FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ishii, Y AF Ishii, Y TI C-13-C-13 dipolar recoupling under very fast magic angle spinning in solid-state nuclear magnetic resonance: Applications to distance measurements, spectral assignments, and high-throughput secondary-structure determination SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ANISOTROPY CORRELATION NMR; TILTED ROTATING-FRAME; CHEMICAL-SHIFT; CORRELATION SPECTROSCOPY; COMPOSITE PULSES; FIBRIL FORMATION; AMINO-ACIDS; BETA-SHEET; PEPTIDE; RESOLUTION AB A technique is presented to recouple homonuclear dipolar couplings between dilute spin pairs such as C-13-C-13 systems under very fast magic angle spinning (MAS) in solid-state nuclear magnetic resonance (NMR) spectroscopy. The presented technique, finite pulse rf driven recoupling (fpRFDR), restores homonuclear dipolar interactions based on constructive usage of finite pulse-width effects in a phase- and symmetry-cycled pi -pulse train in which a rotor-synchronous pi pulse is applied every rotation period. The restored effective dipolar interaction has the form of a zero-quantum dipolar Hamiltonian for static solids, whose symmetry in spin space is different from that obtained by conventional rf driven recoupling (RFDR) techniques. It is demonstrated that the efficiency of recoupling by fpRFDR is not strongly dependent on chemical shift differences or resonance offsets in contrast to previous recoupling methods under very fast MAS. To realize distance measurements without effects of spin relaxation, a constant-time version of fpRFDR (CT-fpRFDR) is introduced, in which the effective evolution period is varied by refocusing dipolar evolution with a rotor-synchronized solid echo while the total recoupling period is kept constant. From CT-fpRFDR experiments at a spinning speed of 30.3 kHz in a field of 17.6 T, the C-13-C-13 distance of [1-C-13]Ala-[1-C-13]Gly-Gly was determined to be 3.27 A, which agrees well with the value of 3.20 Angstrom obtained by x-ray diffraction. Also, two-dimensional (2D) C-13/C-13 chemical-shift correlation NMR spectrum in a field of 9.4 T was obtained with fpRFDR for fibrils of the segmentally C-13- and N-15-labeled Alzheimer's beta -Amyloid fragments, A beta (16-22) (residues 16-22 taken from the 40-residue A beta peptide) in which Leu-17 through Ala-21 are uniformly C-13- and N-15-labeled. Most C-13 resonances for the main chain as well as for the side chains are assigned based on 2D C-13/C-13 chemical-shift correlation patterns specific to amino-acid types. Examination of the obtained C-13 chemical shifts revealed the formation of beta -strand across the entire molecule of A beta (16-22). Possibility of high throughput determination of global main-chain structures based on C-13 shifts obtained from 2D C-13/C-13 chemical-shift correlation under very fast MAS is also discussed for uniformly/segmentally C-13-labeled protein/peptide samples. C1 NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. RP Ishii, Y (reprint author), NIDDK, LCP, Bldg 5,Rm 406, Rockville, MD 20892 USA. RI Ishii, Yoshitaka/F-4558-2014 OI Ishii, Yoshitaka/0000-0002-7724-6469 NR 77 TC 194 Z9 195 U1 7 U2 37 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 15 PY 2001 VL 114 IS 19 BP 8473 EP 8483 DI 10.1063/1.1359445 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 428BC UT WOS:000168440400030 ER PT J AU Hansen, PL Podgornik, R AF Hansen, PL Podgornik, R TI Wormlike chains in the large-d limit SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ELECTROSTATIC PERSISTENCE LENGTH; SINGLE DNA-MOLECULES; RENORMALIZATION-GROUP; POLYELECTROLYTE CHAINS; POLYMERIZED MEMBRANES; CRUMPLING TRANSITION; SEMIFLEXIBLE CHAINS; FLUCTUATIONS; ELASTICITY; COLLAPSE AB We study the properties of an isolated, self-interacting wormlike polymer chain on the basis of a nonperturbative 1/d-expansion, where d denotes the dimension of embedding space. In the absence of an external force, we characterize the dimension R of the chain in embedding space via R similar toL(nu), where L is the internal size. (A) Long-range, repulsive segmental interactions decaying as 1/r(alpha) may control chain conformations that are either rodlike, nu =1(1 < alpha <2), "wrinkled," 1/2 < nu <1(2 < alpha <4), or random-walk-like, nu =1/2(alpha >4). (B) For short-range, screened, repulsive interactions, the crossover between rodlike and random-walk-like behavior is controlled by the persistence length whose interaction part we compute focusing on a Debye-Huckel interaction of strength V-0, with inverse screening length kappa (0). The induced persistence length varies as V(0)(beta)kappa (-gamma)(0), with, as expected, (beta,gamma)=(1,2) when the chain is intrinsically stiff, and, surprisingly, with either (beta,gamma)=(1/6,7/6) or (beta,gamma)=(1,7) when the chain is intrinsically very flexible. The chances of experimentally observing the novel regimes may be limited. For a chain subject to an external stretching force f, we determine the force-extension relation zeta=zeta (f )=zeta (0)+delta zeta (f ), where zeta denotes the chain extension, zeta (0) is the spontaneous extension. (A) If the interaction potential is either screened, or if the decay of a long-range interaction potential is fast, i.e., if alpha >4, the chain spontaneously generates an "effective tension" and responds linearly to weak forces with elastic constants "renormalized" by interactions. By contrast, "tension-free" chains, with either nu =1, where delta zeta similar tof(1/2), or with nu =2/alpha, where delta zeta similar tof(1/3), respond to the weakest force nonlinearly. (B) Near full extension the chain always responds nonlinearly. When the potential is screened, or if alpha >4, we find the 1/rootf corrections typical of wormlike chains. (C) 2001 American Institute of Physics. C1 Univ Calif Santa Barbara, Inst Theoret Phys, Santa Barbara, CA 93106 USA. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Fac Math & Phys, Dept Phys, SI-1000 Ljubljana, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. RP Hansen, PL (reprint author), Univ Calif Santa Barbara, Inst Theoret Phys, Santa Barbara, CA 93106 USA. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 46 TC 19 Z9 19 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 15 PY 2001 VL 114 IS 19 BP 8637 EP 8648 DI 10.1063/1.1355261 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 428BC UT WOS:000168440400047 ER PT J AU Lawrence, JA Adamson, PC Caruso, R Chow, C Kleiner, D Murphy, RF Venzon, DJ Shovlin, M Noone, M Merino, M Cowan, KH Kaiser, M O'Shaughnessy, J Zujewski, JA AF Lawrence, JA Adamson, PC Caruso, R Chow, C Kleiner, D Murphy, RF Venzon, DJ Shovlin, M Noone, M Merino, M Cowan, KH Kaiser, M O'Shaughnessy, J Zujewski, JA TI Phase clinical trial of alitretinoin and tamoxifen in breast cancer patients: Toxicity, pharmacokinetic, and biomarker evaluations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID 9-CIS RETINOIC ACID; CARDIOVASCULAR RISK-FACTORS; TERM FOLLOW-UP; STAGE-I T1N0M0; 9-CIS-RETINOIC ACID; POSTMENOPAUSAL WOMEN; X-RECEPTOR; 13-CIS-RETINOIC ACID; BIOLOGIC MARKERS; THYROID-HORMONE AB Purpose: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitreyinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored. Patients and Methods: Eligible patients herd metastatic breast cancer. Previous tamoxifen therapy was allowed. planned dose levels for alitretinoin ranged from 50 to 140 mg/m(2)/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy. Results: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m(2)/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m(2)/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor-positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained. Conclusion: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m(2)/d with 20 mg/d tamoxifen. (C) 2001 by American Society of Clinical Oncology. C1 NCI, Med Branch, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Pathol Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD USA. RP Zujewski, JA (reprint author), NCI, Med Branch, Pediat Oncol Branch, NIH, Bldg 10,12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 64 TC 39 Z9 39 U1 0 U2 1 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 MAY 15 PY 2001 VL 19 IS 10 BP 2754 EP 2763 PG 10 WC Oncology SC Oncology GA 433JX UT WOS:000168757200020 PM 11352969 ER PT J AU Lee, CK Kim, JK Kim, Y Lee, MK Kim, K Kang, JK Hofmeister, R Durum, SK Han, SS AF Lee, CK Kim, JK Kim, Y Lee, MK Kim, K Kang, JK Hofmeister, R Durum, SK Han, SS TI Generation of macrophages from early T progenitors in vitro SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELL-DEVELOPMENT; NATURAL-KILLER-CELLS; ADULT-MOUSE THYMUS; IN-VITRO; B-CELLS; FETAL THYMOCYTES; PRECURSOR CELLS; BONE-MARROW; IL-7; IDENTIFICATION AB Early T progenitors in the thymus have been reported to have the capacity to develop into B cells, thymic dendritic cells, and NK cells. Here we describe conditions that induce early T progenitors to develop into macrophages. Initially, we observed that early T progenitors could be induced to develop into macrophages by cytokines produced from a thymic stromal cell line, TFGD, and later we found that the cytokine mixture of M-CSF plus IL-6 plus IL-7 also induced macrophage differentiation from pro-T cells. M-CSF by itself was unable to induce macrophage differentiation from early T progenitors. To correlate this observation with the developmental potential of early T progenitors, mouse embryonic thymocytes were sorted into four populations, pro-T1 to pro-T4, based on the expression of CD44 and CD25, and then cultured with TFGD culture supernatant. We found that pro-T1 and pro-T2 cells, but not pro-T3 and pro-T4 cells, generate macrophages. Limiting dilution analysis of the differentiation capability of sorted pro-T2 cells also confirmed that pro-T2 cells could generate macrophages. These results suggest that T cells and thymic macrophages could originate from a common intrathymic precursor. C1 Chungbuk Natl Univ, Coll Pharm, Cheongju 361763, South Korea. Chungbuk Natl Univ, Coll Vet Med, Cheongju 361763, South Korea. Sahm Yook Univ, Dept Pharm, Seoul, South Korea. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Lee, CK (reprint author), Chungbuk Natl Univ, Coll Pharm, Cheongju 361763, South Korea. NR 32 TC 46 Z9 46 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2001 VL 166 IS 10 BP 5964 EP 5969 PG 6 WC Immunology SC Immunology GA 471VC UT WOS:000170948500015 PM 11342611 ER PT J AU Berrey, MM Schacker, T Collier, AC Shea, T Brodie, SJ Mayers, D Coombs, R Krieger, J Chun, TW Fauci, A Self, SG Corey, L AF Berrey, MM Schacker, T Collier, AC Shea, T Brodie, SJ Mayers, D Coombs, R Krieger, J Chun, TW Fauci, A Self, SG Corey, L TI Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 38th Interscience Conference on Antimicrobial Agents and Chemotherapy CY SEP 24-28, 1998 CL SAN DIEGO, CALIFORNIA ID PRIMARY HIV-INFECTION; CD4(+) T-CELLS; CONTROLLED TRIAL; DISEASE PROGRESSION; ANTIVIRAL THERAPY; PLASMA VIREMIA; VIRAL LOAD; ZIDOVUDINE; INDINAVIR; COMBINATION AB Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9-12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS. C1 Fred Hutchinson Canc Res Ctr, Program Infect Dis, Div Clin Res, Seattle, WA 98109 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Washington, Dept Lab Med, Seattle, WA USA. Univ Washington, Dept Urol, Seattle, WA USA. Fred Hutchinson Canc Res Ctr, Dept Biostat, Seattle, WA 98109 USA. Henry Ford Hosp, Detroit, MI 48202 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Corey, L (reprint author), Fred Hutchinson Canc Res Ctr, Program Infect Dis, Div Clin Res, 1100 Fairview Ave N,Rm D3-100,POB 19024, Seattle, WA 98109 USA. FU NIAID NIH HHS [AI-31448, AI-07140, AI-41535] NR 58 TC 80 Z9 80 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2001 VL 183 IS 10 BP 1466 EP 1475 DI 10.1086/320189 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 425HB UT WOS:000168284200005 PM 11319682 ER PT J AU Manthey, D Banach, K Desplantez, T Lee, CG Kozak, CA Traub, O Weingart, R Willecke, K AF Manthey, D Banach, K Desplantez, T Lee, CG Kozak, CA Traub, O Weingart, R Willecke, K TI Intracellular domains of mouse connexin26 and-30 affect diffusional and electrical properties of gap junction channels SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE lucifer yellow; neurobiotin; electrophysiology; chimeric connexins; structure-function relationship ID HUMAN HELA-CELLS; MOLECULAR-CLONING; FUNCTIONAL EXPRESSION; GENE; PROTEINS; BRAIN; LIVER; COMMUNICATION; DEAFNESS; PERMEABILITY AB To evaluate the influence of intracellular domains of connexin (Cx) on channel transfer properties, we analyzed mouse connexin (Cx) Cx26 and Cx30, which show the most similar amino acid sequence identities within the family of gap junction proteins. These connexin genes are tightly linked on mouse chromosome 14. Functional studies were performed on transfected HeLa cells stably expressing both mouse connexins. When we examined homotypic intercellular transfer of microinjected neurobiotin and Lucifer yellow, we Found that gap junctions in Cx30-transfected cells, in contrast to Cx26 cells, were impermeable to Lucifer yellow. Furthermore, we observed heterotypic transfer of neurobiotin between Cx30-transfectants and HeLa cells expressing mouse Cx30.3, Cx40, Cx-43 or Cx45, but not between Cx26 transfectants and HeLa cells of the latter group. The main differences in amino acid sequence between Cx26 and Cx30 are located in the presumptive cytoplasmic loop and C-terminal region of these integral membrane proteins. By exchanging one or both of these domains, using PCR-based mutagenesis, we constructed Cx26/30 chimeric cDNAs, which were also expressed in HeLa cells after transfection. Homotypic intercellular transfer of injected Lucifer yellow was observed exclusively with those chimeric constructs that coded for both cytoplasmic domains of Cx26 in the Cx30 backbone polypeptide chain. In contrast, cells transfected with a construct that coded for the Cx26 backbone with the Cx30 cytoplasmic loop and C-terminal region did not show transfer of Lucifer yellow. Thus, Lucifer yellow transfer can be conferred onto chimeric Cx30 channels by exchanging the cytoplasmic loop and the C-terminal region of these connexins. In turn, the cytoplasmic loop and C-terminal domain of Cx30 prevent Lucifer yellow transfer when swapped with the corresponding domains of Cx26, In chimeric Cx30/Cx26 channels where the cytoplasmic loop and C-terminal domains had been exchanged, the unitary channel conductance was intermediate between those of the parental channels. Moreover, the voltage sensitivity was slightly reduced. This suggests that these cytoplasmic domains interfere directly or indirectly with the diffusivity, the conductance and voltage gating of the channels. C1 Univ Bonn, Genet Inst, Abt Mol Genet, D-53117 Bonn, Germany. Univ Bern, Dept Physiol, CH-3012 Bern, Switzerland. NIAID, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. RP Willecke, K (reprint author), Univ Bonn, Genet Inst, Abt Mol Genet, Romerstr 164, D-53117 Bonn, Germany. NR 55 TC 63 Z9 68 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD MAY 15 PY 2001 VL 181 IS 2 BP 137 EP 148 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 437RQ UT WOS:000169007700007 PM 11420600 ER PT J AU Karl, A Birbaumer, N Lutzenberger, W Cohen, LG Flor, H AF Karl, A Birbaumer, N Lutzenberger, W Cohen, LG Flor, H TI Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cortical plasticity; sensorimotor reorganization; phantom limb pain; amputation; transcranial magnetic stimulation; neuroelectric source imaging ID TRANSCRANIAL MAGNETIC STIMULATION; MASSIVE CORTICAL REORGANIZATION; ISCHEMIC NERVE BLOCK; ADULT HUMAN BRAIN; EXTENSIVE REORGANIZATION; MOTONEURON PLASTICITY; ARM AMPUTATION; OUTPUTS; EXCITABILITY; ORGANIZATION AB Phantom limb pain (PLP) in amputees is associated with reorganizational changes in the somatosensory system. To investigate the relationship between somatosensory and motor reorganization and phantom limb pain, we used focal transcranial magnetic stimulation (TMS) of the motor cortex and neuroelectric source imaging of the somatosensory cortex (SI) in patients with and without phantom limb pain. For transcranial magnetic stimulation, recordings were made bilaterally from the biceps brachii, zygomaticus, and depressor labii inferioris muscles. Neuroelectric source imaging of the EEG was obtained after somatosensory stimulation of the skin overlying face and hand. Patients with phantom limb pain had larger motor- evoked potentials from the biceps brachii, and the map of outputs was larger for muscles on the amputated side compared with the intact side. The optimal scalp positions for stimulation of the zygomaticus and depressor labii inferioris muscles were displaced significantly more medially (toward the missing hand representation) in patients with phantom limb pain only. Neuroelectric source imaging revealed a similar medial displacement of the dipole center for face stimulation in patients with phantom limb pain. There was a high correlation between the magnitude of the shift of the cortical representation of the mouth into the hand area in motor and somatosensory cortex and phantom limb pain. These results show enhanced plasticity in both the motor and somatosensory domains in amputees with phantom limb pain. C1 Univ Heidelberg, Cent Inst Mental Hlth, Dept Clin & Cognit Neurosci, D-68159 Mannheim, Germany. Tech Univ Dresden, Dept Biopsychol, D-01062 Dresden, Germany. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. Univ Padua, Dept Gen Psychol, I-35100 Padua, Italy. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Flor, H (reprint author), Univ Heidelberg, Cent Inst Mental Hlth, Dept Clin & Cognit Neurosci, J5, D-68159 Mannheim, Germany. RI Lutzenberger, Werner/B-4296-2008; OI Karl, Anke/0000-0002-6472-2876; Flor, Herta/0000-0003-4809-5398 NR 87 TC 204 Z9 209 U1 4 U2 33 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 MAY 15 PY 2001 VL 21 IS 10 BP 3609 EP 3618 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 427MQ UT WOS:000168409400036 PM 11331390 ER PT J AU Eells, JB Rives, JE Yeung, SK Nikodem, VM AF Eells, JB Rives, JE Yeung, SK Nikodem, VM TI In vitro regulated expression of tyrosine hydroxylase in ventral midbrain neurons from Nurr1-null mouse pups SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE forskolin; dopamine; brain-derived neurotrophic factor; postnatal mesencephalic cultures ID MESENCEPHALIC DOPAMINERGIC-NEURONS; FIBROBLAST GROWTH-FACTOR; ORPHAN NUCLEAR RECEPTOR; ELEMENT-BINDING PROTEIN; NGFI-B; RESPONSE ELEMENT; GENE-EXPRESSION; STRIATAL NEURONS; MESSENGER-RNAS; CYCLIC-AMP AB The transcription factor Nurr1, an orphan member of the steroid-thyroid hormone nuclear receptor superfamily, is essential for the proper terminal differentiation of ventral midbrain dopaminergic neurons. Disruption of the Nurr1 gene in mice by homologous recombination abolishes synthesis of dopamine (DA) and expression of DA biosynthetic enzymes, including tyrosine hydroxylase (TH), in the ventral midbrain without affecting the synthesis of DA in other areas of the brain. At birth, however, dopaminergic neuron precursors in Nurr1 null (-/-) pups remain as shown by continued expression of residual, untranslated Nurr1 mRNA not altered by homologous recombination. Since Nurr1 disruption is lethal shortly after birth, to further investigate the developmental properties of these neurons, dissociated ventral midbrain neurons from newborn pups were grown for 5 days on an astrocyte feeder layer, subjected to various treatments and then evaluated for expression of TH by fluorescent immunocytochemistry. Initially, a small percentage of neurons (0.26% +/- 0.07%) from the ventral midbrain of Nurr1 -/- pups were TH-immunoreactive (TH-IR). No change in TH expression was observed in the presence of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), or DA alone or in combination. Treatment with forskolin (Fsk), however, significantly increased the percentage of TH-IR neurons (1.36% +/- 0.15%). Combination of Fsk, BNDF, and DA further increased the percentage of TH-IR neurons (2.58% +/- 0.50%). Therefore, these data suggest that dopaminergic neuron precursors, which develop in vivo without Nuur1, remain in an undifferentiated condition that is permissive to the induction of TH in vitro. Published 2001 Wiley-Liss, Inc.(dagger). C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Nikodem, VM (reprint author), NIDDKD, NIH, 9000 Rockville Pike,Bldg 10,Rm 8N317, Bethesda, MD 20892 USA. OI Eells, Jeffrey/0000-0002-6381-1666 NR 73 TC 17 Z9 18 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 MAY 15 PY 2001 VL 64 IS 4 BP 322 EP 330 DI 10.1002/jnr.1082 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 428AP UT WOS:000168439200002 PM 11340638 ER PT J AU Cheng, CM Cohen, M Tseng, V Bondy, CA AF Cheng, CM Cohen, M Tseng, V Bondy, CA TI Endogenous IGF1 enhances cell survival in the postnatal dentate gyrus SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE neurogenesis; hippocampus; apoptosis; mitosis ID GROWTH-FACTOR-I; CENTRAL-NERVOUS-SYSTEM; HIPPOCAMPAL-NEURONS; GENE-EXPRESSION; MESSENGER-RNA; BRAIN; NEUROGENESIS; INSULIN-LIKE-GROWTH-FACTOR-1; PROLIFERATION; MOTONEURONS AB The dentate gyrus is selectively reduced in size in the insulin-like growth factor 1 (IGF1) null mouse brain. The purpose of this study was to determine whether this defect is due to reduced granule cell numbers, and if so, to determine whether altered cell proliferation, survival, or both contribute to attenuation of dentate gyrus size. At postnatal day 10 (P10), granule cell numbers were not significantly different in IGF1 null and littermate wildtype (WT) dentate gyri. The subgranular zone cell population, however, was relatively increased, and the granule cell layer population relatively decreased in the IGF1 null dentate gyrus. By P50, total dentate cell numbers were decreased by 20% (P = 0.01) in the IGF1 null mouse, although IGF1 null subgranular zone progenitor cells remained relatively increased compared with WT (38%, P < 0.05). IGF1 null dentate cell proliferation, assessed by thymidine analogue incorporation, was actually increased at P10 (33%, P < 0.05) and P50 (167%, P = 0.001). Dentate granule cell death, assessed by the appearance of pycnotic cells and DNA fragmentation, was also significantly increased in the IGF1 null dentate (61%, P < 0.05 and 101%, P = 0.03). These data suggest that endogenous IGF1 serves an important role in dentate granule cell survival during the course of postnatal brain development. In addition, this work suggests the potential of a compensatory mechanism promoting increased dentate cell proliferation in the face of impaired cell survival during postnatal neurogenesis. Published 2001 Wiley-Liss, Inc.