Schofield, DJ Satterfield, W Emerson, SU Purcell, RH AF Schofield, DJ Satterfield, W Emerson, SU Purcell, RH TI Four chimpanzee monoclonal antibodies isolated by phage display neutralize hepatitis A virus SO VIROLOGY LA English DT Article DE HAV; neutralization; Fab; phage display; antibody library ID A VIRUS; RECOMBINANT FABS; CAPSID PROTEIN; LIBRARIES; IDENTIFICATION; REPERTOIRE; SITE; SEGMENTS; SURFACE; STRAINS AB Chimpanzee immunoglobulins are virtually identical to human immunoglobulins and may have clinically useful applications. Four chimpanzee monoclonal antibodies (MAbs) to the hepatitis A virus (HAV) capsid were isolated from a combinatorial cDNA library of -gamma1/kappa antibody genes using phage display. Competition assays indicated that three of the MAbs recognized the same or overlapping epitopes, whereas the fourth recognized a different, nonoverlapping epitope on the HAV capsid. All four MAbs neutralized the homologous HAV strain, HM-175, in a radioimmunofocus assay and two of the four MAbs neutralized a heterologous simian HAV strain, AGM-27. From these data, we conclude that the MAbs must recognize at least three epitopes on the HAV capsid. Furthermore, competition assays performed with neutralizing murine MAbs suggested that three of the chimpanzee MAbs recognized epitopes on the HAV capsid which have not been defined previously. (C) 2002 Elsevier Science. C1 NIH, NIAID, Hepatitis Viruses Sect, Infect Dis Lab, Bethesda, MD 20892 USA. NIH, NIAID, Mol Hepatitis Sect, Infect Dis Lab, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Bastrop, TX USA. RP Schofield, DJ (reprint author), NIH, NIAID, Hepatitis Viruses Sect, Infect Dis Lab, Bldg 50,Rm 6533,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 16 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2002 VL 292 IS 1 BP 127 EP 136 DI 10.1006/viro.2001.1252 PG 10 WC Virology SC Virology GA 517QU UT WOS:000173622000014 PM 11878915 ER PT J AU Samuel, W Nagineni, CN Kutty, RK Parks, WT Gordon, JS Prouty, SM Hooks, JJ Wiggert, B AF Samuel, W Nagineni, CN Kutty, RK Parks, WT Gordon, JS Prouty, SM Hooks, JJ Wiggert, B TI Transforming growth factor-beta regulates stearoyl coenzyme A desaturase expression through a smad signaling pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PIGMENT EPITHELIAL-CELLS; COA DESATURASE; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATION; MESSENGER-RNA; TUMOR-CELLS; FATTY-ACIDS; RECEPTOR; PROTEIN; PROMOTER AB The regulation of stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the synthesis of unsaturated fatty acids, is physiologically important because the ratio of saturated to unsaturated fatty acids is thought to control cellular functions by modulating the structural integrity and fluidity of cell membranes. Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, increased SCD mRNA expression in cultured human retinal pigment epithelial cells. This response was elicited by all three TGF-beta isoforms, beta1, beta2, and beta3. However, SCD mRNA expression was not increased either by other members of the TGF-beta family or by other growth factors or cytokines. TGF-beta also increased SCD mRNA expression in several other cell lines tested. The increase in SCD mRNA expression was preceded by a marked increase in Smad2 phosphorylation in TGF-beta-treated human retinal pigment epithelial cells. TGF-beta did not induce SCD mRNA expression in a Smad4-deficient cell line. However, Smad4 overexpression restored the TGF-beta effect in this cell line. Moreover, TGF-beta-induced SCD mRNA expression was effectively blocked by the overexpression of Smad7, an inhibitory Smad. Thus, a TGF-beta signal transduction pathway involving Smad proteins appears to regulate the cellular expression of the SCD gene, and this regulation may play an important role in lipid metabolism. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20878 USA. NEI, Biochem Sect, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20878 USA. NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20878 USA. Johnson & Johnson, Consumer Prod World Wide, Skin Biol Tech Resource Ctr, Skillman, NJ 08558 USA. RW Johnson Pharmaceut Res Inst, Drug Discovery, Spring House, PA 19477 USA. RP Samuel, W (reprint author), NEI, LRCMB, NIH, Rm 338,6 Ctr Dr, Bethesda, MD 20892 USA. NR 67 TC 26 Z9 27 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 4 PY 2002 VL 277 IS 1 BP 59 EP 66 DI 10.1074/jbc.M108730200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900010 PM 11677241 ER PT J AU Sharma, P Veeranna Sharma, M Amin, ND Sihag, RK Grant, P Ahn, N Kulkarni, AB Pant, HC AF Sharma, P Veeranna Sharma, M Amin, ND Sihag, RK Grant, P Ahn, N Kulkarni, AB Pant, HC TI Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; MAMMALIAN-CELLS; P35; EXPRESSION; BRAIN; DIFFERENTIATION; NEURONS; ADULT; TRANSFORMATION; DEFECTS AB Cyclin-dependent protein kinase 5 (cdk5), a member of the cdk family, is active mainly in postmitotic cells and plays important roles in neuronal development and migration, neurite outgrowth, and synaptic transmission. In this study we investigated the relationship between cdk5 activity and regulation of the mitogen-activated protein (MAP) kinase pathway. We report that cdk5 phosphorylates the MAP kinase kinase-1 (MEK1) in vivo as well as the Ras-activated MEK1 in vitro. The phosphorylation of MEK1 by cdk5 resulted in inhibition of MEK1 catalytic activity and the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. In p35 (cdk5 activator) -/- mice, which lack appreciable cdk5 activity, we observed an increase in the phosphorylation of NF-M subunit of neurofilament proteins that correlated with an up-regulation of MEK1 and ERK1/2 activity. The activity of a constitutively active MEK1 with threonine 286 mutated to alanine (within a TPXK cdk5 phosphorylation motif in the proline-rich domain) was not affected by cdk5 phosphorylation, suggesting that Thr(286) might be the cdk5/p35 phosphorylation-dependent regulatory site. These findings support the hypothesis that cdk5 and the MAP kinase pathway cross-talk in the regulation of neuronal functions. Moreover, these data and the recent studies of Harada et al. (Harada, T., Morooka, T., Ogawa, S., and Nishida, E. (2001) Nat. Cell Biol. 3, 453-459) have prompted us to propose a model for feedback down-regulation of the MAP kinase signal cascade by cdk5 inactivation of MEK1. C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Univ Colorado, Dept Biochem, Boulder, CO 80309 USA. NIDCR, Funct Genom Unit, Gene Targeting Facil, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINCDS, Neurochem Lab, NIH, Bldg 36,Rm 4D-04, Bethesda, MD 20892 USA. NR 49 TC 105 Z9 110 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 4 PY 2002 VL 277 IS 1 BP 528 EP 534 DI 10.1074/jbc.M109324200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900070 PM 11684694 ER PT J AU Garcia-Bermejo, ML Leskow, FC Fujii, T Wang, QM Blumberg, PM Ohba, M Kuroki, T Han, KC Lee, J Marquez, VE Kazanietz, MG AF Garcia-Bermejo, ML Leskow, FC Fujii, T Wang, QM Blumberg, PM Ohba, M Kuroki, T Han, KC Lee, J Marquez, VE Kazanietz, MG TI Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKC alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CONFORMATIONALLY CONSTRAINED ANALOGS; ESTER TUMOR PROMOTERS; PHORBOL ESTER; 12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED APOPTOSIS; PROTEOLYTIC ACTIVATION; SUPPRESSES APOPTOSIS; HUMAN KERATINOCYTES; DAG-LACTONES; PHASE-II; IN-VIVO AB Phorbol esters, the archetypical (PKC) activators, induce apoptosis in androgen-sensitive LNCaP prostate cancer cells. In this study we evaluate the effect of a novel class of PKC ligands, the diacylglycerol (DAG)-lactones, as inducers of apoptosis in LNCaP cells. These unique ligands were designed using novel pharmacophore- and receptor-guided approaches to achieve highly potent DAG surrogates. Two of these compounds, HK434 and HK654, induced apoptosis in LNCaP cells with much higher potency than oleoyl-acetyl-glycerol or phorbol 12,13-dibutyrate. Moreover, different PKC isozymes were found to mediate the apoptotic effect of phorbol 12-myristate 13-acetate (PMA) and HK654 in LNCaP cells. Using PKC inhibitors and dominant negative PKC isoforms, we found that both PKCalpha and PKCdelta mediated the apoptotic effect of PMA, whereas only PKCalpha was involved in the effect of the DAG-lactone. The PKCalpha selectivity of HK654 in LNCaP cells contrasts with similar potencies in vitro for binding and activation of PKCalpha and PKCdelta. Consistent with the differences in isoform dependence in intact cells, PMA and HK654 show marked differences in their abilities to translocate PKC isozymes. Both PMA and HK654 induce a marked redistribution of PKCalpha to the plasma membrane. On the other hand, unlike PMA, HK654 translocates PKCdelta predominantly to the nuclear membrane. Thus, DAG-lactones have a unique profile of activation of PKC isozymes for inducing apoptosis in LNCaP cells and represent the first example of a selective activator of a classical PKC in cellular models. An attractive hypothesis is that selective activation of PKC isozymes by pharmacological agents in cells can be achieved by differential intracellular targeting of each PKC. C1 Univ Penn, Sch Med, Ctr Expt Therapeut, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. NCI, Ctr Canc Res, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bethesda, MD 20892 USA. Showa Univ, Sch Pharmaceut Sci, Dept Microbiol, Shinagawa Ku, Tokyo 1428555, Japan. Seoul Natl Univ, Coll Pharm, Lab Med Chem, Kwanak Ku, Seoul 151742, South Korea. NCI, Ctr Canc Res, Lab Med Chem, NIH, Frederick, MD 21701 USA. RP Kazanietz, MG (reprint author), Univ Penn, Sch Med, Ctr Expt Therapeut, 816 Biomed Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. RI Kuroki, Toshio/A-9500-2011; Wang, Qiming/B-6064-2012; Garcia-Bermejo, Maria Laura/E-1542-2015 OI Kuroki, Toshio/0000-0001-6369-4351; FU NCI NIH HHS [R01 CA89202-01A1] NR 58 TC 74 Z9 76 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 4 PY 2002 VL 277 IS 1 BP 645 EP 655 DI 10.1074/jbc.M107639200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900085 PM 11584014 ER PT J AU Carosa, E Kozmik, Z Rall, JE Piatigorsky, J AF Carosa, E Kozmik, Z Rall, JE Piatigorsky, J TI Structure and expression of the scallop Omega-crystallin gene - Evidence for convergent evolution of promoter sequences SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LENS-SPECIFIC EXPRESSION; ALDEHYDE DEHYDROGENASE GENE; GLUTATHIONE S-TRANSFERASES; TRANSGENIC MICE; RETINOIC-ACID; ARGININOSUCCINATE LYASE; DELTA-CRYSTALLIN; ALPHA-CRYSTALLIN; B-CRYSTALLIN; DUCK LENS AB Omega-Crystallin of the scallop lens is an inactive aldehyde dehydrogenase (1A9). Here we have cloned the scallop Omega-crystallin gene. Except for an extra novel first exon, its 14-exon structure agrees well with that of mammalian aldehyde dehydrogenases 1, 2, and 6. The -2120/+63, -714/+63, and -156/+63 Omega-crystallin promoter fragments drive the luciferase reporter gene in transfected alphaTN4-1 lens cells and L929 fibroblasts but not in Cos7 cells. Putative binding sequences for cAMP-responsive element-binding protein (CREB)/Jun, alphaACRYBP1, AP-1, and PAX-6 in the Omega-crystallin promoter are surprisingly similar to the cis-elements used for lens promoter activity of the mouse and chicken alphaA-crystallin genes, which encode proteins homologous to small heat shock proteins. Site-specific mutations in the overlapping CREB/Jun and Pax-6 sites abolished activity of the Omega-crystallin promoter in transfected cells. Gel shift experiments utilizing extracts from the alphaTN4-1, L929, and Cos7 cells and the scallop stomach and oligonucleotides derived from the putative binding sites of the Omega-crystallin promoter showed complex formation. Gel shift experiments showed binding of recombinant Pax-6 and CREB to their respective sites. Our data suggest convergent evolutionary adaptations that underlie the preferential expression of crystallin genes in the lens of vertebrates and invertebrates. C1 NEI, Lab Mol & Dev Biol, Bethesda, MD 20892 USA. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Lab Mol & Dev Biol, 6 Ctr Dr,Bldg 6-Rm 201, Bethesda, MD 20892 USA. RI Kozmik, Zbynek/G-3581-2014; Kozmik, Zbynek/I-8807-2014; OI CAROSA, Eleonora/0000-0002-6593-6833 NR 83 TC 24 Z9 24 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 4 PY 2002 VL 277 IS 1 BP 656 EP 664 DI 10.1074/jbc.M107004200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 508KU UT WOS:000173087900086 PM 11682475 ER PT J AU Kim, HS Ravi, RG Marquez, VE Maddileti, S Wihlborg, AK Erlinge, D Malmsjo, M Boyer, JL Harden, TK Jacobson, KA AF Kim, HS Ravi, RG Marquez, VE Maddileti, S Wihlborg, AK Erlinge, D Malmsjo, M Boyer, JL Harden, TK Jacobson, KA TI Methanocarba modification of uracil and adenine nucleotides: High potency of northern ring conformation at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) but not P2Y(6) receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL-ACTIVITY; PHARMACOLOGICAL CHARACTERIZATION; PHOSPHOLIPASE-C; P2 RECEPTORS; NUCLEOSIDES; AGONISTS; ANALOGS; IDENTIFICATION; SELECTIVITY; ACTIVATION AB The potency of nucleotide antagonists at P2Y(1) receptors was enhanced by replacing the ribose moiety with a constrained carbocyclic ring (Nandanan, et al. J. Med. Chem. 2000, 43, 829842). We have now synthesized ring-constrained methanocarba analogues (in which a fused cyclopropane moiety constrains the pseudosugar ring) of adenine and uracil nucleotides, the endogenous activators of P2Y receptors. Methanocarba-adenosine 5'-triphosphate (ATP) was fixed in either a Northern (N) or a Southern (S) conformation, as defined in the pseudorotational cycle. (N)-Methanocarba-uridine was prepared from the 1-amino-pseudosugar ring by treatment with beta-ethoxyacryloyl cyanate and cyclization to form the uracil ring. Phosphorylation was carried out at the 5'-hydroxyl group through a multistep process: Reaction with phosphoramidite followed by oxidation provided the 5'-monophosphates, which then were treated with 1,1'-carbonyldiimidazole for condensation with additional phosphate groups, The ability of the analogues to stimulate phospholipase C through activation of turkey P2Y(1) or human P2Y(1), P2Y(2), P2Y(4), P2Y(6), and P2Y(11) receptors stably expressed in astrocytoma cells was measured. At recombinant human P2Y(1) and P2Y(2) receptors, (N)-methanocarba-ATP was 138- and 41-fold, respectively, more potent than racemic (S)-methanocarba-ATP as an agonist. (N)methanocarba-ATP activated P2Y(11) receptors with a potency similar to ATP. (N)-Methanocarba-uridine 5'-triphosphate (UTP) was equipotent to UTP as an agonist at human P2Y2 receptors and also activated P2Y(4) receptors with an EC50 of 85 nM. (N)-Methanocarba-uridine 5'-diphosphate (UDP) was inactive at the hP2Y(6) receptor. The vascular effects of (N)-methanocarba-UTP and (N)-methanocarba-UDP were studied in a model of the rat mesenteric artery, The triphosphate was more potent than UTP in inducing a dilatory P2Y(4) response (pEC(50) = 6.1 +/- 0.2), while the diphosphate was inactive as either an agonist or antagonist in a P2Y(6) receptor-mediated contractile response. Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Med Chem Lab, Frederick, MD 21702 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ Lund Hosp, Dept Cardiol, SE-22185 Lund, Sweden. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20]; NHLBI NIH HHS [HL54889, R01 HL054889, R29 HL054889]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 39 TC 83 Z9 83 U1 0 U2 2 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 3 PY 2002 VL 45 IS 1 BP 208 EP 218 DI 10.1021/jm010369c PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 508KZ UT WOS:000173088800018 PM 11754592 ER PT J AU Jayaraman, M Fox, BM Hollingshead, M Kohlhagen, G Pommier, Y Cushman, M AF Jayaraman, M Fox, BM Hollingshead, M Kohlhagen, G Pommier, Y Cushman, M TI Synthesis of new dihydroindeno[1,2-c]isoquinoline and indenoisoquinolinium chloride topoisomerase I inhibitors having high in vivo anticancer activity in the hollow fiber animal model SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BIOLOGICAL-ACTIVITY; CAMPTOTHECIN; DERIVATIVES; SALTS AB A number of novel dihydroindenoisoquinolines and indenoisoquinolinium salts were synthesized and examined for cytotoxicity in cancer cell cultures and for inhibition of topoisomerase I (top R The top1-mediated DNA cleavage patterns produced in the presence of several of the new analogues were also investigated, and a few of the more potent compounds were examined for activity in hollow fiber animal models. Very cytotoxic dihydroindenoisoquinoline and isoquinolinium salts were obtained with mean graph midpoints (MGMs) for growth inhibition in the low submicromolar range. Two of the new dihydroindenoisoquinolines were found to be weaker top1 inhibitors than the lead compound 1, while two of the indenoisoquinolinium salts were more potent. The top1-mediated DNA cleavage patterns of the indenoisoquinolines examined were found to be similar to each other but different from that of camptothecin. Several of the more potent indenoisoquinolines displayed promising anticancer activities in hollow fiber animal models. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Biol Testing Branch, Dev Therapeut Program,Fairview Ctr, Div Canc Treatment & Diagnosis,NIH, Frederick, MD 21701 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. FU NCI NIH HHS [N01-CO-56000, R01 CA89566, 5T32CA09634] NR 16 TC 71 Z9 73 U1 0 U2 2 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 3 PY 2002 VL 45 IS 1 BP 242 EP 249 DI 10.1021/jm000498f PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 508KZ UT WOS:000173088800021 PM 11754595 ER PT J AU Skjaerven, R Wilcox, AJ Lie, RT AF Skjaerven, R Wilcox, AJ Lie, RT TI The interval between pregnancies and the risk of preeclampsia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOW-BIRTH-WEIGHT; PRE-ECLAMPSIA; PRETERM DELIVERY; PATERNITY; WOMEN; ABORTION; SMOKING; DONOR AB Background: The risk of preeclampsia is generally lower in second pregnancies than in first pregnancies, but not if the mother has a new partner for the second pregnancy. One explanation is that the risk is reduced with repeated maternal exposure and adaptation to specific antigens from the same partner. However, the difference in risk might instead be explained by the interval between births. A longer interbirth interval may be associated with both a change of partner and a higher risk of preeclampsia. Methods: We used data from the Medical Birth Registry of Norway, a population-based registry that includes births that occurred between 1967 and 1998. We studied 551,478 women who had two or more singleton deliveries and 209,423 women who had three or more singleton deliveries. Results: Preeclampsia occurred during 3.9 percent of first pregnancies, 1.7 percent of second pregnancies, and 1.8 percent of third pregnancies when the woman had the same partner. The risk in a second or third pregnancy was directly related to the time that had elapsed since the preceding delivery, and when the interbirth interval was 10 years or more, the risk approximated that among nulliparous women. After adjustment for the presence or absence of a change of partner, maternal age, and year of delivery, the odds ratio for preeclampsia for each one-year increase in the interbirth interval was 1.12 (95 percent confidence interval, 1.11 to 1.13). In unadjusted analyses, a pregnancy involving a new partner was associated with higher risk of preeclampsia, but after adjustment for the interbirth interval, the risk of preeclampsia was reduced (odds ratio for preeclampsia with a change of partner, 0.73; 95 percent confidence interval, 0.66 to 0.81). Conclusions: The protective effect of previous pregnancy against preeclampsia is transient. After adjustment for the interval between births, a change of partner is not associated with an increased risk of preeclampsia. (N Engl J Med 2002;346:33-8.) Copyright (C) 2002 Massachusetts Medical Society. C1 Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Med Stat, N-5021 Bergen, Norway. Univ Bergen, Med Birth Registry Norway, Locus Registry Based Epidemiol, N-5021 Bergen, Norway. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Skjaerven, R (reprint author), Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Med Stat, Armauer Hansens Bldg, N-5021 Bergen, Norway. OI Wilcox, Allen/0000-0002-3376-1311 NR 28 TC 185 Z9 191 U1 3 U2 9 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 3 PY 2002 VL 346 IS 1 BP 33 EP 38 DI 10.1056/NEJMoa011379 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 507NB UT WOS:000173033600005 PM 11778000 ER PT J AU Hong, F Kim, WH Tian, ZG Jaruga, B Ishac, E Shen, XN Gao, B AF Hong, F Kim, WH Tian, ZG Jaruga, B Ishac, E Shen, XN Gao, B TI Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-X-L proteins SO ONCOGENE LA English DT Article DE IL-6; Bcl-2; Bax; apoptosis; liver; alcoholic liver disease ID NECROSIS-FACTOR-ALPHA; MEDIATED APOPTOSIS; RAT HEPATOCYTES; PLASMA INTERLEUKIN-6; ALCOHOLIC HEPATITIS; REGENERATING LIVER; OXIDATIVE STRESS; IN-VIVO; DISEASE; MICE AB Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNF alpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-X-L) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-X-L is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-XL but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-X-L. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Pk Bldg,Room 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. RI Tian, Zhigang/J-3512-2013 FU NIAAA NIH HHS [R01AA12637] NR 56 TC 102 Z9 110 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 3 PY 2002 VL 21 IS 1 BP 32 EP 43 DI 10.1038/sj.onc.1205016 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 505AD UT WOS:000172887800004 PM 11791174 ER PT J AU Segrelles, C Ruiz, S Perez, P Murga, C Santos, M Budunova, IV Martinez, J Larcher, F Slaga, TJ Gutkind, JS Jorcano, JL Paramio, JM AF Segrelles, C Ruiz, S Perez, P Murga, C Santos, M Budunova, IV Martinez, J Larcher, F Slaga, TJ Gutkind, JS Jorcano, JL Paramio, JM TI Functional roles of Akt signaling in mouse skin tumorigenesis SO ONCOGENE LA English DT Article DE skin carcinogenesis; signal transduction; ras; Akt; PTEN ID INTEGRIN-LINKED KINASE; PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR RECEPTOR; TUMOR-SUPPRESSOR GENE; CYCLIN D1; PHOSPHOINOSITIDE 3-KINASE; PREMALIGNANT PROGRESSION; INCREASING COMPLEXITY; RAS TRANSFORMATION; CELL-PROLIFERATION AB The mouse skin carcinogenesis protocol is a unique model for understanding the molecular events leading to oncogenic transformation. Mutations in the Ha-ras gene, and the presence of functional cyclin D1 and the EGF receptor, have proven to he important in this system. However, the signal transduction pathways connecting these elements during mouse skin carcinogenesis are poorly understood. This paper studies the relevance of the Akt and ERK pathways in the different stages of chemically induced mouse skin tumors. Akt activity increases throughout the entire process, and its early activation is detected prior to increased cyclin D1 expression. ERK activity rises only during the later stages of malignant conversion. The observed early increase in Akt activity appears to be due to raised PI-3K activity. Other factors acting on Akt such as ILK activation and decreased PTEN phosphatase activity appear to be involved at the conversion stage. To further confirm the involvement of Akt in this process, PB keratinocytes were transfected with Akt and subsequently injected into nude mice. The expression of Akt accelerates tumorigenesis and contributes to increased malignancy of these keratinocytes as demonstrated by the rate of appearance, the growth and the histological characteristics of the tumors. Collectively, these data provide evidence that Akt activation is one of the key elements during the different steps of mouse skin tumorigenesis. C1 CIEMAT, Program Cell & Mol Biol & Gene Therapy, E-28040 Madrid, Spain. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. AMC Canc Res Ctr, Denver, CO 80214 USA. RP Paramio, JM (reprint author), CIEMAT, Program Cell & Mol Biol & Gene Therapy, Ed 7,Av Complutense 22, E-28040 Madrid, Spain. RI Gutkind, J. Silvio/A-1053-2009; Murga, Cristina/E-1965-2014; Paramio, Jesus M/M-8482-2014; Larcher, Fernando/J-1527-2016; OI Murga, Cristina/0000-0002-8964-4077; Paramio, Jesus M/0000-0001-7520-3177; Larcher, Fernando/0000-0002-6771-3561; Perez, Paloma/0000-0002-7166-2824 FU NCI NIH HHS [1R01CA79065-01, CA79065-02] NR 61 TC 130 Z9 130 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 3 PY 2002 VL 21 IS 1 BP 53 EP 64 DI 10.1038/sj.onc.1205032 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 505AD UT WOS:000172887800006 PM 11791176 ER PT J AU Bishop, PC Myers, T Robey, R Fry, DW Liu, ET Blagosklonny, MV Bates, SE AF Bishop, PC Myers, T Robey, R Fry, DW Liu, ET Blagosklonny, MV Bates, SE TI Differential sensitivity of cancer cells to inhibitors of the epidermal growth factor receptor family SO ONCOGENE LA English DT Article DE oncogenes; HER1/HER2 inhibitors; EGF; NCI drug screen; signal transduction ID ANTICANCER DRUG SCREEN; BREAST-CANCER; PROGNOSTIC FACTOR; TUMOR-SUPPRESSOR; ONCOGENE; THERAPY; GENE; P53; AMPLIFICATION; EXPRESSION AB Clinical responses to the HER1 (EGF receptor) inhibitors and HER2/neu/ErbB2 inhibitors correlate with high levels of receptor expression. However, a significant subset of patients with high receptor levels appear to be refractory to treatment. We have observed similar results in the 60 cell lines of the NCI Anti-Cancer Drug Screen using a panel of 11 selective HER1 inhibitors. As expected, low HER1-expressing cell lines were insensitive to HER1 inhibitors. In cell lines with high HER1 expression, low concentrations of HER1 inhibitors potently inhibit both HER1 phosphorylation and the mitogen-activated protein kinase (MAPK) pathway. However, this inhibition did not always correlate with cellular arrest. High HER1-expressing cell lines can be subdivided into two groups based on their sensitivity to HER1 inhibitors. In the sensitive group, receptor and growth inhibition was concordant and occurred at submicromolar concentrations of HER1 inhibitors. In the insensitive group, receptor inhibition occurred at a low concentration (<1 mum) but concentrations that were ten times or higher were required for growth inhibition. Also, neither induction of p21 and cyclin D1 nor p53 status could explain the difference between sensitive and insensitive cells. Although EGF activated the MAPK pathway in all cell lines, only drug-sensitive cell lines responded to EGF (accelerated entry from G1 to S) and to HER1 inhibitors (GI arrest) by changes in cell cycling. Furthermore, an EGF-dependent immortalized mammary epithelial cell line was extremely sensitive to a panel of HER1 inhibitors. We infer that independence from mitogen-mediated signaling confers insensitivity to HER1 inhibitors in a large subset of cancer cell lines. C1 NCI, Med Branch, DCS, MB,NIH, Bethesda, MD 20892 USA. US FDA, CBER, OTRR, DCTDA,Oncol Branch, Rockville, MD 20852 USA. NCI, DTP, Rockville, MD USA. Parke Davis Pharmaceut, Ann Arbor, MI USA. Natl Univ Singapore, Singapore Genom Programme, Singapore, Singapore. New York Med Coll, Dept Med, Valhalla, NY 10595 USA. RP Bates, SE (reprint author), NCI, Med Branch, DCS, MB,NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Liu, Edison/C-4141-2008 NR 33 TC 79 Z9 83 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 3 PY 2002 VL 21 IS 1 BP 119 EP 127 DI 10.1038/sj.onc.1205028 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 505AD UT WOS:000172887800012 PM 11791182 ER PT J AU Yang, L Xia, L Wu, DY Wang, HB Chansky, HA Schubach, WH Hickstein, DD Zhang, Y AF Yang, L Xia, L Wu, DY Wang, HB Chansky, HA Schubach, WH Hickstein, DD Zhang, Y TI Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor SO ONCOGENE LA English DT Article DE histone methyltransferase; ESET; ERG ID HUMAN MYELOID-LEUKEMIA; EWINGS-SARCOMA; CHROMOSOMAL TRANSLOCATION; EWS-ERG; GENE; PROTEINS; DOMAIN; FAMILY; RNA; METHYLATION AB The ets-related gene erg encodes a transcription factor that is implicated in the control of cell growth and differentiation. To identify interacting partners of ERG, we screened a yeast two-hybrid cDNA library constructed from mouse hematopoietic cells using the N-terminal region of ERG as a bait. We isolated a 4.6 kb full-length mouse cDNA encoding a 1307-amino acid protein migrating as a 180 kD band, which was termed ESET (ERG-associated protein with SET domain). ESET is 92% identical to the human protein SETDB1 (SET domain, bifurcated 1). The interaction between ESET and ERG was supported by in vitro pull-down using glutathione S-transferase (GST) fusion protein, by transfection and co-immunoprecipitation experiments, and by association of endogenous SETDB1 with ERG. Since ESET possesses evolutionarily conserved SET, preSET, and postSET domains implicated in histone methylation, we tested the ability of ESET to methylate core histones. The results of these studies demonstrated that ESET is a histone H3-specific methyltransferase, and that mutations within ESET abolished its methyltransferase activity. Together, these findings raise the possibility that transcription factor ERG may participate in transcriptional regulation through ESET-mediated histone methylation. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NCI, Dept Expt Transplantat & Immunol, Bethesda, MD 20892 USA. Univ Washington, Dept Med Oncol, Seattle, WA 98108 USA. Univ Washington, Dept Orthoped, Seattle, WA 98108 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. RP Zhang, Y (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. FU NIGMS NIH HHS [GM63067-01] NR 30 TC 145 Z9 151 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 3 PY 2002 VL 21 IS 1 BP 148 EP 152 DI 10.1038/sj.onc.1204998 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 505AD UT WOS:000172887800015 PM 11791185 ER PT J AU Cannon, RO AF Cannon, RO TI Oral L-arginine (and other active ingredients) for ischemic heart disease? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material ID CORONARY-ARTERY DISEASE; NITRIC-OXIDE SYNTHASE; STABLE ANGINA-PECTORIS; ENDOTHELIAL DYSFUNCTION; VASODILATION; HUMANS; ATHEROSCLEROSIS; DILATATION; GENERATION; INHIBITOR C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B-15,10 Ctr Dr,MSC 1650, Bethesda, MD 20892 USA. NR 31 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 2 PY 2002 VL 39 IS 1 BP 46 EP 48 DI 10.1016/S0735-1097(01)01693-X PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 507BU UT WOS:000173007500007 PM 11755285 ER PT J AU Kramer, BS Chasan, R AF Kramer, BS Chasan, R TI A commencement for the Journal: the inspiration of Janus SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 Journal Natl Canc Inst, Bethesda, MD 20824 USA. RP Kramer, BS (reprint author), Journal Natl Canc Inst, POB 31110, Bethesda, MD 20824 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 2 PY 2002 VL 94 IS 1 BP 3 EP 4 PG 2 WC Oncology SC Oncology GA 507YJ UT WOS:000173058600001 ER PT J AU Ganz, PA Desmond, KA Leedham, B Rowland, JH Meyerowitz, BE Belin, TR AF Ganz, PA Desmond, KA Leedham, B Rowland, JH Meyerowitz, BE Belin, TR TI Quality of life in long-term, disease-free survivors of breast cancer: a follow-up study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURGICAL ADJUVANT BREAST; OF-LIFE; DYADIC ADJUSTMENT; COMMUNITY SAMPLE; 1ST YEAR; HEALTH; MASTECTOMY; SURGERY; SCALES; WOMEN AB Background: Women with breast cancer are the largest group of female survivors of cancer. There is limited information about the long-term quality of life (QOL) in disease-free breast cancer survivors. Methods: Letters of invitation were mailed to 1336 breast cancer survivors who had participated in an earlier survey and now were between 5 and 10 years after their initial diagnosis. The 914 respondents interested in participating were then sent a survey booklet that assessed a broad range of QOL, and survivorship concerns. All P values were two-sided. Results: A total of 817 women completed the follow-up survey (61% response rate), and the 763 disease-free survivors in that group, who had been diagnosed an average of 6.3 years earlier, are the focus of this article. Physical well-being and emotional well-being were excellent; the minimal changes between the baseline and follow-up assessments reflected expected age-related changes. Energy level and social functioning were unchanged. Hot flashes, night sweats, vaginal discharge, and breast sensitivity were less frequent. Symptoms of vaginal dryness and urinary incontinence were increased. Sexual activity with a partner declined statistically significantly between the two assessments (from 65% to 55%, P = .001). Survivors with no past systemic adjuvant therapy had a better QOL than those who had received systemic adjuvant therapy (chemotherapy, tamoxifen, or both together) (physical functioning, P = .003; physical role function, P = .02; bodily pain, P = .01; social functioning, P = .02; and general health, P = .03). In a multivariate analysis, past chemotherapy was a statistically significant predictor of a poorer current QOL (P = .003). Conclusions: Long-term, disease-free breast cancer survivors reported high levels of functioning and QOL many years after primary treatment. However, past systemic adjuvant treatment was associated with poorer functioning on several dimensions of QOL. This information may be useful to patients and physicians who are engaging in discussion of the risks and benefits of systemic adjuvant therapy. C1 Univ Calif Los Angeles, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, Bethesda, MD 20892 USA. Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. RP Ganz, PA (reprint author), Univ Calif Los Angeles, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, Box 956900,Rm A2-125 CHS, Los Angeles, CA 90095 USA. FU NCI NIH HHS [R01CA63028] NR 50 TC 545 Z9 558 U1 6 U2 34 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 2 PY 2002 VL 94 IS 1 BP 39 EP 49 PG 11 WC Oncology SC Oncology GA 507YJ UT WOS:000173058600013 PM 11773281 ER PT B AU Dean, J AF Dean, J BE Acosta, AA TI Oocyte-specific genes and reproduction SO 12TH WORLD CONGRESS ON IN VITRO FERTILIZATION AND MOLECULAR REPRODUCTION LA English DT Proceedings Paper CT 12th World Congress on In Vitro Fertilization and Molecular Reproduction CY MAR 16-19, 2002 CL BUENOS AIRES, ARGENTINA ID ZONA-PELLUCIDA; FIG-ALPHA; MICE; FERTILITY C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD USA. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2316-8 PY 2002 BP 3 EP 7 PG 5 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA BU30U UT WOS:000175617800001 ER PT S AU Seidel, Y Vaquero, JJ Green, MV AF Seidel, Y Vaquero, JJ Green, MV BE Seibert, JA TI Resolution uniformity and sensitivity of the NIH ATLAS small animal PET scanner: Comparison to simulated LSO scanners without depth-of-interaction capability SO 2001 IEEE NUCLEAR SCIENCE SYMPOSIUM, CONFERENCE RECORDS, VOLS 1-4 SE IEEE NUCLEAR SCIENCE SYMPOSIUM - CONFERENCE RECORD LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium CY NOV 04-10, 2001 CL SAN DIEGO, CA SP IEEE, Nucl Plasma Sci Soc ID DETECTOR MODULE; PERFORMANCE AB PET scanners designed to image animals the size of rats and mice should possess simultaneously high and uniform spatial resolution and high sensitivity. ATLAS (Advanced Technology Laboratory Animal Scanner), an 11.8 cm diameter aperture, 2 cm axial field-of-view ring-type research scanner seeks these goals by surrounding the animal with eighteen 15 rum deep, LGSO (7 mm) / GSO (8 mm) phoswich detector modules. A Monte Carlo simulation was used to compare the variation of resolution across the field-of-view and the absolute central point source sensitivity (ACS) of ATLAS to similar systems comprised only of LSO arrays of different depths with no depth-of-interaction (DOT) capability. For ATLAS radial spatial resolution deteriorated by 27% from the center to 3 cm off-axis. Scanners comprised of 15 mm deep, 10 mm deep and 7 mm deep LSO crystals deteriorated by 100%, 51%, and 20% respectively, over the same distance. Simulated ACS (absorbed energies greater than or equal to 250 keV) for ATLAS was 2.0% and for the 15 mm, 10 mm deep and 7 mm deep LSO scanners 2.4%, 1.5%, and 0.9%, respectively. Radial resolution loss 3 cm off-axis and ACS measured for the actual ATLAS scanner were similar to the values obtained by simulation (27% resolution loss, 1.8% ACS). The phoswich design thus achieves good resolution uniformity over a 6 cm FOV while preserving sensitivity compared to equivalent non-DOI LSO scanners with a range of crystal depths. C1 NIH, Bethesda, MD 20892 USA. RP Seidel, Y (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X 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 1082-3654 BN 0-7803-7324-3 J9 IEEE NUCL SCI CONF R PY 2002 BP 1555 EP 1558 PG 4 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Nuclear Science & Technology; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BV30L UT WOS:000178495800339 ER PT B AU Jafari, R AF Jafari, R GP IEEE IEEE TI Cogeneration plant for national institutes of health SO 2002 IEEE INDUSTRIAL AND COMMERCIAL POWER SYSTEMS TECHNICAL CONFERENCE, CONFERENCE RECORD LA English DT Proceedings Paper CT Annual Meeting of the Industrial and Commercial Power Systems CY MAY 05-08, 2002 CL SAVANNAH, GA SP IEEE Ind Applicat Soc, Ind & Commercial Power Syst Dept, IEEE Savannah Sect AB National Institutes of Health in Bethesda, is installing one of the largest cogeneration power plants ever built for the Federal government that will boost energy efficiency, cut costs and reduce air emissions. On site generation of utility using cogeneration, produces reliable electricity, reduces regional pollution and reduces energy costs. Cogeneration is the simultaneous production of electricity and taking advantage of the heat that is normally exhausted to generate steam also called Combined Heat and Power (CHP). C1 NIH, Bethesda, MD 20892 USA. RP Jafari, R (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7483-5 PY 2002 BP 14 EP 16 PG 3 WC Energy & Fuels; Engineering, Electrical & Electronic SC Energy & Fuels; Engineering GA BU59X UT WOS:000176465600002 ER PT S AU Meier-Schellersheim, M AF Meier-Schellersheim, M GP IEEE IEEE TI Understanding information processing in the immune system; Computer modeling and simulations SO 2002 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING, VOLS I-IV, PROCEEDINGS SE International Conference on Acoustics Speech and Signal Processing (ICASSP) LA English DT Proceedings Paper CT IEEE International Conference on Acoustics, Speech, and Signal Processing CY MAY 13-17, 2002 CL ORLANDO, FL SP IEEE Signal Proc Soc ID TOLERANCE AB The immune system protects our organisms against pathogens and aberrant cells. It achieves this capability by processing and evaluating a wide variety of molecular signals many of which are generated by its own agents. Even though the amount of experimental data describing single cellular mechanisms is rapidly growing a satisfactory understanding of the immune system's operations remains very difficult due to the complexity of the system. Simmune, a novel computer program, allows to investigate cellular cooperation within the immune system through simulations on the level of interactions between individual cells. Such simulations may allow to bridge the scale gap between experimentally accessible low level data and higher level multicellular processes which determine the appropriate response to pathogen challenges. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Meier-Schellersheim, M (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 0-7803-7402-9 J9 INT CONF ACOUST SPEE PY 2002 BP 4036 EP 4039 PG 4 WC Acoustics; Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Acoustics; Computer Science; Engineering; Imaging Science & Photographic Technology GA BU96P UT WOS:000177510401010 ER PT B AU Han, W Pai, VN AF Han, W Pai, VN GP IEEE IEEE TI Mapping 3D myocardial wall motion over the left ventricle in a breath-hold SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID STIMULATED-ECHO; HUMAN-HEART; DIFFUSION; TRACKING; NMR AB In magnetic resonance imaging, stimulated-echo based phase-contrast displacement mapping has been developed for various applications. This paper describes the adaptation and technical optimization of this idea for mapping the three-dimensional (313) motion of the left ventricular wall in the human heart. Percentile wall thickening maps are obtained with a rapid and automatic data processing program. Results from normal human subjects and swine infarct models show that this quantitative method is suited for detecting focal areas of abnormal wall motion. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Han, W (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 121 EP 124 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400030 ER PT B AU Jerebko, AK Malley, JD Franaszek, M Summers, RM AF Jerebko, AK Malley, JD Franaszek, M Summers, RM GP IEEE IEEE TI Multi network classification scheme for detection of colonic polyps in CT colonography data sets SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc DE virtual colonoscopy; colon cancer; classification; neural network AB A multi-network decision classification scheme for colonic polyp detection is presented. The approach is based on the results of voting over several neural networks using variable subsets selected from a general set. We used 21 features including region density, Gaussian and mean curvature and sphericity, lesion size, colon wall thickness, and their means and standard deviations. The subsets of variables are weighted by their effectiveness calculated on the basis of the training and test sample misclassification rates. The final decision is based on the majority vote across the networks and takes into account the weighted votes of all nets. This method reduces the false positive rate by a factor of 1.7 compared to single net decisions. The overall sensitivity and specificity rates reached are 100% and 95% correspondingly. Back propagation neural nets trained with the Uvenberg-Marquardt algorithm were used. Ten-fold cross-validation is applied to better estimate the true error rates. C1 NIH, Bethesda, MD 20892 USA. RP Jerebko, AK (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 197 EP 200 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400049 ER PT B AU Green, MV Seidel, J Johnson, CA Vaquero, JJ Pascau, J Desco, M AF Green, MV Seidel, J Johnson, CA Vaquero, JJ Pascau, J Desco, M GP IEEE IEEE TI Towards high performance small animal positron emission tomography SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID MICROPET; SYSTEM AB During the last decade increasingly sophisticated positron emission tomography (PET) scanners have been developed for imaging small laboratory animals. These systems often exhibit performance characteristics, e.g. spatial resolution, substantially better than contemporary human PET scanners and are often the first systems to demonstrate new technologies, e.g. avalanche photodiode-based detector modules. Despite these advances, spatial resolution, sensitivity, resolution uniformity and other performance parameters must continue to be improved if accurate general purpose imaging is to be carried out in the most popular research subject, the mouse. Moreover, as these improvements occur, methods must also be devised to minimize the resolution-degrading effects of positron range, the distance a positron travels from the decaying nucleus before encountering and mutually annihilating an electron. Range effects are particularly important for compounds labeled with "non-traditional" positron-emitters such as I-124 or Tc-94m. In order to illustrate the complex interplay of issues that must be addressed when contemplating such improvements, we describe how we have approached high performance PET imaging in the design and construction of ATLAS (Advanced Technology Laboratory Animal Scanner), a small animal PET scanner now entering service at the National Institutes of Health (NIH) in Bethesda, Md. C1 NIH, Bethesda, MD 20892 USA. RP Green, MV (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009; Desco, Manuel/D-2822-2009; OI Vaquero, Juan Jose/0000-0001-9200-361X; Desco, Manuel/0000-0003-0989-3231; Pascau, Javier/0000-0003-1484-731X NR 5 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 369 EP 372 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400092 ER PT B AU Kellman, P Schnermann, MJ McVeigh, ER AF Kellman, P Schnermann, MJ McVeigh, ER GP IEEE IEEE TI Comparison of 1-D and 2-D surface coil arrays for accelerated volume MR imaging using sensitivity encoding SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID SENSE AB The sensitivity encoding (SENSE) [1] method of parallel MR accelerated imaging is evaluated and compared for 1-d and 2-d surface coil array geometries. Accelerated MR imaging using SENSE may be applied to volume imaging using either 3-d or 2-d multi-slice acquisition strategies. For higher accelerations such as rate R=4, 3-d SENSE may be applied along either or both phase encode directions. Image quality (SENSE g-factor) is compared for R=4 acceleration implemented with a reduced number of phase encodes in the y-direction, and (assuming a 3-d acquisition) with a reduced number of phase encodes in both y- and z-directions. Simulations show that the performance for 1-d and 2-d array geometries depends highly on the slice orientation. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 485 EP 488 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400122 ER PT B AU Seidel, J Vaquero, JJ Pascau, J Desco, M Johnson, CA Green, MV AF Seidel, J Vaquero, JJ Pascau, J Desco, M Johnson, CA Green, MV GP IEEE IEEE TI Features of the NIH atlas small animal PET scanner and its use with a coaxial small animal volume CT scanner SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID PERFORMANCE EVALUATION; MICROPET AB ATLAS (Advanced Technology Laboratory Animal Scanner), a small animal PET scanner designed to image animals the size of rats and mice, is about to enter service on the NIH campus in Bethesda, Maryland. This system is the first small animal PET scanner with a depth-of-interaction capability and the first to use iterative resolution recovery algorithms, rather than conventional filtered back projection, for "production" image reconstruction. ATLAS is also proximate to, and co-axial with, a high, resolution small animal CT scanner. When fully integrated, spatially registered PET and CT images of each animal will be used to correct the emission data for radiation attenuation and to aid in target identification. In this report we describe some of the technical and functional features of this system and illustrate how these features are used in an actual small animal imaging study. C1 NIH, Bethesda, MD 20892 USA. RP Seidel, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009; Desco, Manuel/D-2822-2009; OI Vaquero, Juan Jose/0000-0001-9200-361X; Desco, Manuel/0000-0003-0989-3231; Pascau, Javier/0000-0003-1484-731X NR 9 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 545 EP 548 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400137 ER PT B AU Koretsky, AP AF Koretsky, AP GP IEEE IEEE TI Anatomical, functional, and molecular magnetic resonance imaging in the post-genomic era SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID CELLS; MRI AB Over the last decade there has been rapid progress in development of magnetic resonance imaging (MRI) techniques that give specific anatomical, functional and molecular information. Paralleling these developments there has been tremendous progress in molecular genetics which has generated powerful tools for understanding and manipulating the genetic basis of cell and tissue function. There is now rapidly growing interest in combining advances in MRI and advances in molecular genetics to develop efficient ways to map specific genetic changes onto the complex physiology of an intact tissue. Examples of new developments in MRI are given with applications to phenotyping specific transgenic and knockout mouse models. Some conjecture is offered on integrating MRI into functional genomics. C1 NINDS, NIH, Bethesda, MD USA. RP Koretsky, AP (reprint author), NINDS, NIH, Bethesda, MD USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 709 EP 712 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400178 ER PT B AU Li, KCP Bednarski, MD AF Li, KCP Bednarski, MD GP IEEE IEEE TI Vascular-targeted imaging using MRI SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID PARAMAGNETIC POLYMERIZED LIPOSOMES AB Target specific MRI poses special opportunities and challenges. Although MRI can provide exquisite morphologic details, its relatively low sensitivity has severely hampered the development of target-specific contrast agents that can provide enough signal alteration to be detectable in vivo. In this review, we will present our data on the development of polymerized vesicles for use in vascular-targeted imaging using MRI. Because of the high amount of payload that can be carried to the target site via these particles, they can be detectable with MRI. In addition, the same platform can be used for delivering multiple different types of contrast ions as well as therapeutic agents to vascular target sites. We believe that by using the same platform for imaging and therapy, we can have an accurate way of personalizing treatment. C1 NIH, Ctr Clin, Bethesda, MD USA. RP Li, KCP (reprint author), NIH, Ctr Clin, Bethesda, MD USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 809 EP 810 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400203 ER PT B AU Hoffman, JM AF Hoffman, JM GP IEEE IEEE TI Positron emission tomography (PET): A powerful molecular imaging technique SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID F-18 FLUORODEOXYGLUCOSE; CANCER AB Non-Invasive, In Vivo Molecular Imaging will assume an increasing role in the diagnosis and management of patients with cancer in the future. During the past decade, there has been a revolution in our basic understanding of human disease and cancer in particular. This has been made possible from the rapid development of basic molecular techniques. Associated with the developments in molecular biology, the imaging sciences have made remarkable advances in technology and methodologies. Recently, spectroscopic MRI techniques and positron emission tomography (PET) became available and used routinely in clinical practice. The molecular function of a tumor can be assessed rather than just visualizing the mass on an anatomic imaging study, which may not necessarily change with newer cytostatic therapies. Monitoring the effect of directed therapy is now possible eliminating the need for repeat biopsy or tissue sampling to assess viable tumor. FDG has shown its power as a very important molecular imaging probe in patients with cancer. However, there are many other aspects of malignancy that can be explored and understood by the use of the appropriately labeled radiopharmaceutical using PET technology. Other important aspects of malignancy include determination of proliferative acitivity; hypoxia; tumor blood flow and perfusion; and in-vivo non-invasive determination of certain tumor receptor densities. With the synthesis and characterization of more targeted radio pharmaceuticals it will be possible to characterize tumors and assist the oncologist in selecting the appropriate individualized therapy best for treatment of a particular malignant disease in each and every patient. C1 NCI, Mol Imaging Branch, Biomed Imaging Program, Bethesda, MD 20892 USA. RP Hoffman, JM (reprint author), NCI, Mol Imaging Branch, Biomed Imaging Program, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 811 EP 814 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400204 ER PT B AU Basser, PJ Pajevic, S AF Basser, PJ Pajevic, S GP IEEE IEEE TI A normal distribution for tensor-valued random variables to analyze Diffusion Tensor MRI data SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc AB Diffusion Tensor MRI (DT-MRI) provides a statistical estimate of a symmetric 2(nd)-order diffusion tensor, D, for each voxel within an imaging volume. We propose a new normal distribution, p(D) similar to exp(- 1/2 D:A:D), for a tensor random variable, D. The scalar invariant, D:A:D, is the contraction of a positive definite symmetric 4(th)-order precision tensor, A, and D. A formal correspondence is established between D:A:D and the elastic strain energy density function in continuum mechanics. We show that A can then be classified according to different classical elastic symmetries (i.e., isotropy, transverse isotropy, orthotropy, planar symmetry, and anisotropy). When A is an isotropic tensor, an explicit expression for p(D), and for the distribution of its three eigenvalues, P(gamma(1),gamma(2),gamma(3)), are derived, which are confirmed by Monte Carlo simulations. Sample estimates of A are also obtained using synthetic DT-MRI data. Estimates of p(D) should be useful in feature extraction and in classification of noisy, discrete tensor data. C1 NICHD, STBB, LIMB, NIH, Bethesda, MD USA. RP Basser, PJ (reprint author), NICHD, STBB, LIMB, NIH, Bethesda, MD USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 927 EP 930 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400234 ER PT B AU Pai, VM Wen, H AF Pai, VM Wen, H GP IEEE IEEE TI Isolating the cardiac blood pool position for use as a marker of heart position in free-breathing MRI examinations SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID RESPIRATORY MOTION; ANGIOGRAPHY; REDUCTION AB Chest motion due to patient breathing can give rise to artifacts during conventional cardiac examinations by Magnetic Resonance Imaging (MRI). Typically, patients are asked to hold their breath dining MRI exams to alleviate this problem. However, this can be difficult for sick patients and children, and has also been shown to affect physiology. This article outlines an approach to isolate the position of the blood pool in the heart ventricles and utilizes this position to mark the location of the heart during MRI examinations. A profile registration algorithm is used to shift image slices to the correct position by determining the displacement of the blood pool profile from the initial reference position. This approach is used in a prospective mode with slice tracking to correct the image slice position. Utilization of this approach eliminates uncertainties in correlating diaphragm motion with heart motion, and the need for the patient to breathhold. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Pai, VM (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 939 EP 942 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400237 ER PT B AU Yim, PJ Cebral, JR Vasbinder, B Ho, VB van Engelshoven, JMA Choyke, PL AF Yim, PJ Cebral, JR Vasbinder, B Ho, VB van Engelshoven, JMA Choyke, PL GP IEEE IEEE TI Hemodynamic significance of renal artery stenoses from magnetic resonance imaging SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc AB Hemodynamically significant stenoses of the proximal renal artery reduce blood flow to the kidneys and cause result in ischemic nephropathy and hypertension. However, Conventional techniques for magnetic resonance (MR) renal artery imaging rely primarily on arterial illustration and its morphology. We propose a computational methodology to determine the functional impact of if a stenosis in the renal artery - specifically, if it is causing a significant obstruction to blood flow and, as such, will be likely to benefit from invasive angioplasty. We propose a finite-element methodology that incorporates vessel shape from contrast-enhanced magnetic resonance angiography (MRA) and blood flow rate from phase-contrast (PC) magnetic resonance imaging (MR). We demonstrate that an idealistic axisymmetric flow model produces average errors of 63% and 83% for measuring pressure drops with respect to the finite-element model. We conclude that estimation of pressure drops across renal artery stenoses from MR imaging may be possible but requires finite element modeling. C1 NIH, Imaging Sci Program, Bethesda, MD 20892 USA. RP Yim, PJ (reprint author), NIH, Imaging Sci Program, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 951 EP 954 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400240 ER PT B AU de Zwart, JA Ledden, PJ van Gelderen, P Kellman, P Pang, YX Chu, RX Duyn, JH AF de Zwart, JA Ledden, PJ van Gelderen, P Kellman, P Pang, YX Chu, RX Duyn, JH GP IEEE IEEE TI Optimization of a high sensitivity MRI receive coil for parallel human brain imaging SO 2002 IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Symposium on Biomedical Imaging CY JUL 07-10, 2002 CL WASHINGTON, D.C. SP IEEE Signal Processing Sco, Engn Med & Biol Soc ID PHASED-ARRAY; HEAD-COIL; SENSE AB Two eight-channel MRI receive-only coils were developed to provide whole-brain coverage at 1.5 T and 3.0 T field strength, respectively. Objectives were an image signal-to-noise ratio superior to standard designs throughout the human brain, as well as high parallel imaging performance. Electro-magnetic field simulations were used to determine array diameter and inter-element coil gap. Low mutual inductive coupling was achieved at 1.5 and 3.0 T using high-impedance pre-amplifiers. Coils show an average SNR improvement over commercial birdcage coils of 2.4 and 2.3 for the 1.5 T and 3.0 T design, respectively. The mean of the noise-amplification factor related to reconstruction of under-sampled data (g-factor) was 1.03 for 2-fold under-sampled data (rate-2) and 1.22 for rate-3 at 1.5 T. For data acquired with the 3.0 T coil array, these values were respectively 1.06 for rate-2 and 1.37 for rate-3. C1 NINDS, Adv MRI, LFMI, Bethesda, MD 20892 USA. RP de Zwart, JA (reprint author), NINDS, Adv MRI, LFMI, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7584-X PY 2002 BP 966 EP 969 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BV15G UT WOS:000178000400244 ER PT S AU Cannata, JM Shung, KK AF Cannata, JM Shung, KK BE Yuhas, DE Schneider, SC TI Development of a high frequency (> 20 MHz) linear ultrasonic array using fine grain ceramic elements SO 2002 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 SE ULTRASONICS SYMPOSIUM LA English DT Proceedings Paper CT IEEE International Ultrasonic Symposium CY OCT 08-11, 2002 CL MUNICH, GERMANY SP IEEE Ultrason, Ferroelect & Frequency Control Soc ID TRANSDUCERS AB This study investigates the design tradeoffs involved in the development of a high frequency (35 MHz) 96-element linear array. This array was designed primarily for human eye and skin imaging, and features monolithic elements mechanically diced out of a fine grain high density PZT-5H ceramic. Array elements were spaced with a 50 micron pitch, interconnected via a flexible circuit and matched to the 50 Ohm system electronics via a 75 Ohm transmission line coaxial cable. The final array design was based upon tradeoffs among the level of array encapsulation, suppression of acoustic crosstalk, bandwidth and sensitivity. Several prototype arrays were constructed with promising results. An average center frequency of 34 MHz with a -6 dB bandwidth of at least 45% per element was achieved. The maximum combined electrical and acoustical crosstalk for nearest and next nearest elements was less than -30 dB, and the average -40 dB pulse length was 100 ns. C1 Univ So Calif, NIH, Resource Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. RP Cannata, JM (reprint author), Univ So Calif, NIH, Resource Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 0-7803-7582-3 J9 ULTRASON PY 2002 BP 1243 EP 1247 PG 5 WC Acoustics; Engineering, Electrical & Electronic; Instruments & Instrumentation SC Acoustics; Engineering; Instruments & Instrumentation GA BW47M UT WOS:000182111700278 ER PT B AU Pham, DL AF Pham, DL GP IEEE IEEE TI Fuzzy clustering with spatial constraints SO 2002 INTERNATIONAL CONFERENCE ON IMAGE PROCESSING, VOL II, PROCEEDINGS LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 22-25, 2002 CL ROCHESTER, NY SP IEEE Signal Proc Soc ID IMAGE SEGMENTATION; ALGORITHM AB A novel approach to fuzzy clustering for image segmentation is described. The fuzzy C-means objective function is generalized to include a spatial penalty on the membership functions. The penalty term leads to an iterative algorithm that is only slightly different from the original fuzzy C-means algorithm and allows the estimation of spatially smooth membership functions. To determine the strength of the penalty term, a criterion based on cross-validation is employed. The new algorithm is applied to simulated and real magnetic resonance images and is shown to be more robust to noise and other artifacts than the standard algorithm. C1 NIA, Lab Personal & Cognit, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Pham, DL (reprint author), NIA, Lab Personal & Cognit, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 8 TC 0 Z9 0 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 0-7803-7622-6 PY 2002 BP 65 EP 68 PG 4 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Software Engineering SC Computer Science GA BX43S UT WOS:000185284000017 ER PT B AU Hattery, D Hassan, M Demos, S Gandjbakhche, A AF Hattery, D Hassan, M Demos, S Gandjbakhche, A BE Schaefer, DH TI Hyperspectral Imaging of Kaposi's sarcoma for disease assessment and treatment monitoring SO 31ST APPLIED IMAGERY PATTERN RECOGNITION WORKSHOP, PROCEEDINGS LA English DT Proceedings Paper CT 31st Applied Imagery Pattern Recognition Workshop CY OCT 16-18, 2002 CL WASHINGTON, D.C. SP IEEE Comp Soc AB Light spectroscopic methods are critical to advances in molecular characterization of disease processes. However, these methods have been limited to in-vitro or cell culture studies. In fact, strong scattering in almost all tissue types causes dispersion of the photons paths which results in poor localization and resolution. Hence, quantitative analysis of spectral data obtained from structures below the tissue surface requires accounting for scattering which affects both the penetration of the photons and the path length over which the photons will be subject to molecularly specific absorption. The goal of much current research is to non-invasively obtain diagnostically useful molecular information from embedded sites. We have designed and built a six-band multi-spectral NIR imaging system which we have used on patients with highly vascularized tumors in the skin called Kaposi's Sarcoma. The imaged lesions are undergoing treatment with experimental anti-angiogenesis drugs that are designed to reduce blood flow and hence growth of the tumors. The NIR data is combined with both 3-5 micron and 8-12 micron infrared images, obtained of the same tumors, which are used to identify thermal signatures of blood volume, as well as three-band visible wavelength data which show the visible extent of the lesions. We have developed a layered model of the skin in which specific analytes exist in specific layers. The spectral signatures of analytes such as oxy- and deoxy-hemoglobin are known. To obtain information on the concentration of those analytes in the tissue, however, the diffuse reflectance NIR images from the patients must be corrected for scattering. The scattering is modeled using analytical solutions developed from a random walk model of photon migration in turbid media. When the hyperspectral patient data is fit to the model, physiologically related parameters, such as to blood volume and oxygenation, are obtained. This provides clinically important data that may be used by the physician for evaluations of drug effectiveness, disease assessment and patient treatment monitoring. C1 NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Hattery, D (reprint author), NIH, Lab Integrat & Med Biophys, Bldg 12A,Room 2041, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 2 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA BN 0-7695-1863-X PY 2002 BP 124 EP 130 PG 7 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic; Spectroscopy SC Computer Science; Engineering; Spectroscopy GA BW45Z UT WOS:000182079100017 ER PT B AU Le, DX Straughan, SR Thoma, GR AF Le, DX Straughan, SR Thoma, GR BE Callaos, N Zhou, J Nobesawa, S TI Greek alphabet recognition technique for biomedical documents SO 6TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL III, PROCEEDINGS: IMAGE, ACOUSTIC, SPEECH AND SIGNAL PROCESSING I LA English DT Proceedings Paper CT 6th World Multi-Conference on Systemics, Cybernetics and Informatics (SCI 2002)/8th International Conference on Information Systems Analysis and Synthesis (ISAS 2002) CY JUL 14-18, 2002 CL ORLANDO, FL SP Int Inst Informat & System, World Org System & Cybernet, Ctr Syst Studies, Syst Soc Poland, Soc Appl Syst Res, Slovenian Artificial Intelligence Soc, Simon Bolivar Univ, Polish Syst Soc, Italian Soc System, Int Soc Syst Sci, Int Syst Inst, Int Federat Syst Res, Cybernet & Human Knowing, Journal Second Order Cybernet & Cybersemiot, Blaise Pascal Univ, Engineer Sci Inst, CUST, Univ Las Palmas Gran Canaria, Concurrency & Architecture Grp, Telemat Engn Dept, Tunisian Sci Soc, Acad Non Linear Sci, San Luis Natl Univ, Lab Res Computat Intelligence, Dept Informat, Amer Soc Cybernet (Canada), Wolfram Res Inc, IEEE Comp Soc, Venezuela Chapter, Steacie Inst Molec Sci, Natl Res Council Canada DE Greek character recognition; optical character recognition; automated document data entry; MEDLINE database; National Library of Medicine AB Most current commercial optical character recognition (OCR) systems can accurately recognize the text in documents written in a single language. However, when dealing with Greek characters embedded in predominantly English text, these systems do not perform well, and most OCR systems do not recognize the characters as belonging to the Greek alphabet. As a result, the degree of manual review required to validate and correct OCR errors is high. To handle this problem, we propose a new technique based on features calculated from the output of multiple OCR systems, and combined with string pattern matching and document content analysis to improve the recognition of both Greek characters and regular text. Our proposed technique uses two passes of a document page image through OCR systems that use different recognition languages. Experiments carried out on a sample of medical journals show the feasibility of using the proposed technique for Greek character recognition. Preliminary evaluation conducted on a sample of medical journal page images shows that our approach improves the recognition of Greek characters embedded within predominantly English language text. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Le, DX (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA PY 2002 BP 86 EP 91 PG 6 WC Computer Science, Software Engineering; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BV41C UT WOS:000178869100017 ER PT B AU Wolfe, L Whalen, C Sessions, B AF Wolfe, L Whalen, C Sessions, B BE Callaos, N Zheng, B Kaderali, F TI Making wireless information technology work for biomedical research in Mali, West Africa SO 6TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL IV, PROCEEDINGS: MOBILE/WIRELESS COMPUTING AND COMMUNICATION SYSTEMS I LA English DT Proceedings Paper CT 6th World Multi-Conference on Systemics, Cybernetics and Informatics (SCI 2002)/8th International Conference on Information Systems Analysis and Synthesis (ISAS 2002) CY JUL 14-18, 2002 CL ORLANDO, FL SP Int Inst Informat & System, World Org System & Cybernet, Ctr Syst Studies, Syst Soc Poland, Soc Appl Syst Res, Slovenian Artificial Intelligence Soc, Simon Bolivar Univ, Polish Syst Soc, Italian Soc System, Int Soc Syst Sci, Int Syst Inst, Int Federat Syst Res, Cybernet & Human Knowing, Journal Second Order Cybernet & Cybersemiot, Blaise Pascal Univ, Engineer Sci Inst, CUST, Univ Las Palmas Gran Canaria, Concurrency & Architecture Grp, Telemat Engn Dept, Tunisian Sci Soc, Acad Non Linear Sci, San Luis Natl Univ, Lab Res Computat Intelligence, Dept Informat, Amer Soc Cybernet (Canada), Wolfram Res Inc, IEEE Comp Soc, Venezuela Chapter, Steacie Inst Molec Sci, Natl Res Council Canada DE wireless networks; 802.1lb; satellite systems; packet radio; and HF radio systems AB Design and performance engineering of cost effective wireless networks in developing countries is discussed in this paper. The U.S. National Institute of Allergy and Infectious Diseases was challenged to build a complete computing and telecommunications infrastructure in Mali West Africa to support biomedical research for HIV/AIDS, Ebola, Malaria and other virulent and bioterrorism diseases. Innovative use of microwave, high frequency, wireless, and satellite networks provided a solution to give scientific researchers mobile voice and data capabilities in remote regions and provides an Africa to United States high speed Internet satellite connection. C1 NIAID, Bethesda, MD 20892 USA. RP Wolfe, L (reprint author), NIAID, 31 Ctr Dr,Room 7A32, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA PY 2002 BP 65 EP 72 PG 8 WC Computer Science, Information Systems; Engineering, Electrical & Electronic; Telecommunications SC Computer Science; Engineering; Telecommunications GA BV42D UT WOS:000178906700012 ER PT J AU Lavigne, C Yelle, J Sauve, G Thierry, AR AF Lavigne, C Yelle, J Sauve, G Thierry, AR TI Is antisense an appropriate nomenclature or design for oligodeoxynucleotides aimed at the inhibition of HIV-1 replication? SO AAPS PHARMSCI LA English DT Article DE fibroblast growth factor; keratinocyte growth factor; pharmacology; pharmacokinetics clinical trial ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEQUENCE-SPECIFIC INHIBITION; CHRONICALLY INFECTED-CELLS; PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE; GENE-EXPRESSION; HTLV-III; TYPE-1; OLIGONUCLEOTIDES; PHARMACOKINETICS; RNA AB We have evaluated the specificity and the variation in activity against human immunodeficiency virus (HIV) infection of antisense oligodeoxynucleotides (ODNs) with regard to factors such as dose-response range, number and choice of experimental controls, backbone modifications of the ODNs, type of cell infection, length of assays, and delivery approach. The highest level of inhibition was achieved in our long-term assay with MOLT-3 cells acutely infected with HIV-1 (IIIB) and treated with free phosphorothioate-modified ODNs (PS-ODNs). The highest level of specificity was observed in our short-term assay with MOLT-3 cells acutely infected with HIV-1 (11113) and treated with free PS-ODNs. The highest potency (IC50 level) was observed in our short-term chronic-infection model with (DLS)-delivered ODNs in which the DLS delivery improved the ODN activity up to 106 times compared to the activity of free ODNs. Thus, the near blocking of HIV replication obtained when using PS-ODNs appears because of the addition of extracellular and/or membranar effects. The higher efficacy of PS-ODNs compared to unmodified ODNs, when both are delivered with the DLS system, was demonstrated solely in our short-term assay with MOLT-3 cells. Important variations in the level of sequence specificity were observed and depended on the type of control used and the type of cell assay employed. It seems that all 3 groups of control-tested, random, sense sequence, and non-antisense T30177 ODNs might have distinct activity and, consequently, different modes of action in inhibiting HIV replication. Our data buttress the notion that the contribution of the sequence-specific mediated mode of action is minor compared to the other mechanisms involved in ODN antiviral activity. C1 Lab Def Antivirales & Antitumorales, UMR 5124, MedinCell Project, F-34293 Montpellier 5, France. Univ Quebec, Inst Armand Frappier, Laval, PQ H7N 4Z3, Canada. NCI, Tumor Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Thierry, AR (reprint author), Lab Def Antivirales & Antitumorales, UMR 5124, MedinCell Project, Case Courrier 27,1919,Route Mende, F-34293 Montpellier 5, France. RI thierry, alain/F-9492-2014 NR 45 TC 6 Z9 7 U1 0 U2 0 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ALEXANDRIA PA 1650 KING ST, STE 200, ALEXANDRIA, VA 22314-2747 USA SN 1522-1059 J9 AAPS PHARMSCI JI AAPS Pharmsci PY 2002 VL 4 IS 2 AR 9 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 584MJ UT WOS:000177470100005 ER PT J AU Yarborough, M Sharp, RR AF Yarborough, M Sharp, RR TI Restoring and preserving trust in biomedical research SO ACADEMIC MEDICINE LA English DT Article ID MEDICAL PROFESSIONALISM; CLINICAL RESEARCH; OF-INTEREST; INVESTIGATORS; POLICIES; CONSENT AB Recent media depictions of the dangers of biomedical research have fueled public and regulatory scrutiny of academic research institutions. The authors argue that if these institutions are to preserve the trust that the public has historically bestowed upon them, they must go beyond mere compliance with regulatory mandates. Several steps are Suggested that institutions can take to strengthen and supplement ongoing compliance efforts, steps the authors believe will bolster the public's confidence in the integrity of academic research institutions. These steps grow Out of the authors' analysis of three key components of institutional trustworthiness: (1) shared goals between research institutions and the communities they serve, (2) robust institutional oversight of research activities, and (3) training programs that build professional character. The authors' recommendations include the use of research advisory councils to assure the public that research goals reflect community interest more collaborative relationships between institutional review boards and members of investigative teams, and educational programs that emphasize the importance of professional integrity in biomedical research. These efforts will help preserve public confidence that an institution's research priorities are appropriate and that the research it conducts is ethical. Preserving this public trust is central to the long-term success of biomedical research and the institutions in which such research takes place. C1 NIEHS, Off Sci Director, NIH, Res Triangle Pk, NC 27709 USA. Univ Colorado, Hlth Sci Ctr, Program Hlth Care Eth Humanities & Law, Denver, CO 80262 USA. Duke Univ, Ctr Study Med Eth & Humanieies, Durham, NC 27706 USA. RP Sharp, RR (reprint author), NIEHS, Off Sci Director, NIH, POB 12233,79 Alexander Dr,Bldg 4401,Room 108, Res Triangle Pk, NC 27709 USA. NR 36 TC 23 Z9 23 U1 0 U2 1 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JAN PY 2002 VL 77 IS 1 BP 8 EP 14 DI 10.1097/00001888-200201000-00005 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 512AY UT WOS:000173300000005 PM 11788317 ER PT J AU Sullivan, DC AF Sullivan, DC TI The NCI Biomedical Imaging Program: Five-year progress report SO ACADEMIC RADIOLOGY LA English DT Article C1 NCI, Div Canc Treatment Diag & Ctr, NIH, Rockville, MD USA. RP Sullivan, DC (reprint author), NCI, Div Canc Treatment Diag & Ctr, NIH, Execut Pk N,Room 800,6130 Execut Blvd, Rockville, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JAN PY 2002 VL 9 IS 1 BP 122 EP 125 DI 10.1016/S1076-6332(03)80305-7 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 527ET UT WOS:000174174300013 PM 11918353 ER PT J AU Flippen-Anderson, JL Deschamps, JR George, C Folk, JE Jacobson, AE Rice, KC AF Flippen-Anderson, JL Deschamps, JR George, C Folk, JE Jacobson, AE Rice, KC TI Twinned 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenyl)propyl)piperazinium chloride (GBR12909) SO ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE LA English DT Article ID COCAINE; INHIBITORS AB GBR12909, C28H34F2N2O, is one of the earliest agents found to have high affinity and selectivity for the dopamine transporter (DAT). The triclinic crystal, of the hydrochloride salt of GBR12909, C28H34F2N2O2+. 2Cl(-), exhibited non-merohedral twinning. C1 USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Flippen-Anderson, JL (reprint author), USN, Res Lab, Struct Matter Lab, Code 6030, Washington, DC 20375 USA. NR 10 TC 2 Z9 2 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-5368 J9 ACTA CRYSTALLOGR E JI Acta Crystallogr. Sect. E.-Struct Rep. Online PD JAN PY 2002 VL 58 BP O81 EP O82 DI 10.1107/S1600536801021389 PN 1 PG 2 WC Crystallography SC Crystallography GA 505QK UT WOS:000172926900051 ER PT J AU Filie, AC Simsir, A Fetsch, P Abati, A AF Filie, AC Simsir, A Fetsch, P Abati, A TI Melanoma metastatic to the breast - Utility of fine needle aspiration and immunohistochemistry SO ACTA CYTOLOGICA LA English DT Article DE melanoma; breast neoplasms; metastasis; aspiration biopsy; immunohistochemistry; tyrosinase; Mart-1; HMB45; Melan-A ID T-CELLS MART-1; MALIGNANT-MELANOMA; CYTOLOGY; CARCINOMA; DIAGNOSIS; EXPRESSION; NEOPLASMS; TUMORS AB OBJECTIVE: To describe the morphologic spectrum of metastatic malignant melanoma (MM) cells involving the breast and to explore the diagnostic utility of HMB45, Mart-1, Melan-A and T311 (antityrosinase) antibodies in fine needle aspiration material of MM metastatic to the breast. STUDY DESIGN: Cytologic material from 21 cases (18 women) was reviewed for cytomorphology (epithelioid, spindled, mixed) and immunocytochemical staining attributes for Mart-1, HMB45, T311, Melan-A and cytokeratin based on tissue availability. RESULTS: Seventeen cases (81%) demonstrated epithelioid cell morphology, with 14% exhibiting mixed and 5% spindled morphologies. All 21 cases (100%) were immunoreactive with Mart-1 antibody, with 81% (17121) immunoreactive for HMB45. In 38% of cases there was a similar percentage of cells immunoreactive for Mart-1 and HMB45, while 48% showed a higher percentage of cells immunoreactive for MART-1 than HMB45. Immunoreactivity with T311 was seen in 8 of 11 cases tested (73%). All six cases tested (100%) were immunoreactive with Melan-A. Staining for cytokeratin was negative in all eight cases tested. CONCLUSION: Because the majority of MM metastatic to the breast shows epithelioid cell morphology, it may mimic primary breast carcinoma, Mart-1 should be part of the immunocytochemical panel utilized to confirm the diagnosis of MM metastatic to the breast. C1 NCI, Lab Pathol, Cytopathol Sect, Bethesda, MD 20892 USA. NYU, Med Ctr, Dept Pathol, New York, NY USA. RP Filie, AC (reprint author), NCI, Lab Pathol, Cytopathol Sect, 10 Ctr Dr Bldg 10 Rm 2A19, Bethesda, MD 20892 USA. NR 26 TC 14 Z9 14 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0001-5547 J9 ACTA CYTOL JI Acta Cytol. PD JAN-FEB PY 2002 VL 46 IS 1 BP 13 EP 18 DI 10.1159/000326709 PG 6 WC Pathology SC Pathology GA 517NY UT WOS:000173617900002 PM 11843553 ER PT J AU Welsch, U Unterberger, P Hofter, E Cuttitta, F Martinez, A AF Welsch, U Unterberger, P Hofter, E Cuttitta, F Martinez, A TI Adrenomedullin in mammalian and human skin glands including the mammary gland SO ACTA HISTOCHEMICA LA English DT Article DE adrenomedullin; skin glands; mammary gland; apocrine glands; human; elephant; impala ID HYPOTENSIVE PEPTIDE; NERVOUS-SYSTEM; EXPRESSION; IMMUNOREACTIVITY; GENE AB Adrenomedullin is a peptide that has been ascribed numerous functions. In the present paper, adrenomedullin has been localized immunhistochemically in a variety of skin glands of humans, elephants and impalas: apocrine scent glands, eccrine sweat glands, holocrine glands and mammary glands. In the apocrine glands expression of adrenomedullin varied with respect to staining intensity and intracellular localization. In general, glands which appeared to be actively secreting were more strongly stained than quiescent glands. However, within a single glandular tubule, individual cells differed considerably in the staining intensity of adrenomedullin. Adrenomedullin was present in both non-lactating and lactating mammary secretory epithelia, both ducts and alveoli reacted positively. In human mammary glands displaying apocrine metaplasia, the apical protrusions were strongly positive. Furthermore, positive immunostaining was found in endothelium and often in smooth muscle cells of small arteries and veins and in mast cells as well. Many of the adrenomedullin-positive epithelial cells were most strongly stained in the area of the Golgi apparatus, the cellular apex and particularly close to the basal side of the cell membrane. This pattern suggests packaging of adrenomedullin into secretory granules and secretion both at the apex of cells and at their basis. The first form of secretion suggests exocrine secretion, the latter form endocrine secretion of adrenomedullin. A possible hormonal function is in line with basally located electron dense small secretory granules, which have been found by electron microscopy in the glandular epithelia studied. C1 Univ Munich, Chair 2, Dept Anat, Munich, Germany. City Hosp Munich, Bogenhausen, Dept Plast Surg, Munich, Germany. NCI, Dept Cell & Canc Biol, Bethesda, MD 20892 USA. RP Welsch, U (reprint author), Lehrstuhl 2, Anat Anstalt, Pettenkoferstr 11, D-80336 Munich, Germany. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 22 TC 19 Z9 21 U1 0 U2 1 PU URBAN & FISCHER VERLAG PI JENA PA BRANCH OFFICE JENA, P O BOX 100537, D-07705 JENA, GERMANY SN 0065-1281 J9 ACTA HISTOCHEM JI Acta Histochem. PY 2002 VL 104 IS 1 BP 65 EP 72 DI 10.1078/0065-1281-00623 PG 8 WC Cell Biology SC Cell Biology GA 543WE UT WOS:000175123500008 PM 11993852 ER PT J AU Liberski, PP Bratosiewicz-Wasik, J Gajdusek, DC Brown, P AF Liberski, PP Bratosiewicz-Wasik, J Gajdusek, DC Brown, P TI Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. I. Alterations of myelinated axons SO ACTA NEUROBIOLOGIAE EXPERIMENTALIS LA English DT Article DE scrapie; Creuzfeldt-Jakob disease; prions; ultrastructures ID CHRONIC WASTING DISEASE; NECROSIS-FACTOR-ALPHA; SPONGIFORM ENCEPHALOPATHY; MULE DEER; MICE; PATHOLOGY; PROTEIN; STRAIN; NEUROPATHOLOGY; TRANSMISSION AB Classical and ultrastructural neuropathology of prion diseases are generally well described. Here we report that alterations of myelinated fibres in hamsters infected either with polioencephalopathic strains of scrapie or panencephalopathic strains of CJD (Echigo-1) are virtually identical and differ only quantitatively. In contrast, mice infected with the panencephalopathic Fujisaki strain of CJD exhibited much more elaborate changes of myelinated fibres. C1 Med Acad Lodz, Lab Electron Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. Med Univ Silesia, Dept Virol Diagnost, Chair Mol Biol Biochem & Biopharm, Katowice, Poland. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. RP Liberski, PP (reprint author), Med Acad Lodz, Lab Electron Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. NR 38 TC 5 Z9 5 U1 0 U2 0 PU NENCKI INST EXPERIMENTAL BIOLOGY PI WARSAW PA UL PASTEURA 3, 02-093 WARSAW, POLAND SN 0065-1400 J9 ACTA NEUROBIOL EXP JI Acta Neurobiol. Exp. PY 2002 VL 62 IS 3 BP 121 EP 129 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 590KM UT WOS:000177822100003 PM 12416389 ER PT J AU Liberski, PP Bratosiewiez-Wasik, J Gajdusek, DC Brown, P AF Liberski, PP Bratosiewiez-Wasik, J Gajdusek, DC Brown, P TI Ultrastructural studies of experimental scrapie and Creutzfeldt-Jakob disease in hamsters. II. Astrocytic and macrophage reaction towards axonal destruction SO ACTA NEUROBIOLOGIAE EXPERIMENTALIS LA English DT Article DE scrapie; Creutzfeldt-Jakob disease; prions; ultrastructure ID TUMOR-NECROSIS-FACTOR; FIBRILLARY ACIDIC PROTEIN; FACTOR-ALPHA; PRION PROTEIN; INFECTED MICE; SPONGIFORM ENCEPHALOPATHIES; PANENCEPHALOPATHIC TYPE; ANTIGEN EXPRESSION; INTERLEUKIN-1; INTERFERON AB We report here the microglial (macrophage) and astrocytic reaction in several models of transmissible spongiform encephalopathies (TSEs) or prion diseases. With the low power electron microscopy it was readily apparent that myelinated vacuoles were surrounded by cells and their processes. The latter belonged either to hyperplastic reactive astrocytes or to macrophages. Typically, reactive astrocytes exhibited cytoplasm filled with innumerable glial filaments and, occasionally, other organelles (like cilia) and abundant tortuous intercellular junctions of adhesive plaque junction type. Desmosome-like junctions connecting astrocytic elements were also seen. As described earlier, astrocytic processes were occasionally interdigitated with oligodendroglial cells and their processes. Two types of macrophages were readily described. The majority of them exhibited electron-dense cytoplasm and numerous "empty" vacuoles (digestive chambers) containing cellular debris. Occasional vacuoles were surrounded by a thin collar reminiscent of "lyre-like inclusions" of the second type of macrophages. Several mylinated fibres were clearly engulfed by the cytoplasm of a macrophage containing unusual annulate lamellae. C1 Med Acad Lodz, Lab Electron Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. Med Univ Silesia, Dept Virol Diagnost, Chair Mol Biol Biochem & Biopharm, Katowice, Poland. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. RP Liberski, PP (reprint author), Med Acad Lodz, Lab Electron Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. EM ppliber@csk.am.lodz.pl NR 59 TC 2 Z9 3 U1 0 U2 1 PU NENCKI INST EXPERIMENTAL BIOLOGY PI WARSAW PA UL PASTEURA 3, 02-093 WARSAW, POLAND SN 0065-1400 J9 ACTA NEUROBIOL EXP JI Acta Neurobiol. Exp. PY 2002 VL 62 IS 3 BP 131 EP 139 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 590KM UT WOS:000177822100004 PM 12416390 ER PT J AU Liberski, PP Gajdusek, DC Brown, P AF Liberski, PP Gajdusek, DC Brown, P TI How do neurons degenerate in prion diseases or transmissible spongiform encephalopathies (TSEs): neuronal autophagy revisited SO ACTA NEUROBIOLOGIAE EXPERIMENTALIS LA English DT Article DE scrapie; prion diseases; autophagic vacuoles; apoptosis ID CREUTZFELDT-JAKOB-DISEASE; NUCLEAR-DNA FRAGMENTATION; SCRAPIE-INFECTED MICE; APOPTOTIC CELL-DEATH; PROTEIN-FRAGMENT; NEURODEGENERATIVE DISEASES; MURINE SCRAPIE; PEPTIDE; EXPRESSION; HAMSTERS AB As in other neurodegenerative diseases such as Alzheimer's disease, neurons in prion diseases or transmisible spongiform encephalopathies (TSEs) die via programmed cell death of which the apoptotic process is relatively well characterized. A subcellular alteration linked to apoptosis is the fori-nation of autophagic vacuoles, which we and others demonstrated in CJD- and scrapie-affected rodent brains. Autophagy may co-exist with apoptosis or may precede it and the process may be induced by apoptotic stimuli. Here, we extend these observations using different model of scrapie and CJD. Both scrapie models (the 263K and 22C-H) demonstrated autophagic vacuoles with the same frequency; hence, they will be described together. While the following changes had been observed simultaneously in different areas of the same sample, this description is organised as if it followed a sequence of events. First, a part of the neuronal cytoplasm was sequestrated by concentric arrays of membrane; that part of the cytoplasm closed by membranes appeared relatively normal but its density often appeared increased. Next, electron density of the central dramatically increased. Then, membranes proliferated within the cytoplasm in a labyrinth-like manner and an area sequestrated by these membranes enlarged and became more complex structure consisting of vacuoles, electron-dense area and areas of normally-looking cytoplasm connected with convoluted membranes. Finally, a large area of the cytoplasm was transformed into a collection of autophagic vacuoles of different sizes. Virtually identical alterations, albeit with much lower frequency, were seen in terminally ill CJD-affected hamsters. C1 Med Acad Lodz, Lab Elect Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. RP Liberski, PP (reprint author), Med Acad Lodz, Lab Elect Microscopy & Neuropathol, Dept Mol Biol, Chair Oncol, Lodz, Poland. EM ppliber@csk.am.lodz.pl NR 60 TC 30 Z9 31 U1 0 U2 1 PU NENCKI INST EXPERIMENTAL BIOLOGY PI WARSAW PA UL PASTEURA 3, 02-093 WARSAW, POLAND SN 0065-1400 J9 ACTA NEUROBIOL EXP JI Acta Neurobiol. Exp. PY 2002 VL 62 IS 3 BP 141 EP 147 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 590KM UT WOS:000177822100005 PM 12416391 ER PT J AU Zielinski, K Kosmal, A Mishkin, M Rauschecker, JP Milgram, NW Jastreboff, PJ AF Zielinski, K Kosmal, A Mishkin, M Rauschecker, JP Milgram, NW Jastreboff, PJ TI Danuta Kowalska (1944-2002) SO ACTA NEUROBIOLOGIAE EXPERIMENTALIS LA English DT Biographical-Item C1 M Nencki Inst Expt Biol, Warsaw, Poland. NIMH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC 20057 USA. Univ Toronto, Toronto, ON, Canada. Emory Univ, Atlanta, GA 30322 USA. RP Zielinski, K (reprint author), M Nencki Inst Expt Biol, Warsaw, Poland. RI Rauschecker, Josef/A-4120-2013 NR 0 TC 0 Z9 0 U1 1 U2 1 PU NENCKI INST EXPERIMENTAL BIOLOGY PI WARSAW PA UL PASTEURA 3, 02-093 WARSAW, POLAND SN 0065-1400 J9 ACTA NEUROBIOL EXP JI Acta Neurobiol. Exp. PY 2002 VL 62 IS 4 BP 285 EP 287 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 630VZ UT WOS:000180132000009 ER PT J AU Coleman, CN AF Coleman, CN TI Radiation oncology - Linking technology and biology in the treatment of cancer SO ACTA ONCOLOGICA LA English DT Review ID LOCALIZED PROSTATE-CANCER; PATHOLOGICAL STAGE; TRACK STRUCTURE; ORGAN MOTION; RADIOTHERAPY; ANTIGEN; THERAPY; DNA; ELECTRONS; ERRORS AB Technical advances in radiation oncology including CT-simulation, 3D- conformal and intensity-modulated radiation therapy (IMRT) delivery techniques, and brachytherapy have allowed greater treatment precision and dose escalation. The ability to intensify treatment requires the identification of the critical targets within the treatment field, recognizing the unique biology of tumor, stroma and normal tissue. Precision is technology based while accuracy is biologically based. Therefore, the intensity of IMRT will undoubtedly mean an increase in both irradiation dose and the use of biological agents, the latter considered in the broadest sense. Radiation oncology has the potential and the opportunity to provide major contributions to the linkage between molecular and functional imaging, molecular profiling and novel therapeutics for the emerging molecular targets for cancer treatment. This process of 'credentialing' of molecular targets will require multi disciplinary imaging teams, clinicians and basic scientists. Future advances will depend on the appropriate integration of biology into the training of residents, continuing post graduate education, participation in innovative clinical research and commitment to the support of basic research as an essential component of the practice of radiation oncology. C1 NCI, Radiat Oncol Sci Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Coleman, CN (reprint author), NCI, Radiat Oncol Sci Program, Ctr Canc Res, NIH, Bldg 10,B3-B69, Bethesda, MD 20892 USA. NR 56 TC 14 Z9 14 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 2002 VL 41 IS 1 BP 6 EP 13 PG 8 WC Oncology SC Oncology GA 541QV UT WOS:000174996000002 PM 11990520 ER PT J AU Leon, X Ferlito, A Myer, CM Saffiotti, U Shaha, AR Bradley, PJ Brandwein, MS Anniko, M Elluru, RG Rinaldo, A AF Leon, X Ferlito, A Myer, CM Saffiotti, U Shaha, AR Bradley, PJ Brandwein, MS Anniko, M Elluru, RG Rinaldo, A TI Second primary tumors in head and neck cancer patients SO ACTA OTO-LARYNGOLOGICA LA English DT Review ID SQUAMOUS-CELL CARCINOMA; 2ND PRIMARY TUMORS; MULTIPLE PRIMARY TUMORS; UPPER AERODIGESTIVE TRACT; UPPER DIGESTIVE-TRACT; COMMON CLONAL ORIGIN; LONG-TERM SURVIVORS; PRIMARY MALIGNANCIES; LARYNGEAL-CANCER; LUNG-CANCER C1 Univ Udine, Dept Otolaryngol Head & Neck Surg, Policlin Univ, IT-33100 Udine, Italy. Hosp Santa Creu & Sant Pau, Dept Otolaryngol, Barcelona, Spain. Childrens Hosp, Dept Pediat Otolaryngol, Med Ctr, Cincinnati, OH 45229 USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Head & Neck Serv, New York, NY 10021 USA. Queens Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Nottingham NG7 2UH, England. Mt Sinai Sch Med, Dept Otolaryngol & Pathol, New York, NY USA. Univ Hosp, Dept Otolaryngol Head & Neck Surg, Uppsala, Sweden. RP Ferlito, A (reprint author), Univ Udine, Dept Otolaryngol Head & Neck Surg, Policlin Univ, Piazzale S Maria Misericordia, IT-33100 Udine, Italy. NR 111 TC 43 Z9 44 U1 3 U2 4 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PY 2002 VL 122 IS 7 BP 765 EP 778 DI 10.1080/003655402/000028048 PG 14 WC Otorhinolaryngology SC Otorhinolaryngology GA 611TN UT WOS:000179034000013 PM 12484655 ER PT J AU Schiffmann, R Scott, LJC AF Schiffmann, R Scott, LJC TI Pathophysiology and assessment of neuropathic pain in Fabry disease SO ACTA PAEDIATRICA LA English DT Article; Proceedings Paper CT 2nd International Symposium on Lysosomal Storage Diseases CY APR, 2002 CL CANNES, FRANCE DE enzyme replacement therapy; Fabry disease; hypohidrosis; neuropathic pain; agalsidase alfa ID NERVE; DYSFUNCTION; THERAPY; CARRIER AB Severe neuropathic pain and hypohidrosis are important symptoms of Fabry disease, particularly in the first three decades of life. The pain is associated with a length-dependent small-fibre neuropathy that also causes a selective deficiency of cold perception. Cold exposure often accentuates the pain and worsens thermal perception. The hypohidrosis leads to poor exercise and heat tolerance. The mechanisms by which a-galactosidase A deficiency causes these physiological abnormalities are poorly understood. The stored glycolipid (globotriaosylceramide) may interfere with the function of cellular membrane proteins, such as ion channels, or may lead to cytotoxicity. The characteristic neuropathic pain can be symptomatically treated with various types of anticonvulsant drugs, such as carbamazepine. Improvement in neuropathic pain as a primary outcome measure has been useful in demonstrating that enzyme replacement therapy is effective in improving pain-related quality of life in Fabry disease. Conclusions: The dysfunction of the peripheral nervous system is easily assessable and more readily reversible with specific therapy than the destructive processes that occur in organs such as the kidney. In future, therefore, it is likely that neuropathic pain, quantitative sensory testing and hypohidrosis will serve as clinical outcome measures for studies of specific and effective therapies for Fabry disease. C1 NINDS, Dev & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NIH, Dev & Metab Neurol Branch, Room 3D03,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 34 Z9 36 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PY 2002 VL 91 SU 439 BP 48 EP 52 DI 10.1080/080352502762457923 PG 5 WC Pediatrics SC Pediatrics GA 642VM UT WOS:000180826200012 PM 12572843 ER PT J AU Moore, DF Schiffmann, R Ulug, AM AF Moore, DF Schiffmann, R Ulug, AM TI Elevated CNS average diffusion constant in Fabry disease SO ACTA PAEDIATRICA LA English DT Article; Proceedings Paper CT 2nd International Symposium on Lysosomal Storage Diseases CY APR, 2002 CL CANNES, FRANCE DE average diffusion constant; brain diffusion; Fabry disease; magnetic resonance ID CEREBRAL HYPERPERFUSION; MICE AB Aims: Evaluation of the average brain diffusion constant in Fabry disease. Introduction: Fabry disease is an X-linked recessive lysosomal storage disorder secondary to deficiency of alpha-galactosidase A and resulting in excess tissue globotriaosylceramide, particularly in cerebral blood vessels. This has been associated with cerebral hyperperfusion. Increased tissue perfusion should increase interstitial water by the Starling relationship. This hypothesis was examined by measuring the average CNS diffusion constant (D-av) in patients with Fabry disease using diffusion-weighted magnetic resonance imaging (DWI). Methods: Axial DWI was performed at b = 0 seconds/mm(2) and b = 1000 seconds/mm(2) (TR (pulse repetition time), 10 000; TE (time to echo), 100; FOV (field of view), 22 cm; 3 mm interleaved slices; image matrix, 128 x 128; GE Signa, 1.5T). Eight healthy male volunteers (age range, 21-47 years) and 17 hemizygous patients with Fabry disease (age range, 19-49 years) were examined. Following DWI acquisition, the trace image and the diffusion distribution map were calculated. The diffusion distribution curve was then fitted by a multi-modal Gaussian curve, allowing estimation of D-av. Results: The D-av was 0.743 +/- 0.024 x 10(-5) cm(2)/second (mean +/-SD) for patients with Fabry disease and 0.726 +/- 0.014 x 10(-5) cm(2)/second for the control group. D-av was significantly increased in the patients with Fabry disease compared with the controls (p = 0.029) Conclusions: The elevated D-av indicates increased brain tissue water diffusivity in patients with Fabry disease, a finding consistent with increased extracellular water and increased cerebral blood flow. C1 NINDS, Dev & Metab Neurol Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, New York, NY USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, Ctr Clin, NIH, Room 3D03,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Ulug, Aziz/F-6592-2011 OI Ulug, Aziz/0000-0002-2315-0322 NR 9 TC 11 Z9 11 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PY 2002 VL 91 SU 439 BP 67 EP 68 DI 10.1080/080352502762457969 PG 2 WC Pediatrics SC Pediatrics GA 642VM UT WOS:000180826200016 PM 12572846 ER PT J AU Rao, MR Hediger, ML Levine, RJ Naficy, AB Vik, T AF Rao, MR Hediger, ML Levine, RJ Naficy, AB Vik, T TI Effect of breastfeeding on cognitive development of infants born small for gestational age SO ACTA PAEDIATRICA LA English DT Article DE appropriate for gestational age; breastfeeding; cognitive development; growth; small for gestational age ID MILK; GROWTH; ASSOCIATION; BEHAVIOR; COHORT AB Breastfeeding during infancy appears to result in enhanced cognitive development during childhood, but it is not known whether breastfeeding should be encouraged for infants born small for gestational age (SGA) whose growth might otherwise benefit from nutritional supplementation. To address this issue, duration of exclusive breastfeeding and cognitive development were evaluated prospectively for 220 term children born SGA and 299 term children born appropriate for gestational age (AGA). Cognitive development was assessed using the Bayley Scale of Infant Development at 13 mo and Wechsler Preschool and Primary Scales of Intelligence at 5 y of age. Infants born SGA were given supplemental foods significantly earlier than those born AGA. Growth of infants born SGA was not related to early nutritional supplementation. The salutary effect of exclusive breastfeeding on cognitive development was greater for children born SGA than for those born AGA. Based on a linear association between duration of exclusive breastfeeding and intelligence quotient (IQ), children born SGA and exclusively breastfed for 24 wk were predicted to have an 11-point IQ advantage over those breastfed for 12 wk, as opposed to a 3-point advantage for children born AGA with similar durations of breastfeeding. The IQ distribution of children born SGA and exclusively breastfed for more than 12 wk was not different from that of all children born AGA. Conclusion: Duration of exclusive breastfeeding has a significant impact on cognitive development without compromising growth among children born SGA. These data suggest that mothers should breastfeed exclusively for 24 wk to enhance cognitive development. C1 NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Norwegian Univ Sci & Technol, Dept Community Med & Gen Practice, N-7034 Trondheim, Norway. RP Rao, MR (reprint author), NICHHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. NR 31 TC 51 Z9 58 U1 3 U2 12 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PY 2002 VL 91 IS 3 BP 267 EP 274 DI 10.1080/08035250252833905 PG 8 WC Pediatrics SC Pediatrics GA 538XH UT WOS:000174840100007 PM 12022297 ER PT J AU Merikangas, K AF Merikangas, K TI Genetic epidemiology: bringing genetics to the population - the NAPE Lecture 2001 SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article; Proceedings Paper CT Annual Meeting of the Nordic-Association-for-Psychiatric-Epidemiology (NAPE) CY SEP 01, 2001 CL COPENHAGEN, DENMARK SP Wyeth DE genetics; epidemiology; psychiatric disorders ID ENVIRONMENT INTERACTION; PSYCHIATRIC-DISORDERS; ALZHEIMERS-DISEASE; BIPOLAR DISORDER; MARFAN-SYNDROME; PUBLIC-HEALTH; X-CHROMOSOME; LINKAGE; BREAST; STRATEGIES AB Objective: To present an overview of the status of genetics of mental disorders and to describe the role of genetic epidemiology in the future of the implementation of the human genome initiative. Method: Reviews evidence on familial recurrence risk for major mental disorders and approaches to identify genes for complex disorders. Results: The next decade will witness shifts in approaches of both epidemiology and genetics to address sources of complexity of the mental disorders. Descriptive genetic epidemiology will evolve into analytic genetic epidemiology by shifting the key questions from estimation of the magnitude of mental disorders to identification of risk and protective environmental factors that may be informative both etiology and prevention. Genetics research will expand to population-based studies for complex disorders and will employ designs and methods that incorporate sources of complexity. Conclusion: In summary, the next era of human genetics will witness major shifts in approaches to identify the genes underlying mental disorders. The contributions of genetic epidemiology to translate advances in molecular genetics to public health are discussed. C1 NIMH, MAP, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. RP Merikangas, K (reprint author), NIMH, MAP, Mood & Anxiety Program, NIH, 15K North Dr,Room 210,MSC 2670, Bethesda, MD 20892 USA. NR 60 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JAN PY 2002 VL 105 IS 1 BP 3 EP 13 PG 11 WC Psychiatry SC Psychiatry GA 522KU UT WOS:000173895800001 PM 12086223 ER PT J AU Moolchan, ET Radzius, A Epstein, DH Uhl, G Gorelick, DA Cadet, JL Henningfield, JE AF Moolchan, ET Radzius, A Epstein, DH Uhl, G Gorelick, DA Cadet, JL Henningfield, JE TI The Fagerstrom Test for Nicotine Dependence and the diagnostic interview schedule - Do they diagnose the same smokers? SO ADDICTIVE BEHAVIORS LA English DT Article DE FTND; DSM; nicotine dependence; tobacco; diagnosis ID TOBACCO DEPENDENCE; TOLERANCE QUESTIONNAIRE; SMOKING CESSATION; YOUNG-ADULTS; PREVALENCE AB Two common assessment tools for nicotine dependence are the Fagerstrom Test for Nicotine Dependence (FTND) and the Nicotine Dependence section of the Diagnostic Interview Schedule [(DIS)-III-R or -IV based on the Diagnostic and Statistical Manual (DSM)-III-R and -IV, respectively]. The FT-ND emphasizes morning smoking and overall "heaviness" of smoking. The DSM emphasizes adverse consequences, desire to cut down, and mood changes during withdrawal. We tested (1) how the DSM-III-R diagnosis of Nicotine Dependence is related to FTND score; and (2) how the (a) DSM-III-R or (b) elevated FTND score is related to longer smoking histories, greater psychiatric symptomatology, and tobacco liking scores. Retrospective chart reviews were conducted on 370 smokers, the majority (55.9%) of whom had a current DSM-III-R diagnosis of Substance Dependence other than nicotine. All subjects had completed the FTND, the DIS-III-R, the Symptom Checklist-90-Revised (SCL-90-R), and a survey on drug liking. Agreement statistics were calculated between the DSM-III-R diagnosis of Nicotine Dependence and various cutoff scores values that were assigned as thresholds for nicotine dependence on the FTND. At no cutoff score did the two instruments reliably agree; the highest kappa (at a cutoff of FTND greater than or equal to 7) was 0.205. At cutoffs above 5, the FTND diagnosed fewer cases than the DSM-III-R. Multiple regression analysis showed that DSM diagnosis was associated with greater psychiatric symptomatology on the SCL-90-R, while FTND scores were associated with greater tobacco liking. The FTND and the DSM-III-R appear to measure different aspects of the tobacco dependence process. Specifically, the FTND may provide a stronger measure of physical dependence, while the DSM may tap other domains such as awareness of dependence, behaviors resulting from that awareness, and psychiatric symptomatology. Disagreements between the FTND and the DSM are likely to become greater with the changes in the DSM-IV. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIDA, Clin Pharmacol & Therapeut Res Branch, NIH, Baltimore, MD 21224 USA. NIDA, Mol Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. Pinney Assoc, Res & Hlth Policy, Bethesda, MD USA. RP Moolchan, ET (reprint author), NIDA, Clin Pharmacol & Therapeut Res Branch, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 33 TC 102 Z9 104 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JAN-FEB PY 2002 VL 27 IS 1 BP 101 EP 113 DI 10.1016/S0306-4603(00)00171-4 PG 13 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 502WP UT WOS:000172766000008 PM 11800217 ER PT J AU Hedenfalk, IA Ringner, M Trent, JM Borg, A AF Hedenfalk, IA Ringner, M Trent, JM Borg, A TI Gene expression in inherited breast cancer SO ADVANCES IN CANCER RESEARCH, VOL 84 SE ADVANCES IN CANCER RESEARCH LA English DT Review ID DNA-DAMAGE RESPONSE; MAMMARY EPITHELIAL-CELLS; TISSUE MICROARRAY ANALYSIS; OVARIAN-CANCER; SUSCEPTIBILITY GENE; GERMLINE MUTATIONS; TUMOR-SUPPRESSOR; BRCA1 MUTATIONS; FAMILIAL BREAST; ATAXIA-TELANGIECTASIA C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Oncol, SE-22185 Lund, Sweden. RP Hedenfalk, IA (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RI Ringner, Markus/G-3641-2011 OI Ringner, Markus/0000-0001-5469-8940 NR 166 TC 30 Z9 36 U1 1 U2 3 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 2002 VL 84 BP 1 EP 34 DI 10.1016/S0065-230X(02)84001-5 PG 34 WC Oncology SC Oncology GA BT92F UT WOS:000174461900001 PM 11883525 ER PT J AU Gomez-Angelats, M Cidlowski, JA AF Gomez-Angelats, M Cidlowski, JA TI Cell volume and ion changes during apoptotic cell death SO ADVANCES IN CANCER RESEARCH, VOL 85 SE ADVANCES IN CANCER RESEARCH LA English DT Review ID PROTEIN-KINASE-C; FAS-INDUCED APOPTOSIS; CEREBELLAR GRANULE NEURONS; INDEPENDENT PHOSPHOLIPASE A(2); PLASMA-MEMBRANE DEPOLARIZATION; FORKHEAD TRANSCRIPTION FACTOR; INDUCED THYMOCYTE APOPTOSIS; RADIATION-INDUCED APOPTOSIS; RECOMBINANT CYCLOPHILIN-A; CASPASE-ACTIVATED DNASE C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 140 TC 6 Z9 6 U1 2 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 2002 VL 85 BP 175 EP 201 DI 10.1016/S0065-230X(02)85006-0 PG 27 WC Oncology SC Oncology GA BV38F UT WOS:000178758300006 PM 12374286 ER PT S AU Tamis-LeMonda, CS Bornstein, MH AF Tamis-LeMonda, CS Bornstein, MH BE Kail, RV Reese, HW TI Maternal responsiveness and early language acquisition SO ADVANCES IN CHILD DEVELOPMENT AND BEHAVIOR, VOL 29 SE Advances in Child Development and Behavior LA English DT Article ID MOTHER-CHILD INTERACTION; TODDLER LANGUAGE; 2ND YEAR; 1ST YEAR; PLAY; INFANT; ATTENTION; COMPETENCE; MILESTONES; COMPREHENSION C1 NYU, Dept Appl Psychol, New York, NY 10011 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Tamis-LeMonda, CS (reprint author), NYU, Dept Appl Psychol, New York, NY 10011 USA. NR 94 TC 40 Z9 40 U1 15 U2 22 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2407 BN 0-12-009729-X J9 ADV CHILD DEV BEHAV JI Adv. Child Develop. Behav. PY 2002 VL 29 BP 89 EP 127 DI 10.1016/S0065-2407(02)80052-0 PG 39 WC Psychology, Developmental SC Psychology GA BU23S UT WOS:000175452700003 PM 11957576 ER PT B AU Mohiddin, SA Fananapazir, L AF Mohiddin, SA Fananapazir, L BE Kimchi, A TI Sarcomeric and non-sarcomeric causes of familial hypertrophic cardiomyopathy SO ADVANCES IN HEART FAILURE LA English DT Proceedings Paper CT 8th World Congress on Heart Failure - Mechanisms and Management CY JUL 13-16, 2002 CL WASHINGTON, D.C. ID BETA-CARDIAC MYOSIN; CHAIN GENE-MUTATIONS; ALPHA-TROPOMYOSIN; SKELETAL-MUSCLE; TROPONIN; PHENOTYPE; DISEASE; BINDING; HEART AB Familial hypertrophic cardiomyopathy (FHC) is a genetic disease characterized by left ventricular (LV) wall thickening and myofiber disarray. It has a prevalence of 1 in 500 in the general population. This is probably an underestimate as many subjects with the disease are asymptomatic, and therefore are undiagnosed.(1) The cardiac hypertrophy may be associated with dynamic LV obstruction, LV diastolic dysfunction, myocardial perfusion abnormalities, disabling symptoms, arrhythmia, and increased risk of sudden death.(2) A notable feature of FHC is that the cardiac phenotype differs markedly even in affected family members. Clinical outcomes vary from a benign asymptomatic course to progressive LV systolic dysfunction with severe heart failure and a poor prognosis. FHC also exhibits marked genetic heterogeneity. In about half of the cases it is caused by mutations in proteins of repetitive contractile units known as sarcomeres. The genotype often determines the phenotype and clinical outcome. Some molecular defects cause FHC in some family members but dilated cardiomyopathy (DCM) in other family members. Further, different mutations in the same gene may cause either FHC or DCM. Although FHC has therefore become regarded as a disease of the contractile apparatus, sarcomeric gene mutations account for only about half of the cases, and it is recognized that several other pathways may also lead to myocyte hypertrophy. Recent demonstration of an R302Q mutation of PRAKG2 gene with a complex phenotype that includes FHC confirms that non-sarcomeric genes may also account for some cases of the disease. Disease expression is probably dependent on the interplay of as yet undefined factors and modifying genes and the characterization of these may offer therapeutic strategies. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Mohiddin, SA (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 22 TC 0 Z9 0 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-2713-9 PY 2002 BP 231 EP 240 PG 10 WC Cardiac & Cardiovascular Systems; Surgery; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Surgery GA BX05Y UT WOS:000184146900038 ER PT S AU Bishop, JB AF Bishop, JB BE Robaire, B Hales, BF TI Female-specific reproductive toxicities following preconception exposure to xenobiotics SO ADVANCES IN MALE MEDIATED DEVELOPMENTAL TOXICITY SE ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 2nd International Conference on Male Mediated Developmental Toxicity CY JUN, 2001 CL MONTREAL, CANADA SP NIH, NICHD, NIEHS, NCI ID MARROW MICRONUCLEUS ASSAY; GERM-CELL MUTAGENICITY; CHROMOSOMAL-ABERRATIONS; DOMINANT LETHALITY; MALE-MICE; MOUSE; CHEMICALS; ETOPOSIDE; MEIOSIS; ANEUPLOIDY C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Bishop, JB (reprint author), NIEHS, 1111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 22 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0065-2598 BN 0-306-47480-8 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2002 VL 518 BP 1 EP 9 PG 9 WC Andrology; Medicine, Research & Experimental; Reproductive Biology; Toxicology SC Endocrinology & Metabolism; Research & Experimental Medicine; Reproductive Biology; Toxicology GA BW88Y UT WOS:000183490600001 ER PT B AU Costa, PT McCrae, RR AF Costa, PT McCrae, RR BE Cervone, D Mischel, W TI Looking backward changes in the mean levels of personality traits from 80 to 12 SO ADVANCES IN PERSONALITY SCIENCE LA English DT Proceedings Paper CT Conference of the Association-for-Research-in-Personality CY 2001 CL SAN ANTONIO, TX ID AGE-DIFFERENCES; LIFE-SPAN; ADULTHOOD; SELF; TEMPERAMENT; STABILITY; METAANALYSIS; WOMEN C1 NIA, NIH, Baltimore, MD 21224 USA. NR 62 TC 39 Z9 39 U1 1 U2 2 PU GUILFORD PRESS PI NEW YORK PA 72 SPRING ST, NEW YORK, NY 10012 USA BN 1-57230-737-4 PY 2002 BP 219 EP 237 PG 19 WC Psychology, Developmental SC Psychology GA BV62X UT WOS:000179581600009 ER PT J AU Carrington, M Bontrop, RE AF Carrington, M Bontrop, RE TI Effects of MHC class I on HIV/SIV disease in primates SO AIDS LA English DT Review DE HIV-1; SIV; MHC; HLA; primates ID SIMIAN IMMUNODEFICIENCY VIRUS; T-LYMPHOCYTE RESPONSES; PEPTIDE-BINDING-SPECIFICITY; HIV TYPE-1 INFECTION; HLA-B LOCUS; HISTOCOMPATIBILITY ANTIGEN; LINKAGE DISEQUILIBRIUM; RHESUS MACAQUES; NUCLEOTIDE SUBSTITUTION; OVERDOMINANT SELECTION C1 NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. Biomed Primate Res Ctr, NL-2280 GH Rijswijk, Netherlands. RP Carrington, M (reprint author), NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RI Bontrop, Ronald/J-3628-2012 OI Bontrop, Ronald/0000-0003-0874-6467 FU NCI NIH HHS [N01-CO-12400] NR 114 TC 24 Z9 27 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PY 2002 VL 16 SU 4 BP S105 EP S114 DI 10.1097/00002030-200216004-00015 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 656DT UT WOS:000181594100015 PM 12699007 ER PT J AU Mautino, MR Morgan, RA AF Mautino, MR Morgan, RA TI Gene therapy of HIV-1 infection using lentiviral vectors expressing anti-HIV-1 genes SO AIDS PATIENT CARE AND STDS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; PERIPHERAL-BLOOD LYMPHOCYTES; CD4(+) T-CELLS; A CHAIN GENE; HEMATOPOIETIC STEM-CELLS; CONSTITUTIVE TRANSPORT ELEMENT; INHIBITS VIRAL REPLICATION; MURINE LEUKEMIA-VIRUS; VPR INDUCES APOPTOSIS; RESPONSE RNA DECOY AB The use of vectors based on primate lentiviruses for gene therapy of human immunodeficiency virus type 1 (HIV-1) infection has many potential advantages over the previous murine retroviral vectors used for delivery of genes that inhibit replication of HIV-1. First, lentiviral vectors have the ability to transduce dividing and nondividing cells that constitute the targets of HIV-1 infection such as resting T cells, dendritic cells, and macrophages. Lentiviral vectors can also transfer genes to hematopoietic stem cells with a superior gene transfer efficiency and without affecting the repopulating capacity of these cells. Second, these vectors could be potentially mobilized in vivo by the wild-type virus to secondary target cells, thus expanding the protection to previously untransduced cells. And finally, lentiviral vector backbones have the ability to block HIV-1 replication by several mechanisms that include sequestration of the regulatory proteins Tat and Rev, competition for packaging into virions, and by inhibition of reverse transcription in heterodimeric virions with possible generation of nonfunctional recombinants between the vector and viral genomes. The inhibitory ability of lentiviral vectors can be further increased by expression of anti-HIV-1 genes. In this case, the lentiviral vector packaging system has to be modified to become resistant to the anti-HIV-1 genes expressed by the vector in order to avoid self-inhibition of the vector packaging system during vector production. This review focuses on the use of lentiviral vectors as the main agents to mediate inhibition of HIV-1 replication and discusses the different genetic intervention strategies for gene therapy of HIV-1 infection. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,Bldg 10,Room 2B02, Bethesda, MD 20892 USA. NR 204 TC 20 Z9 21 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JAN PY 2002 VL 16 IS 1 BP 11 EP 26 DI 10.1089/108729102753429361 PG 16 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 518DP UT WOS:000173651600004 PM 11839215 ER PT S AU Duhovny, D Nussinov, R Wolfson, HJ AF Duhovny, D Nussinov, R Wolfson, HJ BE Guigo, R Gusfield, D TI Efficient unbound docking of rigid molecules SO ALGORITHMS IN BIOINFORMATICS, PROCEEDINGS SE LECTURE NOTES IN COMPUTER SCIENCE LA English DT Article; Proceedings Paper CT 2nd International workshop on Algorithms in Bioinformatics CY SEP 17-21, 2002 CL ROME, ITALY ID PROTEIN-PROTEIN INTERFACES; SHAPE COMPLEMENTARITY; GENETIC ALGORITHM; FLEXIBLE DOCKING; SOFT DOCKING; RECOGNITION; ELECTROSTATICS; COMPLEXES; POINTS; SPARSE AB We present a new algorithm for unbound (real life) docking of molecules, whether protein-protein or protein-drug. The algorithm carries out rigid docking, with surface variability/flexibility implicitly addressed through liberal intermolecular penetration. The high efficiency of the algorithm is the outcome of several factors: (i) focusing initial molecular surface fitting on localized, curvature based surface patches; (ii) use of Geometric Hashing and Pose Clustering for initial transformation detection; (iii) accurate computation of shape complementarity utilizing the Distance Transform; (iv) efficient steric clash detection and geometric fit scoring based on a multi-resolution shape representation; and (v) utilization of biological information by focusing on hot spot rich surface patches. The algorithm has been implemented and applied to a large number of cases. C1 Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. NCI, SAIC, Lab Expt & Computat Biol, IRSP,FCRDC, Frederick, MD 21702 USA. RP Duhovny, D (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. RI Wolfson, Haim/A-1837-2011 NR 34 TC 196 Z9 200 U1 0 U2 6 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 3-540-44211-1 J9 LECT NOTES COMPUT SC PY 2002 VL 2452 BP 185 EP 200 PG 16 WC Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Genetics & Heredity; Mathematics, Interdisciplinary Applications SC Biotechnology & Applied Microbiology; Computer Science; Genetics & Heredity; Mathematics GA BY02F UT WOS:000187294100014 ER PT S AU Shatsky, M Nussinov, R Wolfson, HJ AF Shatsky, M Nussinov, R Wolfson, HJ BE Guigo, R Gusfield, D TI MultiProt - A multiple protein structural alignment algorithm SO ALGORITHMS IN BIOINFORMATICS, PROCEEDINGS SE LECTURE NOTES IN COMPUTER SCIENCE LA English DT Article; Proceedings Paper CT 2nd International workshop on Algorithms in Bioinformatics CY SEP 17-21, 2002 CL ROME, ITALY ID SEQUENCES; DOCKING; SETS AB We present a fully automated highly efficient technique which detects the multiple structural alignments of protein structures. Our method, MultiProt, finds the common geometrical cores between the input molecules. To date, only few methods were developed to tackle the structural multiple alignment problem. Most of them require that all the input molecules be aligned, while our method does not require that all the input molecules participate in the alignment. Actually, it efficiently detects high scoring partial multiple alignments for all possible number of molecules from the input. To demonstrate the power of the presented method we provide a number of experimental results performed by the implemented program. Along with the known multiple alignments of protein structures, we present new multiple structural alignment results of protein families from the All beta proteins class in the SCOP classification. C1 Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC,Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Shatsky, M (reprint author), Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. RI Wolfson, Haim/A-1837-2011 NR 28 TC 33 Z9 34 U1 1 U2 3 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 3-540-44211-1 J9 LECT NOTES COMPUT SC PY 2002 VL 2452 BP 235 EP 250 PG 16 WC Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Genetics & Heredity; Mathematics, Interdisciplinary Applications SC Biotechnology & Applied Microbiology; Computer Science; Genetics & Heredity; Mathematics GA BY02F UT WOS:000187294100018 ER PT S AU Desper, R Gascuel, O AF Desper, R Gascuel, O BE Guigo, R Gusfield, D TI Fast and accurate phylogeny reconstruction algorithms based on the minimum-evolution principle SO ALGORITHMS IN BIOINFORMATICS, PROCEEDINGS SE Lecture Notes in Computer Science LA English DT Article; Proceedings Paper CT 2nd International workshop on Algorithms in Bioinformatics CY SEP 17-21, 2002 CL ROME, ITALY ID LEAST-SQUARES; SEQUENCE DATA; TREES; SUBSTITUTIONS; SIMULATION; MODELS; RATES AB This paper investigates the standard ordinary least-squares version [24] and the balanced version [20] of the minimum evolution principle. For the standard version, we provide a greedy construction algorithm (CME) which produces a starting topology in O(n(2)) time, and a tree swapping algorithm (FASTNNI) that searches for the best topology using nearest neighbor interchanges (NNIs), where the cost of doing p NNIs is O(n(2) + pn), i.e. O(n(2)) in practice because p is always much smaller than n. The combination of GME and FASTNNI produces trees which are fairly close to Neighbor Joining (NJ) trees in terms of topological accuracy, especially with large trees. We also provide two closely related algorithms for the balanced version, called BME and BNNI, respectively. BME requires O(n(2) x diam(T)) operations to build the starting tree, and BNNI is in O(n(2) + pn x diam(T)), where diam(T) is the topological diameter of the output tree. In the usual Yule-Harding distribution on phylogenetic trees, the diameter expectation is in log(n), so our algorithms axe in practice faster that NJ. Furthermore, BNNI combined with BME (or GME) has better topological accuracy than NJ, BIONJ and WEIGHBOR (all three in O(n(3))), especially with large trees. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. LIRMM, Dept Informat Fondamentale & Appl, Montpellier, France. RP NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM desper@ncbi.nlm.nih.gov; gascuel@lirmm.fr NR 30 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 3-540-44211-1 J9 LECT NOTES COMPUT SC PY 2002 VL 2452 BP 357 EP 374 PG 18 WC Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Genetics & Heredity; Mathematics, Interdisciplinary Applications SC Biotechnology & Applied Microbiology; Computer Science; Genetics & Heredity; Mathematics GA BY02F UT WOS:000187294100027 ER PT J AU Olin, JT Dagerman, KS Fox, LS Bowers, B Schneider, LS AF Olin, JT Dagerman, KS Fox, LS Bowers, B Schneider, LS TI Increasing ethnic minority participation in Alzheimer disease research SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article; Proceedings Paper CT 12th Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 1999 CL NEW ORLEANS, LOUISIANA SP Amer Assoc Geriatr Psychiat DE Alzheimer disease; clinical trials; ethnic minorities; recruitment ID CLINICAL-TRIALS AB The Alzheimer's Association and National Institutes of Health have emphasized the need for participation of racial/ethnic populations in Alzheimer disease (AD) clinical research. Many articles have described strategies to enhance participation including establishing enduring ties to the community and tailoring the site to be more culturally welcoming or user-friendly to the community. Yet, most of these reports are not data driven. To get a better indication of the knowledge base, this review summarizes research across a broad range of domains (e.g., cancer, kidney disease, AD) that used systematic approaches to identify methods and factors that reduce barriers to recruitment, participation, and retention of a more racially and ethnically diverse population. Overall, 121 reports were found with 8 of these in AD. As a relatively new area of investigation, the literature was primarily descriptive; outcome data were seldom provided. While these studies help to identify areas of potential importance in racial/ethnic participation, hypothesis-driven research remains necessary to tease apart the key techniques that engender racial/ethnic participation in AD studies. This article suggests several recommendations, including the need for prospective research of specific recruitment methods. Fundamentally, researchers should consider that these strategies apply to all potential research participants, and not simply to traditionally underserved racial/ethnic populations. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Univ So Calif, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. Ctr Aging Resources, Pasadena, CA USA. RP Olin, JT (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7160,MSC 9635, Bethesda, MD 20892 USA. FU NIMH NIH HHS [MH01368] NR 5 TC 26 Z9 26 U1 0 U2 2 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. PY 2002 VL 16 SU 2 BP S82 EP S85 DI 10.1097/01.WAD.0000025469.36316.IB PG 4 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 593MT UT WOS:000177995800009 PM 12351920 ER PT S AU White, L Petrovitch, H Hardman, J Nelson, J Davis, DG Ross, GW Masaki, K Launer, L Markesbery, WR AF White, L Petrovitch, H Hardman, J Nelson, J Davis, DG Ross, GW Masaki, K Launer, L Markesbery, WR BE DeLaTorre, JC Kalaria, R Nakajima, K Nagata, K TI Cerebrovascular pathology and dementia in autopsied Honolulu-Asia aging study participants SO ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 3rd World Congress on Vascular Factors in Alzheimers Disease CY APR 07-10, 2002 CL KYOTO, JAPAN SP Banyu Pharmaceut, Commemorat Assoc Japan World Exposit, Esisai Pharmaceut Co Ltd, Janssen-Kyowa Co, Japan Arteriosclerosis Prevent f DE dementia; cognitive impairment; aging; pathology; microinfarct; brain; Alzheimer; vascular dementia ID VASCULAR DEMENTIA; ALZHEIMERS-DISEASE; NEUROPATHOLOGY AB Clinicopathologic data from 285 autopsies were analyzed. The decedents were long-standing participants in the Honolulu-Asia Aging Study, a prospective epidemiologic investigation of stroke, neurodegenerative diseases, and aging. We assessed the prevalence at death of four primary neuropathologic processes using specific microscopic lesions as indicators. An algorithm was developed to assign each decedent to one of six subsets, corresponding to pathologic dominance by microvascular lesions (14% of decedents), Alzheimer lesions (12%), hippocampal sclerosis (5%), cortical Lewy bodies (5%), codominance by two or more primary processes (9%), or without a dominant pathologic process recognized (55%). Definite or probable dementia had been identified in 118 of the decedents. The proportions of men in each subset identified as demented were (in the same order) 57%, 53%, 79%, 57%, 76%, and 25%. In this autopsied panel of older Japanese-American men, the importance of microvascular lesions as a likely explanation for dementia was nearly equal to that of Alzheimer lesions. The cerebrovascular lesion type most essentially and inclusively related to dementia was multiple microinfarction. C1 PHRI, Honolulu, HI 96813 USA. Kuakini Med Ctr, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Dept Pathol & Lab Med, Lexington, KY USA. Dept Vet Affairs, Honolulu, HI USA. NIA, NIH, Bethesda, MD 20892 USA. RP White, L (reprint author), PHRI, Suite 306,846 S Hotel St, Honolulu, HI 96813 USA. FU NIA NIH HHS [N01 AG 42149] NR 14 TC 208 Z9 214 U1 1 U2 11 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-440-4 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2002 VL 977 BP 9 EP 23 PG 15 WC Genetics & Heredity; Multidisciplinary Sciences; Clinical Neurology; Neuroimaging; Pathology SC Genetics & Heredity; Science & Technology - Other Topics; Neurosciences & Neurology; Pathology GA BV68J UT WOS:000179767000002 PM 12480729 ER PT J AU Billington, CJ Epstein, LH Goodwin, NJ Leibel, RL Pi-Sunyer, FX Stern, JS Weinsier, RL Terence, G Wing, RR Yanovski, SZ Hubbard, VS Hoofnagle, JH AF Billington, CJ Epstein, LH Goodwin, NJ Leibel, RL Pi-Sunyer, FX Stern, JS Weinsier, RL Terence, G Wing, RR Yanovski, SZ Hubbard, VS Hoofnagle, JH TI Medical care for obese patients: Advice for health care professionals SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID SLEEP-APNEA; OVERWEIGHT; ATTITUDES; WEIGHT; WOMEN; MEN AB More than 60 percent of adults in the United States are overweight or obese, and obese persons are more likely to be ill than those who are not. Obesity presents challenges to physicians and patients and also has a negative impact on health status. Some patients who are obese may delay medical care because of concerns about disparagement by physicians and health care staff, or fear of being weighed, Simple accommodations, such as providing large-sized examination gowns and armless chairs, as well as weighing patients in a private area, may make the medical setting more accessible and more comfortable for obese patients. Extremely obese patients often have special health needs, such as lower extremity edema or respiratory insufficiency that require targeted evaluation and treatment. Although physical examination may be more difficult in obese patients, their disproportionate risk for some illnesses that are amenable to early detection increases the priority for preventive evaluations. Physicians can encourage improvements in healthy behaviors, regardless of the patient's desire for, or success with, weight loss treatment. Copyright (C) 2002 American Academy of Family Physicians. C1 Vet Affairs Med Ctr, Minneapolis, MN USA. RP Yanovski, SZ (reprint author), NIDDK, 2 Democracy Plaza,Room 665,6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 26 TC 27 Z9 28 U1 2 U2 4 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JAN 1 PY 2002 VL 65 IS 1 BP 81 EP 88 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 512GY UT WOS:000173317700006 ER PT J AU Freedman, J Mascelli, MA Pezzullo, JC Barnathan, ES Frederick, B Jordan, RE Albernethy, DR AF Freedman, J Mascelli, MA Pezzullo, JC Barnathan, ES Frederick, B Jordan, RE Albernethy, DR TI Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects SO AMERICAN HEART JOURNAL LA English DT Article ID IIB/IIIA RECEPTOR BLOCKADE; PLATELET-FUNCTION ASSAY; CORONARY ANGIOPLASTY; IN-VIVO; AGGREGATION; INHIBITION; 7E3; FAB; INTERVENTION; ANTAGONIST AB Objective The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. Methods and Results The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 mug/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 mumol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. Conclusions A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted. C1 Centocor Inc, Malvern, PA 19355 USA. Georgetown Univ, Sch Med, Washington, DC USA. Natl Inst Aging, Baltimore, MD USA. RP Mascelli, MA (reprint author), Centocor Inc, 200 Great Valley Pkwy, Malvern, PA 19355 USA. NR 26 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JAN PY 2002 VL 143 IS 1 BP 87 EP 94 DI 10.1067/mhj.2002.119769 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 511PY UT WOS:000173275800014 PM 11773917 ER PT J AU Swanson, CA AF Swanson, CA TI Suggested guidelines for articles about botanical dietary supplements SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID ALTERNATIVE MEDICINE; UNITED-STATES; NUTRITION; HEALTH AB Recently, The American Journal of Clinical Nutrition (AJCN) began reviewing articles about dietary supplements. The purpose of this commentary is to provide guidelines to authors and reviewers for articles on one category of supplement ingredients. botanicals. The botanicals in the studies published by the AJCN tend to fall into 1 of 2 groups: 1) plants as foods containing nonessential bioactive constituents that may provide health benefits beyond basic nutrition, and 2) plants as herbs, specifically those used as phytomedicines. Research in these areas is relevant to clinical nutrition, but both topics represent relatively new territory to many AJCN reviewers, readers, and contributors. Although studies of botanicals are unique in many respects, the research should be evaluated with the same basic criteria applied to other types of investigations. For example, a study cannot be evaluated or replicated unless the test materials are properly identified and characterized. Investigators must provide an accurate and complete description of the botanical test material regardless of whether it is a finished product, commercial ingredient, extract, or single chemical constituent. For herbal preparations, investigators are advised to follow the criteria used by researchers in the field of pharmacognosy. Finally, the quality of research related to botanical dietary supplements would be improved and cross-study comparisons facilitated if standard reference materials and certified methods of analysis were more broadly available. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Swanson, CA (reprint author), NIH, Off Dietary Supplements, 31 Ctr Dr,1B29, Bethesda, MD 20892 USA. NR 12 TC 24 Z9 24 U1 2 U2 6 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 2002 VL 75 IS 1 BP 8 EP 10 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 504YR UT WOS:000172884400005 PM 11756054 ER PT J AU Busby, MG Jeffcoat, AR Bloedon, LT Koch, MA Black, T Dix, KJ Heizer, WD Thomas, BF Hill, JM Crowell, JA Zeisel, SH AF Busby, MG Jeffcoat, AR Bloedon, LT Koch, MA Black, T Dix, KJ Heizer, WD Thomas, BF Hill, JM Crowell, JA Zeisel, SH TI Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE genistein; daidzein; soy isoflavones; cancer; toxicity; pharmacokinetics; healthy men; North Carolina ID TYROSINE KINASE-ACTIVITY; PROSTATE-CANCER; IN-VITRO; GENISTEIN; CELLS; INHIBITION; GROWTH; PHYTOESTROGENS; ANGIOGENESIS; INDUCTION AB Background: Soy isoflavones are potential cancer chemoprevention treatments. Objective: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism. Design: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2. 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 +/-5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein. Results: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity, Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination half-lives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 It for total daidzein. Conclusions: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine. C1 Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NCI, Chemoprevent Agent Dev Res Grp, Rockville, MD USA. NCI, Div Canc Prevent, Rockville, MD USA. RP Zeisel, SH (reprint author), Univ N Carolina, Dept Nutr, CB 74002212,McGavran Greenberg Bldg, Chapel Hill, NC 27599 USA. OI Thomas, Brian/0000-0002-0097-4804 FU NCI NIH HHS [CA16086, N01-CN-65117]; NCRR NIH HHS [RR00046]; NIDDK NIH HHS [DK56350] NR 42 TC 179 Z9 186 U1 3 U2 9 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2002 VL 75 IS 1 BP 126 EP 136 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 504YR UT WOS:000172884400021 PM 11756070 ER PT J AU Chen, HL Ward, MH Graubard, BI Heineman, EF Markin, RM Potischman, NA Russell, RB Weisenburger, DD Tucker, KL AF Chen, HL Ward, MH Graubard, BI Heineman, EF Markin, RM Potischman, NA Russell, RB Weisenburger, DD Tucker, KL TI Dietary patterns and adenocarcinoma of the esophagus and distal stomach SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE esophagus; stomach; neoplasm; dietary pattern; cluster analysis; cancer ID NUTRITION INTERVENTION TRIALS; CARDIOVASCULAR RISK-FACTORS; DISEASE-SPECIFIC MORTALITY; BETA-CAROTENE; CANCER INCIDENCE; CLUSTER-ANALYSIS; GASTRIC CARDIA; COLON-CANCER; LUNG-CANCER; EATING PATTERNS AB Background: Dietary pattern analysis is a unique approach to studying relations between diet and disease. Objective: Our objective was to describe the dietary patterns of an eastern Nebraska population and investigate the associations between those dietary patterns and risks of adenocarcinoma of the esophagus and distal stomach. Design: We recruited 124 subjects with esophageal adenocarcinoma. 124 subjects with distal stomach adenocarcinoma, and 449 control subjects in a population-based, case-control study. Results: Six dietary patterns were identified with the use of cluster analysis. The first dietary pattern represented healthy food choices and had higher energy contributions from fruit and vegetables and grain products and lower energy contributions from red meats, processed meats, and gravy than did the other dietary patterns. In contrast, a second dietary pattern was high in meats and low in fruit and cereals. The other 4 dietary patterns were each characterized by a concentrated energy source: salty snacks, desserts, milk, and white bread, respectively. The test of overall difference in cancer risk across dietary patterns was significant for distal stomach adenocarcinoma (P=0.04) but not for esophageal adenocarcinoma. Risk of esophageal adenocarcinoma was inversely associated with intakes of dairy products, fish, all vegetables, citrus fruit and juices, and dark bread and was positively associated with gravy intake. Risk of distal stomach adenocarcinoma was positively associated with red meat intake. Conclusions: Our study suggests that a diet high in fruit and vegetables may decrease the risk of esophageal adenocarcinoma and that a diet high in meats may increase the risk of distal stomach adenocarcinoma. C1 Tufts Univ, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Ward, MH (reprint author), NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-8104,MSC-7420, Bethesda, MD 20892 USA. EM wardm@exchange.nih.gov RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X; Chen, Honglei/0000-0003-3446-7779 NR 49 TC 146 Z9 152 U1 2 U2 12 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2002 VL 75 IS 1 BP 137 EP 144 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 504YR UT WOS:000172884400022 PM 11756071 ER PT J AU Montoya, ID Preston, KL Rothman, R Gorelick, DA AF Montoya, ID Preston, KL Rothman, R Gorelick, DA TI Open-label pilot study of bupropion plus bromocriptine for treatment of cocaine dependence SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article; Proceedings Paper CT 57th Annual Scientific Meeting of the College-on-Problems-of-Drug-Dependence CY JUN 11-16, 1995 CL SCOTTSDALE, ARIZONA SP Coll Problems Drug Dependence DE bromocriptine; bupropion; cocaine; dependence; treatment ID DOPAMINE AGONISTS AB Combinations of medications are often used in neuropsychiatry to enhance treatment efficacy. This 8-week, open-label study tested the combination of bupropion (less than or equal to300 mg) and bromocriptine (less than or equal to7.5 mg) daily in 34 cocaine-dependent (DSM-IIIR) outpatients also receiving weekly individual counseling. The first 18 subjects spent one week at maximum dose; the next 16 spent three weeks. Both groups showed significant reductions in self-reported cocaine use, with no significant change in proportion of urine toxicology tests positive for cocaine. There were no significant differences in outcome between groups. These results suggest that the combination of bupropion and bromocriptine is safe in cocaine addicts, but provide ambiguous evidence of its efficacy. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorelick, DA (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS [Z99 DA999999] NR 13 TC 12 Z9 12 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PY 2002 VL 28 IS 1 BP 189 EP 196 DI 10.1081/ADA-120001288 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 520QX UT WOS:000173793500011 PM 11853133 ER PT J AU Maher, BS Marazita, ML Zubenko, WN Kaplan, BB Zubenko, GS AF Maher, BS Marazita, ML Zubenko, WN Kaplan, BB Zubenko, GS TI Genetic segregation analysis of alcohol and other substance-use disorders in families with recurrent, early-onset major depression SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE genetics; complex segregation analysis; major depression; alcoholism; alcohol use disorders; substance-use disorders ID DRUG-ABUSE; UNIPOLAR DEPRESSION; FEMALE TWINS; PSYCHOPATHOLOGY; TRANSMISSION; INHERITANCE; DISEASE; RISK; HERITABILITY; CRIMINALITY AB Objective: The goal of this study was to conduct a complex segregation analysis of alcohol and other substance-use disorders in families identified by probands with recurrent, early-onset major depression (RE-MDD). Method: Eighty-one families were identified through probands over the age of 18, who met criteria for recurrent (greater than or equal to2 episodes), early-onset (less than or equal to25 years), nonpsychotic, unipolar major depression (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0. Results: The best-fitting models for the transmission of "alcohol use disorders" or "alcohol/other substance use disorders" were sex-dependent Mendelian recessive models with significant residual spousal effects. Moreover, the parameter estimates for the models were very similar for these phenotypes. In contrast, the segregation analysis of "substance use disorder" supported a transmissible, but non-Mendelian, major effect. Conclusions: Our results suggest that a major locus contributes to the expression of alcohol use disorders or alcohol/other substance-use disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). Previous studies supported single gene transmission of recurrent major depression and major mood disorders in these families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002,114 (2), 214-221]. Mounting evidence suggests that at least some of this "comorbidity" may result from the effects of shared susceptibility genes or an overlap in the sets of genes that contribute to the vulnerability of developing these mental disorders [Zubenko, G.S. Mol. Psychiatry 2000, 5, 131-136]. C1 Univ Pittsburgh, Sch Dent Med, Div Oral Biol, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Mellon Coll Sci, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Zubenko, GS (reprint author), WPIC, Room E1230,3811 OHara St, Pittsburgh, PA 15213 USA. RI Maher, Brion/F-9185-2010 NR 54 TC 0 Z9 0 U1 3 U2 4 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0095-2990 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PY 2002 VL 28 IS 4 BP 713 EP 733 DI 10.1081/ADA-120015878 PG 21 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 623NX UT WOS:000179710700009 ER PT J AU Klebanoff, MA Levine, RJ Clemens, JD Wilkins, DG AF Klebanoff, MA Levine, RJ Clemens, JD Wilkins, DG TI Maternal serum caffeine metabolites and small-for-gestational age birth SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE caffeine; fetus; infant; newborn; pregnancy outcome ID INTRAUTERINE GROWTH-RETARDATION; FETAL GROWTH; SPONTANEOUS-ABORTION; COFFEE CONSUMPTION; PRETERM BIRTH; PREGNANCY; WEIGHT; SMOKING; ALCOHOL; CIGARETTE AB To determine whether the third-trimester maternal serum concentration of paraxanthine, caffeine's primary metabolite, is associated with delivery of a small-for-gestational age infant (birth weight less than the 10th percentile for gestational age, gender, and ethnicity) and whether this association differs by smoking, the authors studied 2,515 women who participated in the Collaborative Perinatal Project from 1959 to 1966. The women provided a third-trimester serum sample and had been controls for a nested case-control study of spontaneous abortion. The mean serum paraxanthine concentration was greater in women who gave birth to small-for-gestational age infants (754 ng/ml) than to appropriately grown infants (653 ng/ml, p = 0.02). However, the linear trend for increasing serum paraxanthine concentration to be associated with increasing risk of small-for-gestational age birth was confined to women who also smoked (p = 0.03). There was no association between paraxanthine and fetal growth in nonsmokers (p = 0.48). Adjustment for maternal age, prepregnant weight, education, parity, ethnicity, and the number of cigarettes smoked per day did not alter the results substantially, although the p value for trend among smokers increased to 0.07. The authors conclude that maternal third-trimester serum paraxanthine concentration, which reflects caffeine consumption, was associated with a higher risk of reduced fetal growth, particularly among women who smoked. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Univ Utah, Ctr Human Toxicol, Salt Lake City, UT USA. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, 6100 Bldg,Room 7B05, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-7-3262] NR 29 TC 32 Z9 33 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2002 VL 155 IS 1 BP 32 EP 37 DI 10.1093/aje/155.1.32 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 509GC UT WOS:000173137100006 PM 11772782 ER PT J AU Chambless, LE Folsom, AR Davis, V Sharrett, R Heiss, G Sorlie, P Szklo, M Howard, G Evans, GW AF Chambless, LE Folsom, AR Davis, V Sharrett, R Heiss, G Sorlie, P Szklo, M Howard, G Evans, GW TI Risk factors for progression of common carotid atherosclerosis: The atherosclerosis risk in communities study, 1987-1998 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atherosclerosis; carotid arteries; cohort studies; risk factors ID INTIMA-MEDIA THICKNESS; B-MODE ULTRASOUND; CORONARY-ARTERY DISEASE; PREVALENT CARDIOVASCULAR-DISEASE; POPULATION-BASED ULTRASONOGRAPHY; IMPROVED LIPOLYTIC EFFICIENCY; COLESTIPOL-NIACIN THERAPY; CONTROLLED CLINICAL-TRIAL; MIDDLE-AGED MEN; WALL THICKNESS AB Intima-media thickness of the common carotid arteries is a marker of atherosclerosis and has been shown to be associated with prevalent and incident coronary heart disease and with coronary heart disease risk factors. The authors examined the association of baseline risk factors or change in risk factors with change in intima-media thickness over follow-up (1987-1998) in the Atherosclerosis Risk in Communities (ARIC) population-based cohort (baseline: age 45-64 years, n = 15,792). Subjects were members of households sampled in four areas of the United States. Either not adjusting for baseline intima-media thickness or doing so with correction for its measurement error resulted in statistically significant associations of change in intima-media thickness with baseline diabetes, current smoking, high density lipoprotein cholesterol, pulse pressure, white blood cell count, and fibrinogen. The associations were of a similar order of magnitude as anticipated from the authors' cross-sectional findings. Statistically significant associations were found between change in intima-media thickness and change in low density lipoprotein cholesterol and triglycerides and with onset of diabetes and hypertension. In summary, established risk factors for coronary heart disease are associated with the rate of change of subclinical atherosclerosis. C1 Univ N Carolina, Sch Publ Hlth, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth, Winston Salem, NC 27109 USA. RP Chambless, LE (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Biostat, Collaborat Studies Coordinating Ctr, 137 E Franklin St,Bank Amer Plaza,Suite 400,CB 80, Chapel Hill, NC 27514 USA. EM wchambless@unc.edu FU NHLBI NIH HHS [N01-HC-55019, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 82 TC 202 Z9 221 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2002 VL 155 IS 1 BP 38 EP 47 DI 10.1093/aje/155.1.38 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 509GC UT WOS:000173137100007 PM 11772783 ER PT J AU Hediger, ML Ruan, WJ Zemel, BS AF Hediger, ML Ruan, WJ Zemel, BS TI Ethnic and seasonal variation in serum 25-hydroxyvitamin D levels in US. adolescents: the Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 NICHHD, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 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 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD JAN-FEB PY 2002 VL 14 IS 1 MA 30 BP 114 EP 114 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 508PC UT WOS:000173096800045 ER PT J AU Feitosa, MF Borecki, IB Rich, SS Arnett, DK Sholinsky, P Myers, RH Leppert, M Province, MA AF Feitosa, MF Borecki, IB Rich, SS Arnett, DK Sholinsky, P Myers, RH Leppert, M Province, MA TI Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: The National Heart, Lung, and Blood Institute Family Heart Study SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RECEPTOR GENE POLYMORPHISM; AUTOSOMAL GENOMIC SCAN; RESTING METABOLIC-RATE; SIB-PAIR ANALYSIS; HUMAN OB GENE; QUEBEC FAMILY; LINKAGE ANALYSIS; EXTREME OBESITY; RESPIRATORY QUOTIENT; SUSCEPTIBILITY LOCUS AB Obesity is a risk factor for many chronic diseases, including glucose intolerance, lipid disorders, hypertension, and coronary heart disease. Even though the body-mass index (BMI) is a heterogeneous phenotype reflecting the amount of fat, lean mass, and body build, several studies have provided evidence of one or two major loci contributing to the variation in this complex trait. We sought to identify loci with potential influence on BMI in the data obtained from National Heart, Lung, and Blood Institute Family Heart Study. Two complementary samples were studied: (a) 1, 184 subjects in 317 sibships, with 243 markers typed by the Utah Molecular Genetics Laboratory (UMGL) and (b) 3,027 subjects distributed among 401 three-generation families, with 404 markers typed by the Mammalian Genotyping Service (MGS). A genome scan using a variance-components-based linkage approach was performed for each sample, as well as for the combined sample, in which the markers from each analysis were placed on a common genetic map. There was strong evidence for linkage on chromosome 7q32.3 in each sample: the maximum multipoint LOD scores were 4.7 (P<10(-3)) at marker GATA43C11 and 3.2 (P = .00007) at marker D7S1804, for the MGS and UMGL samples, respectively. The linkage result is replicated by the consistent evidence from these two complementary subsets. Furthermore, the evidence for linkage was maintained in the combined sample, with a LOD score of 4.9 (P<10(-5)) for both markers, which map to the same location. This signal is very near the published location for the leptin gene, which is the most prominent candidate gene in this region. For the combined-sample analysis, evidence of linkage was also found on chromosome 13q14, with D13S257 (LOD score 3.2, P = .00006), and other, weaker signals (LOD scores 1.5-1. 9) were found on chromosomes 1, 2, 3, 5, 6, 14, and 15. C1 Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Epidemiol & Biometry Program, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Univ Utah, Eccles Inst Human Genet, Salt Lake City, UT USA. RP Feitosa, MF (reprint author), Washington Univ, Sch Med, Div Biostat, Campus Box 8067,660 S Euclid, St Louis, MO 63110 USA. RI Feitosa, Mary/K-8044-2012 OI Feitosa, Mary/0000-0002-0933-2410 FU NHLBI NIH HHS [U01 HL56565, U01 HL056567, U01 HL56563, U01 HL56564, U01 HL56566, U01 HL56567, U01 HL56568, U01 HL56569] NR 65 TC 107 Z9 110 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2002 VL 70 IS 1 BP 72 EP 82 DI 10.1086/338144 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 499LD UT WOS:000172571900008 PM 11713718 ER PT J AU van Geel, M Eichler, EE Beck, AF Shan, ZH Haaf, T van der Maarel, SM Frants, RR de Jong, PJ AF van Geel, M Eichler, EE Beck, AF Shan, ZH Haaf, T van der Maarel, SM Frants, RR de Jong, PJ TI A cascade of complex subtelomeric duplications during the evolution of the hominoid and old world monkey genomes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; RECEPTOR GENE FAMILY; GLOBIN GENE; REGION; IDENTIFICATION; CHROMOSOMES; PSEUDOGENES; MEMBERS; FISH; 4Q35 AB Subtelomeric duplications of an obscure tubulin "genic" segment located near the telomere of human chromosome 4q35 have occurred at different evolutionary time points within the last 25 million years of the catarrhine (i.e., hominoid and Old World monkey) evolution. The analyses of these segments reported here indicate an exceptional level of evolutionary instability. Substantial intra- and interspecific differences in copy number and distribution are observed among cercopithecoid (Old World monkey) and hominoid genomes. Characterization of the hominoid duplicated segments reveals a strong positional bias within pericentromeric and subtelomeric regions of the genome. On the basis of phylogenetic analysis from predicted proteins and comparisons of nucleotide-substitution rates, we present evidence of a conserved b-tubulin gene among the duplications. Remarkably, the evolutionary conservation has occurred in a nonorthologous fashion, such that the functional copy has shifted its positional context between hominoids and cercopithecoids. We propose that, in a chimpanzee-human common ancestor, one of the paralogous copies assumed the original function, whereas the ancestral copy acquired mutations and eventually became silenced. Our analysis emphasizes the dynamic nature of duplication-mediated genome evolution and the delicate balance between gene acquisition and silencing. C1 Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Case Western Reserve Univ, Sch Med, Ctr Human Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. NCI, Mol Cytogenet Sect, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Max Planck Inst Mol Genet, Berlin, Germany. Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands. RP de Jong, PJ (reprint author), Childrens Hosp Oakland, 747 52nd St, Oakland, CA 94609 USA. NR 26 TC 22 Z9 25 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN PY 2002 VL 70 IS 1 BP 269 EP 278 DI 10.1086/338307 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 499LD UT WOS:000172571900026 PM 11731935 ER PT J AU Mackey, RH Sutton-Tyrrell, K Vaitkevicius, PV Sakkinen, PA Lyles, MF Spurgeon, HA Lakatta, EG Kuller, LH AF Mackey, RH Sutton-Tyrrell, K Vaitkevicius, PV Sakkinen, PA Lyles, MF Spurgeon, HA Lakatta, EG Kuller, LH TI Correlates of aortic stiffness in elderly individuals: A subgroup of the Cardiovascular Health Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE pulse wave velocity; aging; arterial stiffness; insulin resistance; heart rate ID PULSE-WAVE VELOCITY; ARTERIAL DISTENSIBILITY; RISK-FACTORS; HEART-RATE; ASSOCIATION; DISEASE; WOMEN; TERM; MEN; ATHEROSCLEROSIS AB Background: Arterial stiffness has been associated with aging, hypertension, and diabetes; however, little data has been published examining risk factors associated with arterial stiffness in elderly individuals. Methods: Longitudinal associations were made between aortic stiffness and risk factors measured approximately 4 years earlier. Aortic pulse wave velocity (PWV), an established index of arterial stiffness, was measured in 356 participants (53.4% women, 25.3% African American), aged 70 to 96 years, from the Pittsburgh site of the Cardiovascular Health Study during 1996 to 1998. Results: Mean aortic pulse wave velocity (850 cm/sec, range 365 to 1863) did not differ by ethnicity or sex. Increased aortic stiffness was positively associated with higher systolic blood pressure (SBP), age, fasting and 2-h postload glucose, fasting and 2-h insulin, triglycerides, waist circumference, body mass index, truncal fat, decreased physical activity, heart rate, and common carotid artery wall thickness (P < .05). After controlling for age and SBP, the strongest predictors of aortic stiffness in men were heart rate (P = .001) and 2-h glucose (P = .063). In women, PWV was positively associated with heart rate (P = .018), use of antihypertensive medication (P = .035), waist circumference (P = .030), and triglycerides (P = .081), and was negatively associated with physical activity (P = .111). Results, were similar when the analysis was repeated in nondiabetic individuals and in those free of clinical or subclinical cardiovascular disease in 1992 to 1993. Conclusions: In these elderly participants, aortic stiffness was positively associated with risk factors associated with the insulin resistance syndrome, increased common carotid intima-media thickness, heart rate, and decreased physical activity measured several years earlier. (C) 2002 American Journal of Hypertension, Ltd. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Michigan, Sch Med, Div Geriatr Med, Vet Affairs Ann Arbor Healthcare Syst Geriatr, Ann Arbor, MI USA. Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. Wake Forest Univ, Sch Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27109 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Sutton-Tyrrell, K (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 DeSoto St, Pittsburgh, PA 15261 USA. OI Mackey, Rachel/0000-0001-6088-2664 FU NHLBI NIH HHS [N01-HC-85082] NR 29 TC 113 Z9 115 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JAN PY 2002 VL 15 IS 1 BP 16 EP 23 DI 10.1016/S0895-7061(01)02228-2 PN 1 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 515PH UT WOS:000173504200004 PM 11824854 ER PT J AU Couper, DJ Klein, R Hubbard, LD Wong, TY Sorlie, PD Cooper, LS Brothers, RJ Nieto, FJ AF Couper, DJ Klein, R Hubbard, LD Wong, TY Sorlie, PD Cooper, LS Brothers, RJ Nieto, FJ TI Reliability of retinal photography in the assessment of retinal microvascular characteristics: The atherosclerosis risk in communities study SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID HYPERTENSION; RETINOPATHY; AGREEMENT AB PURPOSE: Retinal microvascular characteristics, as graded from retinal photography, have been shown to predict stroke. We evaluated the reliability of retinal photographic grading in the Atherosclerosis Risk in Communities Study. DESIGN: Cohort study. METHODS: Retinal photographs were taken of all subjects who attended the third Atherosclerosis Risk in Communities Study examination (1993 to 1995). These were graded using standardized protocols. Focal retinal characteristics were graded using a "light box" system. Generalized retinal arteriolar narrowing was quantified from computer assisted measurements of digitized photographs. Two substudies were conducted to investigate the reliability of these grading methods. In the Individual Variability Study, selected subjects (n = 206) had two retinal photographs taken on one day, and a further one or two photographs taken 3 weeks later. In the Grader Variability Study, a stratified random sample of photographs had repeat retinal grading (n = 495 photographs for light box grading; n = 276 photographs for computer-assisted grading). RESULTS: Reliability of the computer-assisted quantification of generalized retinal arteriolar narrowing was high in both studies (reliability coefficients 0.64 to 0.69 for Individual Variability Study, and 0.79 to 0.83 for the Grader Variability Study). There was more variability for focal abnormalities graded using the light box system. Variability for Individual Variability Study (same individuals, repeat photographs) tended to be greater than for the Grader Variability Study (same photographs, repeat gradings). CONCLUSION: Retinal microvascular characteristics, especially computer-assisted quantification of generalized retinal arteriolar narrowing, can be ascertained reliably by standardized photographic grading methods, supporting the validity of their associations with cardiovascular disease. However, these characteristics appear to vary somewhat between eyes and over time in a single individual. C1 Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. NHLBI, Clin Applicat & Epidemiol Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. RP Couper, DJ (reprint author), Univ N Carolina, Dept Biostat, 137 E Franklin St,CB 8030, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55021, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55022] NR 30 TC 97 Z9 100 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JAN PY 2002 VL 133 IS 1 BP 78 EP 88 DI 10.1016/S0002-9394(01)01315-0 PG 11 WC Ophthalmology SC Ophthalmology GA 509JL UT WOS:000173144600009 PM 11755842 ER PT J AU Hertle, RW Maybodi, M Mellow, SD Yang, DS AF Hertle, RW Maybodi, M Mellow, SD Yang, DS TI Clinical and oculographic response to Tenuate Dospan (diethylpropionate) in a patient with congenital nystagmus SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: We report a female adult with congenital nystagmus who responded with improved visual function and oculographic parameters after taking the anorexic diet drug Tenuate Dospan (diethylproprionate; Watson Laboratories, Inc., Corona, California). METHODS: Observational case report. Clinical ophthalmic examination and ocular motility recordings were per, formed before and after administration of the drug Tenuate Dospan. RESULTS: The binocular visual acuity of the patient improved from 20/70 to 20/50, her exotropic deviation decreased from 12 to 4 prism diopters, her stereopsis increased from none to 200 seconds/arc, and her ocular motility recordings showed increased foveation periods and a broadened null zone. CONCLUSION: For unexplained reasons, the anorexic stimulant Tenuate Dospan "paradoxically" improved the nystagmus and binocular function in this patient with congenital nystagmus. This observation may be the basis for investigation of a new pharmacological treatment approach to patients with congenital nystagmus or strabismus. C1 NEI, Pediat Ophthalmol Strabismus & eye Movement Serv, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hertle, RW (reprint author), Pediat Ophthalmol Associates, 555 S 18th,Suite 4C, Columbus, OH 43205 USA. NR 7 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JAN PY 2002 VL 133 IS 1 BP 159 EP 160 DI 10.1016/S0002-9394(01)01195-3 PG 2 WC Ophthalmology SC Ophthalmology GA 509JL UT WOS:000173144600030 PM 11755862 ER PT J AU Cleveland, A Trenkle, M Lussier, I Higley, J Westergaard, G AF Cleveland, A Trenkle, M Lussier, I Higley, J Westergaard, G TI CSF5-HIAA, life history and aggression in captive female rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Labs Virginia Inc, Div Res, Charleston, SC 29414 USA. NIAAA, Rockville, MD 20852 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 2002 SU 34 BP 55 EP 55 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 534VG UT WOS:000174609700085 ER PT J AU Gannon, P Kheck, N Goldin-Meadow, S Valachovic, A AF Gannon, P Kheck, N Goldin-Meadow, S Valachovic, A TI Everyday US sign language: A new look at Hewes' hypothesis for a gestural origin of spoken language. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 CUNY Mt Sinai Sch Med, Dept Otolaryngol, New York, NY 10029 USA. Univ Chicago, Dept Psychol, Chicago, IL 60637 USA. CUNY Mt Sinai Sch Med, Dept Rehabil Med, New York, NY 10029 USA. NIH, Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RI Galantucci, Bruno/E-5770-2010 NR 0 TC 0 Z9 0 U1 2 U2 5 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 2002 SU 34 BP 74 EP 74 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 534VG UT WOS:000174609700165 ER PT J AU Wyman, BT Hunter, WC Prinzen, FW Faris, OP McVeigh, ER AF Wyman, BT Hunter, WC Prinzen, FW Faris, OP McVeigh, ER TI Effects of single- and biventricular pacing on temporal and spatial dynamics of ventricular contraction SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE magnetic resonance imaging; tagging; cardiac mechanics; conduction abnormalities; cardiac mapping ID INTRAVENTRICULAR-CONDUCTION DELAY; TAGGED MR-IMAGES; DILATED CARDIOMYOPATHY; ENDOCARDIAL ACTIVATION; MECHANICAL ACTIVATION; HEART-FAILURE; PACED HEART; SEQUENCE AB Resynchronization is frequently used for the treatment of heart failure, but the mechanism for improvement is not entirely clear. In the present study, the temporal synchrony and spatiotemporal distribution of left ventricular (LV) contraction was investigated in eight dogs during right atrial (RA), right ventricular apex (RVa), and biventricular (BiV) pacing using tagged magnetic resonance imaging. Mechanical activation (MA; the onset of circumferential shortening) was calculated from the images throughout the left ventricle for each pacing protocol. MA width (time for 20-90% of the left ventricle to contract) was significantly shorter during RA (43.6 +/- 17.1 ms) than BiV and RVa pacing (67.4 +/- 15.2 and 77.6 +/- 16.4 ms, respectively). The activation delay vector (net delay in MA from one side of the left ventricle to the other) was significantly shorter during RA (18.9 +/- 8.1 ms) and BiV (34.2 +/- 18.3 ms) than during RVa (73.8 +/- 16.3 ms) pacing. Rate of LV pressure increase was significantly lower during RVa than RA pacing (1,070 +/- 370 vs. 1,560 +/- 300 mmHg/s) with intermediate values for BiV pacing (1,310 +/- 220 mmHg/s). BiV pacing has a greater impact on correcting the spatial distribution of LV contraction than on improving the temporal synchronization of contraction. Spatiotemporal distribution of contraction may be an important determinant of ventricular function. C1 Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. Univ Maastricht, Dept Physiol, Cardiovasc Res Inst Maastricht, NL-6200 MD Maastricht, Netherlands. RP McVeigh, ER (reprint author), NHLBI, Bldg 10,Rm B1D416, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL004609-08]; NHLBI NIH HHS [HL-45683] NR 24 TC 94 Z9 98 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JAN PY 2002 VL 282 IS 1 BP H372 EP H379 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 505QQ UT WOS:000172927400044 PM 11748084 ER PT J AU Briggs, JP AF Briggs, JP TI The zebrafish: A new model organism for integrative physiology SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Review DE Danio rerio; genomics ID DANIO-RERIO; MUTATIONS; GENOME; DIFFERENTIATION; MUTANT; GENE; PRONEPHROS; INDUCTION; EMBRYOS; NEURONS AB This brief review summarizes features of the zebrafish, Danio rerio, that make it a suitable model organism for studies of regulatory physiology. The review presents the argument that random mutagenesis screens are a valuable gene-finding strategy to identify genes of functional importance and that their utility, although well established for developmental issues, will extend to a variety of topics of interest to the regulatory physiologist. Particular attention is drawn to the range of functional responses amenable to mutagenesis screens in larval zebrafish. Other virtues of the organism, the range of genomic tools, the potential for innovative optical methods, and the tractability for genetic and other experimental manipulations, are also described. Finally, the review provides examples of functional studies in zebrafish, including studies in sensory neurons, cardiac rhythm disturbances, gastrointestinal function, and studies of the developing kidney, that illustrate potential applications. Because of the relative ease with which combinatorial studies can be performed, the zebrafish may eventually be particularly valuable in understanding the functional interaction between subtle gene defects that cause polygenic disorders. C1 NIDDK, KUH Div, NIH, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), NIDDK, KUH Div, NIH, Bldg 31 C,Rm 9A17,31 Ctr Dr, Bethesda, MD 20892 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 53 TC 106 Z9 108 U1 3 U2 18 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JAN PY 2002 VL 282 IS 1 BP R3 EP R9 PG 7 WC Physiology SC Physiology GA 502AW UT WOS:000172722000002 PM 11742817 ER PT J AU Miller, DS Graeff, C Droulle, L Fricker, S Fricker, G AF Miller, DS Graeff, C Droulle, L Fricker, S Fricker, G TI Xenobiotic efflux pumps in isolated fish brain capillaries SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article ID P-GLYCOPROTEIN; ENDOTHELIAL-CELLS; BARRIER; EXPRESSION; TRANSPORT; DRUGS; MICROVESSELS; PENETRATION; MICE; GENE AB To identify specific transporters that drive xenobiotics from the central nervous system to blood, the accumulation of fluorescent drugs was studied in isolated capillaries from killifish and dogfish shark brain using confocal microscopy and quantitative image analysis. In killifish brain capillaries, luminal accumulation of fluorescent derivatives of cyclosporin A and verapamil was concentrative, specific, and energy dependent (inhibition by KCN). Transport was reduced by PSC-833, but not by leukotriene C-4, indicating the involvement of P-glycoprotein. The ability of capillaries to transport the cyclosporin A derivative was unchanged over 20 h, demonstrating the long-term viability of the preparation. Luminal accumulation of the fluorescent organic anions sulforhodamine 101 and fluorescein-methotrexate was also concentrative, specific, and energy dependent. Transport of these compounds was reduced by leukotriene C-4, but not by PSC-833, indicating the involvement of a multidrug resistance-associated protein (Mrp). Similar results were obtained for isolated capillaries from dogfish shark. Immunostaining localized P-glycoprotein and Mrp2 to the luminal surface of the killifish brain capillary endothelium. These findings validate a new and long-lived comparative model for studying drug transport across the blood-brain barrier and, as in mammals, implicate P-glycoprotein and Mrp2 in transport from the central nervous system to blood in fish. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ Reims, Unite Format & Rech Pharm, F-51100 Reims, France. Inst Pharmazeut Technol & Biopharm, INF 366, D-69120 Heidelberg, Germany. Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [ES-03828] NR 21 TC 48 Z9 49 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JAN PY 2002 VL 282 IS 1 BP R191 EP R198 PG 8 WC Physiology SC Physiology GA 502AW UT WOS:000172722000023 PM 11742838 ER PT J AU Wall, SM Fischer, MP Kim, GH Nguyen, BM Hassell, KA AF Wall, SM Fischer, MP Kim, GH Nguyen, BM Hassell, KA TI In rat inner medullary collecting duct, NH4+ uptake by the Na,K-ATPase is increased during hypokalemia SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE sodium; hydrogen-adenosinetriphosphatase; terminal inner medullary collecting duct; potassium; ammonium ID NA+-K+-ATPASE; ALPHA-SUBUNIT; DISTAL COLON; BETA-SUBUNIT; CELLS; EXPRESSION; NEPHRON; LOCALIZATION; VASOPRESSIN; INHIBITION AB In rat terminal inner medullary collecting duct (tIMCD), the Na,K-ATPase mediates NH4+ uptake, which increases secretion of net H+ equivalents. K+ and NH4+ compete for a common binding site on the Na,K-ATPase. Therefore, NH4+ uptake should increase during hypokalemia because interstitial K+ concentration is reduced. We asked whether upregulation of the Na,K-ATPase during hypokalemia also increases basolateral NH4+ uptake. To induce hypokalemia, rats ate a diet with a low K+ content. In tIMCD tubules from rats given 3 days of dietary K+ restriction, Na,K-ATPase beta (1)-subunit (NK-beta (1)) protein expression increased although NK-alpha (1) protein expression and Na,K-ATPase activity were unchanged relative to K+-replete controls. However, after 7 days of K+ restriction, both NK-alpha (1) and NK-beta (1) subunit protein expression and Na,K-ATPase activity increased. The magnitude of Na,K-ATPase- mediated NH4+ uptake across the basolateral membrane (J(NH 4)(+)) was determined in tIMCD tubules perfused in vitro from rats after 3 days of a normal or a K+-restricted diet. J(NH 4)(+) was the same in tubules from rats on either diet when measured at the same extracellular K+ concentration. However, in either treatment group, increasing K+ concentration from 10 to 30 mM reduced J(NH 4)(+) >60%. In conclusion, with 3 days of K+ restriction, NH4+ uptake by Na,K-ATPase is increased in the tIMCD primarily from the reduced interstitial K+ concentration. C1 Univ Texas, Sch Med, Div Renal Dis & Hypertens, Houston, TX 77030 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Wall, SM (reprint author), Univ Texas, Sch Med, Div Renal Dis & Hypertens, 6431 Fannin,MSB 4-148, Houston, TX 77030 USA. EM susan.m.wall@uth.tmc.edu FU NIDDK NIH HHS [DK-52935] NR 47 TC 15 Z9 16 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 2002 VL 282 IS 1 BP F91 EP F102 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 500XX UT WOS:000172654900012 PM 11739117 ER PT J AU Wang, WD Kwon, TH Li, CL Frokiaer, J Knepper, MA Nielsen, S AF Wang, WD Kwon, TH Li, CL Frokiaer, J Knepper, MA Nielsen, S TI Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE countercurrent multiplication; natriuresis; sodium transport; thick ascending limb; urinary concentration mechanism ID THICK ASCENDING LIMB; K-CL COTRANSPORTER; ANTI-DIURETIC HORMONE; RENAL DISTAL TUBULE; CONCENTRATING DEFECT; PARATHYROID-HORMONE; ALTERED EXPRESSION; MOLECULAR-CLONING; NEPHRON SEGMENTS; NA+ TRANSPORTERS AB Chronic hypercalcemia (HC) is accompanied by urinary concentration defects, and functional studies indicate defects in the thick ascending limb (TAL). We hypothesize that dysregulation of renal sodium transporters may play an important role in this. Vitamin D-induced HC in rats resulted in polyuria, natriuresis, and phosphaturia. Immunoblotting revealed a marked reduction in the abundance of rat type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) in inner stripe of the outer medullary (ISOM; 36 +/-5%) and whole kidney (51 +/- 11%) in HC. Consistent with this finding, immunocytochemistry and immunoelectron microscopy demonstrated reduced BSC-1 labeling of the apical plasma membrane. Immunoblotting and immunohistochemical labeling of the K channel Kir 1.1 (ROMK) was also reduced in HC. In contrast, there were no reductions in the expression of Na/H exchanger (NHE)3 and Na,K-ATPase in ISOM. The abundance of the proximal tubule type II Na-P(i) cotransporter (NaPi-2) (but not Na,K-ATPase and NHE3) was significantly reduced (25 +/-4%), consistent with a dramatic increase in urinary phosphate excretion. In conclusion, 1) the reduced abundance of BSC-1 and ROMK in TAL is likely to play a major role in the urinary concentration defects associated with HC and 2) the reduced abundance of NaPi-2 is likely to play a role in the increased urinary phosphate excretion. C1 Aarhus Univ, Inst Anat, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Dongguk Univ, Sch Med, Dept Physiol, Kyungju 780714, South Korea. Aarhus Univ Hosp, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Inst Expt Clin Res, DK-8200 Aarhus N, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Inst Anat, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 67 TC 34 Z9 36 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2002 VL 282 IS 1 BP F34 EP F44 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 500XX UT WOS:000172654900005 PM 11739110 ER PT J AU Clark, MA Rakowski, W Ehrich, B Rimer, BK Velicer, WF Dube, CE Pearlman, DN Peterson, KK Goldstein, M AF Clark, MA Rakowski, W Ehrich, B Rimer, BK Velicer, WF Dube, CE Pearlman, DN Peterson, KK Goldstein, M TI The effect of a stage-matched and tailored intervention on repeat mammography SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT 19th Annual Meeting of the Society-for-Behavioral-Medicine CY MAR, 1998 CL NEW ORLEANS, LOUISIANA SP Soc Behav Med, MacArthur Fdn Res Network Successful Aging DE health behavior, knowledge, attitudes, practice; mammography; preventive health services; psychological theory; women's health ID SCREENING MAMMOGRAPHY; BREAST-CANCER; TRANSTHEORETICAL MODEL; BEHAVIOR-CHANGE; HEALTH-CARE; WOMEN; PHYSICIAN AB Background: Our objective was to determine whether a tailored, stage-matched educational intervention, guided by the transtheoretical model (TTM), would increase rates of repeat-screening mammography. Design Setting/Participants A total of 1324 women (N=1026 after attrition) aged 50 to 74 years were recruited from a Setting/staff-model health maintenance organization. Some of the women were not due for Participants: mammograms at the time of recruitment. Intervention: Women were randomly assigned to one of three intervention conditions: Group 1, no educational materials (usual care); Group 2, standard materials; and Group 3, stage-matched/tailored materials. Women in Groups 2 and 3 received a mailed education packet after both a baseline and a follow-up telephone interview. All women in Group 2 received the same materials regardless of differences in baseline mammography-related attitudes and behaviors. Each woman in Group 3 received materials based on her stage of adoption for mammography and TTM constructs. Main Outcome: Using clinical records, repeat screening was defined as receipt of a second mammogram within 14 months after obtaining an initial postbaseline mammogram. Results: Women in Group 3 were more likely to obtain repeat-screening mammograms than women in Group 1 (44.2% vs 35.8%; adjusted rate ratio = 1.29, 95% confidence interval [CI]=1.11-1.46; adjusted rate difference = 0.06, 95% CI=-0.01-0.13). The screening percentage in Group 2 was intermediate (39.3%), and did not differ from either Group 3 or Group 1. Conclusions: The effect of the stage-matched/tailored intervention was sustained for repeat screening, although no educational materials were delivered to coincide with the timing for a second mammogram, However, the stage-matched/tailored intervention was not sufficient to have a substantial impact on screening beyond the effect of standard educational materials. Future interventions may need to administer "booster" sessions to increase repeat screenings. C1 Brown Univ, Ctr Gerontol & Hlth Care Res, Providence, RI 02912 USA. Brown Univ, Dept Commuity Hlth, Providence, RI 02912 USA. Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Bethesda, MD USA. Duke Univ, Comprehens Canc Ctr, Durham, NC USA. Univ Rhode Isl, Canc Prevent Res Ctr, Kingston, RI USA. Univ Rhode Isl, Dept Psychol, Kingston, RI USA. Bayer Inst Hlth Care Commun, West Haven, CT USA. Miriam Hosp, Div Behav & Prevent Med, Providence, RI USA. RP Clark, MA (reprint author), Brown Univ, Ctr Gerontol & Hlth Care Res, Box G-H, Providence, RI 02912 USA. RI Pearlman, Deborah/I-4438-2014 FU NCI NIH HHS [R01-CA55917] NR 35 TC 48 Z9 48 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2002 VL 22 IS 1 BP 1 EP 7 AR PII S0749-3797(01)00406-8 DI 10.1016/S0749-3797(01)00406-8 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 528BA UT WOS:000174222500001 PM 11777672 ER PT J AU Roudebush, WE Gerald, MS Cano, JA Lussier, ID Westergaard, G Higley, JD AF Roudebush, WE Gerald, MS Cano, JA Lussier, ID Westergaard, G Higley, JD TI Relationship between platelet-activating factor concentration in rhesus monkey (Macaca mulatta) spermatozoa and sperm motility SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the American-Society-of-Primatologists CY AUG 08-11, 2001 CL ARMSTRONG ATLANTIC STATE UNIV, SAVANNAH, GEORGIA SP Amer Soc Prinatol HO ARMSTRONG ATLANTIC STATE UNIV DE rhesus macaque; spermatozoa; motility; platelet-activating factor (PAF) ID FACTOR ACETYLHYDROLASE ACTIVITY; BOVINE SEMINAL PLASMA; FACTOR RECEPTOR; RABBIT OOCYTES; FERTILIZATION; RELEASE; INVITRO; ACID; RATS AB Platelet-activating factor (PAF) is a potent signaling phospholipid that has been implicated in a number of biological activities. PAF concentration in primate spermatozoa has a positive correlation with fertility. While PAF is present in rhesus spermatozoa, there are no relational reports on its concentration and the cell's motility. The study objective was to determine if PAF concentration in rhesus spermatozoa was correlated with motility indices (percent motility and forward progression). Semen was collected from sexually mature males and cell counts, and percent motilities and forward progressions were recorded prior to PAF measurement by radioimmunoassay. Spermatozoa-derived PAF concentration ranged from a low of 0.9 picomoles/10(6) cells to a high of 13.0 picomoles/10(6) cells. The overall mean (+/-SEM) PAF concentration was 4.6 (+/-1.6) picomoles/10(6) spermatozoa. Regression analysis revealed a positive and significant relationship between PAF concentration in the spermatozoa and percent motility (R-2 = 0.914; P < 0.01) as well as forward progression (R-2 = 0.849; P < 0.05). A receiver-operator characteristic curve and the calculation of the probability that a positive forward progression will be predicted indicated a cutoff limit of 1.5 picomoles/106 cells for PAF concentration in rhesus sperm. Rhesus monkey spermatozoa motility was significantly greater (P < 0.01) in the high-PAF (2 picomoles/10(6) cells) group (31.0 +/- 7.6) than in the low-PAF (<2 picomoles/10(6) cells) group (6.8 +/- 2.1). Rhesus monkey spermatozoa forward progression was significantly greater (P < 0.05) in the high-PAF (greater than or equal to2 picomoles/10(6) cells) group (3.0 +/- 1.0) than in the low-PAF (<2 picomoles/ 10(6) cells) group (0.7 +/- 0.3). The data demonstrate that PAF concentration in rhesus spermatozoa has a significant relationship with percent motility and the cell's forward progression. Determining PAF concentration in spermatozoa may be a significant predictor of fertility in the primate. Additional studies will elucidate the role of PAF in spermatozoa function and the significance PAF plays in primate fertility. Am. J. Primatol. 56:1-7, 2002. (C) 2002 Wiley-Liss, Inc. C1 Reprod Biol Associates, Atlanta, GA 30342 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. NIAAA, NIH, Anim Ctr, Lab Clin Studies,Div Intramural Clin & Biol Res, Poolesville, MD USA. LABS Virginia Inc, Yemassee, SC USA. RP Roudebush, WE (reprint author), Reprod Biol Associates, 1150 Lake Hearn Dr,Suite 400, Atlanta, GA 30342 USA. FU NCRR NIH HHS [R24RR09983] NR 34 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD JAN PY 2002 VL 56 IS 1 BP 1 EP 7 DI 10.1002/ajp.1059 PG 7 WC Zoology SC Zoology GA 506YH UT WOS:000172999000001 PM 11793409 ER PT J AU Rotondo, A Mazzanti, C Dell'Osso, L Rucci, P Sullivan, P Bouanani, S Gonnelli, C Goldman, D Cassano, GB AF Rotondo, A Mazzanti, C Dell'Osso, L Rucci, P Sullivan, P Bouanani, S Gonnelli, C Goldman, D Cassano, GB TI Catechol O-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID LOW-ACTIVITY ALLELE; MANIC-DEPRESSIVE ILLNESS; PSYCHIATRIC-DISORDERS; ASSOCIATION ANALYSIS; I DISORDER; POPULATION; UNIPOLAR; SUSCEPTIBILITY; EXPRESSION; LIFETIME AB Objective: Genetic epidemiologic and clinical data suggest that comorbid panic disorder may define a subtype of bipolar disorder. Comorbid panic disorder might thereby influence the strength of association between bipolar disorder and genes that have been implicated in bipolar disorder on the basis of their function in monoamine neurotransmission and previously reported linkage results. Polymorphic markers at catechol O-methyltransferase (COMT), serotonin transporter (5-HTT), and tryptophan hydroxylase (TPH) genes were analyzed in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. Method: Unrelated subjects of Italian descent meeting DSM-III-R criteria for lifetime bipolar disorder (N=111), with (N=49) or without (N=62) comorbid lifetime panic disorder, were compared to 127 healthy subjects. DNA was extracted from blood leukocytes. The frequencies of COMT Val158Met, 5-HTTLPR, and TPH IVS7+21BC>A polymorphisms were determined. Genotype and allele frequency comparisons between affected (bipolar disorder, bipolar disorder without panic disorder, or bipolar disorder with panic disorder) and unaffected individuals were carried out with chi-square tests or Fisher's exact tests. Results. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT Met158 and the short 5-HTTLPR alleles and genotypes. The differences in the frequencies of the TPH IVS7+21 SA alleles and genotypes approached statistical significance, Conclusions: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders. C1 Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, I-56100 Pisa, Italy. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. RP Rotondo, A (reprint author), Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, Via Roma 67, I-56100 Pisa, Italy. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 51 TC 118 Z9 121 U1 1 U2 1 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 2002 VL 159 IS 1 BP 23 EP 29 DI 10.1176/appi.ajp.159.1.23 PG 7 WC Psychiatry SC Psychiatry GA 508FZ UT WOS:000173079200007 PM 11772685 ER PT J AU Krasuski, JS Alexander, GE Horwitz, B Rapoport, SI Schapiro, MB AF Krasuski, JS Alexander, GE Horwitz, B Rapoport, SI Schapiro, MB TI Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: Implications for the prodromal phase of Alzheimer's disease SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; MILD COGNITIVE IMPAIRMENT; HIPPOCAMPAL VOLUME; APOLIPOPROTEIN-E; BRAIN MORPHOLOGY; SENILE DEMENTIA; HEALTHY-MEN; GRAY-MATTER; MRI VOLUMES AB Objective: in Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. Method: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3,15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemi-spheres. These data were normalized to the total intracranial volume. Results: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. Conclusions: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease. C1 NIA, Neurosci Lab, Bethesda, MD 20892 USA. RP Schapiro, MB (reprint author), Childrens Hosp, Med Ctr, Div Neurol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. NR 47 TC 68 Z9 68 U1 0 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2002 VL 159 IS 1 BP 74 EP 81 DI 10.1176/appi.ajp.159.1.74 PG 8 WC Psychiatry SC Psychiatry GA 508FZ UT WOS:000173079200015 PM 11772693 ER PT J AU Fee, E Brown, TM Lazarus, J Theerman, P AF Fee, E Brown, TM Lazarus, J Theerman, P TI The tooth puller [L'arracheur de dents] SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Hist Med Div, NIH, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2002 VL 92 IS 1 BP 35 EP 35 DI 10.2105/AJPH.92.1.35 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 504VB UT WOS:000172875600013 PM 11772755 ER PT J AU Suzuki, R Freed, AN AF Suzuki, R Freed, AN TI Neparin inhibits hyperventilation-induced late-phase hyperreactivity in dogs SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE airway hyperreactivity; dry air challenge; eicosanoid mediator; heparin; hyperventilation-induced bronchoconstriction; peripheral airway resistance ID EXERCISE-INDUCED ASTHMA; BRONCHIAL EPITHELIAL-CELLS; CANINE PERIPHERAL AIRWAYS; MOLECULAR-WEIGHT HEPARIN; VASCULAR SMOOTH-MUSCLE; INDUCED BRONCHOCONSTRICTION; INHALED HEPARIN; DRY AIR; GUINEA-PIGS; RESPONSES AB Inhalation of heparin attenuates hyperventilation-induced bronchoconstriction in humans and dogs. The purpose of this study was to determine whether heparin inhibits the late-phase response to hyperventilation, which is characterized by increased peripheral airway resistance (RP), eicosanoid mediator production, neutrophilic/eosinophilic inflammation, and airway hyperreactivity (AHR) at 5 h after dry air challenge (DAC). Fiberoptic bronchoscopy was used to record RP and airway reactivity (DeltaRP) to aerosol and intravenous histamine before and 5 In after DAC. Bronchoalveolar lavage fluid (BALF) cells and eicosanoid mediators were also measured similar to 5 h after DAC. DAC of vehicle-treated bronchi resulted in late-phase air, way obstruction (similar to 120% increase over baseline RP), inflammation, increased BALF concentrations of leukotriene (LT) C-4, LTD4, and LTE4 and prostaglandin (PG)D-2, and AHR. Pretreatment with aerosolized heparin attenuated late-phase airway obstruction by 50%, inhibited eosinophil infiltration, reduced BALF concentrations of LTC4, LTD4, and LTE4 and PGD(2), and abolished AHR. We conclude that heparin inhibits hyperventilation-induced late-phase changes in peripheral airway function, and does so in part via the inhibition of eosinophil migration and eicosanoid mediator production and release. C1 Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Freed, AN (reprint author), NHLBI, Rockledge Ctr 2, Suite 7190,6701 Rockledge Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL63186, HL51930] NR 61 TC 3 Z9 5 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 1 PY 2002 VL 165 IS 1 BP 27 EP 33 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 509VY UT WOS:000173171500007 PM 11779726 ER PT J AU Cho, HY Jedlicka, AE Reddy, SPM Zhang, LY Kensler, TW Kleeberger, SR AF Cho, HY Jedlicka, AE Reddy, SPM Zhang, LY Kensler, TW Kleeberger, SR TI Linkage analysis of susceptibility to hyperoxia - Nrf2 is a candidate gene SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID ELEMENT-MEDIATED EXPRESSION; PULMONARY OXYGEN-TOXICITY; SYNTHETASE-HEAVY SUBUNIT; SPRAGUE-DAWLEY RATS; FACTOR-KAPPA-B; LUNG INJURY; SUPEROXIDE-DISMUTASE; TRANSCRIPTION FACTOR; HEME OXYGENASE-1; INDUCTION AB A strong role for reactive oxygen species (ROS) has been proposed in the pathogenesis of a number of lung diseases. Hyperoxia (> 95% oxygen) generates ROS and extensive lung damage, and has been used as a model of oxidant injury. However, the precise mechanisms of hyperoxia-induced toxicity have not been completely clarified. This study was designed to identify hyperoxia susceptibility genes in C57BL/6J (susceptible) and C3H/HeJ (resistant) mice. The quantitative phenotypes used for this analysis were pulmonary inflammatory cell influx, epithelial cell sloughing, and hyperpermeability. Genome-wide linkage analyses of intercross (F-2) and recombinant inbred cohorts identified significant and suggestive quantitative trait loci on chromosomes 2 (hyperoxia susceptibility locus 1 [Hsl1]) and 3 (Hsl2), respectively. Comparative mapping of Hsl1 identified a strong candidate gene, Nfe2/2 (nuclear factor, erythroid derived 2, like 2 or Nrf2) that encodes a transcription factor NRF2 which regulates antioxidant and phase 2 gene expression. Strain-specific variation in lung Nrf2 messenger RNA expression and a T --> C substitution in the B6 Nrf2 promoter that cosegregated with susceptibility phenotypes in F-2 animals supported Nrf2 as a candidate gene. Results from this study have important implications for understanding the mechanisms through which oxidants mediate the pathogenesis of lung disease. C1 Johns Hopkins Univ, Sch Publ Hlth, Dept Environm Hlth Sci, Div Physiol, Baltimore, MD 21205 USA. RP Kleeberger, SR (reprint author), NIEHS, Pulm Pathobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RI Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NCI NIH HHS [CA-44530]; NHLBI NIH HHS [HL-58122, HL-66109, HL-57142]; NIEHS NIH HHS [ES-03819, ES-09606] NR 58 TC 112 Z9 120 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JAN PY 2002 VL 26 IS 1 BP 42 EP 51 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 510YX UT WOS:000173236100007 PM 11751202 ER PT J AU Premkumar, A Perry, MB Dwyer, AJ Gerber, LH Johnson, D Venzon, D Shawker, TH AF Premkumar, A Perry, MB Dwyer, AJ Gerber, LH Johnson, D Venzon, D Shawker, TH TI Sonography and MR imaging of posterior tibial tendinopathy SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Roentgen-Ray-Society CY MAY, 1999 CL NEW ORLEANS, LOUISIANA SP Amer Roentgen Ray Soc ID TENDON DYSFUNCTION; ANKLE; FOOT; ULTRASONOGRAPHY; ABNORMALITIES; DIAGNOSIS; HINDFOOT AB OBJECTIVE. The purpose of the study is to describe the appearance of the posterior tibialis tendon on MR imaging and high-resolution sonography with color and power Doppler a and to determine whether sonography is as accurate for diagnosing tendinosis as MR imaging. SUBJECTS AND METHODS. Fifteen healthy volunteers and 31 patients (44 tendons) who were clinically suspected of having posterior tibial tendinopathy were prospectively evaluated with MR imaging and sonography. RESULTS. On MR imaging, the normal tendon was elliptic on cross section and showed low signal intensity on all sequences. Minimal peritendinous enhancement and fluid were seen. On sonography, the tendon showed homogeneous longitudinal echogenic fibers. No flow was seen in or around the tendon. Tendinopathy was characterized by enhancement of the tendon on MR imaging (19/44 tendons); intratendinous flow on color Doppler sonography (16/44 tendons); increase in the anteroposterior diameter causing a rounding of the tendon (18/44 tendons); and inhomogeneity of the tendon (16/44 tendons on MR imaging and 21/44 tendons on sonography). Periterdinosis was characterized by peritendinous enhancement on MR imaging (29/44 tendons); flow on color Doppler sonography (20/44 tendons); and increased soft tissue (20/44 tendons on MR imaging and 27/44 tendons on sonography). When compared with MR imaging, the sensitivity and specificity of sonography for diagnosing tendinopathy were 80% and 90%, respectively, and for diagnosing peritendinosis were 90% and 80%. Addition of abnormal size to the structural abnormality criteria did not improve diagnostic ability. CONCLUSION. Sonography can be useful as the initial imaging study in evaluating abnormalities caused by posterior tibial tendinopathy. C1 NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. NCI, Div Biostat, NIH, Bethesda, MD 20892 USA. RP Premkumar, A (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bldg 10,Rm 1C660,10 Center Dr,MSC 1182, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 27 TC 43 Z9 45 U1 1 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JAN PY 2002 VL 178 IS 1 BP 223 EP 232 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 505QW UT WOS:000172927900042 PM 11756125 ER PT J AU Tao, JG Shelat, SG Jaffe, ES Bagg, A AF Tao, JG Shelat, SG Jaffe, ES Bagg, A TI Aggressive Epstein-Barr virus-associated, CD8+, CD30+, CD56+, surface CD3-, natural killer (NK)- like cytotoxic T-Cell lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE EBV; CD30; natural killer cell; NKT cell; NK1.1; lymphoma ID FETAL NK CELLS; LYMPHOCYTES-T; DIFFERENTIATION; EXPRESSION; LEUKEMIAS; PROTEINS; ANTIGEN; ENTITY; ORIGIN; LOCUS AB We report an unusual case of aggressive natural killer (NK)-like cytotoxic T-cell lymphoma in a previously healthy immunocompetent West African male. He presented with a fever of unknown origin, subsequently developed erythematous skin nodules, generalized lymphadenopathy, and hepatosplenomegaly, and then died of multiple organ failure. A skin nodule and lymph node biopsy showed an infiltrate of pleomorphic atypical medium and large lymphoid cells with extensive necrosis and prominent apoptosis. Peripheral blood and ascites also harbored these cells, with cytology revealing irregular nuclear folding and basophilic cytoplasm, and some with azurophilic cytoplasmic granules. Flow cytometry and immunohistochemistry demonstrated the expression of CD2, CD7. CD8. CD30, CD56, and cytoplasmic but not surface CD3. In situ hybridization demonstrated Epstein-Barr virus transcripts. A monoclonal T-cell receptor gamma chain gene rearrangement was detected by polymerase chain reaction. This is the first reported case of an NK-like T-cell lymphoma with these unusual features, making precise classification difficult. Some features suggest an NK1.1 or NKT lymphocyte origin. Because the earliest clinical manifestation was splenomegaly and abnormal liver function, the normal cellular counterpart may be a distinct subset of NK1.1 cells normally present in hepatosplenic sinusoids. This tumor disseminated early and pursued a fulminant clinical course, thus emphasizing the importance of early recognition and diagnosis. C1 Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Bagg, A (reprint author), Hosp Univ Penn, Dept Pathol & Lab Med, 3400 Spruce St,7-103 Founders Pavil, Philadelphia, PA 19104 USA. NR 38 TC 15 Z9 16 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JAN PY 2002 VL 26 IS 1 BP 111 EP 118 DI 10.1097/00000478-200201000-00015 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 508PL UT WOS:000173097600015 PM 11756778 ER PT J AU Swanson, SJ Hypolite, IO Agodoa, LYC Batty, DS Hshieh, PB Cruess, D Kirk, AD Peters, TG Abbott, KC AF Swanson, SJ Hypolite, IO Agodoa, LYC Batty, DS Hshieh, PB Cruess, D Kirk, AD Peters, TG Abbott, KC TI Effect of donor factors on early graft survival in adult cadaveric renal transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE African American donor; body mass index; cadaveric renal transplantation; donor death; donor/recipient weight ratio; graft survival ID ALLOGRAFT SURVIVAL; AFRICAN-AMERICANS; SERUM CREATININE; RECIPIENTS; TERM; AGE; DISEASE; KIDNEYS; HYPERTENSION; DYSFUNCTION AB Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from I July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/ recipient age ratio ( greater than or equal to 1.10, e.g. a 55-year-old donor given to a recipient age 50 years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (Cl) 2.36-4.39) and African American donor kidneys (AHR 1.64, 95% Cl, 1.24-2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. NIH, Organ Transplant Serv, Bethesda, MD 20892 USA. NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Jacksonville Transplant Ctr Shands, Jacksonville, FL USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. RI Kirk, Allan/B-6905-2012; OI Abbott, Kevin/0000-0003-2111-7112 NR 52 TC 54 Z9 55 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2002 VL 2 IS 1 BP 68 EP 75 DI 10.1034/j.1600-6143.2002.020112.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 534AA UT WOS:000174561400011 PM 12095059 ER PT B AU Bodenreider, O Mitchell, JA McCray, AT AF Bodenreider, O Mitchell, JA McCray, AT BE Kohane, IS TI Evaluation of the UMLS as a terminology and knowledge resource for biomedical informatics SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB Objectives: Terminology and knowledge resources are essential components of interoperability among disparate systems. This paper evaluates whether names and relationships needed in biomedical informatics are present in the UMLS. Methods: Terms for five broad categories of concepts were extracted from LocusLink and mapped to the UMLS Metathesausus. Relationships between gene products and the other four categories (phenotype, molecular function, biological process, and cellular component) were searched for in the Metathesaurus. All gene products in the Gene Ontology database were also mapped to the UMLS in order to evaluate its global coverage of the domain. Results: The coverage of concepts ranged from 2% (gene product symbols) to 44% (molecular functions). The coverage of relationships ranged from 60% for Gene product Biological process to 83% for Gene product Molecular function. Discussion: Terminology and ontology issues are discussed, as well as the need for integrating additional resources to the UMLS. C1 Natl Lib Med, Bethesda, MD USA. RP Bodenreider, O (reprint author), Natl Lib Med, Bethesda, MD USA. NR 7 TC 2 Z9 2 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 61 EP 65 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100013 ER PT B AU Kim, W Wilbur, WJ AF Kim, W Wilbur, WJ BE Kohane, IS TI DNA splice site detection: A comparison of specific and general methods SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc ID PROTEIN-CODING REGIONS; PREDICTION; IDENTIFICATION; SEQUENCES AB In an era when whole organism genomes are being routinely sequenced, the problem of gene finding has become a key issue on the road to understanding. For eukaryotic organisms a large part of locating the genes is accomplished by predicting the likely location of splice sites on a DNA strand This problem of splice site location has been approached using a number of machine learning or statistical methods tailored more or less specifically to the nature of the problem. Recently large margin classifiers and boosting methods have been found to give improvements over more traditional methods in a number of areas. Here we compare large margin classifiers (SVM and CMLS) and boosted decision trees with the three most common models used for splice site detection (WMM, WAM, and MDT). We find that the newer methods compare favorably in all cases and can yield significant improvement in some cases. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Kim, W (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 33 TC 1 Z9 1 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 390 EP 394 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100079 ER PT B AU McCray, AT Browne, AC Bodenreider, O AF McCray, AT Browne, AC Bodenreider, O BE Kohane, IS TI The lexical properties of the Gene Ontology (GO) SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc ID KNOWLEDGE AB The Gene Ontology (GO) is a construct developed for the purpose of annotating molecular information about genes and their products. The ontology is a shared resource developed by the GO Consortium, a group of scientists who work on a variety of model organisms. In this paper we investigate the nature of the strings found in the Gene Ontology and evaluate them for their usefulness in natural language processing (NLP). We extend previous work that identified a set of properties that reliably identifies natural language phrases in the Unified Medical Language System (UMLS). The results indicate that a large percentage (79%) of GO terms are potentially useful for NLP applications. Some 35% of the GO terms were found in a corpus derived from the MEDLINE bibliographic database, and 27% of the terms were found in the current edition of the UMLS. C1 Natl Lib Med, Bethesda, MD 20209 USA. RP McCray, AT (reprint author), Natl Lib Med, Bethesda, MD 20209 USA. NR 11 TC 2 Z9 2 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 504 EP 508 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100102 ER PT B AU Nelson, SJ Brown, SH Erlbaum, MS Olson, N Powell, T Carlsen, B Carter, J Tuttle, MS Hole, WT AF Nelson, SJ Brown, SH Erlbaum, MS Olson, N Powell, T Carlsen, B Carter, J Tuttle, MS Hole, WT BE Kohane, IS TI A semantic normal form for clinical drugs in the UMLS: Early experiences with the VANDF SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB A semantic normal form (SNF) for a clinical drug, designed to represent the meaning of an expression typically seen in a practitioner's medication order, has been developed and is being created in the UMLS Metathesaurus. The long term goal is to establish a relationship for every concept in the Metathesaurus with semantic type "clinical drug" with one or more of these semantic normal forms. First steps have been taken using the Veterans Administration National Drug File (VANDF). 70% of the entries in the VANDF could be parsed algorithmically into the SNF. Next steps include parsing other drug vocabularies included in the UMLS Metathesaurus and performing human review of the parsed vocabularies. After machine Parsed forms have been merged in the Metathesaurus Information Database (MID), editors will be able to edit matched SNFs for accuracy and establish relationships and relationship attributes with other clinical drug concepts. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Nelson, SJ (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 5 TC 3 Z9 4 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 557 EP 561 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100113 ER PT B AU Powell, T Srinivasan, S Nelson, SJ Hole, WT Roth, L Olenichev, V AF Powell, T Srinivasan, S Nelson, SJ Hole, WT Roth, L Olenichev, V BE Kohane, IS TI Tracking meaning over time in the UMLS (R) Metathesaurus (R) SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc ID CONTROLLED MEDICAL VOCABULARIES AB The Unified Medical Language SystemS (UMLS) Metathesaurus contains records arranged by concept or meaning. Each concept contains a unique identifier (CUI) that can be used to track the concept over time. Since the January 2001 release, the Metathesaurus has included the file MRCUI that contains mappings for CUIs that disappear. This paper describes the processes that facilitated this effort and the ongoing effort to find suitable mappings for concepts whose meanings no longer exist in the Metathesaurus. This study highlights the need to identify missed synonymy prior to a release. It also shows a need to work more closely with source providers to identify the closest match in the Metathesaurus when they eliminate terms from their vocabularies. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Powell, T (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 622 EP 626 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100126 ER PT B AU Spaeder, JA AF Spaeder, JA BE Kohane, IS TI Pilot study optimizing MEDLINE queries in an automated disease management telemedicine system SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc ID CONGESTIVE-HEART-FAILURE; RANDOMIZED TRIAL; READMISSION; CARE AB Clinicians encounter many medical questions while providing outpatient medical care. A significant number of these questions can be answered using MEDLINE; however it has proven to be difficult to incorporate MEDLINE into routine clinical workflow and for clinicians to generate well constructed MEDLINE queries. This study however hypothesized that that well-constructed MEDLINE queries could be semi-automatically generated by an application named LitButton which was incorporated into the TeleWatch telemedicine system. The LitButton application was then prospectively evaluated in a pilot study by four nurse case managers (NCM) who monitored sixty-eight outpatients for three weeks. During this period the NCMs used the LitButton application sixteen times, and they subjectively reported in real-time that they obtained an answer in 56% of the cases, but that none of the successful information retrieval events resulted in a change in a patient's clinical management. The small number of LitButton events and lack of clinical impact was likely due to the fact that the LitButton function was designed to search MEDLINE for treatment related information; however the NCMs had limited medical decision making responsibilities. As a result there was a mismatch between the user's information needs and the system capabilities. C1 Natl Lib Med, Bethesda, MD 20209 USA. RP Spaeder, JA (reprint author), Natl Lib Med, Bethesda, MD 20209 USA. NR 15 TC 0 Z9 0 U1 0 U2 2 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 717 EP 721 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100145 ER PT B AU Srinivasan, S Rindflesch, TC Hole, WT Aronson, AR Mork, JG AF Srinivasan, S Rindflesch, TC Hole, WT Aronson, AR Mork, JG BE Kohane, IS TI Finding UMLS Metathesaurus concepts in MEDLINE SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB The entire collection of about 11.5 million MEDLINE abstracts was processed to extract 549 million noun phrases using a shallow syntactic parser. English language strings in the 2002 and 2001 releases of the UMLS Metathesaurus were then matched against these phrases using flexible matching techniques. 34% of the Metathesaurus names occurring in 30% of the concepts were found in the titles and abstracts of articles in the literature. The matching concepts are fairly evenly chemical and non-chemical in nature and span a wide spectrum of semantic types. This paper details the approach taken and the results of the analysis. C1 Natl Lib Med, Bethesda, MD 20209 USA. RP Srinivasan, S (reprint author), Natl Lib Med, Bethesda, MD 20209 USA. NR 11 TC 3 Z9 3 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 727 EP 731 PG 5 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100147 ER PT B AU Bodenreider, O AF Bodenreider, O BE Kohane, IS TI GenNav: Visualizing gene ontology as a graph SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc C1 Natl Lib Med, Bethesda, MD 20209 USA. RP Bodenreider, O (reprint author), Natl Lib Med, Bethesda, MD 20209 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 978 EP 978 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100212 ER PT B AU Locatis, C Fontelo, P Ackerman, M Sneiderman, C AF Locatis, C Fontelo, P Ackerman, M Sneiderman, C BE Kohane, IS TI Feasibility studies in IP videoconferencing, streaming, and wireless communication SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB Two feasibility studies were undertaken to determine how to use video streaming with other technologies over IP. One involved wireless technology to stream video live from the 2001 AMIA Symposium in Washington, DC The other involved simultaneously webcasting a multipoint videoconference to a viewing audience that could communicate with the conference panelist using chat. The results of these tests are reported along with recommendations for further experiments. The outcomes have implications for the use of broadband synchronous communication in distance learning. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Locatis, C (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1090 EP 1090 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100324 ER PT B AU Mitchell, JA McCray, AT Bodenreider, O AF Mitchell, JA McCray, AT Bodenreider, O BE Kohane, IS TI From phenotype to genotype: Experiences in navigating the available information resources SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB As part of an investigation of connecting health professionals and the lay public to both the disease and genomic information, we assessed the availability and nature of the data from the Human Genome Project relating to human genetic diseases. We focused on a set of single gene diseases selected from main topics in MEDLINEplus. We used publicly available websites to investigate specific questions about the genes and gene products associated with the diseases. We also investigated questions of knowledge and data representation for the information resources and navigational issues. We assessed the major challenges encountered when navigating from phenotype to genotype. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Mitchell, JA (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1109 EP 1109 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100343 ER PT B AU Shah, H Thoma, GR AF Shah, H Thoma, GR BE Kohane, IS TI A software tool for editing and executing knowledge component based clinical guidelines SO AMIA 2002 SYMPOSIUM, PROCEEDINGS: BIOMEDICAL INFORMATICS: ONE DISCIPLINE LA English DT Proceedings Paper CT Annual Symposium of the American-Medical-Informatics-Association CY NOV 09, 2002 CL San Antonio, TX SP Amer Med Informat Assoc AB Ease of editability and reuse of executable knowledge components are among the key features in the Proteus model for clinical guidelines, where these are composed of modular knowledge components representing clinical activities. To validate the Proteus approach, we have developed software tools such as Protean, which demonstrates how a guideline created in the Proteus format can be authored and executed It also demonstrates how pre-created knowledge can be reused While executing, the data entered and decisions taken are stored in the electronic medical record of the patient. C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Shah, H (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 PU HANLEY & BELFUS INC MED PUBLISHERS PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA BN 1-56053-600-4 PY 2002 BP 1161 EP 1161 PG 1 WC Computer Science, Information Systems; Medical Informatics SC Computer Science; Medical Informatics GA BY60A UT WOS:000189418100394 ER PT J AU Zhu, D Lipsky, RH Marini, AM AF Zhu, D Lipsky, RH Marini, AM TI Co-activation of the phosphatidylinositol-3-kinase/Akt signaling pathway by N-methyl-D-aspartate and TrkB receptors in cerebellar granule cell neurons SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 7th International Congress on Amino Acids and proteins CY AUG 06-10, 2001 CL VIENNA, AUSTRIA DE N-methyl-D-aspartate; brain-derived neurotrophic factor; rat cerebellar granule cells; phosphatidylinositol 3-kinase/Akt; TrkB receptor; neuroprotection ID NERVE GROWTH-FACTOR; FACTOR-KAPPA-B; NEUROTROPHIC FACTOR; MEDIATED NEUROPROTECTION; FACTOR FAMILY; SURVIVAL; GLUTAMATE; 3-KINASE; AKT; NEUROTOXICITY AB Neuroprotective concentrations of N-methyl-D-aspartate (NMDA) promote survival of cerebellar granule cell neurons against glutamate excitotoxicity through a TrkB receptor-mediated brain-derived neurotrophic factor (BDNF) autocrine loop. However, the intracellular signaling pathway(s) are not clear. Our results show that PI-3 kinase/Akt is activated by either NMDA or BDNF displaying differential kinetics. BDNF and NMDA increased Akt phosphorylation within 5 minutes but maximal activation NMDA was observed at 3 hours. Akt phosphorylation was completely blocked by the PI-3 kinase inhibitor LY294002. NMDA-mediated activation of Akt was completely blocked by MK-801 and partially blocked by the TrkB receptor inhibitor, K252a, indicating the requirement of TrkB receptors for maximal activation by NMDA. In contrast, BDNF-induced Akt phosphorylation was abolished by K252a, but not by the addition of MK-801. Therefore, the PI-3 kinase/Akt pathway is co-activated by NMDA and TrkB receptors. The kinetics of BDNF and NMDA-mediated activation of PI-3 kinase/Akt suggests that they have different roles in intraneuronal time-related events. C1 Uniformed Serv Univ Hlth Sci, Dept Neurol & Neurosci, Bethesda, MD 20814 USA. NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Marini, AM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. OI Lipsky, Robert/0000-0001-7753-1473 NR 39 TC 30 Z9 31 U1 0 U2 0 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 2002 VL 23 IS 1-3 BP 11 EP 17 DI 10.1007/s00726-001-0103-9 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 600VJ UT WOS:000178412200003 PM 12373512 ER PT J AU Oh, JD Chase, TN AF Oh, JD Chase, TN TI Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson's disease SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 7th International Congress on Amino Acids and proteins CY AUG 06-10, 2001 CL VIENNA, AUSTRIA DE NMDA receptor; AMPA receptor; medium spiny neuron; phosphorylation; signal transduction ID LEVODOPA-INDUCED DYSKINESIAS; NMDA RECEPTOR SUBUNITS; MPTP-TREATED MONKEYS; DOPA-INDUCED DYSKINESIAS; CENTRAL-NERVOUS-SYSTEM; MESSENGER-RNA; TYROSINE PHOSPHORYLATION; RAT STRIATUM; DOPAMINERGIC DENERVATION; GENE-EXPRESSION AB Chronically administered levodopa to Parkinson's disease (PD) patients ultimately produces alterations in motor response. Similarly, in 6-hydroxydopamine lesioned hemi-parkinsonian rats, chronic twice-daily administration of levodopa progressively shortens the duration of contralateral turning, an index of, the wearing-off fluctuations that occur in parkinsonian patients. The pathogenesis of these response alterations involves, in part, upregulation of corticostriatal glutamatergic synaptic transmission. Changes involving kinase and phosphatase signaling pathways within striatal dopaminoceptive medium-spiny neurons now appear to contribute to increased synaptic efficacy of glutamatergic receptors in these neurons. Glutamate-mediated striatal sensitization subsequently modifies basal ganglia output in ways that favor the appearance of parkinsonian motor complications. At the molecular level, transcriptional activation of striatal CREB and cdk5 may contribute to the persistent expression of these levodopa-induced response alterations. Conceivably, a safer and more effective therapy for PD can be provided by drugs that target signaling proteins within striatal spiny neurons or those that interact extracellularly with non-dopaminergic receptors such as AMPA and NMDA, adenosine, adrenergic, opioid, and serotonergic. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Cent Michigan Univ, Dept Psychol, Mt Pleasant, MI 48859 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. NR 98 TC 44 Z9 52 U1 1 U2 1 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 2002 VL 23 IS 1-3 BP 133 EP 139 DI 10.1007/s00726-001-0118-2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 600VJ UT WOS:000178412200018 PM 12373527 ER PT J AU Levine, KE Fernando, RA Ross, GT Lang, M Morgan, DL Collins, BJ AF Levine, KE Fernando, RA Ross, GT Lang, M Morgan, DL Collins, BJ TI Development and validation of a method for the determination of mercury in small rat brain tissue samples by cold vapor atomic fluorescence spectrometry SO ANALYTICAL LETTERS LA English DT Article DE mercury; cold vapor atomic fluorescence spectrometry; brain tissue; neonatal brain; fetal brain; small sample size ID GUINEA-PIGS; LONG-TERM; EXPOSURE; METHYLMERCURY; CHLORIDE; PLASMA; LEVEL AB A rugged, sensitive, semi-automated method for the determination of trace-level mercury in small rat brain tissue samples by cold vapor atomic fluorescence spectrometry (CVAFS) is described. Small tissue aliquots (100 mg) are digested for 6-8 h at an elevated temperature in a mixture of nitric and sulfuric acids. Following digestion, samples are oxidized with potassium bromate/bromide at room temperature and treated with a continuous flow of stannous chloride to generate mercury vapor. The experimentally determined method quantitation limit (MQL) in the rat brain matrix is 10 pg Hg/mL, which corresponds to 1.5 ng Hg/g brain tissue. Replicate matrix spike preparations (n=4) at this level were determined with a high level of accuracy (89.8%) and precision (6.9% RSD). Replicates (n=36) of a certified reference material (DOLT-2, trace metals in dogfish liver) were prepared and analyzed over a four year period in order to assess the ruggedness and accuracy of the method. The average recovery for mercury in this material was 99.9% of the certified level. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Levine, KE (reprint author), Res Triangle Inst, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. NR 23 TC 8 Z9 8 U1 0 U2 4 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0003-2719 J9 ANAL LETT JI Anal. Lett. PY 2002 VL 35 IS 9 BP 1505 EP 1517 DI 10.1081/AL-120006726 PG 13 WC Chemistry, Analytical SC Chemistry GA 588TL UT WOS:000177716700005 ER PT J AU Hendee, WR Chien, S Maynard, CD Dean, DJ AF Hendee, WR Chien, S Maynard, CD Dean, DJ TI The National Institute of Biomedical Imaging and Bioengineering: History, status, and potential impact SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE biomedical engineering; biomedical imaging; bioinformatics AB This paper describes the history, current status, and objectives and potential impact of the new National Institute of Biomedical Imaging and Bioengineering (NIBIB). Three of the authors (Hendee, Chien, and Maynard) have been involved over several years in the effort to raise the identity of biomedical imaging and bioengineering at the National Institutes of Health. The fourth author (Dean) is the Acting Director of the newly formed NIBIB. These individuals have an extensive collective knowledge of the events that led to formation of the NIBIB, and are intimately involved in shaping its objectives and implementation strategy. This special report provides a historical record of activities leading to establishment of the NIBIB, and an accounting of present and potential advances in biomedical engineering and imaging that will be facilitated and enhanced by NIBIB. The National Institute of Biomedical Imaging and Bioengineering represents a "coming of age" of biomedical engineering and imaging, and offers great potential to expand the research frontiers of these disciplines to unparalleled heights. (C) 2002 Biomedical Engineering Society. C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Calif San Diego, Whitaker Inst Biomed Engn, San Diego, CA 92103 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Hendee, WR (reprint author), Med Coll Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. NR 10 TC 8 Z9 8 U1 1 U2 4 PU BIOMEDICAL ENGINEERING SOC AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD JAN PY 2002 VL 30 IS 1 BP 2 EP 10 DI 10.1114/1.1433491 PG 9 WC Engineering, Biomedical SC Engineering GA 523FF UT WOS:000173942800001 PM 11874139 ER PT J AU Hoppin, JA Tolbert, PE Taylor, JA Schroeder, JC Holly, EA AF Hoppin, JA Tolbert, PE Taylor, JA Schroeder, JC Holly, EA TI Potential for selection bias with tumor tissue retrieval in molecular epidemiology studies SO ANNALS OF EPIDEMIOLOGY LA English DT Editorial Material DE molecular epidemiology; selection bias; tumor tissue AB Molecular epidemiological studies of cancer generally require tumor tissue to evaluate somatic genetic alterations. Frequently this requires retrieval of fixed tissue blocks from hospital pathology archives. The availability of this material may be associated with disease severity, diagnostic practices, hospitals, or risk factors for disease. Tumor material is not available when the diagnosis is made clinically without histological confirmation, These characteristics create difficulties in defining the study base population. Incomplete access to tumor tissue has implications for description of the natural history of disease, estimates of the prevalence of mutation in the population, and evaluation of environmental exposures and critical target gene mutations. Differential diagnostic practices by age groups or across hospitals may create a biased population with respect to potential risk factors. However, this will not bias case-case comparisons unless the mutation of interest is associated both with the exposure of interest and the presence of a tumor block. VA-ten subjects with less severe disease are more likely to have biopsies, information regarding the natural history of the disease will be obscured. Investigation of the interaction of environmental agents and critical target gene mutations may be limited if, for example, an environmental agent is associated with a more aggressive form of the disease. Using an ongoing pancreatic cancer case-control study as an example, we discuss the potential for bias associated with differential availability of tumor blocks including consideration of tumor, patient, and hospital characteristics. Due to incomplete retrieval of tissue, the determinants of selection should be described in all studies using tumor tissue, and the implications for generalizability, power, and interpretation of findings in population-based studies should be considered. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. RI Tolbert, Paige/A-5676-2015; OI taylor, jack/0000-0001-5303-6398 NR 9 TC 42 Z9 42 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JAN PY 2002 VL 12 IS 1 BP 1 EP 6 DI 10.1016/S1047-2797(01)00250-2 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 507DT UT WOS:000173012300001 PM 11750233 ER PT J AU McGriff, NJ Csako, G Gourgiotis, L Guthrie, LC Pucino, F Sarlis, NJ AF McGriff, NJ Csako, G Gourgiotis, L Guthrie, LC Pucino, F Sarlis, NJ TI Effects of thyroid hormone suppression therapy on aciverse clinical outcomes in thyroia cancer SO ANNALS OF MEDICINE LA English DT Article DE levothyroxine; meta-analysis; outcome; progression; suppression; survival; thyroid cancer; thyroid hormone ID LONG-TERM MANAGEMENT; TSH RECEPTOR GENE; THYROTROPIN SUPPRESSION; FOLLOW-UP; PAPILLARY CARCINOMA; PROGNOSTIC FACTORS; MEDICAL THERAPY; IMPACT; DISEASE; GROWTH AB BACKGROUND. Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role - if any - of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear. AIM: Evaluation of the effect of THST on the clinical outcomes of papillary and/or follicular ThyrCa. METHODS. By using a quantitative research synthesis approach in a cumulative ThyrCa cohort, we evaluated the effect of THST on the likelihood of major adverse clinical events (disease progression/recurrence and death). A total of 28 clinical trials published during the period 1934-2001 were identified; only 10 were amenable to meta-analysis. Causality was assessed by Hill criteria. RESULTS: Out of 4,174 patients with ThyrCa, 2, 880 (69%) were reported as being on THST. Meta-analysis showed that the group of patients who received THST had a decreased risk of major adverse clinical events (RR = 0.73; Cl = 0.60-0.88; P less than or equal to 0.05). Further, by applying a Likert scale, 15/17 interpretable studies showed either a 'likely' or 'questionable' beneficial effect of THST. Assessment of causality between TSHT and reduction of major adverse clinical events suggested a probable association. CONCLUSIONS: THST appears justified in ThyrCa patients following initial therapy. As most primary studies were imperfect, future research will better define the effect of THST upon ThyrCa clinical outcomes. C1 NIDDKD, Div Intramural Res, NIH, Bethesda, MD 20892 USA. NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. RP Sarlis, NJ (reprint author), NIDDK, DIR, NIH, Bldg 10,Room 8D12C,10 Ctr Dr,MSC 1758, Bethesda, MD 20892 USA. NR 74 TC 87 Z9 94 U1 1 U2 5 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1M 8AE, ENGLAND SN 0785-3890 J9 ANN MED JI Ann. Med. PY 2002 VL 34 IS 7-8 BP 554 EP 564 DI 10.1080/078538902321117760 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 637UK UT WOS:000180532000008 PM 12553495 ER PT J AU Gwinn-Hardy, K Farrer, M AF Gwinn-Hardy, K Farrer, M TI Parkinson's genetics: An embarrassment of riches SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID ALPHA-SYNUCLEIN; DISEASE; ONSET; SUSCEPTIBILITY; MUTATIONS; FAMILIES; UBIQUITINATION; LOCUS C1 NINCDS, NIH, Bethesda, MD 20892 USA. Mayo Clin Jacksonville, Neurogenet Lab, Jacksonville, FL 32224 USA. RP Gwinn-Hardy, K (reprint author), NINCDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 23 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2002 VL 51 IS 1 BP 7 EP 8 DI 10.1002/ana.10091 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508JK UT WOS:000173084800001 PM 11782975 ER PT J AU Butefisch, CM Davis, BC Sawaki, L Waldvogel, D Classen, J Kopylev, L Cohen, LG AF Butefisch, CM Davis, BC Sawaki, L Waldvogel, D Classen, J Kopylev, L Cohen, LG TI Modulation of use-dependent plasticity by D-amphetamine SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; MOTOR CORTEX EXCITABILITY; LONG-TERM POTENTIATION; CORTICAL INJURY; LOCUS-COERULEUS; RECOVERY; RAT; MECHANISMS; DEPRESSION; APHASIA AB Use-dependent plasticity, thought to contribute to functional recovery after bra-in injury, is elicited by motor training. The purpose of this study was to determine if administration of d-amphetamine facilitates the effects of motor training on use-dependent plasticity. Healthy human volunteers underwent a training period of voluntary thumb movements under the effects of placebo or d-amphetamine in different sessions in a randomized double-blind, counterbalanced design. Previous work in a drug-naive condition showed that such training causes changes in the direction of thumb movements evoked by transcranial magnetic stimulation and in transcranial magnetic stimulation-evoked electromyographic responses. The endpoint measure of the study was the magnitude of training-induced changes in transcranial magnetic stimulation-evoked kinematic and electromyographic responses in the d-amphetamine and in the placebo conditions. Motor training resulted in increased magnitude, faster development and longer lasting duration of use-dependent plasticity under d-amphetamine compared to the placebo session. These results document a facilitatory effect of d-amphetamine on use-dependent plasticity, a possible mechanism mediating the beneficial effect of this drug on functional recovery after cortical lesions. C1 NINCDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Rostock, Dept Neurol, Rostock, Germany. NINCDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINCDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N234, Bethesda, MD 20892 USA. NR 43 TC 126 Z9 127 U1 1 U2 8 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2002 VL 51 IS 1 BP 59 EP 68 DI 10.1002/ana.10056 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508JK UT WOS:000173084800010 PM 11782985 ER PT J AU Levy, LM Hallett, M AF Levy, LM Hallett, M TI Impaired brain GABA in focal dystonia SO ANNALS OF NEUROLOGY LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; GAMMA-AMINOBUTYRIC-ACID; POSITRON-EMISSION-TOMOGRAPHY; PRIMARY SOMATOSENSORY CORTEX; REPETITIVE STRAIN INJURY; MUTANT HAMSTER MODEL; H-1 MR SPECTROSCOPY; WRITERS CRAMP; NMR-SPECTROSCOPY; BASAL GANGLIA AB Patients with task-specific dystonia (writer's cramp) have impaired cortical inhibition likely arising from striatal dysfunction. However, the levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brains of these patients are not known. In this study, we evaluated 7 patients with right-sided focal, task-specific dystonia and 17 normal control subjects. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy revealed that brain GABA levels are decreased in specific brain regions of the focal dystonia patients compared to normal controls. A significant decrease in GABA level was observed in the sensorimotor cortex and lentiform nuclei contralateral to the affected hand, while there was only a small nonsignificant decrease in the ipsilateral sensorimotor cortex and lentiform nuclei. GABA changes in the posterior occipital region of patients were not significant. The impaired cortical GABA level correlates with prior physiologic studies showing reduced intracortical inhibition. Reduced GABA in the striatum is consistent with striatal dysfunction since GABA is a principal neurotransmitter in that region. The reduction of brain GABA in dystonia patients may explain the clinical symptomatology of focal dystonia. Magnetic resonance spectroscopy may be a useful noninvasive tool in the evaluation of regional brain GABA changes and in monitoring the effects of various therapies. C1 NINCDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. NINCDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Levy, LM (reprint author), NINCDS, Neuroimaging Branch, NIH, Bldg 10,5D20, Bethesda, MD 20892 USA. NR 88 TC 112 Z9 117 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2002 VL 51 IS 1 BP 93 EP 101 DI 10.1002/ana.10073 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508JK UT WOS:000173084800013 PM 11782988 ER PT J AU Conforto, AB Kaelin-Lang, A Cohen, LG AF Conforto, AB Kaelin-Lang, A Cohen, LG TI Increase in hand muscle strength of stroke patients after somatosensory stimulation SO ANNALS OF NEUROLOGY LA English DT Article ID PERIPHERAL-NERVE STIMULATION; MAGNETIC STIMULATION; MOTOR CORTEX; PLASTICITY; EXTENSION; WRIST; MAPS AB It has been proposed that somatosensory input in the form of peripheral nerve stimulation can influence functional measures of motor performance. We studied the effects of median nerve stimulation on pinch muscle strength (a function mediated predominantly by median nerve innervated muscles) in the affected hand of chronic stroke patients. A 2-hour period of median nerve stimulation elicited an increase in pinch strength that outlasted the stimulation period. The improvement in muscle strength correlated with stimulus intensity and was identified in the absence of motor training. These results suggest that somatosensory stimulation may be a promising adjuvant to rehabilitation of the motor deficits in stroke patients. C1 NINCDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINCDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N23,10 Ctr Dr,MSC 1430, Bethesda, MD 20892 USA. NR 13 TC 142 Z9 150 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 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JAN PY 2002 VL 51 IS 1 BP 122 EP 125 DI 10.1002/ana.10070 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 508JK UT WOS:000173084800017 PM 11782992 ER PT J AU Rudiger, T Gascoyne, RD Jaffe, ES de Jong, D Delabie, J De Wolf-Peeters, C Poppema, S Xerri, L Gisselbrecht, C Wiedenmann, S Muller-Hermelink, HK AF Rudiger, T Gascoyne, RD Jaffe, ES de Jong, D Delabie, J De Wolf-Peeters, C Poppema, S Xerri, L Gisselbrecht, C Wiedenmann, S Muller-Hermelink, HK TI Workshop on the relationship between nodular lymphocyte predominant Hodgkin's lymphoma and T cell/histiocyte-rich B cell lymphoma SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 5th International Symposium on Hodgkins Lymphoma CY SEP 22-25, 2001 CL COLOGNE, GERMANY ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; EUROPEAN TASK-FORCE; DISEASE; ADOLESCENCE; SURVIVORS; PROJECT C1 Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. NCI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Netherlands Canc Inst, Amsterdam, Netherlands. Norwegian Radium Hosp, Oslo, Norway. Inst Canc Res, Oslo, Norway. Univ Ziekenhuizen Leuven, Louvain, Belgium. Univ Groningen Hosp, Groningen, Netherlands. Inst J Paoli I Calmettes, F-13009 Marseille, France. Hop St Louis, Paris, France. Univ Cologne, Clin Internal Med 1, Cologne, Germany. RP Rudiger, T (reprint author), Univ Wurzburg, Dept Pathol, Josef Schneider Str 2, D-97080 Wurzburg, Germany. RI Poppema, Sibrand/D-1204-2012; OI Delabie, Jan/0000-0001-5023-0689 NR 23 TC 53 Z9 56 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PY 2002 VL 13 SU 1 BP 44 EP 51 DI 10.1093/annonc/mdf608 PG 8 WC Oncology SC Oncology GA 556MA UT WOS:000175852500009 PM 12078902 ER PT J AU Normanno, N Campiglio, M De Luca, A Somenzi, G Maiello, M Ciardiello, F Gianni, L Salomon, DS Menard, S AF Normanno, N Campiglio, M De Luca, A Somenzi, G Maiello, M Ciardiello, F Gianni, L Salomon, DS Menard, S TI Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth SO ANNALS OF ONCOLOGY LA English DT Article DE antibodies; breast cancer; EGF receptor; ErbB-2; therapy; tyrosine kinase inhibitors ID HER2/NEU-OVEREXPRESSING METASTATIC BREAST; ERBB-2 ANTISENSE OLIGONUCLEOTIDES; TYROSINE KINASE INHIBITOR; MONOCLONAL-ANTIBODY; FACTOR RECEPTOR; CARCINOMA CELLS; C-ERBB-2 ONCOPROTEIN; FACTOR-ALPHA; PHASE-II; EXPRESSION AB Background: Co-expression of the epidermal growth factor receptor (EGFR) and of ErbB-2 is found in a subset of primary human breast cancer. Materials and methods: The antiproliferative effects of anti-EGFR and anti-ErbB-2 agents were evaluated using a monolayer assay. The effects of these agents on the activation of EGFR, ErbB-2, AKT and p42/p44 MAP kinases (MAPK) were investigated by western blot analysis. Results: We found that both ZD1839 (Iressa), a specific EGFR tyrosine kinase inhibitor, and trastuzumab (Herceptin) (TRA), a humanized ami-ErbB-2 monoclonal antibody, were able to inhibit the growth of SK-Br-3 and BT-474 breast carcinoma cells, which express both EGFR and ErbB-2. Treatment of breast carcinoma cells with a combination of ZD1839 and TRA resulted in a synergistic inhibitory effect. Treatment of SK-Br-3 cells with ZD1839 produced a significant, dose-dependent reduction of the tyrosine phosphorylation of both EGFR and ErbB-2. Phosphorylation of MAPK and AKT were significantly reduced in SK-Br-3 cells following treatment with ZD1839, whereas treatment with TRA produced a reduction of AKT but not MAPK phosphorylation. Finally, treatment with ZD1839, but not with TRA, produced a significant increase in fragmented DNA in breast carcinoma cells. However, a more pronounced increase in the levels of fragmented DNA was observed following combined treatment with ZD1839 and TRA. Conclusions: These data suggest that combined treatment with drugs that target EGFR and ErbB-2 might result in an efficient inhibition of tumor growth in those breast carcinoma patients whose tumors co-express both receptors. C1 Ist Tumori Milano, Mol Targeting Unit, Milan, Italy. Univ Naples Federico II, Cattedra Oncol Med, Naples, Italy. Ist Tumori Milano, Med Oncol Unit A, Milan, Italy. NCI, TGFS, LTIB, Bethesda, MD 20892 USA. RP Normanno, N (reprint author), ITN Fdn Pascale, I-80131 Naples, Italy. RI De Luca, Antonella/J-8737-2016; OI De Luca, Antonella/0000-0001-5762-447X; Ciardiello, Fortunato/0000-0002-3369-4841; Normanno, Nicola/0000-0002-7158-2605 NR 37 TC 215 Z9 226 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JAN PY 2002 VL 13 IS 1 BP 65 EP 72 DI 10.1093/annonc/mdf020 PG 8 WC Oncology SC Oncology GA 525GQ UT WOS:000174060900023 PM 11863114 ER PT J AU Fraker, DL Alexander, HR Ross, M Bartlett, DL Tyler, D Libutti, LS Boddie, A Briele, H Karakousis, G AF Fraker, DL Alexander, HR Ross, M Bartlett, DL Tyler, D Libutti, LS Boddie, A Briele, H Karakousis, G TI A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF) plus interferon-gamma (IFN) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Penn, Philadelphia, PA 19104 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Duke Univ, Durham, NC USA. Univ Illinois, Chicago, IL USA. NR 0 TC 27 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA 1 BP S8 EP S8 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700002 ER PT J AU Kavanagh, MA Johns, J Alexander, HR Xu, H McCart, JA Bartlett, DL AF Kavanagh, MA Johns, J Alexander, HR Xu, H McCart, JA Bartlett, DL TI Improved anti-tumor response and decreased toxicity with a replicating vaccinia virus (VV) expressing Fas ligand SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA P20 BP S45 EP S46 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700116 ER PT J AU Weinreich, DM Puhlmann, M Turner, EM Paciotti, G Tamarkin, L Myer, L Alexander, HR AF Weinreich, DM Puhlmann, M Turner, EM Paciotti, G Tamarkin, L Myer, L Alexander, HR TI Antitumor efficacy and safety of tumor necrosis factor (TNF) bound to collodial gold (cAu) microspheres in mice SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2002 VL 9 IS 1 SU S MA P14 BP S44 EP S44 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 516ZM UT WOS:000173586700110 ER PT J AU Jacobson, KA AF Jacobson, KA TI Purine and pyrimidine nucleotide (P2) receptors SO ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 37 SE ANNUAL REPORTS IN MEDICINAL CHEMISTRY LA English DT Review ID PROTEIN-COUPLED RECEPTOR; HUMAN P2Y(1) RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; P-2Y-PURINOCEPTOR AGONISTS; BIOLOGICAL-ACTIVITY; P2X(1) RECEPTORS; ANTAGONISTS; IDENTIFICATION; DERIVATIVES; ADENOSINE C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 51 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-7743 J9 ANNU REP MED CHEM PY 2002 VL 37 BP 75 EP 84 DI 10.1016/S0065-7743(02)37009-X PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BV53J UT WOS:000179270200008 ER PT J AU Stadtman, TC AF Stadtman, TC TI Discoveries of vitamin B-12 and selenium enzymes SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE anaerobic metabolism; methane biosynthesis; selenocysteine; thioredoxin reductase ID CLOSTRIDIAL GLYCINE REDUCTASE; FORMATE DEHYDROGENASE-H; HUMAN THIOREDOXIN REDUCTASE; LUNG ADENOCARCINOMA CELLS; ESCHERICHIA-COLI; GLUTATHIONE-PEROXIDASE; TRANSFER-RNAS; PROTEIN-COMPONENTS; CATALYTIC ACTIVITY; ACETYL PHOSPHATE AB My undergraduate education at Cornell University was followed by graduate studies on methane fermentations under the guidance of H.A. Barker at the University of California, Berkeley. My Ph.D. degree was granted in June 1949. Two anaerobic microorganisms isolated from the mud flats of San Francisco Bay served as sources of biochemical research material for later studies at the National Institutes of Health in Bethesda. These organisms, Methanococcus vannielii and Clostridium sticklandii, proved to be especially rich sources of selenium-dependent enzymes and seleno-tRNAs. New B-12 coenzyme-dependent enzymes that catalyzed intermediate steps in the anaerobic conversion of lysine to fatty acids and ammonia were isolated from C. sticklandii and characterized. My research efforts since 1970 have dealt primarily with various aspects of selenium biochemistry. We have shown that selenium is an essential constituent of several enzymes in prokaryotes. Se is present in these either as a selenocysteine residue in the protein or alternatively, in a few molybdoenzymes, as a component of a bound cofactor. Recent studies with a human adenocarcinoma cell line led to the unexpected discovery that selenocysteine occurs in mammalian thioredoxin reductase. The selenium located in a redox center of this enzyme is essential for catalytic activity. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 68 TC 39 Z9 40 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 0066-4154 J9 ANNU REV BIOCHEM JI Annu. Rev. Biochem. PY 2002 VL 71 BP 1 EP 16 DI 10.1146/annurev.biochem.71.083101.134224 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582MJ UT WOS:000177352600002 PM 12045088 ER PT J AU Gellert, M AF Gellert, M TI V(D)J recombination: RAG proteins, repair factors, and regulation SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE immunoglobulin; T-cell receptor; DNA breakage; hairpin; transposition ID STRAND-BREAK-REPAIR; T-CELL RECEPTOR; DNA-LIGASE-IV; IMMUNOGLOBULIN GENE REARRANGEMENT; COMBINED IMMUNE-DEFICIENCY; HAIRPIN FORMATION STEP; VARIABLE-REGION GENES; IN-VITRO; SIGNAL SEQUENCES; TARGETED DISRUPTION AB V(D)J recombination is the specialized DNA rearrangement used by cells of the immune system to assemble immunoglobulin and T-cell receptor genes from the preexisting gene segments. Because there is a large choice of segments to join, this process accounts for much of the diversity of the immune response. Recombination is initiated by the lymphoid-specific RAG1 and RAG2 proteins, which cooperate to make double-strand breaks at specific recognition sequences (recombination signal sequences, RSSs). The neighboring coding DNA is converted to a hairpin during breakage. Broken ends are then processed and joined with the help of several factors also involved in repair of radiation-damaged DNA, including the DNA-dependent protein kinase (DNA-PK) and the Ku, Artemis, DNA ligase IV, and Xrcc4 proteins, and possibly histone H2AX and the Mre11/Rad50/Nbs1 complex. There may be other factors not yet known. V(D)J recombination is strongly regulated by limiting access to RSS sites within chromatin, so that particular sites are available only in certain cell types and developmental stages. The roles of enhancers, histone acetylation, and chromatin remodeling factors in controlling accessibility are discussed. The RAG proteins are also capable of transposing RSS-ended fragments into new DNA sites. This transposition helps to explain the mechanism of RAG action and supports earlier proposals that V(D)J recombination evolved from an ancient mobile DNA element. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gellert, M (reprint author), NIDDKD, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 206 TC 475 Z9 489 U1 6 U2 33 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 2002 VL 71 BP 101 EP 132 DI 10.1146/annurev.biochem.71.090501.150203 PG 32 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582MJ UT WOS:000177352600006 PM 12045092 ER PT J AU Shih, IH Been, MD AF Shih, IH Been, MD TI Catalytic strategies of the hepatitis delta virus ribozymes SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE ribozyme; HDV; RNA; acid-base catalysis; metal ion catalysis ID RIBOSOMAL PEPTIDYL TRANSFERASE; SELF-CLEAVAGE ACTIVITY; CENTER-DOT-U; TETRAHYMENA-THERMOPHILA RIBOZYME; TERTIARY STRUCTURE FORMATION; PYRENE-LABELED SUBSTRATE; INTRINSIC BINDING-ENERGY; SUBTILIS RIBONUCLEASE-P; DETECTED STOPPED-FLOW; GENOMIC HDV RIBOZYME AB The(1) hepatitis delta virus (HDV) ribozymes are self-cleaving RNA sequences critical to the replication of a small RNA genome. A recently determined crystal structure together with biochemical and biophysical studies provides new insight into the possible catalytic mechanism of these ribozymes. The HDV ribozymes are examples of naturally occurring small ribozymes that catalyze cleavage of the RNA backbone with a rate enhancement of 10(6)- to 10(7)-fold over the uncatalyzed rate. To achieve this level of rate enhancement, the HDV ribozymes have been proposed to employ several catalytic strategies that include the use of metal ions, intrinsic binding energy, and a novel example of general acid-base catalysis with a cytosine side chain acting as a proton donor or acceptor. C1 Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Shih, IH (reprint author), Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. FU NIGMS NIH HHS [GM47233] NR 149 TC 88 Z9 91 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 0066-4154 J9 ANNU REV BIOCHEM JI Annu. Rev. Biochem. PY 2002 VL 71 BP 887 EP 917 DI 10.1146/annurev.biochem.71.110601.135349 PG 31 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 582MJ UT WOS:000177352600028 PM 12045114 ER PT J AU Fields, KA Hackstadt, T AF Fields, KA Hackstadt, T TI The chlamydial inclusion: Escape from the endocytic pathway SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE intracellular parasitism; vesicle trafficking; bacterial pathogenesis ID OUTER-MEMBRANE PROTEIN; ENDOGENOUSLY SYNTHESIZED SPHINGOMYELIN; MYCOBACTERIUM-TUBERCULOSIS PHAGOSOME; OBLIGATE INTRACELLULAR PATHOGEN; PNEUMONIAE-INFECTED CELLS; HOST-CELL; EPITHELIAL-CELLS; ELECTRON-MICROSCOPY; GOLGI-APPARATUS; HELA-CELLS AB Chlamydiae, bacterial obligate intracellular pathogens, are the etiologic agents of several human diseases. A large part of the chlamydial intracellular survival strategy involves the formation of a unique organelle called the inclusion that provides a protected site within which they replicate. The chlamydial inclusion is effectively isolated from endocytic pathways but is fusogenic with a subset of exocytic vesicles that deliver sphingomyelin from the Golgi apparatus to the plasma membrane. A combination of host and parasite functions contribute to the biogenesis of this compartment. Establishment of the mature inclusion is accompanied by the insertion of multiple chlamydial proteins, suggesting that chlamydiae actively modify the inclusion to define its interactions with the eukaryotic host cell. Despite being sequestered within a membrane-bound vacuole, chlamydiae clearly communicate with and manipulate the host cell from within this privileged intracellular niche. C1 NIAID, Rocky Mt Labs, Host Parasite Interact Sect, Intracellular Parasites Lab,NIH, Hamilton, MT 59840 USA. RP Fields, KA (reprint author), NIAID, Rocky Mt Labs, Host Parasite Interact Sect, Intracellular Parasites Lab,NIH, Hamilton, MT 59840 USA. NR 152 TC 130 Z9 133 U1 0 U2 7 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 2002 VL 18 BP 221 EP 245 DI 10.1146/annurev.cellbio.18.012502.105845 PG 25 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 618HV UT WOS:000179413400010 PM 12142274 ER PT J AU Court, DL Sawitzke, JA Thomason, LC AF Court, DL Sawitzke, JA Thomason, LC TI Genetic engineering using homologous recombination SO ANNUAL REVIEW OF GENETICS LA English DT Review DE DNA replication forks; strand annealing; in vivo cloning; oligo recombination; recombineering ID ESCHERICHIA-COLI K-12; SINGLE-STRANDED-DNA; BACTERIAL ARTIFICIAL CHROMOSOMES; LAMBDA-GAM PROTEIN; PHAGE-LAMBDA; BACTERIOPHAGE-LAMBDA; BETA-PROTEIN; RECBCD ENZYME; BREAK REPAIR; IN-VIVO AB In the past few years, in vivo technologies have emerged that, due to their efficiency and simplicity, may one day replace standard genetic engineering techniques. Constructs can be made on plasmids or directly on the Escherichia coli chromosome from PCR products or synthetic oligonucleotides by homologous recombination. This is possible because bacteriophage-encoded recombination functions efficiently recombine sequences with homologies as short as 35 to 50 base pairs. This technology, termed recombineering, is providing new ways to modify genes and segments of the chromosome. This review describes not only recombineering and its applications, but also summarizes homologous recombination in E. coli and early uses of homologous recombination to modify the bacterial chromosome. Finally, based on the premise that phage-mediated recombination functions act at replication forks, specific molecular models are proposed. C1 NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM court@ncifcrf.gov; sawitzke@ncifcrf.gov; lthomason@ncifcrf.gov NR 159 TC 263 Z9 288 U1 13 U2 77 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4197 EI 1545-2948 J9 ANNU REV GENET JI Annu. Rev. Genet. PY 2002 VL 36 BP 361 EP 388 DI 10.1146/annurev.genet.36.061102.093104 PG 32 WC Genetics & Heredity SC Genetics & Heredity GA 634WM UT WOS:000180365100014 PM 12429697 ER PT J AU O'Brien, SJ Menotti-Raymond, M Murphy, WJ Yuhki, N AF O'Brien, SJ Menotti-Raymond, M Murphy, WJ Yuhki, N TI The Feline Genome Project SO ANNUAL REVIEW OF GENETICS LA English DT Review DE feline; comparative; genome; genetic map; cat ID BETA-GLUCURONIDASE DEFICIENCY; MAJOR HISTOCOMPATIBILITY COMPLEX; MUCOPOLYSACCHARIDOSIS TYPE VI; ARYLSULFATASE-B DEFICIENCY; GENETIC-LINKAGE MAP; CHROMOSOME-BANDING PATTERNS; DUCHENNE MUSCULAR-DYSTROPHY; BONE-MARROW TRANSPLANTATION; LYSOSOMAL ALPHA-MANNOSIDASE; PLACENTAL MAMMAL RADIATION AB The compilation of a dense gene map and eventually a whole genome sequence (WGS) of the domestic cat holds considerable value for human genome annotation, for veterinary medicine, and for insight into the evolution of genome organization among mammals. Human association and veterinary studies of the cat, its domestic breeds, and its charismatic wild relatives of the family Felidae have rendered the species a powerful model for human hereditary diseases, for infectious disease agents, for adaptive evolutionary divergence, for conservation genetics, and for forensic applications. Here we review the advantages, rationale, and present strategy of a feline genome project, and we describe the disease models, comparative genomics, and biological applications posed by the full resolution of the cat's genome. C1 NCI, Lab Genomic Divers, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genomic Divers, Frederick, MD 21702 USA. EM OBRIEN@ncifcrf.gov NR 192 TC 47 Z9 48 U1 1 U2 13 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4197 EI 1545-2948 J9 ANNU REV GENET JI Annu. Rev. Genet. PY 2002 VL 36 BP 657 EP 686 DI 10.1146/annurev.genet.36.060602.145553 PG 34 WC Genetics & Heredity SC Genetics & Heredity GA 634WM UT WOS:000180365100022 PM 12359739 ER PT J AU Dean, M Carrington, M O'Brien, SJ AF Dean, M Carrington, M O'Brien, SJ TI Balanced polymorphism selected by genetic versus infectious human disease SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS LA English DT Review DE infection; HIV-1; HLA; chemokine receptors ID MAJOR HISTOCOMPATIBILITY COMPLEX; CC-CHEMOKINE RECEPTOR-5; HUMAN-LEUKOCYTE ANTIGEN; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INFLAMMATORY-BOWEL-DISEASE; VIRUS TYPE-1 TRANSMISSION; CLASS-I POLYMORPHISM; HEPATITIS-B VIRUS; CYSTIC-FIBROSIS; HIV-1 INFECTION AB The polymorphisms within the human genome include several functional variants that cause debilitating inherited diseases. An elevated frequency of some of these deleterious mutations can be explained by a beneficial effect that confers a selective advantage owing to disease resistance in carriers of such mutations during an infectious disease outbreak. We here review plausible examples of balanced functional. polymorphisms and their roles in the defense against pathogens. The genome organization of the chemokine receptor and HLA gene clusters and their influence on the HIV/AIDS epidemic provides compelling evidence for the interaction of infectious and genetic diseases in recent human history. C1 NCI, Sci Applicat Int Corp, Lab Genomic Divers, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. RP Dean, M (reprint author), NCI, Sci Applicat Int Corp, Lab Genomic Divers, Frederick, MD 21702 USA. RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 154 TC 115 Z9 123 U1 3 U2 8 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 2002 VL 3 BP 263 EP 292 DI 10.1146/annurev.genom.3.022502.103149 PG 32 WC Genetics & Heredity SC Genetics & Heredity GA 605LF UT WOS:000178678800011 PM 12142357 ER PT J AU Webster, JI Tonelli, L Sternberg, EM AF Webster, JI Tonelli, L Sternberg, EM TI Neuroendocrine regulation of immunity SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE glucocorticoid; immune response; inflammatory/autoimmune disease; HPA axis; cytokines ID PITUITARY-ADRENAL AXIS; NF-KAPPA-B; GLUCOCORTICOID RECEPTOR-BETA; CORTICOTROPIN-RELEASING HORMONE; TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; CHRONIC-FATIGUE-SYNDROME; CENTRAL-NERVOUS-SYSTEM; MONOCYTIC THP-1 CELLS AB A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects-on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules. C1 NIMH, Sect Neuroimmune Immunol & Behav, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroimmune Immunol & Behav, Bldg 36,Room 1A 23,MSC 4020,36 Convent Dr, Bethesda, MD 20892 USA. RI Webster Marketon, Jeanette/H-5613-2011 OI Webster Marketon, Jeanette/0000-0002-3627-1094 NR 218 TC 490 Z9 510 U1 3 U2 45 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 2002 VL 20 BP 125 EP 163 DI 10.1146/annurev.immunol.20.082401.104914 PG 39 WC Immunology SC Immunology GA 541XV UT WOS:000175012600007 PM 11861600 ER PT J AU Samelson, LE AF Samelson, LE TI Signal transduction mediated by the T cell antigen receptor: The role of adapter proteins SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE signaling pathways; linker for activation of T cells (LAT); plasma membrane microdomains; cytoskeleton; protein tyrosine kinases; tyrosine kinase substrates ID SRC HOMOLOGY-2 DOMAIN; TYROSINE-PHOSPHORYLATED SLP-76; RESISTANT MEMBRANE DOMAINS; VAV PROTOONCOGENE PRODUCT; GPI-ANCHORED PROTEINS; PHOSPHOLIPASE C-GAMMA-1; ARP2/3 COMPLEX; SH2 DOMAIN; INTERLEUKIN-2 PRODUCTION; IMMUNOLOGICAL SYNAPSE AB Engagement of the T cell antigen receptor (TCR) leads to a complex series of molecular changes at the plasma membrane, in the cytoplasm, and at the nucleus that lead ultimately to T cell effector function. Activation at the TCR of a set of protein tyrosine kinases (PTKs) is an early event in this process. This chapter reviews some of the critical substrates of these PTKs, the adapter proteins that, following phosphorylation on tyrosine residues, serve as binding sites for many of the critical effector enzymes and other adapter proteins required for T cell activation. The role of these adapters in binding various proteins, the interaction of adapters with plasma membrane microdomains, and the function of adapter proteins in control of the cytoskeleton are discussed. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Bldg 37,Room 1E24, Bethesda, MD 20892 USA. NR 129 TC 386 Z9 397 U1 1 U2 11 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 2002 VL 20 BP 371 EP 394 DI 10.1146/annurev.immunol.20.092601.111357 PG 26 WC Immunology SC Immunology GA 541XV UT WOS:000175012600014 PM 11861607 ER PT J AU Strober, W Fuss, IJ Blumberg, RS AF Strober, W Fuss, IJ Blumberg, RS TI The immunology of mucosal models of inflammation SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE Crohn's disease; ulcerative colitis; tolerance; cytokines; Th1/Th2 ID CD4(+) T-CELLS; DEXTRAN SULFATE SODIUM; ALPHA-MUTANT MICE; CHAIN-DEFICIENT MICE; GROWTH-FACTOR-BETA; CHRONIC INTESTINAL INFLAMMATION; HAPTEN-INDUCED COLITIS; NF-KAPPA-B; BOWEL-DISEASE; CROHNS-DISEASE AB In recent years the status of the inflammatory bowel diseases (IBDs) as canonical autoimmune diseases has risen steadily with the recognition that these diseases are, at their crux, abnormalities in mucosal responses to normally harmless antigens in the mucosal microflora and therefore responses to antigens that by their proximity and persistence are equivalent to self-antigens. This new paradigm is in no small measure traceable to the advent of multiple models of mucosal inflammation whose very existence is indicative of the fact that many types of immune imbalance can lead to loss of tolerance for mucosal antigens and thus inflammation centered in the gastrointestinal tract. We analyze the immunology of the IBDs through the lens of the murine models, first by drawing attention to their common features and then by considering individual models at a level of detail necessary to reveal their individual capacities to provide insight into IBD pathogenesis. What emerges is that murine models of mucosal inflammation have given us a road map that allows us to begin to define the immunology of the IBDs in all its complexity and to find unexpected ways to treat these diseases. C1 NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NR 212 TC 875 Z9 902 U1 11 U2 85 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 2002 VL 20 BP 495 EP 549 DI 10.1146/annurev.immunol.20.100301.064816 PG 55 WC Immunology SC Immunology GA 541XV UT WOS:000175012600018 PM 11861611 ER PT J AU Natarajan, K Dimasi, N Wang, J Mariuzza, RA Margulies, DH AF Natarajan, K Dimasi, N Wang, J Mariuzza, RA Margulies, DH TI Structure and function of natural killer cell receptors: Multiple molecular solutions to self, nonself discrimination SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE natural killer (NK) cells; NK receptors; missing self; inhibitory and activating receptors; T cell receptors (TCR); MHC; NUCA; RAE-1; ULBP ID MHC CLASS-I; C-TYPE LECTIN; IMMUNOGLOBULIN-LIKE RECEPTORS; BONE-MARROW ALLOGRAFTS; DELTA T-CELLS; HISTOCOMPATIBILITY COMPLEX-MOLECULES; H-2-DEFICIENT LYMPHOMA VARIANTS; PEPTIDE BINDING-SPECIFICITY; INHIBITORY RECEPTOR; CRYSTAL-STRUCTURE AB In contrast to T cell receptors, signal transducing cell surface membrane molecules involved in the regulation of responses by cells of the innate immune system employ structures that are encoded in the genome rather than generated by somatic recombination and that recognize either classical MHC-I molecules or their structural relatives (such as MICA, RAE-1, or H-60). Considerable progress has recently been made in our understanding of molecular recognition by such molecules based on the determination of their three-dimensional structure, either in isolation or in complex with their MHC-I ligands. Those best studied are the receptors that are expressed on natural killer (NK) cells, but others are found on populations of T cells and other hematopoietic cells. These molecules fall into two major structural classes, those of the immunoglobulin superfamily (KIRs and LIRs) and of the C-type lectin-like family (Ly49, NKG2D, and CD94/NKG2). Here we summarize, in a functional context, the structures of the murine and human molecules that have recently been determined, with emphasis on how they bind different regions of their MBC-I ligands, and how this allows the discrimination of tumor or virus-infected cells from normal cells of the host. C1 NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Keck Lab Struct Biol, Rockville, MD 20850 USA. RP Natarajan, K (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM knatarajan@niaid.nih.gov; dimasi@carb.nist.gov; jianwang@niaid.nih.gov; mariuzza@carb.nist.gov; dhm@nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 182 TC 221 Z9 240 U1 3 U2 7 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 2002 VL 20 BP 853 EP 885 DI 10.1146/annurev.immunol.20.100301.064812 PG 41 WC Immunology SC Immunology GA 541XV UT WOS:000175012600027 PM 11861620 ER PT J AU Graham, BS AF Graham, BS TI Clinical trials of HIV vaccines SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE AIDS; virus; immunity; neutralizing antibody; cytotoxic T lymphocyte ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-LYMPHOCYTE RESPONSES; NEUTRALIZING ANTIBODY-RESPONSES; IMMUNE-RESPONSES; VIRAL REPLICATION; UNINFECTED VOLUNTEERS; PASSIVE-IMMUNIZATION; CYNOMOLGUS MONKEYS; RHESUS MACAQUES; TYPE-1 ENVELOPE AB Development of a preventive vaccine for HIV is the best hope of controlling the AIDS pandemic. Evidence from natural history studies and experiments in animal models indicates that immunity against HIV is possible, suggesting that vaccine development is feasible. These studies have shown that sufficient levels of neutralizing antibody against HIV can prevent infection, although the effect is type-specific. In contrast, HIV-specific cytotoxic T lymphocyte (CTL) activity has broad cross-reactivity, and although CTL activity alone cannot prevent HIV infection, it can control the level of viremia at a low level. Evaluation of candidate vaccines in human trials has focused on approaches that can safely elicit HIV-specific antibody and T cell responses. Current strategies have been unable to induce antibody with broad neutralizing activity against primary HIV isolates. However, recombinant poxvirus and DNA vaccines have elicited CTL responses that are broadly cross-reactive against primary HIV isolates from diverse clades. Future advances will require the discovery of new immunogens that can induce neutralizing antibody, as well as efficacy trial evaluation of regimens optimized for CTL induction. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 2502,MSC-3017, Bethesda, MD 20892 USA. NR 74 TC 79 Z9 81 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 207 EP 221 DI 10.1146/annurev.med.53.082901.104035 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500016 PM 11818471 ER PT J AU Staudt, LM AF Staudt, LM TI Gene expression profiling of lymphoid malignancies SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE genomics; microarray; lymphoma; leukemia; BCL-6 ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GERMINAL-CENTER FORMATION; CENTER B-CELLS; NON-HODGKINS-LYMPHOMA; DOUBLE-STRAND BREAKS; MOLECULAR CLASSIFICATION; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; BCL-6; PROTEIN AB Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-kappaB signaling pathway is a new molecular therapeutic target in DLBCL. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 59 TC 86 Z9 87 U1 2 U2 5 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 303 EP 318 DI 10.1146/annurev.med.53.082901.103941 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500021 PM 11818476 ER PT J AU Wlodawer, A AF Wlodawer, A TI Rational approach to AIDS drug design through structural biology SO ANNUAL REVIEW OF MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-PROTEASE INHIBITOR; ORALLY BIOAVAILABLE INHIBITOR; CRYSTAL-STRUCTURE; REVERSE-TRANSCRIPTASE; TYPE-1 PROTEASE; FREE-ENERGY; RETROVIRAL PROTEASES; CATALYTIC DOMAIN; TRANSITION-STATE AB The discovery and development of more than a dozen drugs in the past 15 years for the treatment of AIDS offer an excellent example of progress in the field of rational drug design. At this time, the principal targets are reverse transcriptase and protease, enzymes encoded by the human immunodeficiency virus. The introduction of protease inhibitors, in particular, has drastically decreased the mortality and morbidity associated with AIDS. This review presents the methods used to develop such drugs and discusses the remaining problems, such as the rapid emergence of drug resistance. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. NR 106 TC 87 Z9 89 U1 2 U2 14 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 595 EP 614 DI 10.1146/annurev.med.53.052901.131947 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500036 PM 11818491 ER PT J AU Gottesman, MM AF Gottesman, MM TI Mechanisms of cancer drug resistance SO ANNUAL REVIEW OF MEDICINE LA English DT Review DE cancer; multidrug resistance; ABC transporters; drug transport; chemotherapy ID P-GLYCOPROTEIN EXPRESSION; BONE-MARROW CELLS; MULTIDRUG-RESISTANCE; TRANSPORTER GENE; ACUTE-LEUKEMIA; HUMAN MDR1; IN-VIVO; PROTEINS; CHEMOTHERAPY; ACCUMULATION AB The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common. The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energy-dependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms probably play an important role in acquired anticancer drug resistance. Studies on mechanisms of cancer drug resistance have yielded important information about how to circumvent this resistance to improve cancer chemotherapy and have implications for pharmacokinetics of many commonly used drugs. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. NR 62 TC 1176 Z9 1217 U1 35 U2 194 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2002 VL 53 BP 615 EP 627 DI 10.1146/annurev.med.53.082901.103929 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 531KL UT WOS:000174414500037 PM 11818492 ER PT J AU Cowan, WM Kopnisky, KL Hyman, SE AF Cowan, WM Kopnisky, KL Hyman, SE TI The human genome project and its impact on psychiatry SO ANNUAL REVIEW OF NEUROSCIENCE LA English DT Review DE schizophrenia; bipolar disorder; autism; linkage analysis; SNPs; human genome ID BIPOLAR AFFECTIVE-DISORDER; MANIC-DEPRESSIVE ILLNESS; X-CHROMOSOME MARKERS; SCHIZOPHRENIA SUSCEPTIBILITY LOCUS; NONPARAMETRIC LINKAGE ANALYSIS; GENETICS INITIATIVE PEDIGREES; CARDIO-FACIAL SYNDROME; VULNERABILITY LOCUS; AUTISTIC DISORDER; WIDE SEARCH AB There has been substantial evidence for more than three decades that the major psychiatric illnesses such as schizophrenia, bipolar disorder, autism, and alcoholism have a strong genetic basis. During the past 15 years considerable effort has been expended in trying to establish the genetic loci associated with susceptibility to these and other mental disorders using principally linkage analysis. Despite this, only a handful of specific genes have been identified, and it is now generally recognized that further advances along these lines will require the analysis of literally hundreds of affected individuals and their families. Fortunately, the emergence in the past three years of a number of new approaches and more effective tools has given new hope to those engaged in the search for the underlying genetic and environmental factors involved in causing these illnesses, which collectively are among the most serious in all societies. Chief among these new tools is the availability of the entire human genome sequence and the prospect that within the next several years the entire complement of human genes will be known and the functions of most of their protein products elucidated. In the meantime the search for susceptibility loci is being facilitated by the availability of single nucleotide polymorphisms (SNPs) and by the beginning of haplotype mapping, which tracks the distribution of clusters of SNPs that segregate as a group. Together with high throughput DNA sequencing, microarrays for whole genome scanning, advances in proteomics, and the development of more sophisticated computer programs for analyzing sequence and association data, these advances hold promise of greatly accelerating the search for the genetic basis of most mental illnesses while, at the same time, providing molecular targets for the development of new and more effective therapies. C1 NIMH, Bethesda, MD 20892 USA. RP Cowan, WM (reprint author), NIMH, Bethesda, MD 20892 USA. EM mcowan1@mail.nih.gov; kkopnisk@mail.nih.gov; shyman@mail.nih.gov NR 158 TC 58 Z9 60 U1 7 U2 14 PU ANNUAL REVIEWS 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 2002 VL 25 BP 1 EP 50 DI 10.1146/annurev.neuro.25.112701.142853 PG 50 WC Neurosciences SC Neurosciences & Neurology GA 582MK UT WOS:000177354800001 PM 12052903 ER PT J AU Steinman, L Martin, R Bernard, C Conlon, P Oksenberg, JR AF Steinman, L Martin, R Bernard, C Conlon, P Oksenberg, JR TI Multiple sclerosis: Deeper understanding of its pathogenesis reveals new targets for therapy SO ANNUAL REVIEW OF NEUROSCIENCE LA English DT Review DE microarray; proteomics; osteopontin; immunotherapy; genomics ID CENTRAL-NERVOUS-SYSTEM; MYELIN BASIC-PROTEIN; ALTERED PEPTIDE LIGAND; T-CELL RESPONSES; DEMYELINATING DISEASE; BRAIN-LESIONS; B-CELL; AUTOIMMUNE ENCEPHALOMYELITIS; TRANSGENIC MICE; TNF-ALPHA AB Recent technological breakthroughs allowing for large-scale analysis of gene transcripts and large-scale monitoring of the immune response with protein chips are revealing new participants in the pathogenesis of multiple sclerosis. Some of these participants may be useful targets for therapy. C1 Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. La Trobe Univ, Dept Biochem, Neuroimmunol Lab, Bundoora, Vic 3083, Australia. Neurocrine Biosci, San Diego, CA USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Steinman, L (reprint author), Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. NR 46 TC 185 Z9 189 U1 0 U2 11 PU ANNUAL REVIEWS 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 2002 VL 25 BP 491 EP 505 DI 10.1146/annurev.neuro.25.112701.142913 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 582MK UT WOS:000177354800016 PM 12052918 ER PT J AU Reitman, ML AF Reitman, ML TI Metabolic lessons from genetically lean mice SO ANNUAL REVIEW OF NUTRITION LA English DT Review DE lipoatrophy/lipodystrophy; insulin resistance; diabetes; leptin; energy homeostasis ID DIET-INDUCED OBESITY; PROTEIN-KINASE-A; MUSCARINIC ACETYLCHOLINE-RECEPTOR; MELANIN-CONCENTRATING HORMONE; TRANSGENIC INSERTIONAL MUTANT; ACYLATION-STIMULATING PROTEIN; INCREASED INSULIN SENSITIVITY; LIPOPROTEIN-LIPASE CAUSES; G(S)ALPHA KNOCKOUT MICE; DYSTROPHY FLD MUTATION AB Different types of lean mice have been produced by genetic manipulation. Leanness can result from deficiency of stored energy or a lack of adipocytes to store the lipid. Mice lacking functional adipocytes are usually insulin resistant and have fatty livers, and elevated circulating triglyceride levels. Insulin resistance may result from the lack of adipocyte hormones (such as leptin) and increased metabolite (such as triglyceride) levels in nonadipose tissue. Mice with depleted adipocyte triglyceride levels typically are insulin sensitive and have normal or low liver and circulating triglycerides. Mechanisms to produce depleted adipocytes include increased energy expenditure by peripheral tissues, peripheral mechanisms to decrease food intake, and altered central regulation of these processes. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), Merck Res Labs, Rahway, NJ 07065 USA. EM marc_reitman@merck.com RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 NR 113 TC 52 Z9 53 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0199-9885 J9 ANNU REV NUTR JI Annu. Rev. Nutr. PY 2002 VL 22 BP 459 EP 482 DI 10.1146/annurev.nutr.22.010402.102849 PG 24 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 627DR UT WOS:000179917900021 PM 12055354 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI Cellular mechanisms for the repression of apoptosis SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY LA English DT Review DE programmed cell death; inhibition; Bcl-2; IAPs; ions ID TUMOR-NECROSIS-FACTOR; MITOCHONDRIAL PERMEABILITY TRANSITION; BACULOVIRUS P35 PROTEIN; INTERLEUKIN-1-BETA CONVERTING-ENZYME; ADENINE-NUCLEOTIDE TRANSLOCATOR; NEMATODE CAENORHABDITIS-ELEGANS; CEREBELLAR GRANULE NEURONS; VIRUS SERPIN CRMA; VOLUME REGULATION; CYTOCHROME-C AB Apoptosis, also known as programmed cell death, is a ubiquitous mode of cell death known to play an important role during embryogenesis, development, and adult cellular homeostasis. Disruption of this normal physiological cell death process can result in either excessive or insufficient apoptosis, which can lead to various disease states and pathology. Since most cells contain the machinery that brings about apoptosis, it is clear that living cells must contain inherent repressive mechanisms to keep the death process in check. In this review, we examine several modes of repression of apoptosis that exist in cells. 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 155 TC 95 Z9 97 U1 1 U2 3 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0362-1642 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2002 VL 42 BP 259 EP 281 DI 10.1146/annurev.pharmtox.42.083101.143836 PG 27 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 524XU UT WOS:000174038800013 PM 11807173 ER PT J AU Lee, SK Heo, YH Steele, VE Pezzuto, JM AF Lee, SK Heo, YH Steele, VE Pezzuto, JM TI Induction of apoptosis by 1,4-phenylenebis(methylene)selenocyanate in cultured human colon cancer cells SO ANTICANCER RESEARCH LA English DT Article DE 1,4-phenylenebis(methylene)selenocyanate (p-XSC); apoptosis; human colon carcinoma cells (Col 2); cancer chemoprevention ID ORGANOSELENIUM COMPOUND 1,4-PHENYLENEBIS(METHYLENE)SELENOCYANATE; FEMALE CD RATS; CHEMOPREVENTIVE ACTIVITY; MOUSE LUNG; F344 RATS; INHIBITION; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE; CARCINOGENESIS; SELENIUM; BENZO(A)PYRENE AB Using a cultured human colon cancer cell line (Col 2), a structurally diverse group of chemopreventive agents was evaluated for their potential to induce apoptosis. As a result, 1, 4-phenylenebis(methylene)selenocyanate (p-xylylselenocyanate; p-XSC) was found to be active in this process. p-XSC, a synthetic organoselenium compound, has been shown to inhibit tobacco-specific 4-(methylnitrosoamino)-(3-pyridyl)-1-blitanone-induced tumorigenesis in A/J mouse lung, rat tongue carcinogenesis and colon cancer. Known chemopreventive mechanisms include inhibition of DNA methylation, inhibition of thymidine kinase and reduction of oxidative DNA damage. In order to assess apoptosis induction, the cells were exposed to various concentrations of test substances for 48 hours. Enrichment of mono- and oligonucleosomes in the cytoplasm was monitored as an indication of apoptosis using an ELISA kit. As a result, p-XSC caused dose-dependent enrichment of fragmented nucleosomes. In further studies, p-XSC was found to induce DNA laddering in a dose-dependent manner, while apoptotic cells accumulated in a time-dependent manner lip to 96 hours. The apoptotic peaks after treatment of p-XSC were also found as confirmed by the flow cytometric analysis of cell cycle distribution. In an additional study, however, p-XSC-mediated apoptosis was not shown to be dependent on p53 expression. Taken together, these results suggest that induction of apoptosis is one possible mechanism for the cancer chemopreventive activity mediated by p-XSC. C1 Univ Illinois, Program Collaborat Res Pharmaceut Sci MC 877, Coll Pharm, Chicago, IL 60612 USA. Univ Illinois, Dept Med Chem & Pharmacognosy, Coll Pharm, Chicago, IL 60612 USA. Ewha Womans Univ, Coll Pharm, Seoul 120750, South Korea. NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, NIH, Bethesda, MD 20892 USA. RP Pezzuto, JM (reprint author), Univ Illinois, Program Collaborat Res Pharmaceut Sci MC 877, Coll Pharm, 833 S Wood St, Chicago, IL 60612 USA. FU NCI NIH HHS [N01-CN-75119] NR 30 TC 36 Z9 39 U1 0 U2 4 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN-FEB PY 2002 VL 22 IS 1A BP 97 EP 102 PG 6 WC Oncology SC Oncology GA 547UZ UT WOS:000175351900014 PM 12017340 ER PT J AU Woodson, K Triantos, S Hartman, T Taylor, PR Virtamo, J Albanes, D AF Woodson, K Triantos, S Hartman, T Taylor, PR Virtamo, J Albanes, D TI Long-term alpha-tocopherol supplementation is associated with lower serum vascular endothelial growth factor levels SO ANTICANCER RESEARCH LA English DT Article DE alpha-tocopherol; VEGF; prostate cancer; cancer prevention; angiogenesis ID BETA-CAROTENE SUPPLEMENTS; PROSTATE-CANCER; UP-REGULATION; VITAMIN-E; EXPRESSION; ANGIOGENESIS; RECEPTORS; PLATELETS; ANDROGENS; TRIAL AB Background: We previously reported that daily supplementation with a-tocopherol reduced prostate cancer risk in a large, randomized trial, the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study. One potential mechanism explaining this is that a-tocopherol inhibited tumor angiogenesis, an effect demonstrated in animal models. Patients and Methods: We evaluated whether long-term supplementation with alpha-tocopherol modified serum vascular endothelial growth factor (VEGF) levels, a cytokine integrally involved in angiogenesis, in men who were not diagnosed with cancer and had baseline and follow-up blood available. One hundred of these men who received a-tocopherol (50 mg daily) were randomly selected and matched on age, study center and time between blood draws to 100 men who received placebo (median follow-up 3.7 years). VEGF levels were measured by, enzyme-linked immunosorbent assay. The effect of alpha-tocopherol supplementation on serum VEGF was evaluated using a matched-paired t-test for differences in the change in VEGF over the intervention period between groups. Results: There was an 11% reduction in VEGF levels in the a-tocopherol group as compared with a 10% increase in the placebo group (p =0.03). Conclusion: Our findings suggest that one of the mechanisms behind the inhibition of prostate carcinogenesis by a-tocopherol in the ATBC Study may have been through reduced VEGF concentrations and the suppression of tumor angiogenesis and therefore growth. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, SF-00300 Helsinki, Finland. RP Woodson, K (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, 6116 Execut Blvd MSC 8314,Suite 705, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01 CN 45165] NR 35 TC 20 Z9 20 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN-FEB PY 2002 VL 22 IS 1A BP 375 EP 378 PG 4 WC Oncology SC Oncology GA 547UZ UT WOS:000175351900058 PM 12017317 ER PT J AU Petraitiene, R Petraitis, V Groll, AH Sein, T Schaufele, RL Francesconi, A Bacher, J Avila, NA Walsh, TJ AF Petraitiene, R Petraitis, V Groll, AH Sein, T Schaufele, RL Francesconi, A Bacher, J Avila, NA Walsh, TJ TI Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: Pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; IN-VITRO ACTIVITY; CT HALO SIGN; INVASIVE ASPERGILLOSIS; ECHINOCANDIN ANTIFUNGAL; AMPHOTERICIN-B; (1,3)-BETA-D-GLUCAN SYNTHASE; FILAMENTOUS FUNGI; MK-991 L-743,872; CANDIDA AB The antifungal efficacy, pharmacokinetics, and safety of caspofungin (CAS) were investigated in the treatment and prophylaxis of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of 1, 3, or 6 mg of CAS/kg of body weight/day (CAS1, CAS3, and CAS6, respectively) or 1 mg of deoxycholate amphotericin B (AMB)/kg/day intravenously for 12 days starting 24 h after endotracheal inoculation. Prophylaxis (CASI) was initiated 4 days before endotracheal inoculation. Rabbits treated with CAS had significant improvement in survival and reduction in organism-mediated pulmonary injury (OMPI) measured by pulmonary infarct score and total lung weight (P < 0.01). However, animals treated with CAS demonstrated a paradoxical trend toward increased residual fungal burden (log CFU per gram) and increased serum galactomannan antigen index (GMI) despite improved survival. Rabbits receiving prophylactic CASI also showed significant improvement in survival and reduction in OMPI (P < 0.01), but there was no effect on residual fungal burden. In vitro tetrazolium. salt hyphal damage assays and histologic studies demonstrated that CAS had concentration- and dose-dependent effects on hyphal structural integrity. In parallel with a decline in GMI, AMB significantly reduced the pulmonary tissue burden of A. fumigatus (P less than or equal to 0.01). The CAS1, CAS3, and CAS6 dose regimens demonstrated dose-proportional exposure and maintained drug levels in plasma above the MIC for the entire 24-h dosing interval at doses that were greater than or equal to3 mg/kg/day. As serial galactomannan antigen levels may be used for therapeutic monitoring, one should be aware that profoundly neutropenic patients receiving echinocandins for aspergillosis might have persistent galactomannan antigenemia despite clinical improvement. CAS improved survival, reduced pulmonary injury, and caused dose-dependent hyphal damage but with no reduction in residual fungal burden or galactomannan antigenemia in persistently neutropenic rabbits with invasive pulmonary aspergillosis. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. NIH, Dept Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 56 TC 131 Z9 133 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2002 VL 46 IS 1 BP 12 EP 23 DI 10.1128/AAC.46.1.12-23.2002 PG 12 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 504QP UT WOS:000172867600002 PM 11751105 ER PT J AU Wheat, LJ Connolly, P Haddad, N Le Monte, A Brizendine, E Hafner, R AF Wheat, LJ Connolly, P Haddad, N Le Monte, A Brizendine, E Hafner, R TI Antigen clearance during treatment of disseminated histoplasmosis with itraconazole versus fluconazole in patients with AIDS SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CAPSULATUM ANTIGEN; AMPHOTERICIN-B; DIAGNOSIS AB Antifungal treatment reduces the concentration of Histoplasma antigen in blood and urine, supporting a hypothesis that antigen clearance could be used to compare the activity of new agents for treating histoplasmosis. In separate trials in patients with AIDS, clinical response was similar with itraconazole (85%) and fluconazole (74%). Fungal blood cultures at week 4, however, were negative in a significantly higher proportion of patients treated with itraconazole (92.3%) than in those treated with fluconazole (61.9%) (P = 0.017). Baseline antigen concentrations were similar in the two groups: serum, P = 0.7235; and urine, P = 0.1360. After 4 weeks of treatment, the decline in antigen from baseline in serum was similar in the two treatment groups (P = 0.5237), as it was in urine (P = 0.4679). At week 12, the decline in antigen from baseline in serum also was similar in the two groups (P = 0.4911) and in urine (P = 0.2786). More rapid clearance of fungemia suggests that itraconazole is more effective than fluconazole in treating histoplasmosis. This study demonstrates that clearance of fungemia is a better measure of antifungal effect than clearance of antigen. C1 Indiana Univ, Sch Med, Histoplasmosis Reference Lab, Indianapolis, IN 46202 USA. Vet Affairs Med Ctr, Indianapolis, IN USA. NIAID, Div Aids, NIH, Rockville, MD USA. RP Wheat, LJ (reprint author), Indiana Univ, Sch Med, Histoplasmosis Reference Lab, 1001 W 10th St,OPW 430, Indianapolis, IN 46202 USA. FU NIAID NIH HHS [N01-AI65296, U01 AI025859, N01 AI065296, AI 25859] NR 11 TC 24 Z9 27 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JAN PY 2002 VL 46 IS 1 BP 248 EP 250 DI 10.1128/AAC.46.1.248-250.2002 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 504QP UT WOS:000172867600043 PM 11751146 ER PT B AU Levine, M Wang, YH Padayatty, SJ AF Levine, M Wang, YH Padayatty, SJ BE Packer, L Traber, MG Kraemer, K Frei, B TI Vitamin C pharmacokinetics in healthy men and women SO ANTIOXIDANT VITAMINS C AND E LA English DT Proceedings Paper CT Symposium on the Antioxidant Vitamins C and E CY MAR 06-09, 2002 CL SANTA BARBARA, CA SP Linus Pauling Inst, Oxygen Club Calif ID RECOMMENDED DIETARY ALLOWANCE; PLASMA ASCORBIC-ACID; DEPLETION; TRANSPORTERS; SUPPLEMENTATION; REQUIREMENTS; POPULATION; VOLUNTEERS; REPLETION; YOUNG C1 NIDDKD, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDKD, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. RI Padayatty, Sebastian/A-8581-2012 OI Padayatty, Sebastian/0000-0001-8758-3170 NR 40 TC 3 Z9 3 U1 3 U2 6 PU AMER OIL CHEMISTS SOC PI CHAMPAIGN PA 508 S 6TH ST, CHAMPAIGN, IL 61820 USA BN 1-893997-29-4 PY 2002 BP 17 EP 31 PG 15 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA BW46Z UT WOS:000182085900002 ER PT B AU Loria, CM AF Loria, CM BE Packer, L Traber, MG Kraemer, K Frei, B TI Vitamin C status and cardiovascular disease: A review of prospective studies SO ANTIOXIDANT VITAMINS C AND E LA English DT Proceedings Paper CT Symposium on the Antioxidant Vitamins C and E CY MAR 06-09, 2002 CL SANTA BARBARA, CA SP Linus Pauling Inst, Oxygen Club Calif ID CORONARY HEART-DISEASE; LOW-DENSITY-LIPOPROTEIN; ASCORBIC-ACID; ANTIOXIDANT VITAMINS; POSTMENOPAUSAL WOMEN; BETA-CAROTENE; US ADULTS; MORTALITY; RISK; STROKE C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Loria, CM (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bldg 10, Bethesda, MD 20892 USA. NR 32 TC 3 Z9 3 U1 1 U2 1 PU AMER OIL CHEMISTS SOC PI CHAMPAIGN PA 508 S 6TH ST, CHAMPAIGN, IL 61820 USA BN 1-893997-29-4 PY 2002 BP 105 EP 115 PG 11 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA BW46Z UT WOS:000182085900007 ER PT J AU Ambrose, Z Hughes, SH KewalRamani, VN AF Ambrose, Z Hughes, SH KewalRamani, VN TI A new reverse transcriptase-SHIV to study HIV-1 non-nucleoside reverse transcriptase inhibitor-resistance in pigtailed macaques SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 51 BP S58 EP S58 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300052 ER PT J AU Boyer, PL Sarafianos, SG Arnold, E Hughes, SH AF Boyer, PL Sarafianos, SG Arnold, E Hughes, SH TI Mechanisms of nucleoside analogue resistance SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Biol Chem, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 27 BP S32 EP S32 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300028 ER PT J AU Maldarelli, F Kearney, M Palmer, S Rock, D Falloon, J Mican, J Liu, S Pau, A VanHoutte, M Michels, L Hurtogs, K Metcalf, J Stephens, R Mellors, J Coffin, J AF Maldarelli, F Kearney, M Palmer, S Rock, D Falloon, J Mican, J Liu, S Pau, A VanHoutte, M Michels, L Hurtogs, K Metcalf, J Stephens, R Mellors, J Coffin, J TI Detailed analysis of genetic variation in vivo suggests HIV effective population size is large SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. NIAID, CCMD Clin, NIH, Bethesda, MD 20892 USA. NIAID, Mol Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIH, CC Pharm, Bethesda, MD 20892 USA. VIRCO, Mechelen, Belgium. SAIC, Frederick, MD USA. Univ Pittsburgh, Dept Infect Dis, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 68 BP S75 EP S75 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300069 ER PT J AU Palmer, S Kearney, M Maldarelli, F Kottilil, S Lucey, D Metcalf, J Rock, D VanHoutte, M Michels, L Hertogs, K Mellors, J Coffin, J AF Palmer, S Kearney, M Maldarelli, F Kottilil, S Lucey, D Metcalf, J Rock, D VanHoutte, M Michels, L Hertogs, K Mellors, J Coffin, J TI Genetics of HIV-1 populations in acute and chronic infection SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Dept Infect Dis, Washington, DC 20010 USA. VIRCO, Mechelen, Belgium. Univ Pittsburgh, Dept Infect Dis, Pittsburgh, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 50 BP S57 EP S57 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300051 ER PT J AU Svarovskaia, ES Barr, R Zhang, X Pais, GCG Marchand, C Pommier, Y Burke, TR Pathak, VK AF Svarovskaia, ES Barr, R Zhang, X Pais, GCG Marchand, C Pommier, Y Burke, TR Pathak, VK TI Azide group containing 3-aryl-1,3-diketo acid derivatives are potent inhibitors of HIV-1 replication SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NCI, Med Chem Lab, Frederick, MD 21701 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RI Burke, Terrence/N-2601-2014; Marchand, Christophe/D-8559-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 15 BP S17 EP S17 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300016 ER PT J AU Vrang, L Zhang, H Palmer, S Kim, EY Merigan, T Oberg, B AF Vrang, L Zhang, H Palmer, S Kim, EY Merigan, T Oberg, B TI In vitro effects of MIV-310 (alovudine, 3 '-fluorodeoxy thymidine, FLT) against HIV mutants SO ANTIVIRAL THERAPY LA English DT Meeting Abstract C1 Medivir, Huddinge, Sweden. NCI, HIV Drug Resistance Program, Frederick, MD USA. Stanford Univ, Ctr AIDS Res, Stanford, CA 94305 USA. Karolinska Inst, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2002 VL 7 SU 1 MA 23 BP S25 EP S25 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 583HM UT WOS:000177401300024 ER PT J AU Beja, O Koonin, EV Aravind, L Taylor, LT Seitz, H Stein, JL Bensen, DC Feldman, RA Swanson, RV DeLong, EF AF Beja, O Koonin, EV Aravind, L Taylor, LT Seitz, H Stein, JL Bensen, DC Feldman, RA Swanson, RV DeLong, EF TI Comparative genomic analysis of archaeal genotypic variants in a single population and in two different oceanic provinces SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MARINE PLANKTONIC ARCHAEA; IN-SITU HYBRIDIZATION; CENARCHAEUM-SYMBIOSUM; VERTICAL-DISTRIBUTION; DIVERSITY; SEQUENCES; BACTERIAL; PROTEINS; EUKARYOTES; IDENTIFICATION AB Planktonic crenarchaeotes are present in high abundance in Antarctic winter surface waters, and they also make up a large proportion of total cell numbers throughout deep ocean waters. To better characterize these uncultivated marine crenarchaeotes, we analyzed large genome fragments from individuals recovered from a single Antarctic picoplankton population and compared them to those from a representative obtained from deeper waters of the temperate North Pacific. Sequencing and analysis of the entire DNA insert from one Antarctic marine archaeon (fosmid 74A4) revealed differences in genome structure and content between Antarctic surface water and temperate deepwater archaea. Analysis of the predicted gene products encoded by the 74A4 sequence and those derived from a temperate, deepwater planktonic crenarchaeote (fosmid 4137) revealed many typical archaeal proteins but also several proteins that so far have not been detected in archaea. The unique fraction of marine archaeal genes included, among others, those for a predicted RNA-binding protein of the bacterial cold shock family and a eukaryote-type Zn finger protein. Comparison of closely related archaea originating from a single population revealed significant genomic divergence that was not evident from 16S rRNA sequence variation. The data suggest that considerable functional diversity may exist within single populations of coexisting microbial strains, even those with identical 16S rRNA sequences. Our results also demonstrate that genomic approaches can provide high-resolution information relevant to microbial population genetics, ecology, and evolution, even for microbes that have not yet been cultivated. C1 Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Diversa Corp, San Diego, CA 92121 USA. Univ Calif Santa Barbara, Inst Marine Sci, Santa Barbara, CA 93106 USA. RP DeLong, EF (reprint author), Monterey Bay Aquarium Res Inst, 7700 Sandholdt Rd,POB 628, Moss Landing, CA 95039 USA. OI Swanson, Ronald/0000-0002-6486-2676 NR 48 TC 134 Z9 148 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JAN PY 2002 VL 68 IS 1 BP 335 EP 345 DI 10.1128/AEM.68.1.335-345.2002 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 508JM UT WOS:000173085000042 PM 11772643 ER PT J AU Romanyukha, AA Desrosiers, M Sleptchonok, O Land, C Luckyanov, N Gusev, BI AF Romanyukha, AA Desrosiers, M Sleptchonok, O Land, C Luckyanov, N Gusev, BI TI EPR dose reconstruction of two Kazakh villages near the Semipalatinsk nuclear test site SO APPLIED MAGNETIC RESONANCE LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; TOOTH ENAMEL; SPIN-RESONANCE; DOSIMETRY; ESR AB Electron paramagnetic resonance (EPR) dose reconstruction has been performed on archived tooth samples from residents of two villages near the Semipalatinsk nuclear test site in Kazakstan. The context of this work is a large multidisciplinary study of thyroid disease prevalence and radiation dose among long-term residents of villages near that nuclear test site, in which EPR is used for biodosimetric validation of the gamma-ray component of dose reconstruction algorithms applied to the data for various villages whose residents were exposed to radioactive fallout during 1949-1962, the period of above-ground atomic bomb testing. The tooth samples, nine from the village of Kainar and 23 from the village of Znamenka, were extracted in 1964 and 1967, respectively, and stored indoors in closed boxes in Semipalatinsk. According to provided information, some time in the past, the teeth from Kainar were heated to 80degreesC for one day. Experiments carried out on 12 teeth from US sources to determine the effects of long-term storage and heat treatment found that EPR assay findings were not compromised for storage times less than 35 years and annealing at temperatures below 200degreesC. For tooth enamel samples prepared from molars and premolars the average reconstructed gamma dose was 390 +/- 70 mGy for Kainar residents and 95 +/- 40 mGy for Znamenka residents. C1 Kazakh Sci Res Inst Radiat Med & Ecol, Semipalatinsk, Kazakhstan. NCI, Radiat Epidemiol Branch, NIH, Rockville, MD USA. NIST, Ionizing Radiat Div, Gaithersburg, MD 20899 USA. RP Romanyukha, AA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol, Bldg 53,Room 123,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 21 TC 8 Z9 8 U1 0 U2 1 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0937-9347 EI 1613-7507 J9 APPL MAGN RESON JI Appl. Magn. Reson. PY 2002 VL 22 IS 3 BP 347 EP 356 DI 10.1007/BF03166116 PG 10 WC Physics, Atomic, Molecular & Chemical; Spectroscopy SC Physics; Spectroscopy GA 567ZE UT WOS:000176517300003 ER PT S AU Cebral, J Lohner, R Choyke, PL Yim, PJ AF Cebral, J Lohner, R Choyke, PL Yim, PJ BE Fagerholm, J Haataja, J Jarvinen, J Lyly, M Raback, P Savolainen, V TI Parallel patient-specific computational haemodynamics SO APPLIED PARALLEL COMPUTING: ADVANCED SCIENTIFIC COMPUTING SE Lecture Notes in Computer Science LA English DT Article; Proceedings Paper CT 6th International Conference on Applied Parallel Computing CY JUN 15-18, 2002 CL ESPOO, FINLAND SP IBM, Acad Finland, City Espoo, WM data Ltd, SAS, Springer Verlag ID NAVIER-STOKES EQUATIONS; FINITE-ELEMENT METHODS; FREE IMPLICIT METHOD; UNSTRUCTURED GRIDS; AEROELASTIC COMPUTATIONS; SURFACE RECONSTRUCTION; FLOW PROBLEMS; BLOOD-FLOW; ALGORITHMS; MESHES AB A methodology for the prediction of patient-specific bloodflow (haemodynamics) is presented. All aspects required for such predictions: image processing and segmentation, surface extraction, problem definition, grid generation, coupled fluid/structure solution, as well as visualization and data reduction are considered. Emphasis is placed on fast execution on parallel machines, particularly those with shared memory architectures. C1 George Mason Univ, Sch Computat Sci, Fairfax, VA 22030 USA. NIH, Imaging Sci Program, Bethesda, MD 20892 USA. RP Cebral, J (reprint author), George Mason Univ, Sch Computat Sci, MS 4C7, Fairfax, VA 22030 USA. EM jcebral@gmu.edu NR 59 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 3-540-43786-X J9 LECT NOTES COMPUT SC PY 2002 VL 2367 BP 18 EP 34 PG 17 WC Computer Science, Theory & Methods; Mathematics, Applied SC Computer Science; Mathematics GA BW57R UT WOS:000182460300002 ER PT S AU Cebral, J Lohner, R Choyke, PL Yim, PJ AF Cebral, J Lohner, R Choyke, PL Yim, PJ BE Fagerholm, J Haataja, J Jarvinen, J Lyly, M Raback, P Savolainen, V TI Parallel patient-specific computational haemodynamics SO APPLIED PARALLEL COMPUTING: ADVANCED SCIENTIFIC COMPUTING SE LECTURE NOTES IN COMPUTER SCIENCE LA English DT Article; Proceedings Paper CT 6th International Conference on Applied Parallel Computing CY JUN 15-18, 2002 CL ESPOO, FINLAND SP IBM, Acad Finland, City Espoo, WM data Ltd, SAS, Springer Verlag ID NAVIER-STOKES EQUATIONS; FREE IMPLICIT METHOD; UNSTRUCTURED GRIDS; AEROELASTIC COMPUTATIONS; SURFACE RECONSTRUCTION; BLOOD-FLOW; ALGORITHMS; MESHES; TRIANGULATIONS; SEGMENTATION AB A methodology for the prediction of patient-specific blood-flow (haemodynamics) is presented. All aspects required for such predictions: image processing and segmentation, surface extraction, problem definition, grid generation, coupled fluid/structure solution, as well as visualization and data reduction are considered. Emphasis is placed on fast execution on parallel machines, particularly those with shared memory architectures. C1 George Mason Univ, Sch Computat Sci, Fairfax, VA 22030 USA. NIH, Imaging Sci Program, Bethesda, MD 20892 USA. RP Cebral, J (reprint author), George Mason Univ, Sch Computat Sci, MS 4C7, Fairfax, VA 22030 USA. NR 58 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 3-540-43786-X J9 LECT NOTES COMPUT SC PY 2002 VL 2367 BP 18 EP 34 PG 17 WC Computer Science, Theory & Methods; Mathematics, Applied SC Computer Science; Mathematics GA BV79P UT WOS:000180068100002 ER PT J AU Lasch, P Haensch, W Lewis, EN Kidder, LH Naumann, D AF Lasch, P Haensch, W Lewis, EN Kidder, LH Naumann, D TI Characterization of colorectal adenocarcinoma sections by spatially resolved FT-IR microspectroscopy SO APPLIED SPECTROSCOPY LA English DT Article DE biomedical spectroscopy; FT-IR microspectroscopy; colorectal adenocarcinoma; imaging; pattern recognition; tissue classification; cluster analysis; artificial neural network analysis ID ARTIFICIAL NEURAL NETWORKS; CARCINOMA THIN-SECTIONS; INFRARED-SPECTROSCOPY; HUMAN TISSUE; SPECTRA; MICROSCOPY; DIAGNOSIS; CELLS AB A combination of Fourier transform infrared (FT-IR) spectroscopy and microscopy, FT-IR microspectroscopy, has been used to characterize sections of human colorectal adenocarcinoma. In this report, a database of 2601 high quality FT-IR point spectra from 26 patient samples and seven different histological structures was recorded and analyzed. The computer-based analysis of the IR spectra was carried out in four steps: (1) an initial test for spectral quality, (2) data pre-processing, (3) data reduction and feature selection, and (4) classification of the tissue spectra by multivariate pattern recognition techniques such as hierarchical clustering and artificial neural network analysis. Furthermore, an example of how spectral databases can be utilized to reassemble false color images of tissue samples is presented. The overall classification accuracy attained by optimized artificial neural networks reached 95%, highlighting the great potential of FT-IR microspectroscopy as a potentially valuable, reagent-free technique for the characterization of tissue specimens. However, technical improvements and the compilation of validated spectral databases are essential prerequisites to make the infrared technique applicable to routine and experimental clinical analysis. C1 Robert Koch Inst, D-13353 Berlin, Germany. Humboldt Univ, Fac Med Charite, Robert Rossle Klin, Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Robert Koch Inst, Nordufer 20, D-13353 Berlin, Germany. OI Lasch, Peter/0000-0001-6193-3144 NR 28 TC 59 Z9 61 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-7028 EI 1943-3530 J9 APPL SPECTROSC JI Appl. Spectrosc. PD JAN PY 2002 VL 56 IS 1 BP 1 EP 9 DI 10.1366/0003702021954322 PG 9 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 523HA UT WOS:000173946900002 ER PT J AU Miller, C Folkes, LK Mottley, C Wardman, P Mason, RP AF Miller, C Folkes, LK Mottley, C Wardman, P Mason, RP TI Revisiting the interaction of the radical anion metabolite of nitrofurantoin with glutathione SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE free radical; glutathione; nitrofurantoin; electron spin resonance; pulse radiolysis; stopped flow ID GENERATION; REDUCTION; TOXICITY; NITROREDUCTASE; METRONIDAZOLE; MECHANISM; PRODUCTS; ENZYMES; LIVER; EPR AB There have been several conflicting reports as to the scavenging nature of glutathione toward the nitro radical anion of the drug nitrofurantoin. We produced the radical anion enzymatically using the xanthine oxidase/hypoxanthine system at pH 7.4 and pH 9.0 in the presence of various levels of glutathione from 10 to 100 mM and monitored any changes in the radical concentration via electron spin resonance spectroscopy. Independent of glutathione concentration, there was no decrease in the steady-state concentration of the radical. In fact, there was an average 30% increase in the concentration of the radical anion, which suggests enhanced enzyme activity in the presence of glutathione (GSH). These results, together with observations of the effects of glutathione on the stability of the radical anion generated by radiolysis or dithionite, rule out any detectable reaction between the nitrofurantoin radical anion and GSH under physiologically relevant conditions. (C) 2001 Elsevier Science. C1 John Carroll Univ, Dept Chem, Cleveland, OH 44118 USA. Mt Vernon Hosp, Gray Lab, Canc Res Trust, Northwood HA6 2JR, Middx, England. Luther Coll, Dept Chem, Decorah, IA 52101 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, C (reprint author), John Carroll Univ, Dept Chem, 20700 N Pk Blvd, Cleveland, OH 44118 USA. NR 41 TC 3 Z9 3 U1 3 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2002 VL 397 IS 1 BP 113 EP 118 DI 10.1006/abbi.2001.2670 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 510UH UT WOS:000173225300014 PM 11747317 ER PT J AU Holsinger, T Steffens, DC Phillips, C Helms, MJ Havlik, RJ Breitner, JCS Guralnik, JM Plassman, BL AF Holsinger, T Steffens, DC Phillips, C Helms, MJ Havlik, RJ Breitner, JCS Guralnik, JM Plassman, BL TI Head injury in early adulthood and the lifetime risk of depression SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY FEB 23-26, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Assoc Geriatr Psychiat ID TRAUMATIC BRAIN INJURY; PSYCHIATRIC-DISORDERS; ALZHEIMERS-DISEASE; PERFORMANCE-CHARACTERISTICS; FUNCTIONAL DISABILITY; DEMENTIA; SYMPTOMS; HEALTH; QUESTIONNAIRE; ASSOCIATION AB Background: Depressive symptoms are common and can be debilitating in the months after head injury. Head injury can also have long-term cognitive effects, but little is known about the long-term risk of depression associated with head injury. We investigated the lifetime rates of depressive illness 50 years after closed head injury. Methods: Participants were male World War II veterans who served during 1944-1945 and were hospitalized at that time for a head injury, pneumonia, or laceration, puncture, or incision wounds. We used military medical records to establish the presence and severity of closed head injuries. Veterans with (n=520) and without (n=1198) head injuries were inter-viewed in 19961997 for their lifetime history of depressive illness. Men,with dementia were excluded. Results: Veterans with head injury were more likely to report major depression in subsequent years and were more often currently depressed. Using logistic regression and controlling for age and education, the lifetime prevalence of major depression in the head injured group was 18.5% vs 13.4% in those with no head injury (odds ratio=1.54, 95% confidence interval=1.17-2.04). Current major depression was detected in 11.2% of the veterans with head injuries vs 8.5% of those without head injury (odds ratio= 1.63, 95% confidence interval=1.07-2.50). This increase in depression could not be explained by a history of myocardial infarction, a history of cerebrovascular accident, or history of alcohol abuse. The lifetime risk of depression increased with severity of the head injury. Conclusion: The risk of depression remains elevated for decades following head injury and seems to be highest in those who have had a severe head injury. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. RP Plassman, BL (reprint author), 905 W Main St,Box 41, Durham, NC USA. NR 37 TC 123 Z9 125 U1 4 U2 15 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 2002 VL 59 IS 1 BP 17 EP 22 DI 10.1001/archpsyc.59.1.17 PG 6 WC Psychiatry SC Psychiatry GA 508XV UT WOS:000173115800004 PM 11779276 ER PT J AU Tohen, M Chengappa, KNR Suppes, T Zarate, CA Calabrese, JR Bowden, CL Sachs, GS Kupfer, DJ Baker, RW Risser, RC Keeter, EL Feldman, PD Tollefson, GD Breier, A AF Tohen, M Chengappa, KNR Suppes, T Zarate, CA Calabrese, JR Bowden, CL Sachs, GS Kupfer, DJ Baker, RW Risser, RC Keeter, EL Feldman, PD Tollefson, GD Breier, A TI Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 153rd Annual Meeting of the American-Psychiatric-Association CY MAY 13-18, 2000 CL CHICAGO, ILLINOIS SP Amer Psychiat Assoc ID WEIGHT-GAIN; RATING-SCALE; DISORDERS; PLACEBO AB Background: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. Methods: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). Results: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P=.003). Clinical response rates ( greater than or equal to50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P<.001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P<.001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of greater than or equal to20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P<.001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. Conclusion: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes. C1 Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA USA. SW Texas State Univ, Med Ctr, Dept Psychiat, Dallas, TX USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02138 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. RP Tohen, M (reprint author), Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. NR 23 TC 296 Z9 303 U1 4 U2 12 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 2002 VL 59 IS 1 BP 62 EP 69 DI 10.1001/archpsyc.59.1.62 PG 8 WC Psychiatry SC Psychiatry GA 508XV UT WOS:000173115800013 PM 11779284 ER PT J AU Leon-Sarmiento, FE AF Leon-Sarmiento, FE TI Blink reflex and discomplete facial nerve palsy SO ARCHIVES OF MEDICAL RESEARCH LA English DT Article DE facial palsy; R3; blink reflex; gamma motoneuron; C fibers; motor control ID R3 COMPONENT; INHIBITION AB Background. Electrophysiologic findings of the blink reflex in patients with Bell's palsy are usually said to be either prolonged latencies and/or absent early and middle responses of it. Methods. Facial nerve conduction and blink reflex studies were performed on a 42-yearold male patient with right-side Bell's palsy. Studies were done using protocols previously validated and published elsewhere. Results. The right compound muscle action potential was not found after stimulation of the right facial nerve as expected. Absence of the short (R1) and middle (R2) responses of the blink reflex were also noted after right and left supraorbital nerve stimulation. Further, the late (R3) response of the blink reflex was displayed on the abnormal side when electrical stimuli were applied to the right supraorbital nerve while the patient attempted to perform voluntary movement of the paralyzed facial muscles including eye closing. Conclusions. The recording of R3-a late response following fibers and using motoneurons other than those employed by R1 and R2-on the paralyzed side after performing some reinforcement maneuvers allows us to suggest that, in some facial nerve palsies, there are some structures remaining alive that may be useful for carrying out a more timely and accurate diagnosis and follow-up. (C) 2002 IMSS. Published by Elsevier Science Inc. C1 NINCDS, Brain Stimulat Unit, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Ind Santander, Fac Salud, Unidad Neurol, Dept Med Interna & Ciencias Basicas, Bucaramanga, Colombia. RP Leon-Sarmiento, FE (reprint author), NINCDS, Brain Stimulat Unit, Med Neurol Branch, NIH, Bldg 10,Room 5N234, Bethesda, MD 20892 USA. NR 22 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0188-4409 J9 ARCH MED RES JI Arch. Med. Res. PD JAN-FEB PY 2002 VL 33 IS 1 BP 85 EP 87 AR PII s0188-4409(01)00341-1 DI 10.1016/S0188-4409(01)00341-1 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 524DQ UT WOS:000173997200015 PM 11825637 ER PT J AU Felius, J Thompson, DA Khan, NW Bingham, EL Jamison, JA Kemp, JA Sieving, PA AF Felius, J Thompson, DA Khan, NW Bingham, EL Jamison, JA Kemp, JA Sieving, PA TI Clinical course and visual function in a family with mutations in the RPE65 gene SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID RETINALDEHYDE-BINDING PROTEIN; LEBER CONGENITAL AMAUROSIS; RECESSIVE RETINITIS-PIGMENTOSA; 11-CIS RETINOL DEHYDROGENASE; MACULAR DEGENERATION; STARGARDT-DISEASE; DYSTROPHY; ABCR; PHOTORECEPTORS; ADAPTATION AB Objective: To evaluate the phenotype of affected and carrier members of a family with mutations in RPE65 (a retinal pigment epithelium gene). Methods: RPE65 mutation screening was performed on DNA from 2 affected brothers, I unaffected brother, both parents, and 3 surviving grandparents using cycle sequencing. Ophthalmic examinations included ophthalmoscopic fundus examination; visual function testing; 2-color, static, dark-adapted threshold perimetry; and rod electroretinographic a-wave phototransduction analysis. Results: The 2 affected brothers carried RPE65 mutations in compound heterozygous form: a maternal Y368H (1156T-->C) missense mutation and a paternal IVS1 + 5g-->a splice-site mutation. Severe visual deficits and an absence of rod and cone electroretinographic responses were diagnosed in both affected boys before the age of 5 years. Visual acuities of about 20/100 during grade school declined to hand movements by the teenage years, and only a rudimentary peripheral temporal visual field remained by the ages of 25 and 29 years. Both parents had normal central visual function, as measured by visual acuity, contrast sensitivity, color vision, and Humphrey 10-2 fields. However, the 50-yearold father showed hundreds of tiny whitish hard drusen in both eyes and had abnormal peripheral function on dark-adapted perimetry, with extended field defects of 15 to 20 dB outside 30degrees eccentricity. His rod photoreceptor sensitivity and amplitude, calculated by fitting the rod a waves by a model of activation of phototransduction, were normal, but the flicker electroretinographic response was delayed. Conclusions: The RPE65 mutations Y368H and IVS1+5g-->a present in compound heterozygous form cause severe visual compromise in childhood and progress to nearly total vision loss by the second to third decades of life. The retinal and functional changes in the father carrying a presumed functional null allele suggest that some RPE65 heterozygous carriers may manifest visual symptoms. C1 Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI USA. Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA. RP Sieving, PA (reprint author), NEI, MSC, 31 Ctr Dr, Bethesda, MD 20892 USA. FU NEI NIH HHS [R01-EY06094, P30-EY07003, R01-EY12298] NR 37 TC 32 Z9 32 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JAN PY 2002 VL 120 IS 1 BP 55 EP 61 PG 7 WC Ophthalmology SC Ophthalmology GA 510BH UT WOS:000173188500007 PM 11786058 ER PT J AU Griffith, AJ Friedman, TB AF Griffith, AJ Friedman, TB TI Auditory function and the M34T allele of connexin 26 SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Letter C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Ct,Room 2A-02, Rockville, MD 20850 USA. NR 4 TC 5 Z9 5 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 2002 VL 128 IS 1 BP 94 EP 94 PG 1 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 510MM UT WOS:000173211900026 PM 11784272 ER PT J AU Emerson, SU AF Emerson, SU TI In memoriam Robert R. Wagner (1923-2001) - Obituary SO ARCHIVES OF VIROLOGY LA English DT Biographical-Item C1 NIAID, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. RP Emerson, SU (reprint author), NIAID, Hepatitis Viruses Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 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 2002 VL 147 IS 4 BP 871 EP 873 PG 3 WC Virology SC Virology GA 538YG UT WOS:000174842300020 ER PT J AU Iribarren, P Cui, YH Le, YY Wang, JM AF Iribarren, P Cui, YH Le, YY Wang, JM TI The role of dendritic cells in neurodegenerative diseases SO ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS LA English DT Review DE dendritic cells; neurodegenerative diseases; CNS ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTIGEN-PRESENTING CELLS; TUMOR-NECROSIS-FACTOR; MYELIN BASIC-PROTEIN; BLOOD-BRAIN-BARRIER; MULTIPLE-SCLEROSIS; ALZHEIMER-DISEASE; PRION PROTEIN; T-CELL AB Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the induction of adaptive immune responses. The presence of DCs in the central nervous system (CNS) and the active participation of the immune system in a variety of neurodegenerative diseases have been demonstrated. This review will discuss recent findings pertinent to DCs and other antigen-presenting cells in the CNS in health and disease states. C1 NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Iribarren, P (reprint author), NCI, Mol Immunoregulat Lab, Ctr Canc Res, Bldg 560,Room 31-40, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 91 TC 18 Z9 18 U1 1 U2 1 PU INST IMMUNOLOGY & EXPERIMENTAL THERAPY PI WROCLAW PA POLISH ACADEMY OF SCIENCES CZERSKA 12, 53-114 WROCLAW, POLAND SN 0004-069X J9 ARCH IMMUNOL THER EX JI Arch. Immunol. Ther. Exp. PY 2002 VL 50 IS 3 BP 187 EP 196 PG 10 WC Immunology SC Immunology GA 563PA UT WOS:000176263700005 PM 12098934 ER PT J AU Shum, L Nuckolls, G AF Shum, L Nuckolls, G TI The life cycle of chondrocytes in the developing skeleton SO ARTHRITIS RESEARCH LA English DT Review DE cartilage; chondrogenesis; endochondral ossification; limb bud; neural crest cells ID GROWTH-FACTOR RECEPTOR-3; BONE MORPHOGENETIC PROTEIN-2; TRANSCRIPTION FACTOR CBFA1; INDIAN HEDGEHOG; OSTEOBLAST DIFFERENTIATION; MOLECULAR INSIGHTS; MOUSE LIMB; CELL-DEATH; CARTILAGE DIFFERENTIATION; THANATOPHORIC DYSPLASIA AB Cartilage serves multiple functions in the developing embryo and in postnatal life. Genetic mutations affecting cartilage development are relatively common and lead to skeletal malformations, dysfunction or increased susceptibility to disease or injury. Characterization of these mutations and investigation of the molecular pathways in which these genes function have contributed to an understanding of the mechanisms regulating skeletal patterning, chondrogenesis, endochondral ossification and joint formation. Extracellular growth and differentiation factors including bone morphogenetic proteins, fibroblast growth factors, parathyroid hormone-related peptide, extracellular matrix components, and members of the hedgehog and Wnt families provide important signals for the regulation of cell proliferation, differentiation and apoptosis. Transduction of these signals within the developing mesenchymal cells and chondrocytes results in changes in gene expression mediated by transcription factors including Smads, Msx2, Sox9, signal transducer and activator of transcription (STAT), and core-binding factor alpha 1. Further investigation of the interactions of these signaling pathways will contribute to an understanding of cartilage growth and development, and will allow for the development of strategies for the early detection, prevention and treatment of diseases and disorders affecting the skeleton. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Nuckolls, G (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, 6 Ctr Dr,Bldg 6,Room 324,MSC2745, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [Z01 AR 41114] NR 112 TC 74 Z9 76 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2002 VL 4 IS 2 BP 94 EP 106 DI 10.1186/ar396 PG 13 WC Rheumatology SC Rheumatology GA 541MY UT WOS:000174989400005 PM 11879545 ER PT J AU Dorner, T Lipsky, PE AF Dorner, T Lipsky, PE TI Abnormalities of B cell phenotype, immunoglobulin gene expression and the emergence of autoimmunity in Sjogren's syndrome SO ARTHRITIS RESEARCH LA English DT Review DE autoimmunity; B cells; IgV gene usage; lymphocytes; Sjogren's syndrome ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ARTHRITIS SYNOVIAL TISSUE; LABIAL SALIVARY-GLANDS; J-LAMBDA REPERTOIRE; RHEUMATOID-ARTHRITIS; PERIPHERAL-BLOOD; PLASMA-CELLS; SOMATIC HYPERMUTATION; CD27/CD70 INTERACTION; MOLECULAR MECHANISMS AB Primary Sjogren's syndrome (pSS) is an autoimmune disorder characterized by specific pathologic features and the production of typical autoantibodies. In addition, characteristic changes in the distribution of peripheral B cell subsets and differences in use of immunoglobulin variable-region genes are also features of pSS. Comparison of B cells from the blood and parotid gland of patients with pSS with those of normal donors suggests that there is a depletion of memory B cells from the peripheral blood and an accumulation or retention of these antigen-experienced B cells in the parotids. Because disordered selection leads to considerable differences in the B cell repertoire in these patients, the delineation of its nature should provide important further clues to the pathogenesis of this autoimmune inflammatory disorder. C1 Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, Berlin, Germany. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Dorner, T (reprint author), Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, Berlin, Germany. FU NIAID NIH HHS [AI 31229] NR 97 TC 22 Z9 24 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2002 VL 4 IS 6 BP 360 EP 371 DI 10.1186/ar603 PG 12 WC Rheumatology SC Rheumatology GA 604BU UT WOS:000178596400008 PM 12453312 ER PT J AU Jacobi, AM Hansen, A Kaufmann, O Pruss, A Burmester, GR Lipsky, PE Dorner, T AF Jacobi, AM Hansen, A Kaufmann, O Pruss, A Burmester, GR Lipsky, PE Dorner, T TI Analysis of immunoglobulin light chain rearrangements in the salivary gland and blood of a patient with Sjogren's syndrome SO ARTHRITIS RESEARCH LA English DT Review DE B cells; parotid gland; Sjogren's syndrome; somatic mutation; V light chain genes ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; B-CELLS; RHEUMATOID-FACTOR; SOMATIC HYPERMUTATION; MOLECULAR MECHANISMS; MUTATIONAL ACTIVITY; REPERTOIRE; GENES; TISSUE; KAPPA AB Patients with Sjogren's syndrome (SS) have characteristic lymphocytic infiltrates of the salivary glands. To determine whether the B cells accumulating in the salivary glands of SS patients represent a distinct population and to delineate their potential immunopathologic impact, individual B cells obtained from the parotid gland and from the peripheral blood were analyzed for immunglobulin light chain gene rearrangements by PCR amplification of genomic DNA. The productive immunglobulin light chain repertoire in the parotid gland of the SS patient was found to be restricted, showing a preferential usage of particular variable lambda chain genes (Vlambda2E) and variable kappa chain genes (VkappaA27). Moreover, clonally related V-L chain rearrangements were identified; namely, VkappaA27-Jkappa5 and VkappaA19-Jkappa2 in the parotid gland, and Vlambda1C-Jlambda3 in the parotid gland and the peripheral blood. Vkappa and Vlambda rearrangements from the parotid gland exhibited a significantly elevated mutational frequency compared with those from the peripheral blood (P < 0.001). Mutational analysis revealed a pattern of somatic hypermutation similar to that found in normal donors, and a comparable impact of selection of mutated rearrangements in both the peripheral blood and the parotid gland. These data indicate that there is biased usage of V-L chain genes caused by selection and clonal expansion of B cells expressing particular V-L genes. In addition, the data document an accumulation of B cells bearing mutated V-L gene rearrangements within the parotid gland of the SS patient. These results suggest a role of antigen-activated and selected B cells in the local autoimmune process in SS. C1 Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, D-10098 Berlin, Germany. Univ Hosp Charite, Outpatients Dept, D-10098 Berlin, Germany. Univ Hosp Charite, Inst Pathol, D-10098 Berlin, Germany. Univ Hosp Charite, Inst Transfus Med, D-10098 Berlin, Germany. NIAMS, NIH, Bethesda, MD USA. RP Dorner, T (reprint author), Univ Hosp Charite, Dept Med Rheumatol & Clin Immunol, Schumannstr 20-21, D-10098 Berlin, Germany. NR 27 TC 17 Z9 17 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9913 J9 ARTHRITIS RES JI Arthritis Res. PY 2002 VL 4 IS 4 AR UNSP R4 DI 10.1186/ar423 PG 12 WC Rheumatology SC Rheumatology GA 564YN UT WOS:000176341300004 PM 12106503 ER PT J AU Kraan, TCTMV van Gaalen, FA Kasperkovitz, P Verbeet, N Alizadeh, AA Fero, M Huizinga, TWJ Pieterman, E Breedveld, FC Staudt, LM Botstein, D Brown, PO Verweij, CL AF Kraan, T. C. T. M. van der Pouw van Gaalen, F. A. Kasperkovitz, P. Verbeet, N. Alizadeh, A. A. Fero, M. Huizinga, T. W. J. Pieterman, E. Breedveld, F. C. Staudt, L. M. Botstein, D. Brown, P. O. Verweij, C. L. TI Discovery of distinctive gene expression profiles in human arthritides by cDNA micro-array analysis SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract C1 [Kraan, T. C. T. M. van der Pouw; Kasperkovitz, P.; Verbeet, N.] Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol, Amsterdam, Netherlands. [Kraan, T. C. T. M. van der Pouw; van Gaalen, F. A.; Huizinga, T. W. J.; Pieterman, E.; Breedveld, F. C.; Verweij, C. L.] LUMC, Dept Rheumatol, Leiden, Netherlands. [Kraan, T. C. T. M. van der Pouw; Alizadeh, A. A.; Brown, P. O.; Verweij, C. L.] Stanford Univ, Dept Biochem, Stanford, CA 94305 USA. [Fero, M.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Botstein, D.; Brown, P. O.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Staudt, L. M.] NIH, Div Clin Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2002 VL 4 SU 1 MA 28 PG 1 WC Rheumatology SC Rheumatology GA V31MW UT WOS:000208888700029 ER PT J AU Skapenko, A Lipsky, PE Kalden, JR Schulze-Koops, H AF Skapenko, A. Lipsky, P. E. Kalden, J. R. Schulze-Koops, H. TI Induction of Th2 cell differentiation by cognate interaction of CD4 memory T cells SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract C1 Univ Erlangen Nurnberg, Dept Internal Med 3, Nurnberg, Germany. NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2002 VL 4 SU 1 MA 69 PG 1 WC Rheumatology SC Rheumatology GA V31MW UT WOS:000208888700070 ER PT J AU Skapenko, A Wendler, J Lipsky, PE Kalden, JR Schulze-Koops, H AF Skapenko, A. Wendler, J. Lipsky, P. E. Kalden, J. R. Schulze-Koops, H. TI The bias for Th1 cell differentiation of rheumatoid arthritis T cells is characteristic of memory but not of naive T cells SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract C1 Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, Nurnberg, Germany. Univ Erlangen Nurnberg, Dept Internal Med 3, Nurnberg, Germany. NIAMS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2002 VL 4 SU 1 MA 68 PG 1 WC Rheumatology SC Rheumatology GA V31MW UT WOS:000208888700069 ER PT J AU Pandeya, SN Yogeeswari, P Sausville, EA Mauger, AB Narayanan, VL AF Pandeya, SN Yogeeswari, P Sausville, EA Mauger, AB Narayanan, VL TI Synthesis and antitumour evaluation of 4-bromophenyl semicarbazones SO ARZNEIMITTEL-FORSCHUNG-DRUG RESEARCH LA English DT Article DE antitumor drugs; 4-bromophenyl semicarbazones, antitumor evaluation, in vitro studies, synthesis ID ANTICONVULSANT; CANCER AB 4-Bromophenyl semicarbazone derivatives have been synthesized and their chemical structures have been confirmed by means of their IR, H-1-NMR data and by elemental analyses. The In vitro evaluation in the 3-cell line, one dose primary anticancer assay Is described. The 4-bromo substituted p-nitrobenzylidene phenyl semicarbazone (5) showed significant activity against breast MCF7 cell line and was further evaluated for potential anticancer activity In an in vitro human disease-oriented tumour cell line screening panel that consisted of 59 human tumour cell lines arranged in nine subpanels, representing diverse histologies. Melanoma UACC-62 cell line was relatively more sensitive to compounds 5 (growth inhibition: GI(50) = 15.3 mumol/l). C1 Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Pandeya, SN (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. NR 15 TC 1 Z9 1 U1 0 U2 0 PU ECV-EDITIO CANTOR VERLAG MEDIZIN NATURWISSENSCHAFTEN PI AULENDORF PA BANDELSTOCKWEG 20, POSTFACH 1255, D-88322 AULENDORF, GERMANY SN 0004-4172 J9 ARZNEIMITTEL-FORSCH JI Arzneimittelforschung PY 2002 VL 52 IS 2 BP 103 EP 108 PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 529ZV UT WOS:000174331900005 PM 11878197 ER PT J AU Nugent, RA AF Nugent, RA TI Contributions and constraints from agriculture in achieving a nutrition strategy to prevent chronic diseases SO ASIA PACIFIC JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop on Diet, Lifestyle and Chronic Disease Risk CY AUG 27-31, 2001 CL VIENNA, AUSTRIA DE agriculture; chronic disease; nutrition AB Improved nutrition has potential to stem the growth in chronic diseases seen in developed and developing countries alike. The ability of the agricultural sector to feed a country's population is an important factor in achieving better nutrition, particularly among populations that cannot buy imported food. How to address chronic disease must be considered in the very different contexts-of both developed and developing countries, as well as among wealthy and poor sub-populations. The limitations of agriculture in most developing countries to satisfy the nutritional needs of the population are revealed in the persistently high rates of under-nutrition in the developing world, and increases in over-nutrition. This paper develops the argument that agriculture must change dramatically in many countries to be able to provide the needed opportunities for improving nutrition for reduction of chronic disease risk. C1 US NIH, John E Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Nugent, RA (reprint author), US NIH, John E Fogarty Int Ctr, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0964-7058 J9 ASIA PAC J CLIN NUTR JI Asia Pac. J. Clin. Nutr. PY 2002 VL 11 SU S BP S767 EP S771 DI 10.1046/j.1440-6047.11.s.4.x PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 676EV UT WOS:000182739100005 PM 12656682 ER PT S AU McClure, CR Bertot, JC Sprehe, JT Griffith, JB AF McClure, CR Bertot, JC Sprehe, JT Griffith, JB BE Toms, EG TI Update on US federal information policies SO ASIST 2002: PROCEEDINGS OF THE 65TH ASIST ANNUAL MEETING, VOL 39, 2002 SE PROCEEDINGS OF THE ASIST ANNUAL MEETING LA English DT Article; Proceedings Paper CT 65th Annual Meeting of the American-Society-for-Information-Science-and-Technology CY NOV 18-21, 2002 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Informat Sci & Technol C1 Florida State Univ, Inst Informat, Tallahassee, FL 32306 USA. Sprehe Informat Management Associates, Washington, DC USA. Natl Lib Med, Bethesda, MD USA. RP McClure, CR (reprint author), Florida State Univ, Inst Informat, Tallahassee, FL 32306 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMATION TODAY INC PI MEDFORD PA 143 OLD MARLTON PIKE, MEDFORD, NJ 08055 USA SN 0044-7870 BN 1-57387-167-2 J9 P ASIST ANNU PY 2002 VL 39 BP 458 EP 459 DI 10.1002/meet.1450390156 PG 2 WC Computer Science, Information Systems; Information Science & Library Science; Social Issues SC Computer Science; Information Science & Library Science; Social Issues GA BV87V UT WOS:000180277800056 ER PT S AU Morris, TA Corn, M AF Morris, TA Corn, M BE Toms, EG TI The structure of medical Informatics SO ASIST 2002: PROCEEDINGS OF THE 65TH ASIST ANNUAL MEETING, VOL 39, 2002 SE PROCEEDINGS OF THE ASIST ANNUAL MEETING LA English DT Article; Proceedings Paper CT 65th Annual Meeting of the American-Society-for-Information-Science-and-Technology CY NOV 18-21, 2002 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Informat Sci & Technol AB This panel program discusses the nature of medical informatics as an information discipline: what constitutes Medical Informatics, how does it related to other disciplines, and what educational requirements do its information works face? Presenters are among the foremost researchers and spokespersons for the field. C1 Kent State Univ, Lib & Informat Sci, Columbus, OH 43210 USA. Natl Lib Med, Bethesda, MD 20892 USA. RP Morris, TA (reprint author), Kent State Univ, Lib & Informat Sci, 124 Mt Hall,1050 Carmack Rd, Columbus, OH 43210 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU INFORMATION TODAY INC PI MEDFORD PA 143 OLD MARLTON PIKE, MEDFORD, NJ 08055 USA SN 0044-7870 BN 1-57387-167-2 J9 P ASIST ANNU PY 2002 VL 39 BP 466 EP 466 DI 10.1002/meet.1450390162 PG 1 WC Computer Science, Information Systems; Information Science & Library Science; Social Issues SC Computer Science; Information Science & Library Science; Social Issues GA BV87V UT WOS:000180277800062 ER PT J AU Wenthold, RJ Safieddine, S Ly, CD Wang, YX Lee, HK Wang, CY Kachar, B Petralia, RS AF Wenthold, RJ Safieddine, S Ly, CD Wang, YX Lee, HK Wang, CY Kachar, B Petralia, RS TI Vesicle targeting in hair cells SO AUDIOLOGY AND NEURO-OTOLOGY LA English DT Article; Proceedings Paper CT Symposium on Auditory Function and Dysfunction: Molecular and Physiological Mechanisms CY AUG, 2001 CL AUCKLAND, NEW ZEALAND DE synapse; soluble-N-ethylmaleimide-sensitive fusion; protein receptor; hair cell; endosome ID MEMBRANE-FUSION; RIBBON SYNAPSES; SNARE COMPLEX; TRAFFICKING; PERSPECTIVES; PROTEINS; POLARITY AB The mammalian hair cell has two distinct plasma membrane domains separated by tight junctions, the apical domain which contains the stereocilia and the basolateral domain which contains the presynaptic region. Little is known concerning the mechanisms that regulate vesicle trafficking to these two domains. Using SNAP 25 and syntaxin as baits, we carried out a yeast two-hybrid screen of the organ of Corti. We identified a novel syntaxin interacting protein, ocsyn, that is enriched in inner hair cells and concentrated at the apical pole. Our results are consistent with ocsyn playing a role in vesicle trafficking to the apical membrane of the hair cell. Copyright (C) 2002 S. Karger AG, Basel. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIDCD, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wenthold, RJ (reprint author), NIDCD, Neurochem Lab, NIH, Bldg 50,Room 4140, Bethesda, MD 20892 USA. NR 21 TC 6 Z9 6 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1420-3030 J9 AUDIOL NEURO-OTOL JI Audiol. Neuro-Otol. PD JAN-FEB PY 2002 VL 7 IS 1 BP 45 EP 48 DI 10.1159/000046863 PG 4 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 535PL UT WOS:000174652800011 PM 11914526 ER PT B AU Alpan, O AF Alpan, O BE Hadziselimovic, F TI Gut-oriented immune responses and oral tolerance to dietary antigens SO AUTOIMMUNE DISEASES IN PEDIATRIC GASTROENTEROLOGY SE FALK SYMPOSIUM LA English DT Proceedings Paper CT 4th International FALK Symposium on Paediatric Gastroenterology CY NOV 08-09, 2001 CL BASEL, SWITZERLAND SP Falk Fdn ID DENDRITIC CELLS; LYMPHOID-TISSUE; PEYERS PATCH; T-HELPER; INDUCTION; MICE C1 NIH, Lab Cell & Mol Immunol, Bethesda, MD 20850 USA. RP Alpan, O (reprint author), NIH, Lab Cell & Mol Immunol, Bldg 3,Room 1011,900 Rockville Pike, Bethesda, MD 20850 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-8778-3 J9 FALK SYMP PY 2002 VL 127 BP 4 EP 8 PG 5 WC Gastroenterology & Hepatology; Immunology; Pediatrics SC Gastroenterology & Hepatology; Immunology; Pediatrics GA BW11K UT WOS:000180922700002 ER PT J AU Ojaimi, C Brooks, C Akins, D Casjens, S Rosa, P Elias, A Barbour, A Jasinskas, A Benach, J Katonah, L Radolf, J Caimano, M Skare, J Swingle, K Sims, S Schwartz, I AF Ojaimi, C Brooks, C Akins, D Casjens, S Rosa, P Elias, A Barbour, A Jasinskas, A Benach, J Katonah, L Radolf, J Caimano, M Skare, J Swingle, K Sims, S Schwartz, I TI Borrelia burgdorferi gene expression profiling with membrane-based arrays SO BACTERIAL PATHOGENESIS, PT C SE METHODS IN ENZYMOLOGY LA English DT Review ID LYME-DISEASE SPIROCHETE; OUTER-SURFACE-PROTEIN; DIFFERENTIAL EXPRESSION; ESCHERICHIA-COLI; BORNE DISEASES; IN-VITRO; TEMPERATURE; SEQUENCE C1 New York Med Coll, Dept Immunol & Microbiol, Valhalla, NY 10595 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Immunol & Microbiol, Oklahoma City, OK 73104 USA. Univ Utah, Med Ctr, Dept Pathol, Salt Lake City, UT 84132 USA. NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. SUNY Stony Brook, Ctr Infect Dis, Stony Brook, NY 11794 USA. Univ Connecticut, Ctr Microbial Pathogenesis, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06030 USA. Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. Texas A&M Univ, Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. Sigma Genosys, The Woodlands, TX 77380 USA. New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. RP Ojaimi, C (reprint author), New York Med Coll, Dept Immunol & Microbiol, Valhalla, NY 10595 USA. FU NCRR NIH HHS [RR15564]; NIAID NIH HHS [R01 AI045801, R01 AI045801-05A1, AI27044, AI29735, AI37248, AI42345, AI45801, R01 AI045801-04] NR 21 TC 26 Z9 26 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 2002 VL 358 BP 165 EP 177 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BV73G UT WOS:000179914700012 PM 12474386 ER PT B AU Vacchio, MS AF Vacchio, MS BE Leuschner, U Berg, PA Holtmeier, J TI Induction of immunological tolerance to fetal antigens during pregnancy SO BILE ACIDS AND PREGNANCY SE FALK SYMPOSIUM LA English DT Proceedings Paper CT Falk Workshop on Bile Acids and Pregnancy CY JUN 02, 2002 CL FREIBURG, GERMANY ID T-CELL TOLERANCE; HISTOCOMPATIBILITY COMPLEX ANTIGENS; RESTRICTED CROSS-PRESENTATION; RECEPTOR TRANSGENIC MICE; INDUCED APOPTOSIS; SELF-ANTIGENS; TRYPTOPHAN CATABOLISM; LYMPHOCYTE SUBSETS; IMMUNE PRIVILEGE; DELETION C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Vacchio, MS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B10, Bethesda, MD 20892 USA. NR 49 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-8782-1 J9 FALK SYMP PY 2002 VL 129A BP 6 EP 16 PG 11 WC Gastroenterology & Hepatology; Immunology; Obstetrics & Gynecology SC Gastroenterology & Hepatology; Immunology; Obstetrics & Gynecology GA BW07Z UT WOS:000180814700002 ER PT B AU Zhao, Q Principe, J Fitzsimmons, J Bradley, M Lang, P AF Zhao, Q Principe, J Fitzsimmons, J Bradley, M Lang, P BE Pardalos, PM Principe, J TI Functional magnetic resonance imaging data analysis with information-theoretic approaches SO BIOCOMPUTING SE BIOCOMPUTING (SERIES) LA English DT Proceedings Paper CT Conference on Biocomputing CY FEB 25-27, 2001 CL UNIV FLORIDA, GAINESVILLE, FL SP Ctr Appl Optimizat, Computat Neuroengn Ctr, Biomed Engn Program, Brain Inst, Sch Engn HO UNIV FLORIDA ID MUTUAL INFORMATION; ACTIVATION; MRI AB An information-theoretic approach is presented for functional Magnetic Resonance Imaging (fMRI) analysis to detect neural activations. Two divergence measures are employed to estimate the difference between two data distributions, obtained by segmenting the voxel time series based on the experimental protocol time-line. In order to validate the new technique activation signals were acquired from a specially constructed dynamic fMRI phantom placed in the scanner, instead of computer simulated signals. The data analysis shows that the divergence measure is more robust in quantifying the difference between two distributions than the methods that utilize only the first and second order statistics. More importantly, the divergence measure is a method for calculating the brain activation map that makes no assumptions about the data distribution (e.g., Gaussian distribution). Results are also shown based on data of visual task study of subjects. C1 Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. RP Zhao, Q (reprint author), Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. RI Zhao, Qun/C-3813-2011 NR 25 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 1-4020-0641-1 J9 BIOCOMP SER PY 2002 VL 1 BP 159 EP 173 PG 15 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematics, Interdisciplinary Applications; Clinical Neurology SC Computer Science; Engineering; Mathematics; Neurosciences & Neurology GA BV44Y UT WOS:000179012400009 ER PT J AU Igietseme, JU Black, CM Caldwell, HD AF Igietseme, JU Black, CM Caldwell, HD TI Chlamydia vaccines - Strategies and status SO BIODRUGS LA English DT Review ID OUTER-MEMBRANE-PROTEIN; GENITAL-TRACT INFECTION; GENE KNOCKOUT MICE; CYTOTOXIC T-LYMPHOCYTES; MUCOSAL IMMUNE-SYSTEM; TUMOR-NECROSIS-FACTOR; PROTECTIVE MONOCLONAL-ANTIBODIES; MOUSE PNEUMONITIS BIOVAR; NITRIC-OXIDE PRODUCTION; CORONARY HEART-DISEASE AB The ultimate goal of current chlamydial vaccine efforts is to utilise either conventional or modern vaccinology approaches to produce a suitable immunisation regimen capable of inducing a sterilising, long-Lived heterotypic protective immunity at mucosal sites of infection to curb the severe morbidity and worldwide prevalence of chlamydial infections. This lofty goal poses tremendous challenges that include the need to clearly define the relevant effectors mediating immunity, the antigens responsible for inducing these effectors, the anti-chlamydial action(s) of effectors, and establishment of the most effective method of vaccine delivery. Tackling these challenges is further compounded by the biological complexity of chlamydia, the existence of multiple serovariants, the capacity to induce both protective and deleterious immune effectors, and the occurrence of asymptomatic and persistent infections. Thus, novel molecular, immunological and genetic approaches are urgently needed to extend the frontiers of current knowledge, and develop new paradigms to guide the production of an effective vaccine regimen. Progress made in the last 15 years has culminated in various paradigm shifts in the approaches to designing chlamydial vaccines. The dawn of the current immunological paradigm for antichlamydial vaccine design has its antecedence in the recognition that chlamydial immunity is mediated primarily by a T helper type 1 (Th1) response, requiring the induction and recruitment of specific T cells into the mucosal microenvironment. Additionally, the ancillary role of humoral immune response in complementing the Th1-driven protective immunity, through ensuring adequate memory and optimal Th1 response during a reinfection, has been recognised. With continued progress in chlamydial genomics and proteomics, select chlamydial proteins, including structural, membrane and secretory proteins, are being targeted as potential subunit vaccine candidates. However, the development of an effective adjuvant, delivery vehicle or system for a potential subunit vaccine is still an elusive objective in these efforts. Promising delivery vehicles include DNA and virus vectors, bacterial ghosts and dendritic cells. Finally, a vaccine still represents the best approach to protect the greatest number of people against the ocular, pulmonary and genital diseases caused by chlamydial infections. Therefore, considering the urgency and the enormity of these challenges, a partially protective vaccine preventing certain severe sequelae would constitute an acceptable short-term goal to control Chlamydia. However, more research efforts and support are needed to achieve the worthy goal of protecting a significant number of the world's population from the devastating consequences of chlamydial invasion of the human mucosal epithelia. C1 Morehouse Sch Med, Atlanta, GA 30310 USA. CDC, Sci Resources Program, NCID, Atlanta, GA USA. NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Igietseme, JU (reprint author), Morehouse Sch Med, 720 Westview Dr, Atlanta, GA 30310 USA. FU NCRR NIH HHS [RR 03034]; NIAID NIH HHS [AI 41231]; NIGMS NIH HHS [GM 08248] NR 210 TC 47 Z9 51 U1 0 U2 1 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1173-8804 J9 BIODRUGS JI Biodrugs PY 2002 VL 16 IS 1 BP 19 EP 35 DI 10.2165/00063030-200216010-00003 PG 17 WC Oncology; Immunology; Pharmacology & Pharmacy SC Oncology; Immunology; Pharmacology & Pharmacy GA 541NF UT WOS:000174990100003 PM 11908999 ER PT J AU Otsu, M Candotti, F AF Otsu, M Candotti, F TI Gene therapy in infants with severe combined immunodeficiency SO BIODRUGS LA English DT Review ID RECEPTOR-GAMMA-CHAIN; ADENOSINE-DEAMINASE DEFICIENCY; HEMATOPOIETIC STEM-CELLS; BONE-MARROW TRANSPLANTATION; COMBINED IMMUNE-DEFICIENCY; APE LEUKEMIA-VIRUS; INACTIVATING LENTIVIRUS VECTOR; DEFECTIVE LYMPHOID DEVELOPMENT; THYMIC ORGAN-CULTURES; MICE LACKING JAK3 AB Severe combined immunodeficiencies (SCID) are rare disorders that represent paediatric medical emergencies, as the outcome for affected patients can easily be fatal unless proper treatment is performed. The only curative treatment for SCID is reconstitution of the patient's immunity. For more than 30 years, allogeneic bone marrow transplantation (BMT) has been extremely successful for SCID. However, BMT often results in only incomplete restoration of B cell function in treated patients, especially when haploidentical donors are used. In addition, BMT can be associated with severe complications such as graft-versus-host disease (GVHD). Alternative forms of therapy for SCID are therefore desirable. Genetic correction of peripheral T lymphocytes and/or haematopoietic stem cells (HSCs) by retrovirally mediated gene transfer has been attempted for patients with SCID due to adenosine deaminase deficiency, the first genetic disease targeted in clinical gene therapy trials with very limited success, overall. After these pioneer trials, recent progress has led to significant improvement of gene transfer techniques and better understanding of HSC biology which has culminated in the recent success of a gene therapy trial for patients affected with X-linked SCID (X-SCID). In this trial, patients with X-SCID received autologous bone marrow stem/progenitor cells which had been retrovirally transduced with a therapeutic gene. Based on the current follow-up, the overall efficacy of this gene therapy procedure is to be considered similar to or even better than that achievable by allogeneic BMT, because patients were not exposed to the risks of GVHD. Although these exciting results have clearly demonstrated that gene therapy is a feasible therapeutic option for X-SCID, they have also raised important questions regarding the long-term outcome of this experimental procedure and the possibility of translating this success into applications for other forms of SCID. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Rm 10C103,Bldg 10,MSC 1851,10 Ctr Dr, Bethesda, MD 20892 USA. OI Otsu, Makoto/0000-0002-9769-0217 NR 114 TC 11 Z9 11 U1 0 U2 6 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1173-8804 J9 BIODRUGS JI Biodrugs PY 2002 VL 16 IS 4 BP 229 EP 239 DI 10.2165/00063030-200216040-00001 PG 11 WC Oncology; Immunology; Pharmacology & Pharmacy SC Oncology; Immunology; Pharmacology & Pharmacy GA 598XL UT WOS:000178301800001 PM 12196037 ER PT J AU Kaune, WT Miller, MC Linet, MS Hatch, EE Kleinerman, RA Wacholder, S Mohr, AH Tarone, RE Haines, C AF Kaune, WT Miller, MC Linet, MS Hatch, EE Kleinerman, RA Wacholder, S Mohr, AH Tarone, RE Haines, C TI Magnetic fields produced by hand held hair dryers, stereo headsets, home sewing machines, and electric clocks SO BIOELECTROMAGNETICS LA English DT Article DE ELF; VLF; appliances; residential; exposure assessment; television sets ID APPLIANCES; EXPOSURE AB A recent epidemiologic study reported associations between leukemia risk in children and their personal use of television (TV) sets, hair dryers, and stereo headsets, and the prenatal use by their mothers of sewing machines. To provide exposure data to aid in the interpretation of these findings, extremely and very low frequency (ELF and VLF) magnetic fields, produced by a sample of each type of appliance were characterized in a field study of volunteers conducted in Washington DC and its Maryland suburbs. Questionnaire data regarding children's or mothers' patterns of usage of each type of appliance were also collected. ELF magnetic fields measured 10 cm from the nozzles of flair dryers were elevated over the ambient by a mean factor of 17 when these devices were in use. Fields near headsets being used to listen to music were not distinguishable from ambient levels except at frequencies below and well above 60 Hz and, even then, field levels were < 0.01 T. Home sewing machines produced ELF magnetic fields that were elevated by a factor of 2.8 over ambient levels at the front surfaces of the lower abdomens of mothers. Estimated mean daily times of usage of flair dryers, stereo headsets, and sewing machines were 2.6, 19, and 17 minutes, respectively. These data and previously published data on TV sets, do not provide a consistent picture of increased (or decreased) leukemia risk in relation to increasing peak or time weighted average (TWA) ELF magnetic field exposure. The data could, however, conceivably be compatible with some more complex biophysical model with unknown properties. Overall, the results of this study provide little evidence supporting the hypothesis that peak or TWA ELF magnetic fields produced by appliances are causally related to the risk of childhood leukemia in children. Bioelectromagnetics 23:14-25, 2002. (C) 2002 Wiley-Liss, Inc. C1 EM Factors, Richland, WA USA. NCI, Rockville, MD USA. Westat Corp, Rockville, MD USA. RP Kaune, WT (reprint author), 111 Piper Ct, Richland, WA 99352 USA. OI Kleinerman, Ruth/0000-0001-7415-2478; Hatch, Elizabeth/0000-0001-7901-3928 FU NCI NIH HHS [N01-CP-81121] NR 14 TC 13 Z9 14 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 0197-8462 J9 BIOELECTROMAGNETICS JI Bioelectromagnetics PD JAN PY 2002 VL 23 IS 1 BP 14 EP 25 DI 10.1002/bem.94 PG 12 WC Biology; Biophysics SC Life Sciences & Biomedicine - Other Topics; Biophysics GA 507XR UT WOS:000173057000003 PM 11793402 ER PT J AU Bohr, VA Brosh, RM von Kobbe, C Opresko, P Karmakar, P AF Bohr, VA Brosh, RM von Kobbe, C Opresko, P Karmakar, P TI Pathways defective in the human premature aging disease Werner syndrome SO BIOGERONTOLOGY LA English DT Article; Proceedings Paper CT International Conference on Biotechnology the Genome and Human Ageing CY MAR 19-22, 2001 CL MELBOURNE, AUSTRALIA SP Australian Soc Cellular Molec Gerontol (ASCMG) DE aging; DNA metabolism; DNA repair; Werner syndrome ID DNA-POLYMERASE-DELTA; SYNDROME PROTEIN; SYNDROME CELLS; SYNDROME GENE; SYNDROME FIBROBLASTS; HELICASE; WRN; EXONUCLEASE; INTERACTS; APOPTOSIS AB Werner syndrome is the hallmark premature aging disease, where the patients appear much older than their chronological age. The Werner protein, defective in this disorder, is a DNA helicase and an exonuclease, and it participates in pathways of DNA repair, recombination, transcription and replication. The function and role of this protein is discussed in the light of how it functions in the aging process. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Opresko, Patricia/0000-0002-6470-2189 NR 30 TC 10 Z9 10 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-5729 J9 BIOGERONTOLOGY JI Biogerontology PY 2002 VL 3 IS 1-2 BP 89 EP 94 DI 10.1023/A:1015223917491 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 541LT UT WOS:000174986600018 PM 12014850 ER PT J AU Hofmann, A Wlodawer, A AF Hofmann, A Wlodawer, A TI PCSB - a program collection for structural biology and biophysical chemistry SO BIOINFORMATICS LA English DT Article AB We present the first package of Java classes specifically aimed at the handling of structural and biophysical problems. To enable object-oriented programming a basis of fundamental Java classes is required which deals with basic operations of vectors, matrices, amino acid sequences, crystal symmetries and PDB files. Five classes, which carry out these basic operations, were constructed and bundled together with several utility functions in the PCSB package. Furthermore, to demonstrate their applicability and to obtain programs handling common tasks in structural laboratories, we present the first six applications of PCSB. All applications are portable to different platforms and require only the Java Runtime Environment to be installed on the system. Availability: http://www24.brinkster.com/hofmanna/pcsb/ Contact: hofmanna@ncifcrf.gov Supplementary information: A manual for PCSB describing the Java classes as well as the applications is available as PDF file. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Hofmann, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Hofmann, Andreas/B-9515-2008 OI Hofmann, Andreas/0000-0003-4408-5467 NR 7 TC 24 Z9 24 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN PY 2002 VL 18 IS 1 BP 209 EP 210 DI 10.1093/bioinformatics/18.1.209 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 520RG UT WOS:000173794400033 PM 11836236 ER PT J AU Cuthbert, BN AF Cuthbert, BN TI Social anxiety disorder: Trends and translational research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID AVOIDANT PERSONALITY-DISORDER; PHOBIA; SUBTYPES; DIAGNOSIS; PSYCHOPATHOLOGY; IDENTIFICATION; EPIDEMIOLOGY; AGORAPHOBIA; BEHAVIORS; COMMUNITY C1 NIMH, Adult Psychopathol & Prevent Res Branch, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, Adult Psychopathol & Prevent Res Branch, Bethesda, MD 20892 USA. NR 50 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2002 VL 51 IS 1 BP 4 EP 10 DI 10.1016/S0006-3223(01)01326-9 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 512NG UT WOS:000173330000002 PM 11801226 ER PT J AU Haxby, JV Hoffman, EA Gobbini, MI AF Haxby, JV Hoffman, EA Gobbini, MI TI Human neural systems for face recognition and social communication SO BIOLOGICAL PSYCHIATRY LA English DT Article DE face perception; functional brain imaging; spatial attention; emotion; facial expression; semantic knowledge ID POSITRON EMISSION TOMOGRAPHY; HUMAN EXTRASTRIATE CORTEX; HUMAN FUSIFORM GYRUS; TEMPORAL CORTEX; HUMAN AMYGDALA; FACIAL EXPRESSIONS; OCCIPITOTEMPORAL CORTEX; FUNCTIONAL-ORGANIZATION; VISUOSPATIAL ATTENTION; ORBITOFRONTAL CORTEX AB Face perception is mediated by a distributed neural system in humans that consists of multiple, bilateral regions. The functional organization of this system embodies a distinction between the representation of invariant aspects of faces, which is the basis for recognizing individuals, and the representation of changeable aspects, such as eye gaze, expression, and lip movement, which underlies the perception of information that facilitates social communication. The system also has a hierarchical organization. A core system, consisting of occipitotemporal regions in extrastriate visual cortex, mediates the visual analysis of faces. An extended system consists of regions from neural systems for other cognitive functions that can act in concert with the core system to extract meaning from faces. Of regions in the extended system for face perception, the amygdala plays a central role in processing the social relevance of information gleaned from faces, particularly when that information may signal a potential threat. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Haxby, JV (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104,10 Ctr Dr,MSC 1366, Bethesda, MD 20892 USA. RI X, Simon/F-4678-2011; Frank, David/E-8213-2012 NR 77 TC 619 Z9 635 U1 12 U2 90 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2002 VL 51 IS 1 BP 59 EP 67 DI 10.1016/S0006-3223(01)01330-0 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 512NG UT WOS:000173330000007 PM 11801231 ER PT J AU Merikangas, KR Avenevoli, S Acharyya, S Zhang, HP Angst, J AF Merikangas, KR Avenevoli, S Acharyya, S Zhang, HP Angst, J TI The spectrum of social phobia in the Zurich cohort study of young adults SO BIOLOGICAL PSYCHIATRY LA English DT Article DE social anxiety; social phobia; spectrum.; epidemiology; subthreshold; community study ID NATIONAL-COMORBIDITY-SURVEY; DIAGNOSTIC INTERVIEW SCHEDULE; QUALITY-OF-LIFE; ANXIETY DISORDERS; PSYCHIATRIC-DISORDERS; BEHAVIORAL-INHIBITION; CO-MORBIDITY; FAMILIAL AGGREGATION; DEPRESSIVE SPECTRUM; MENTAL-DISORDERS AB Background: The goals of the present study are to describe the prevalence, risk factors, course, and impact of social phobia in a 15-year prospective longitudinal community study; and to examine an expanded conceptualization of social phobia with respect to clinical indicators of severity, as well as gender differences, personality traits, and stability over 15 years. Methods: The sample is a cohort of 591 young adults aged 18-19 from the general population of Zurich, Switzerland at study entry who have been followed to age 35. Results: Six percent of participants met lifetime criteria for social phobia at the diagnostic level, 12% at the subthreshold level, and 24% had social phobia symptoms alone. Women had higher lifetime rates of diagnostic and subthreshold-level social phobia, whereas there was an equal gender ratio of social phobia symptoms. There was a direct association between strictness of the diagnostic threshold and severity, such that work impairment, social impairment, treatment rate, medication use, and subjective distress decreased from the diagnostic to the symptom level. Similarly, family history of phobias, autonomic lability, and comorbidity decreased across the spectrum. Although there was a substantial degree of longitudinal stability at each level of the spectrum, significant oscillation across levels suggests that the spectrum concept better characterizes the longitudinal course of social phobia. Conclusions: These findings demonstrate the utility of the social phobia spectrum. Application of the spectrum concept provides coverage of treated but undiagnosed cases of social phobia as well as those who vacillate across the diagnostic threshold over time. (C) 2002 Society of Biological Psychiatry. C1 NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. Univ Zurich, Dept Psychiat, Zurich, Switzerland. RP Merikangas, KR (reprint author), NIMH, Mood & Anxiety Program, NIH, 15K North Dr,MSC2670, Bethesda, MD 20892 USA. FU NIAAA NIH HHS [AA 12044]; NIDA NIH HHS [DA 00293, K02-DA 00293]; NIMH NIH HHS [MH 46376] NR 76 TC 75 Z9 77 U1 6 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2002 VL 51 IS 1 BP 81 EP 91 DI 10.1016/S0006-3223(01)01309-9 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 512NG UT WOS:000173330000009 PM 11801233 ER PT J AU Razik, MA Cidlowski, JA AF Razik, MA Cidlowski, JA TI Molecular interplay between ion channels and the regulation of apoptosis SO BIOLOGICAL RESEARCH LA English DT Article ID PLASMA-MEMBRANE DEPOLARIZATION; FAS-INDUCED APOPTOSIS; ACTIVATION; K+; DEGRADATION; PROTEINS; CASPASES; EFFLUX; DEATH AB Apoptosis is the programmed and deliberate destruction of specific cells. This process occurs during normal development and maintains cellular homeostasis. Disruption or malfunction of apoptosis is implicated in diseases like cancer, AIDS as well as neurodegenerative disorders. The movement of monovalent ions appears to set the stage for the induction of the self-destruction machinery by creating an intracellular environment that favors activation and coordinated execution of the apoptotic program. Understanding the components and steps involved in this intricate process can further our insight to diseases and reveal new approaches for therapeutic treatment. C1 NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, Mol Endocrinol Grp, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 20 TC 13 Z9 14 U1 0 U2 0 PU SOCIEDAD BIOLGIA CHILE PI SANTIAGO PA CASILLA 16164, SANTIAGO 9, CHILE SN 0716-9760 J9 BIOL RES JI Biol. Res. PY 2002 VL 35 IS 2 BP 203 EP 207 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 598VE UT WOS:000178296500011 PM 12415737 ER EF