(dagger). C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Cheng, CM (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 34 TC 54 Z9 55 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 MAY 15 PY 2001 VL 64 IS 4 BP 341 EP 347 DI 10.1002/jnr.1084 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 428AP UT WOS:000168439200004 PM 11340640 ER PT J AU Forbes, JG Jin, AJ Wang, K AF Forbes, JG Jin, AJ Wang, K TI Atomic force microscope study of the effect of the immobilization substrate on the structure and force-extension curves of a multimeric protein SO LANGMUIR LA English DT Article ID BETA-AMYLOID PEPTIDE; ESCHERICHIA-COLI; ENTAMOEBA-HISTOLYTICA; ENTROPIC ELASTICITY; HIGH-RESOLUTION; REAL-TIME; MOLECULES; DNA; AFM; IMMUNOGLOBULIN AB Atomic force microscopy (AFM) of soluble proteins requires that the protein be immobilized on a flat substrate. Many different substrates have been used successfully for imaging proteins, with mica and gold on mica being the most commonly used. Successful imaging of a soluble protein requires that the protein adhere to the substrate; substrate adhesion is often the primary determinant in choosing a surface for AFM imaging. As a result of the constraint on substrate adhesion, little data is available on how the substrate can affect the conformation of proteins and the resulting images. The AdhE protein of Escherichia coli is a multienzyme that forms supramolecular structures composed of 20-60 subunits. We have used atomic force microscopy to study the aggregation state of the purified protein on different substrates and its elastic properties as measured by AFM. We have obtained both contact mode and noncontact (MAC mode) images of the protein assemblies immobilized on a substrate and imaged under buffer. Noncontact mode time pes on a mica surface show elongated structures as previously observed via electron microscopy, whereas the contact mode images on a gold surface over mica are dominated by globular particles composed of 1-8 monomers. Forced extension of the polypeptide chains yields force versus distance curves which may be fit with the wormlike chain (WLC) model. Our results are consistent with the subnanometer persistence length expected for a typical polypeptide chain. These results indicate that the extension of a protein chain in a supramolecular assembly is not significantly affected by the neighboring proteins. C1 NIAMS, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem Engn, College Pk, MD 20742 USA. RP Wang, K (reprint author), NIAMS, Phys Biol Lab, NIH, Bldg 6,Room 408, Bethesda, MD 20892 USA. OI Jin, Albert/0000-0003-3826-1081 NR 53 TC 24 Z9 24 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD MAY 15 PY 2001 VL 17 IS 10 BP 3067 EP 3075 DI 10.1021/la001559f PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 431EJ UT WOS:000168618600025 ER PT J AU Cote, CA Peculis, BA AF Cote, CA Peculis, BA TI Role of the ITS2-proximal stem and evidence for indirect recognition of processing sites in pre-rRNA processing in yeast SO NUCLEIC ACIDS RESEARCH LA English DT Article ID INTERNAL TRANSCRIBED SPACER-2; PRECURSOR RIBOSOMAL-RNA; SACCHAROMYCES-CEREVISIAE; ANGSTROM RESOLUTION; SECONDARY STRUCTURE; FUNCTIONAL-ANALYSIS; SEQUENCE; 5.8S; SUBUNIT; RDNA AB Eucaryotic cis-acting sequences and transacting factors, including snoRNAs. We have used directed mutagenesis of rDNA plasmids in yeast to identify critical sequence and structural elements within and flanking the ITS2-proximal stem. This base paired structure, present in the mature ribosome, is formed between the 5'-end of 25S and the 3'-end of 5.8S rRNAs. Previously we demonstrated that formation of this structure was critical for pre-rRNA processing in yeast. Here we show that there are no sequence-specific recognition elements within the ITS2-proximal stem, rather the structure of this stem is critical for processing. This stem cannot exceed a specific length, but there are different length restrictions for different regions within this tripartite stem. Neither the conserved unpaired nucleotides within the stem nor the sequence of the mature rRNA at the processing sites are required for processing. Collectively, these results suggest a measuring model whereby initial cleavage within ITS2 at the C2 processing site and termination of subsequent exonuclease activity yielding the mature termini are affected by the relative position of sequence and structural elements within the ITS2-proximal stem. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Peculis, BA (reprint author), NIDDK, Genet & Biochem Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 44 Z9 46 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 MAY 15 PY 2001 VL 29 IS 10 BP 2106 EP 2116 DI 10.1093/nar/29.10.2106 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 433GW UT WOS:000168752700013 PM 11353080 ER PT J AU Leibowitz, N Fligelman, ZY Nussinov, R Wolfson, HJ AF Leibowitz, N Fligelman, ZY Nussinov, R Wolfson, HJ TI Automated multiple structure alignment and detection of a common substructural motif SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE multiple structural alignment; geometric hashing; invariants; structural core; multiple structural comparison ID PROTEIN DATA-BANK; MOLECULAR-SURFACE; REPRESENTATION; INTERFACES; CORE AB While a number of approaches have been geared toward multiple sequence alignments, to date there have been very few approaches to multiple structure alignment and detection of a recurring substructural motif. Among these, none performs both multiple structure comparison and motif detection simultaneously. Further, none considers all structures at the same time, rather than initiating from pairwise molecular comparisons. We present such a multiple structural alignment algorithm. Given an ensemble of protein structures, the algorithm automatically finds the largest common substructure (core) of C, atoms that appears in all the molecules in the ensemble. The detection of the core and the structural alignment are done simultaneously. Additional structural alignments also are obtained and are ranked by the sizes of the substructural motifs, which are present in the entire ensemble. The method is based on the geometric hashing paradigm, As in our previous structural comparison algorithms, it compares the structures in an amino acid sequence order-independent way, and hence the resulting alignment is unaffected by insertions, deletions and protein chain directionality, As such, it can be applied to protein surfaces, protein-protein interfaces and protein cores to find the optimally, and suboptimally spatially recurring substructural motifs. There is no predefinition of the motif. We describe the algorithm, demonstrating its efficiency. In particular, we present a range of results for several protein ensembles, with different folds and belonging to the same, or to different, families. Since the algorithm treats molecules as collections of points in three-dimensional space, it can also be applied to other molecules, such as RNA, or drugs. (C) 2001 Wiley-Liss, Inc. C1 NCI, FCRDC, Lab Expt & Computat Biol, SAIC,Intramural Res Support Program, Ft Detrick, MD 21702 USA. Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP NCI, FCRDC, Lab Expt & Computat Biol, SAIC,Intramural Res Support Program, Bldg 469,Room 151, Ft Detrick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-56000] NR 18 TC 44 Z9 46 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAY 15 PY 2001 VL 43 IS 3 BP 235 EP 245 DI 10.1002/prot.1034 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 424EJ UT WOS:000168218900001 PM 11288173 ER PT J AU Portier, CJ AF Portier, CJ TI Linking toxicology and epidemiology: the role of mechanistic modelling SO STATISTICS IN MEDICINE LA English DT Article ID METABOLISM; PRIMIDONE; HUMANS; RAT C1 NIEHS, Div Intramural Res, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Biol Program, Res Triangle Pk, NC 27709 USA. RP Portier, CJ (reprint author), NIEHS, Div Intramural Res, Lab Computat Biol & Risk Anal, Box 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 21 TC 3 Z9 3 U1 0 U2 0 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 MAY 15 PY 2001 VL 20 IS 9-10 BP 1387 EP 1393 DI 10.1002/sim.676 PG 7 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 429JR UT WOS:000168513900010 PM 11343360 ER PT J AU Wyde, ME Eldridge, SR Lucier, GW Walker, NJ AF Wyde, ME Eldridge, SR Lucier, GW Walker, NJ TI Regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced tumor promotion by 17 beta-estradiol in female Sprague-Dawley rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE 2,3,7,8-tetrachlorodibenzo-p-dioxin; 17 beta-estradiol; Sprague-Dawley rats; liver; altered hepatocellular foci; ovariectomized; diethylnitrosamine; BrdU; 5-bromo-2 '-deoxyuridine ID INDUCED CELL-PROLIFERATION; ENZYME-ALTERED FOCI; ETHINYL ESTRADIOL; HAMSTER-KIDNEY; OVARIECTOMIZED RATS; CATECHOL ESTROGENS; CHRONIC EXPOSURE; POSITIVE FOCI; AH-RECEPTOR; LIVER DNA AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatocarcinogen in female but not in male rats. In an initiation-promotion model, ovariectomy inhibits TCDD-induced cell replication and reduces both TCDD-induced tumor formation and the promotion of enzyme-altered hepatocellular foci (AHF). The aim of this study was to determine the involvement of the ovarian hormone 17 beta -estradiol in the induction of cell proliferation and development of putative preneoplastic AHF following chronic exposure to TCDD. Diethylnitrosamine (DEN)-initiated ovariectomized (OVX) female rats were treated with TCDD for 20 or 30 weeks in the presence and absence of 17 beta -estradiol administered continuously by implanted 90-day release pellets. Following 20 weeks of treatment, cell proliferation in TCDD-treated rats was decreased regardless of ovarian hormones. Following 30 weeks of exposureTCDD, only significantly induced cell proliferation in OVX rats receiving supplemental 17 beta -estradiol, These data demonstrate that the the transitory mitoinhibition of cell replication by TCDD is not hormonally responsive, but that induction of cell replication at later time paints is. TCDD exposure resulted in elevated AHF expressing gamma -glutamyltranspeptidase (GGT) in intact, but not OVX rats at both time points. TCDD also induced GGT-positive AHF in 17 beta -estradiol-supplemented OVX rats. TCDD induced AHF expressing the placental form of glutathione-S-transferase (PGST) in both intact and OVX rats regardless of 17 beta -estradiol exposure, indicating that the modulating effect of 17 beta -estradiol on AHF was specific to the GGT-positive phenotype. (C) 2001 Academic Press diethylnitrosamine; BrdU; 5-bromo-2'-deoxyuridine. C1 NIEHS, Lab Computat Biol & Risk Anal, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27514 USA. Pathol Associates Int, Frederick, MD USA. RP Walker, NJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, Environm Toxicol Program, MD D4-01, POB 12233, Res Triangle Pk, NC 27709 USA. RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 59 TC 16 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 15 PY 2001 VL 173 IS 1 BP 7 EP 17 DI 10.1006/taap.2001.9166 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 438NT UT WOS:000169060500002 PM 11350210 ER PT J AU Psaty, BM Furberg, CD Kuller, LH Cushman, M Savage, P Levine, D O'Leary, DH Bryan, RN Anderson, M Lumley, T AF Psaty, BM Furberg, CD Kuller, LH Cushman, M Savage, P Levine, D O'Leary, DH Bryan, RN Anderson, M Lumley, T TI Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality - The cardiovascular health study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ISOLATED SYSTOLIC HYPERTENSION; CORONARY HEART-DISEASE; PULSE PRESSURE; OLDER ADULTS; METAANALYSIS; OUTCOMES AB Background: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. Methods: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. Results: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SEP was associated with total mortality. Importantly, SEP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SEP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SEP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SEP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. Conclusion: In this population-based study of older adults, although all measures of blood pressure were strongly and. directly related to the risk of coronary and cerebrovascular events, SEP was the best single predictor of cardiovascular events. C1 Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Vermont, Dept Med, Colchester, VT USA. Univ Vermont, Dept Pathol, Colchester, VT USA. NHLBI, Div Epidemiol & Clin Applicat, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Tufts Univ, New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Wake Forest Univ, Electrocardiog Reading Ctr, Winston Salem, NC 27109 USA. Univ Calif Davis, Davis, CA 95616 USA. Johns Hopkins Univ, MRI Reading Ctr, Baltimore, MD 21205 USA. Univ Calif Irvine, Echocardiog Reading Ctr Baseline, Irvine, CA 92697 USA. Georgetown Med Ctr, Echocardiog Reading Ctr, Washington, DC USA. New England Med Ctr, Ultrasound Reading Ctr, Boston, MA 02111 USA. Univ Vermont, Cent Blood Anal Lab, Colchester, VT USA. Univ Arizona, Pulmonary Reading Ctr, Tucson, AZ 85721 USA. Univ Washington, Coordinating Ctr, Seattle, WA 98195 USA. NHLBI, Project Off, Bethesda, MD 20892 USA. RP Psaty, BM (reprint author), Coordinat Ctr, Cardiovasc Hlth Study, Plaza 600,Bldg 600,Stewart St,Suite 700, Seattle, WA 98101 USA. RI Bryan, R. Nick/P-1661-2014 FU NHLBI NIH HHS [N01-HC-85083, HL43201, N01-HC-85080, HL35129, N01-HC-85084, N01-HC-85086, N01-HC-85082, N01-HC-85079, HL15103, N01-HC-85081, N01-HC-85085]; NIA NIH HHS [AG09556] NR 37 TC 202 Z9 215 U1 0 U2 5 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 MAY 14 PY 2001 VL 161 IS 9 BP 1183 EP 1192 DI 10.1001/archinte.161.9.1183 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 431HB UT WOS:000168624800006 PM 11343441 ER PT J AU Coresh, J Wei, L McQuillan, G Brancati, FL Levey, AS Jones, C Klag, MJ AF Coresh, J Wei, L McQuillan, G Brancati, FL Levey, AS Jones, C Klag, MJ TI Prevalence of high blood pressure and elevated serum creatinine level in the United States - Findings from the Third National Health and Nutrition Examination Survey (1988-1994) SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION RATE; FACTOR INTERVENTION TRIAL; CARDIOVASCULAR-DISEASE; AFRICAN-AMERICAN; RISK-FACTORS; HYPERTENSION; MORTALITY; PREDICTION; CLEARANCE AB Background: The prevalence and incidence of endstage renal disease in the United States are increasing, but milder renal disease is much more common and may often go undiagnosed and undertreated. Methods: A cross-sectional study of a representative sample of the US population was conducted using 16589 adult participants aged 17 years and older in the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994. An elevated serum creatinine level was defined as 141 mu mol/L or higher (greater than or equal to1.6 mg/dL) for men and 124 mu mol/L or higher (greater than or equal to1.4 mg/dL) for women (>99th percentile for healthy young adults) and was the main outcome measure. Results: Higher systolic and diastolic blood pressures, presence of hypertension, antihypertensive medication use, older age, and diabetes mellitus were all associated with higher serum creatinine levels. An estimated 3.0% (5.6 million) of the civilian, noninstitutionalized US population had elevated serum creatinine levels, 70% of whom were hypertensive. Among hypertensive individuals with an elevated serum creatinine level, 75% received treatment. However, only 11% of all individuals with hypertension had their blood pressure reduced to lower than 130/85 mm Hg (the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommendation for hypertensive individuals with renal disease); 27% had a blood pressure lower than 140/90 mm Hg. Treated hypertensive individuals with an elevated creatinine level had a mean blood pressure of 147/77 mm Hg, 48% of whom were prescribed one antihypertensive medication. Conclusion: Elevated serum creatinine level, an indicator of chronic renal disease, is common and strongly related to inadequate treatment of high blood pressure. C1 Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21218 USA. Johns Hopkins Univ, Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21218 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Hyattsville, MD 20782 USA. Tufts Univ, New England Med Ctr, Dept Med, Div Nephrol, Boston, MA 02111 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Coresh, J (reprint author), 2024 E Monument St,Suite 2-600, Baltimore, MD 21205 USA. FU NCRR NIH HHS [5M01RR00722, RR00035]; NIDDK NIH HHS [R29-DK48362] NR 41 TC 332 Z9 347 U1 1 U2 10 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 MAY 14 PY 2001 VL 161 IS 9 BP 1207 EP 1216 DI 10.1001/archinte.161.9.1207 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 431HB UT WOS:000168624800008 PM 11343443 ER PT J AU Ehler, E Horowits, R Zuppinger, C Price, RL Perriard, E Leu, M Caroni, P Sussman, M Eppenberger, HM Perriard, JC AF Ehler, E Horowits, R Zuppinger, C Price, RL Perriard, E Leu, M Caroni, P Sussman, M Eppenberger, HM Perriard, JC TI Alterations at the intercalated disk associated with the absence of muscle LIM protein SO JOURNAL OF CELL BIOLOGY LA English DT Article DE dilated cardiomyopathy; N-RAP; tropomodulin; adherens junction; gap junction ID FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; SCANNING CONFOCAL MICROSCOPY; NEBULIN-RELATED PROTEIN; DILATED CARDIOMYOPATHY; GAP-JUNCTIONS; VENTRICULAR MYOCARDIUM; STRIATED-MUSCLE; HEART-FAILURE; N-RAP; EXTRACELLULAR-MATRIX AB In this study, we investigated cardiomyocyte cytoarchitecture in a mouse model for dilated cardiomyopathy (DCM), the muscle LIM protein (MLP) knockout mouse and substantiated several observations in a second DCM model, the tropomodulin-over-expressing transgenic (TOT) mouse. Freshly isolated cardiomyocytes from both strains are characterized by a more irregular shape compared with wild-type cells. Alterations are observed at the intercalated disks, the specialized areas of mechanical coupling between cardiomyocytes, whereas the subcellular organization of contractile proteins in the sarcomeres of MLP knock-out mice appears unchanged. Distinct parts of the intercalated disks are affected differently. Components from the adherens junctions are upregulated, desmosomal proteins are unchanged, and gap junction proteins are: downregulated. In addition, the expression of N-RAP, a LIM domain- containing protein located at the intercalated disks, is upregulated in MLP knockout as well as in TOT mice. Detailed analysis of intercalated disk composition during postnatal development reveals that an upregulation of N-RAP expression might serve as an early marker for the development of DCM. Altered expression levels of cytoskeletal proteins (either the lack of MLP or an increased expression of tropomodulin) apparently lead to impaired function of the myofibrillar apparatus and to physiological stress that ultimately results in DCM and is accompanied by an altered appearance and composition of the intercalated disks. C1 ETH Zurich, Inst Cell Biol, CH-8093 Zurich, Switzerland. NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. Univ S Carolina, Dept Dev Biol & Anat, Columbia, SC 29208 USA. Miescher Inst Basel, CH-4002 Basel, Switzerland. Childrens Hosp & Res Fdn, Cincinnati, OH 45229 USA. RP Perriard, JC (reprint author), ETH Honggerberg, Inst Cell Biol, CH-8093 Zurich, Switzerland. OI Ehler, Elisabeth/0000-0001-5646-5964; Zuppinger, Christian/0000-0003-1786-0800 FU NHLBI NIH HHS [HL-58224] NR 55 TC 120 Z9 121 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 14 PY 2001 VL 153 IS 4 BP 763 EP 772 DI 10.1083/jcb.153.4.763 PG 10 WC Cell Biology SC Cell Biology GA 433QH UT WOS:000168770900013 PM 11352937 ER PT J AU Maraia, RJ AF Maraia, RJ TI La protein and the trafficking of nascent RNA polymerase III transcripts SO JOURNAL OF CELL BIOLOGY LA English DT Review ID 5S RIBOSOMAL-RNA; RECOGNITION PARTICLE RNA; XENOPUS-LAEVIS OOCYTES; METHIONYL-TRANSFER-RNA; U6 SPLICEOSOMAL RNA; LUPUS ANTIGEN-LA; SACCHAROMYCES-CEREVISIAE; NUCLEOLAR LOCALIZATION; MAMMALIAN-CELLS; NUCLEAR EXPORT C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, 6 Ctr Dr,Rm 416, Bethesda, MD 20892 USA. NR 50 TC 31 Z9 34 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 14 PY 2001 VL 153 IS 4 BP F13 EP F17 DI 10.1083/jcb.153.4.F13 PG 5 WC Cell Biology SC Cell Biology GA 433QH UT WOS:000168770900002 PM 11352926 ER PT J AU Santagada, V Fiorino, F Severino, B Salvadori, S Lazarus, LH Bryant, SD Caliendo, G AF Santagada, V Fiorino, F Severino, B Salvadori, S Lazarus, LH Bryant, SD Caliendo, G TI A convenient synthesis of N-Fmoc-N,N '-bis-Boc-7-guanyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (Fmoc-N,N '-bis-Boc-7-guanyl-Tic-OH, GTIC) SO TETRAHEDRON LETTERS LA English DT Article DE unconventional amino acid; synthesis; GTIC ID ANTAGONISTS; RESIDUE AB Fmoc-N,N'-Bis-Boc-7-guanyl-Tic-OH (GTIC), a conformationally constrained amino acid with basic properties, has been synthesized in four steps. This amino acid can be incorporated into peptides using standard Fmoc solid phase synthesis, and to test its potential for biological activity applications, we prepared an analog of H-Dmt-Tic-NH2. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy. Univ Ferrara, Dipartimento Sci Farmaceut, I-4100 Ferrara, Italy. NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. RP Santagada, V (reprint author), Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, Via D Montesano 49, I-80131 Naples, Italy. RI Wang, Rui/E-6585-2010; Severino, Beatrice/C-7466-2012; OI Severino, Beatrice/0000-0002-3887-8869; Caliendo, Giuseppe/0000-0002-5098-6045; SALVADORI, Severo/0000-0002-8224-2358 NR 10 TC 7 Z9 7 U1 0 U2 6 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 MAY 14 PY 2001 VL 42 IS 20 BP 3507 EP 3509 DI 10.1016/S0040-4039(01)00491-9 PG 3 WC Chemistry, Organic SC Chemistry GA 429GE UT WOS:000168507100028 ER PT J AU Hodge, JW Grosenbach, DW Rad, AN Giuliano, M Sabzevari, H Schlom, J AF Hodge, JW Grosenbach, DW Rad, AN Giuliano, M Sabzevari, H Schlom, J TI Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules SO VACCINE LA English DT Article DE splenocytes; costimulation; fowlpox; vaccinia; vaccine; T cells ID CYTOTOXIC T-LYMPHOCYTES; RECOMBINANT VACCINIA VIRUS; DENDRITIC CELLS; BONE-MARROW; TUMOR-IMMUNITY; PLASMODIUM-FALCIPARUM; ANTITUMOR IMMUNITY; MONONUCLEAR-CELLS; IN-VIVO; ACTIVATION AB Recombinant orthopox vectors (both replication-defective fowlpox [rF]. and replication competent vaccinia [rV] have been developed that simultaneously express three T-cell costimulatory molecule transgenes. The constituents of this, triad of costimulatory molecules (designated TRICOM) are B7-1, ICAM-1, and LFA-3. We have previously shown that infection of murine dendritic cells (DCs) with TRICOM vectors increases their level of expression of the triad of costimulatory molecules and enhances the efficacy of DCs to activate T cells. While DCs are arguably the most potent antigen presenting cell (APC), limitations clearly exist in their use due to the level of effort and cost for their generation. The studies reported here demonstrate that a generic APC population, murine splenocytes, can be made markedly more efficient as APCs by infection with either rF-TRICOM or rV-TRICOM vectors. Infection of splenocytes with either TRICOM vector led to significant improvement of APC capabilities in terms of: (a) enhancement of mixed lymphocyte reactions, (b) a reduction in the amount of signal 1 to activate naive T cells; and (c) a reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. TRICOM-enhanced T-cell activation was shown to correspond to increases in type-1 cytokines and a reduced level of apoptosis. compared with T cells activated with uninfected or control vector-infected splenocytes. In vitro and in vivo experiments compared DCs with TRICOM-infected splenocytes. Infection of splenocytes with TRICOM vectors markedly enhanced their ability to activate T cells to levels approaching that of DCs. These studies thus demonstrate for the first time that an abundant and accessible population of APCs obtainable without lengthy culture or the use of costly exogenous cytokines tin contrast to that of DCs) can be made more potent as APCs with the use of vectors that express a triad of costimulatory molecules. Published by Elsevier Science Ltd. C1 Natl Canc Inst, Tumor Immunol & Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), Natl Canc Inst, Tumor Immunol & Biol Lab, Natl Inst Hlth, Bldg 10,Room 8B07,10 Ctr Dr, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 42 TC 33 Z9 34 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 14 PY 2001 VL 19 IS 25-26 BP 3552 EP 3567 DI 10.1016/S0264-410X(01)00062-7 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 437LF UT WOS:000168992600029 PM 11348723 ER PT J AU Ludvig, N George, MA Tang, HM Gonzales, RA Bungay, PM AF Ludvig, N George, MA Tang, HM Gonzales, RA Bungay, PM TI Evidence for the ability of hippocampal neurons to develop acute tolerance to ethanol in behaving rats SO BRAIN RESEARCH LA English DT Article DE ethanol; rat; hippocampal neuron; acute tolerance ID QUANTITATIVE MICRODIALYSIS; PLACE CELLS; ALCOHOL; INHIBITION; ANIMALS; LINES; MICE AB Background: The cellular mechanisms underlying acute tolerance to alcohol are unclear. This study aimed to determine whether hippocampal neurons have the ability to develop acute tolerance to alcohol in behaving rats. Methods: Intrahippocampal microdialysis was performed in freely behaving rats, and the tiring of single neurons in the dialysis area was recorded. The control microdialysis fluid, artificial cerebrospinal fluid (ACSF), was replaced with 1 M ethanol in ACSF for a 30 min period. One hour later, the ethanol perfusion was repeated. To test the functional integrity of the microdialysis probe in situ, each microdialysis session was completed with recording the effect of a 10-20 min perfusion of 500 muM N-methyl-D-aspartate (NMDA). The extracellular concentration profile of ethanol during intrahippocampal microdialysis with 1 M ethanol was estimated in a separate study in anesthetized rats. The ethanol content was measured in tissue slices surrounding the probe with gas chromatography (GC), and the generated data were analyzed with a mathematical model for microdialysis to estimate the concentration of ethanol at the recording site. Results: The predominant effect of the first intrahippocampal microdialysis with ethanol was a decrease in firing rate in both pyramidal cells and interneurons. In contrast, such tiring rate decrease did not develop during the second ethanol perfusion. Subsequent NMDA perfusion still induced robust changes in the electrical activity of the neurons. The estimated extracellular ethanol concentration at the recording site was 45-70 mM. Conclusion: This study revealed that hippocampal neurons have the ability to develop acute tolerance to a single exposure of clinically relevant concentrations of ethanol in behaving rats, without influences from the rest of the body. (C) 2001 Elsevier Science B.V. All rights reserved. C1 SUNY Hlth Sci Ctr, Hlth Sci Ctr, Dept Physiol & Pharmacol, Brooklyn, NY 11203 USA. Univ Texas, Coll Pharm, Austin, TX 78712 USA. NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. RP Ludvig, N (reprint author), SUNY Hlth Sci Ctr, Hlth Sci Ctr, Dept Physiol & Pharmacol, 450 Clarkson Ave,Box 31, Brooklyn, NY 11203 USA. FU NIAAA NIH HHS [AA 08484, AA 10814] NR 27 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 11 PY 2001 VL 900 IS 2 BP 252 EP 260 DI 10.1016/S0006-8993(01)02319-8 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 429BQ UT WOS:000168496500013 PM 11334805 ER PT J AU Johnston, RE Dillon-Carter, O Freed, WJ Borlongan, CV AF Johnston, RE Dillon-Carter, O Freed, WJ Borlongan, CV TI Trophic factor secreting kidney cell lines: in vitro characterization and functional effects following transplantation in ischemic rats SO BRAIN RESEARCH LA English DT Article DE glial cell line-derived neurotrophic factor; kidney cell line; cerebral ischemia; growth factor; behavioral recovery; volume of infarction ID MIDDLE CEREBRAL-ARTERY; FIBROBLAST-GROWTH-FACTOR; MICE LACKING GDNF; POSSIBLE NEUROPROTECTIVE MECHANISM; NEUROTROPHIC FACTOR PROTECTS; BRAIN INJURY; NEURONAL APOPTOSIS; SURVIVAL FACTOR; NERVOUS-SYSTEM; MESSENGER-RNA AB Several kidney cell lines were investigated for their ability to produce glial cell line-derived neurotrophic factor (GDNF). Cell line-conditioned medium was analyzed using ELISA and two cell lines were identified which produce GDNF in physiologically active concentrations. ELISA analyses revealed that conditioned medium from these two cell lines also contained PDGF. bFGF, TGF beta1 and TGF beta2. Both of these cell lines were then transplanted into the striatal penumbra of rats. 1 h following middle cerebral artery occlusion. Behavioral testing revealed that both cell lines reduced the deficit associated with cerebral ischemia and reduced the infarct volume relative to controls. Reduction of infarct volume was likely achieved by the action of GDNF and/or other growth factors produced by the cells. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NIDA, Dev & Plast Sect, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. RP Johnston, RE (reprint author), NIDA, Dev & Plast Sect, Cellular Neurobiol Res Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Borlongan, Cesar/0000-0002-2966-9782 NR 63 TC 36 Z9 39 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 11 PY 2001 VL 900 IS 2 BP 268 EP 276 DI 10.1016/S0006-8993(01)02327-7 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 429BQ UT WOS:000168496500015 PM 11334807 ER PT J AU Shen, XH Knutson, JR AF Shen, XH Knutson, JR TI Femtosecond internal conversion and reorientation of 5-methoxyindole in hexadecane SO CHEMICAL PHYSICS LETTERS LA English DT Article ID INDOLE; RESOLUTION; TRYPTOPHAN AB The femtosecond internal conversion (IC) of the tryptophan sidechain analog 5-methoxyindole (5MI) in hexadecane (HD) was observed using fluorescence upconversion. The time constant for internal conversion between L-1(a), and L-1(b) was estimated at 10-40 fs. A triple-exponential emission anisotropy decay, due to molecular reorientation, was also observed. The dependence of initial anisotropy upon excitation wavelength sets limits on L-1(a) vs. L-1(b) transition oscillator orientations. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Opt Spect Sect, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Knutson, JR (reprint author), NHLBI, Opt Spect Sect, Biophys Chem Lab, NIH, Bldg 10,Rm 5D14, Bethesda, MD 20892 USA. NR 11 TC 15 Z9 15 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD MAY 11 PY 2001 VL 339 IS 3-4 BP 191 EP 196 DI 10.1016/S0009-2614(01)00325-6 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 434BM UT WOS:000168795300006 ER PT J AU Acquas, E Pisanu, A Marrocu, P Goldberg, SR Di Chiara, G AF Acquas, E Pisanu, A Marrocu, P Goldberg, SR Di Chiara, G TI Delta(9)-tetrahydrocannabinol enhances cortical and hippocampal acetylcholine release in vivo: a microdialysis study SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE acetylcholine; hippocampus; Delta(9)-tetrahydrocannabinol; microdialysis, in vivo; cortex, prefrontal; SR 141716A ID CANNABINOID RECEPTOR AGONIST; MEDIAL-PREFRONTAL CORTEX; FREELY MOVING RATS; MEMORY; DELTA-9-TETRAHYDROCANNABINOL; ANANDAMIDE; ACTIVATION; MECHANISM AB The intravenous administration of synthetic cannabinoid agonists was recently shown to dose dependently increase acetylcholine release from the rat prefrontal cortex and hippocampus (Eur. J. Pharmacol. 401 (2000) 179]. We report here that the active ingredient of cannabis preparations, Delta (9)-tetrahydrocannabinol, administered at 10, 37.5, 75 and 150 mug/kg, dose dependently stimulated acetylcholine release from rat prefrontal cortex and hippocampus estimated by means of in vivo brain microdialysis with vertical concentric probes. At these doses, Delta (9)-tetrahydrocannabinol induced behavioural stimulation. The administration of the CB1 receptor antagonist, ((N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidie)HCl) SR 141716A (200 mug/kg i.p.) significantly reduced the effect of Delta (9)-tetrahydrocannabinol (75 mug/kg i.v.) on acetylcholine release from rat prefrontal cortex and hippocampus. (C) 2001 Published by Elsevier Science B.V. C1 Univ Cagliari, Dept Toxicol, I-09126 Cagliari, Italy. CNR, Ctr Neuropharmacol, I-09126 Cagliari, Italy. NIDA, Preclin Pharmacol Sect, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. RP Di Chiara, G (reprint author), Univ Cagliari, Dept Toxicol, Via le A Diaz 182, I-09126 Cagliari, Italy. RI Acquas, Elio/G-1705-2010; Di Chiara, Gaetano/I-7835-2013; Pisanu, Augusta/B-8143-2015 OI Pisanu, Augusta/0000-0003-2633-8627 NR 21 TC 40 Z9 40 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 11 PY 2001 VL 419 IS 2-3 BP 155 EP 161 DI 10.1016/S0014-2999(01)00967-0 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 435MP UT WOS:000168885500007 PM 11426837 ER PT J AU Matsumoto, RR McCracken, KA Friedman, MJ Pouw, B De Costa, BR Bowen, WD AF Matsumoto, RR McCracken, KA Friedman, MJ Pouw, B De Costa, BR Bowen, WD TI Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma(1) receptors produce anti-cocaine effects in mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE antisense; cocaine; convulsion; locomotor activity; psychomotor activity; sigma receptor; toxicity ID BIOLOGICAL EVALUATION; INDUCED CONVULSIONS; RAT-BRAIN; LIGANDS; BINDING; MODULATION; STIMULATION; AFFINITY; COMPLEX; RELEASE AB Cocaine's ability to interact with a receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel a receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane). BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine and LR132 (1R,2S-(+)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl) Competition binding assays demonstrated that all three compounds have high affinities for a, receptors. The three compounds vary in their affinities for a, receptors and exhibit negligible affinities for dopamine, opioid, GABA, and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized a receptor agonist di-o-tolylguanidine (DTG) and the novel a receptor agonist BD1031 (3R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of a receptors, an antisense oligodeoxynucleotide against a, receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of a receptors is capable of attenuating a number of cocaine-induced behaviors. (C) 2001 Published by Elsevier Science B.V. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Matsumoto, RR (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, POB 26901,CPB 337, Oklahoma City, OK 73190 USA. FU NIDA NIH HHS [DA11979]; NIMH NIH HHS [MH50564] NR 62 TC 49 Z9 50 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 11 PY 2001 VL 419 IS 2-3 BP 163 EP 174 DI 10.1016/S0014-2999(01)00968-2 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 435MP UT WOS:000168885500008 PM 11426838 ER PT J AU Bour, S Perrin, C Akari, H Strebel, K AF Bour, S Perrin, C Akari, H Strebel, K TI The human immunodeficiency virus type 1 Vpu protein inhibits NF-kappa B activation by interfering with beta TrCP-mediated degradation of I kappa B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS FACTOR-ALPHA; HIV-1-INFECTED MYELOID CELLS; TRANSCRIPTION FACTORS; RAPID DEGRADATION; ENVELOPE PROTEIN; PARTICLE RELEASE; GENE-EXPRESSION; TRANSGENIC MICE; PLASMA-MEMBRANE; MAMMALIAN-CELLS AB The human immunodeficiency virus type 1 (HIV-1) Vpu protein binds to the CD4 receptor and induces its degradation by cytosolic proteasomes. This process involves the recruitment of human beta TrCP (TrCP), a key member of the SkpI-Cdc53-F-box E3 ubiquitin ligase complex that specifically interacts with phosphorylated Vpu molecules. Interestingly, Vpu itself, unlike other TrCP-interacting proteins, is not targeted for degradation by proteasomes. We now report that, by virtue of its affinity for TrCP and resistance to degradation, Vpu, but not a phosphorylation mutant unable to interact with TrCP, has a dominant negative effect on TrCP function. As a consequence, expression of Vpu in HIV-infected T cells or in HeLa cells inhibited TNF-alpha -induced degradation of I kappaB-alpha. Vpu did not inhibit TNF-alpha -mediated activation of the I kappaB kinase but instead interfered with the subsequent TrCP-dependent degradation of phosphorylated I kappaB-alpha. This resulted in a pronounced reduction of NF-kappaB activity. We also observed that in cells producing Vpu-defective virus, NF-kappaB activity was significantly increased even in the absence of cytokine stimulation. However, in the presence of Vpu, this HIV-mediated NF-kappaB activation was markedly reduced. These results suggest that Vpu modulates both virus- and cytokine-induced activation of NF-kappaB in HIV-1-infected cells. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, NIH, 4-312,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. NR 64 TC 118 Z9 121 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 15920 EP 15928 DI 10.1074/jbc.M010533200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100049 PM 11278695 ER PT J AU Broad, LM Braun, FJ Lievremont, JP Bird, GSJ Kurosaki, T Putney, JW AF Broad, LM Braun, FJ Lievremont, JP Bird, GSJ Kurosaki, T Putney, JW TI Role of the phospholipase C-inositol 1,4,5-trisphosphate pathway in calcium release-activated calcium current and capacitative calcium entry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION; XENOPUS OOCYTES; INFLUX FACTOR; DIFFUSIBLE MESSENGER; HUMAN PLATELETS; ACINAR-CELLS; CA2+ ENTRY; RECEPTOR; TRISPHOSPHATE; DROSOPHILA AB We investigated the putative roles of phospholipase C, polyphosphoinositides, and inositol 1,4,5-trisphosphate (IP3) in capacitative calcium entry and calcium release-activated calcium current (I-crac) in lacrimal acinar cells, rat basophilic leukemia cells, and DT40 B-lymphocytes, Inhibition of phospholipase C with U73122 blocked calcium entry and I-crac activation whether in response to a phospholipase C-coupled agonist or to calcium store depletion with thapsigargin. Run-down of cellular polyphosphoinositides by concentrations of wortmannin that block phosphatidylinositol 4-kinase completely blocked calcium entry and I-crac. The membrane-permeant IP3 receptor inhibitor, 2-aminoethoxydiphenyl borane, blocked both capacitative calcium entry and I-crac. However, it is likely that 2-aminoethoxydipheny1 borane does not inhibit through an action on the IP3 receptor because the drug was equally effective in wild-type DT40 B-cells and in DT40 B-cells whose genes for all three IP3 receptors had been disrupted. Intracellular application of another potent IP3 receptor antagonist, heparin, failed to inhibit activation of I-crac. Finally, the inhibition of I-crac activation by U73122 or wortmannin was not reversed or prevented by direct intracellular application of IP3. These findings indicate a requirement for phospholipase C and for polyphosphoinositides for activation of capacitative calcium entry. However, the results call into question the previously suggested roles of IP3 and IP3 receptor in this mechanism, at least in these particular cell types. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Kansai Med Univ, Inst Liver Res, Dept Mol Genet, Moriguchi, Osaka 5708506, Japan. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Kurosaki, Tomohiro/D-1306-2009 OI Kurosaki, Tomohiro/0000-0002-6352-304X NR 44 TC 162 Z9 168 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 15945 EP 15952 DI 10.1074/jbc.M011571200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100052 PM 11278938 ER PT J AU Node, K Ruan, XL Dai, JW Yang, SX Graham, L Zeldin, DC Liao, JK AF Node, K Ruan, XL Dai, JW Yang, SX Graham, L Zeldin, DC Liao, JK TI Activation of G alpha(s) mediates induction of tissue-type plasminogen activator gene transcription by epoxyeicosatrienoic acids SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARTERIAL SMOOTH-MUSCLE; ARACHIDONIC-ACID; ENDOTHELIAL-CELLS; RELAXING FACTOR; CYCLIC-AMP; 11,12-EPOXYEICOSATRIENOIC ACID; HYPERPOLARIZING FACTORS; CORONARY-ARTERIES; MOLECULAR-CLONING; ADP-RIBOSYLATION AB The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 (CYP) epoxygenases that have vasodilatory and anti-inflammatory properties. Here we report that EETs have additional fibrinolytic properties. In vascular endothelial cells, physiological concentrations of EETs, particularly 11,12-EET, or overexpression of the endothelial epoxygenase, CYP2J2, increased tissue plasminogen activator (t-PA) expression by 2.5-fold without affecting plasminogen activator inhibitor-1 expression. This increase in t-PA expression correlated with a 4-fold induction in t-PA gene transcription and a 3-fold increase in t-PA fibrinolytic activity and was blocked by the CYP inhibitor, SKF525A, but not by the calcium-activated potassium channel blocker, charybdotoxin, indicating a mechanism that does not involve endothelial cell hyperpolarization. The t-PA promoter is cAMP-responsive, and induction of t-PA gene transcription by EETs correlated with increases in intracellular cAMP levels and, functionally, with cAMP-driven promoter activity. To determine whether increases in intracellular cAMP levels were due to modulation of guanine nucleotide-binding proteins, we assessed the effects of EETs on G alpha (s) and G alpha (i2). Treatment with EETs increased G alpha (s), but not G alpha (i2), GTP-binding activity by 3.5-fold. These findings indicate that EETs possess fibrinolytic properties through the induction of t-PA and suggest that endothelial CYP2J2 may play an important role in regulating vascular hemostasis. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Therapeut, Osaka 5650871, Japan. NIEHS, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Brigham & Womens Hosp, Div Cardiovasc, 221 Longwood Ave,LMRC-322, Boston, MA 02115 USA. EM jliao@rics.bwh.harvard.edu FU NHLBI NIH HHS [HL-48743, HL-52233] NR 35 TC 163 Z9 177 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 15983 EP 15989 DI 10.1074/jbc.M100439200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100057 PM 11279071 ER PT J AU Jo, SH Son, MK Koh, HJ Lee, SM Song, IH Kim, YO Lee, YS Jeong, KS Kim, WB Park, JW Song, BJ Huhe, TL AF Jo, SH Son, MK Koh, HJ Lee, SM Song, IH Kim, YO Lee, YS Jeong, KS Kim, WB Park, JW Song, BJ Huhe, TL TI Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP(+)-dependent isocitrate dehydrogenase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IN-SITU HYBRIDIZATION; GLUTATHIONE-PEROXIDASE; SUPEROXIDE-DISMUTASE; NUCLEOTIDE-SEQUENCE; REDUCED GLUTATHIONE; IDH2 GENE; APOPTOSIS; EXPRESSION; HYDROPEROXIDE; INVOLVEMENT AB Mitochondria are the major organelles that produce reactive oxygen species (ROS) and the main target of ROS-induced damage as observed in various pathological states including aging. Production of NADPH required for the regeneration of glutathione in the mitochondria is critical for scavenging mitochondrial ROS through glutathione reductase and peroxidase systems. We investigated the role of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) in controlling the mitochondrial redox balance and subsequent cellular defense against oxidative damage. We demonstrate in this report that IDPm is induced by ROS and that decreased expression of IDPm markedly elevates the ROS generation, DNA fragmentation, lipid peroxidation, and concurrent mitochondrial damage with a significant reduction in ATP level. Conversely, overproduction of IDPm protein efficiently protected the cells from ROS-induced damage. The protective role of IDPm against oxidative damage may be attributed to increased levels of a reducing equivalent, NADPH, needed for regeneration of glutathione in the mitochondria. Our results strongly indicate that IDPm is a major NADPH producer in the mitochondria and thus plays a key role in cellular defense against oxidative stress-induced damage. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, Taegu 702701, South Korea. Kyungpook Natl Univ, Dept Biochem, Taegu 702701, South Korea. Kyungpook Natl Univ, TG Biotech Co Ltd, Taegu 702701, South Korea. Yeungnam Univ, Coll Med, Dept Anat, Taegu 705717, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. Dong A Pharmacia Co Ltd, Res Lab, Youngin 449900, Kyungi Do, South Korea. RP Huhe, TL (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Genet Engn, 1370 Sankyuk Dong, Taegu 702701, South Korea. NR 69 TC 277 Z9 290 U1 3 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 16168 EP 16176 DI 10.1074/jbc.M010120200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100081 PM 11278619 ER PT J AU Tiwari, S Weissman, AM AF Tiwari, S Weissman, AM TI Endoplasmic reticulum (ER)-associated degradation of T cell receptor subunits - Involvement of ER-associated ubiquitin-conjugating enzymes (E2s) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEASOME PATHWAY; 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE; ANTIGEN RECEPTOR; MEMBRANE-PROTEIN; IDENTIFICATION; CHAINS; RETROTRANSLOCATION; LOCALIZATION; ANTIBODY; HOMOLOG AB Degradation of proteins from the endoplasmic reticulum is fundamental to quality control within the secretory pathway, serves as a way of regulating levels of crucial proteins, and is utilized by viruses to enhance pathogenesis. In yeast two ubiquitin-conjugating enzymes (E2s), UBC6p and UBC7p are implicated in this process. We now report the characterization of murine homologs of these E2s. MmUBC6 is an integral membrane protein that is anchored via its hydrophobic C-terminal tail to the endoplasmic reticulum. MmUBC7, which is not an integral membrane protein, shows significant endoplasmic reticulum colocalization with MmUBC6. Overexpression of catalytically inactive MmUBC7 significantly delayed degradation from the endoplasmic reticulum of two T cell antigen receptor subunits, alpha and CD3-delta, and suggests a role for the ubiquitin conjugating system at the initiation of retrograde movement from the endoplasmic reticulum. These findings also implicate, for the first time, a specific E2 in degradation from the endoplasmic reticulum in mammalian cells. C1 NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Weissman, AM (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 36 TC 93 Z9 97 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 16193 EP 16200 DI 10.1074/jbc.M007640200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100084 PM 11278356 ER PT J AU Mercatante, DR Bortner, CD Cidlowski, JA Kole, R AF Mercatante, DR Bortner, CD Cidlowski, JA Kole, R TI Modification of alternative splicing of Bcl-x Pre-mRNA in prostate and breast cancer cells - Analysis of apoptosis and cell death SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANTISENSE OLIGONUCLEOTIDES; MESSENGER-RNA; IMMUNOHISTOCHEMICAL ANALYSIS; BCL-X(S) ADENOVIRUS; REGULATORY GENES; DRUG-RESISTANCE; PROTEIN FAMILY; MAMMARY-TUMORS; IN-VIVO; EXPRESSION AB There is ample evidence that deregulation of apoptosis results in the development, progression, and/or maintenance of cancer. Since many apoptotic regulatory genes (e.g. bcl-x) code for alternatively spliced protein variants with opposing functions, the manipulation of alternative splicing presents a unique way of regulating the apoptotic response. Here we have targeted oligonucleotides antisense to the 5'-splice site of bcl-x(L), an anti-apoptotic gene that is overexpressed in various cancers, and shifted the splicing pattern of Bcl-x pre-mRNA from Bcl-x(L) to Bcl-x(S), a pro-apoptotic splice variant. This approach induced significant apoptosis in PC-3 prostate cancer cells. In contrast, the same olgonucleotide treatment elicited a much weaker apoptotic response in MCF-7 breast cancer cells. Moreover, although the shift in Bcl-x pre-mRNA splicing inhibited colony formation in both cell lines, this effect was much less pronounced in MCF-7 cells. These differences in responses to oligonucleotide treatment were analyzed in the context of expression of Bcl-x(L), Bcl-x(S), and Bcl-2 proteins. The results indicate that despite the presence of Bcl-x pre-mRNA in a number of cell types, the effects of modification of its splicing by antisense oligonucleotides vary depending on the expression profile of the treated cells. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Kole, R (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, CB 7295, Chapel Hill, NC 27599 USA. FU NHLBI NIH HHS [HL-51940-05]; PHS HHS [P01-59299] NR 47 TC 93 Z9 97 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 16411 EP 16417 DI 10.1074/jbc.M009256200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100112 PM 11278482 ER PT J AU Radaev, S Motyka, S Fridman, WH Sautes-Fridman, C Sun, PD AF Radaev, S Motyka, S Fridman, WH Sautes-Fridman, C Sun, PD TI The structure of a human type III Fc gamma receptor in complex with Fc SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VARIANT ANTIDANSYL ANTIBODIES; LOW-AFFINITY RECEPTOR; EPSILON-RI-ALPHA; IGG BINDING-SITE; CRYSTAL-STRUCTURE; MOLECULAR REPLACEMENT; MONOCLONAL-ANTIBODY; DOMAIN; FRAGMENT; IDENTIFICATION AB Fc gamma receptors mediate antibody-dependent inflammatory responses and cytotoxicity as well as certain autoimmune dysfunctions. Here we report the crystal structure of a human Fc receptor (Fc gamma RIIIB) in complex with an Fc fragment of human IgG1 determined from orthorhombic and hexagonal crystal forms at 3.0- and 3.5-Angstrom resolution, respectively. The refined structures from the two crystal forms are nearly identical with no significant discrepancies between the coordinates. Regions of the C-terminal domain of Fc gamma RIII, including the BC, C'E, FG loops, and the C' beta -strand, bind asymmetrically to the lower hinge region, residues Leu(234)-Pro(238), Of both Fe chains creating a 1:1 receptor-ligand stoichiometry. Minor conformational changes are observed in both the receptor and Fc upon complex formation. Hydrophobic residues, hydrogen bonds, and salt bridges are distributed throughout the receptor le interface. Sequence comparisons of the receptor-ligand interface residues suggest a conserved binding mode common to all members of immunoglobulin-like Fc receptors, Structural comparison between Fc gamma RIII.Fc and Fc epsilon RI.Fc complexes highlights the differences in ligand recognition between the high and low affinity receptors, Although not in direct contact with the receptor, the carbohydrate attached to the conserved glycosylation residue Asn(297) On Fc may stabilize the conformation of the receptor-binding epitope on Fc. An antibody-Fc gamma RIII model suggests two possible ligand-induced receptor aggregations. C1 NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Johns Hopkins Univ, Sch Med, Biochem Cellular & Mol Biol Program, Baltimore, MD 21205 USA. Inst Curie, INSERM, U255, Lab Cellular & Clin Immunol, F-75005 Paris, France. RP Sun, PD (reprint author), NIAID, Struct Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 46 TC 222 Z9 224 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 16469 EP 16477 DI 10.1074/jbc.M100350200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100120 PM 11297532 ER PT J AU Radaev, S Sun, PD AF Radaev, S Sun, PD TI Recognition of IgG by Fc gamma receptor - The role of Fc glycosylation and the binding of peptide inhibitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY RECEPTOR; EFFECTOR FUNCTIONS; CRYSTAL-STRUCTURE; IMMUNOGLOBULIN-G; IN-VIVO; FRAGMENT; COMPLEX; RIII; IDENTIFICATION; SUBCLASSES AB Recently determined crystal structures of the complex between immunoglobulin constant regions (Fc) and their Fc-respective receptors (FcR) have revealed the detailed molecular interactions of this receptor-ligand pair. Of particular interest is the contribution of a glycosylation at Asn(297) of the C(H)2 domain of IgG to receptor recognition. The carbohydrate moieties are found outside the receptor Fe interface in all receptor Fe complex structures. To understand the role of glycosylation in FcR recognition, the receptor affinities of a deglycosylated IgG1 and its Fc fragment were determined by solution binding studies using surface plasmon resonance. The removal of carbohydrates resulted in a non-detectable receptor binding to the Fc alone and a 15- to 20-fold reduction of the receptor binding to IgG1, suggesting that the carbohydrates are important in the function of the Fc gamma RIII. Structurally, the carbohydrates attached to Asn(297) fill the cavity between the C(H)2 domains of Fc functioning equivalently as a hydrophobic core. This may stabilize a favorable lower hinge conformation for the receptor binding, The structure of the complex also revealed the dominance of the lower hinge region in receptor.Fc recognition, To evaluate the potential of designing small molecular ligands to inhibit the receptor function, four lower hinge peptides were investigated for their ability to bind to the receptor Fc gamma RIII, These peptides bind specifically to Fc gamma RIII with affinities 20- to 100-fold lower than IgG1 and are able to compete with Fc in receptor binding. The results of peptide binding illustrate new ways of designing therapeutic compounds to block Fc receptor activation. C1 NIAID, Struct Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Biol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. NR 26 TC 90 Z9 91 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2001 VL 276 IS 19 BP 16478 EP 16483 DI 10.1074/jbc.M100351200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431GH UT WOS:000168623100121 PM 11297533 ER PT J AU Wei, Y Zhang, TY Ito, Y AF Wei, Y Zhang, TY Ito, Y TI Counter-current chromatographic separation of glycoprotein components from Morchella esculenta (L.) with a polymer phase system by a cross-axis coil planet centrifuge SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE counter-current chromatography; Morchella esculenta; glycoproteins; proteins AB Using a cross-axis coil planet centrifuge, glycoproteins were separated from fermentation media of Morchella esculenta (L.) by high-speed counter-current chromatography. The performance of the apparatus was optimized with four standard proteins including pepsin, lysozyme, ovalbumin and hemoglobin and a polymer phase system composed of 12.5% (w/w) polyethylene glycol 8000 and 25% (w/w) potassium phosphate in distilled water at various pH values. Separations were performed by eluting the lower phosphate-rich phase at a flow-rate of 1.0 ml/min. Under the optimized conditions three glycoprotein components in Morchella esculenta (L.) were resolved within 6 h. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing Res Ctr Separat & Purificat Techno Nat Pr, Beijing 100035, Peoples R China. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10,Room 7N322,10 Ctr Dr NSC 1676, Bethesda, MD 20892 USA. NR 7 TC 6 Z9 8 U1 0 U2 6 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 MAY 11 PY 2001 VL 917 IS 1-2 BP 347 EP 351 DI 10.1016/S0021-9673(01)00665-3 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 431CC UT WOS:000168613500033 PM 11403487 ER PT J AU Campos-Olivas, R Horr, I Bormann, C Jung, G Gronenborn, AM AF Campos-Olivas, R Horr, I Bormann, C Jung, G Gronenborn, AM TI Solution structure, backbone dynamics and chitin binding of the anti-fungal protein from Streptomyces tendae TU901 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE AFP1; anti-fungal protein; chitin binding; NMR ID ROTATIONAL DIFFUSION ANISOTROPY; MAGNETIC-RESONANCE SPECTROSCOPY; BACILLUS-CIRCULANS WL-12; CELLULOMONAS-FIMI; NMR-SPECTROSCOPY; ALPHA-CHITIN; DOMAIN; PROGRAM; RELAXATION; N-15 AB AFP1 is a recently discovered anti-fungal, chitin-binding protein from Streptomyces tendae Tu901. Mature AFP1 comprises 86 residues and exhibits limited sequence similarity to the cellulose-binding domains of bacterial cellulases and xylanases. No similarity to the Cys and Gly-rich domains of plant chitin-binding proteins (e.g. agglutinins, lectins, hevein) is observed. AFP1 is the first chitin-binding protein from a bacterium for which anti-fungal activity was shown. Here, we report the three-dimensional solution structure of AFP1, determined by nuclear magnetic resonance spectroscopy. The protein contains two antiparallel P-sheets (five and four P-strands each), that pack against each other in a parallel P-sandwich. This type of architecture is conserved in the functionally related family IT of cellulose-binding domains, albeit with different connectivity. A similar fold is also observed in other unrelated proteins (spore coat protein from Myxococcus xanthus, beta -B-2 and gamma -B crystallins from Bos taurus, canavalin from Jack bean). AFP1 is therefore classified as a new member of the py-crystallin superfamily. The dynamics of the protein was characterized by NMR using amide N-15 relaxation and solvent exchange data. We demonstrate that the protein exhibits an axially sym metric (oblate-like) rotational diffusion tenser whose principal axis coincides to within 15 degrees with that of the inertial tenser. After completion of the present structure of AFP1, an identical fold was reported for a Streptomyces killer toxin-like protein. Based on sequence comparisons and clustering of conserved residues on the protein surface for different cellulose and chitin-binding proteins, we postulate a putative sugar-binding site for AFP1. The inability of the protein to bind short chitin fragments suggests that certain particular architectural features of the solid chitin surface are crucial for the interaction. (C) 2001 Academic Press. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Tubingen, Inst Mikrobiol Biotechnol, D-72076 Tubingen, Germany. RP NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM gronenborn@nih.gov RI Campos-Olivas, Ramon/L-9173-2014; OI Campos-Olivas, Ramon/0000-0002-5743-2221; Gronenborn, Angela M/0000-0001-9072-3525 NR 52 TC 14 Z9 15 U1 0 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 11 PY 2001 VL 308 IS 4 BP 765 EP 782 DI 10.1006/jmbi.2001.4622 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 438BW UT WOS:000169034700014 PM 11350173 ER PT J AU Vorel, SR Liu, XH Hayes, RJ Spector, JA Gardner, EL AF Vorel, SR Liu, XH Hayes, RJ Spector, JA Gardner, EL TI Relapse to cocaine-seeking after hippocampal theta burst stimulation SO SCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; SELF-ADMINISTRATION BEHAVIOR; NUCLEUS-ACCUMBENS; DOPAMINE NEURONS; EXTRACELLULAR DOPAMINE; PREFRONTAL CORTEX; RAT-BRAIN; IN-VIVO; AMYGDALA; REWARD AB Treatment efforts for cocaine addiction are hampered by high relapse rates. To map brain areas underlying relapse, we used electrical brain stimulation and intracranial injection of pharmacological compounds after extinction of cocaine self-administration behavior in rats. Electrical stimulation of the hippocampus containing glutamatergic fibers, but not the medial forebrain bundle containing dopaminergic fibers, elicited cocaine-seeking behavior dependent on glutamate in the ventral tegmental area. This suggests a role for glutamatergic neurotransmission in relapse to cocaine abuse. The medial forebrain bundle electrodes supported intense electrical self-stimulation. These findings suggest a dissociation of neural systems subserving positive reinforcement (self-stimulation) and incentive motivation (relapse). C1 Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10461 USA. NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Vorel, SR (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, 1300 Morris Pk Ave, Bronx, NY 10461 USA. NR 63 TC 314 Z9 326 U1 4 U2 21 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 MAY 11 PY 2001 VL 292 IS 5519 BP 1175 EP 1178 DI 10.1126/science.1058043 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 431AF UT WOS:000168609200063 PM 11349151 ER PT J AU Nair, AR Boersma, LJ Schiltz, L Chaudry, A Muschel, RJ AF Nair, AR Boersma, LJ Schiltz, L Chaudry, A Muschel, RJ TI Paradoxical effects of trichostatin A: inhibition of NF-Y-associated histone acetyltransferase activity, phosphorylation of hGCN5 and downregulation of cyclin A and B1 mRNA SO CANCER LETTERS LA English DT Article DE trichostatin A; histone acetyltransferase; cyclin B ID TRANSCRIPTIONAL REGULATION; COACTIVATORS P300; IN-VIVO; GENE; ACETYLATION; DEACETYLASE; GCN5; ACTIVATION; YEAST; CELL AB Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), is widely used to study the role of histone acetylation in gene expression, since genes that use histone acetylation as a means of regulating expression may be up regulated when TSA is added. In this study, however, we show that TSA has an unexpected paradoxical effect leading to inhibition of NF-Y-associated histone acetyl transferase (HAT) activity and phosphorylation of the HAT, hGCN5. TSA treatment of cells resulted in diminished levels of NF-Y-associated HAT activity without changes in NF-Y(A) amount, hGCN5 is one of the HATs known to associate with NF-Y. The association of hGCN5 with NF-Y was not altered by TSA treatment. The enzymatic activity of hGCN5 is known to be inhibited by phosphorylation. TSA treatment of Hela cells resulted in phosphorylation of hGCN5. Exposure of the NF-Y immunoprecipitates from TSA-treated cells to a phosphatase resulted in enhanced HAT activity. We have also shown that the mRNA levels of several genes, cyclin B1 and cyclin A, are downregulated by TSA; these effects do not require protein synthesis and the downregulation of cyclin B1 by TSA occurs through transcription. These results suggest that TSA can have contradictory effects, on one hand stimulating HAT activity in general by inhibition of HDACs, but also resulting in inhibition of NF-Y-associated HAT activity acid phosphorylation of hGCN5. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Muschel, RJ (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 269 John Morgan Bldg,36th Hamilton Walk, Philadelphia, PA 19104 USA. FU NIGMS NIH HHS [GM 47439] NR 37 TC 37 Z9 37 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAY 10 PY 2001 VL 166 IS 1 BP 55 EP 64 DI 10.1016/S0304-3835(01)00418-9 PG 10 WC Oncology SC Oncology GA 433PE UT WOS:000168768300008 PM 11295287 ER PT J AU Rogan, WJ Dietrich, KN Ware, JH Dockery, DW Salganik, M Radcliffe, J Jones, RL Ragan, NB Chisolm, JJ Rhoads, GG AF Rogan, WJ Dietrich, KN Ware, JH Dockery, DW Salganik, M Radcliffe, J Jones, RL Ragan, NB Chisolm, JJ Rhoads, GG CA Treatment Lead Exposed Children Tr TI The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Toxicology CY MAR 27, 2001 CL SAN FRANCISCO, CALIFORNIA SP Soc Toxicol ID PORT-PIRIE COHORT; COGNITIVE FUNCTION; CINCINNATI LEAD; CLINICAL-TRIAL; INTELLIGENCE; AGE AB Background: Thousands of children, especially poor children living in deteriorated urban housing, are exposed to enough lead to produce cognitive impairment. It is not known whether treatment to reduce blood lead levels prevents or reduces such impairment. Methods: We enrolled 780 children with blood lead levels of 20 to 44 mug per deciliter (1.0 to 2.1 mu mol per liter) in a randomized, placebo-controlled, double-blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered orally. The children lived in deteriorating inner-city housing and were 12 to 33 months of age at enrollment; 77 percent were black, and 5 percent were Hispanic. Follow-up included tests of cognitive, motor, behavioral, and neuropsychological function over a period of 36 months. Results: During the first six months of the trial, the mean blood lead level in the children given succimer was 4.5 mug per deciliter (0.2 mu mol per liter) lower than the mean level in the children given placebo (95 percent confidence interval, 3.7 to 5.3 mug per deciliter [0.2 to 0.3 mu mol per liter]). At 36 months of follow-up, the mean IQ score of children given succimer was 1 point lower than that of children given placebo, and the behavior of children given succimer was slightly worse as rated by a parent. However, the children given succimer scored slightly better on the Developmental Neuropsychological Assessment, a battery of tests designed to measure neuropsychological deficits thought to interfere with learning. All these differences were small, and none were statistically significant. Conclusions: Treatment with succimer lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 mug per deciliter. Since succimer is as effective as any lead chelator currently available, chelation therapy is not indicated for children with these blood lead levels. (N Engl J Med 2001;344:1421-6.) Copyright (C) 2001 Massachusetts Medical Society. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Childrens Hosp Philadelphia, Dept Psychol, Philadelphia, PA 19104 USA. Ctr Dis Control & Prevent, Nutr Biochem Branch, Atlanta, GA USA. Kennedy Krieger Inst, Baltimore, MD USA. Univ Med & Dent New Jersey, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. RI Jones, Robert/E-1170-2011; Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 25 TC 176 Z9 186 U1 3 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 10 PY 2001 VL 344 IS 19 BP 1421 EP 1426 DI 10.1056/NEJM200105103441902 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 430BQ UT WOS:000168554000002 PM 11346806 ER PT J AU Sutherland, LC Lerman, M Williams, GT Miller, BA AF Sutherland, LC Lerman, M Williams, GT Miller, BA TI LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells SO ONCOGENE LA English DT Article DE LUCA-15; 3p21.3; apoptosis; CD95; staurosporine; Jurkat ID CHEMOTHERAPY-INDUCED APOPTOSIS; MOLECULAR-GENETIC CHANGES; CYTOCHROME-C RELEASE; RNA-BINDING PROTEIN; LUNG-CANCER; HOMOZYGOUS DELETION; CHROMOSOME 3P21.3; TUMOR-GROWTH; EXPRESSION PATTERNS; MICROCELL HYBRIDS AB The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis, An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis, Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs Drier to the final execution stage of the CD95 signalling pathway, and is associated with upregulation of the apoptosis inhibitory protein Bcl-2, LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide, These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis. C1 Sigfried & Janet Weis Ctr Res, Geisinger Clin, Henry Hood Res Program, Danville, PA 17822 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat,Div Hematol Oncol, Hershey, PA 17033 USA. NCI, Immunobiol Lab, FCRDC, Frederick, MD 21702 USA. Univ Keele, Sch Life Sci, Keele ST5 5BG, Staffs, England. RP Sutherland, LC (reprint author), Sigfried & Janet Weis Ctr Res, Geisinger Clin, Henry Hood Res Program, 100 N Acad Ave, Danville, PA 17822 USA. FU NCI NIH HHS [N01-CO-56000]; NCRR NIH HHS [M01RR10732]; NIDDK NIH HHS [DK46778] NR 50 TC 29 Z9 30 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 10 PY 2001 VL 20 IS 21 BP 2713 EP 2719 DI 10.1038/sj.onc.1204371 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 431VN UT WOS:000168652600012 PM 11420683 ER PT J AU Vanakoski, J Virkkunen, M Naukkarinen, H Goldman, D AF Vanakoski, J Virkkunen, M Naukkarinen, H Goldman, D TI No association of CCK and CCKB receptor polymorphisms with alcohol dependence SO PSYCHIATRY RESEARCH LA English DT Article DE cholecystokinin; cholecystokinin receptors; polymorphism; alcohol dependence ID CHOLECYSTOKININ GENE PROMOTER; PANIC DISORDER; ANXIETY DISORDERS; SP1; ANTAGONISTS; REGION; BRAIN AB Cholecystokinin (CCK) is the most widely distributed neuropeptide in the central nervous system. One of its several functions is to modulate the release of dopamine in brain areas involved in reinforcement and reward behavior. The aim of this study was to investigate the association of CCK system genes (CCK, CCK, and CCK, receptor genes) with alcohol dependence using single nucleotide polymorphisms (SNPs) as genetic markers, A total of 257 psychiatrically interviewed Finns were genotyped for CCK (-45C > T), CCKA (Val365IIe) and CCKB (Val125Ile) receptor polymorphisms. Allele frequencies were compared between 150 unrelated healthy Finnish controls and 107 unrelated alcohol-dependent subjects (DSM-III-R criteria), who were also criminal offenders, The frequency of the CCK -45T allele was not significantly different between controls [0.07] and alcoholics [0.09], The CCK, receptor polymorphism Val125Ile was also not associated with alcoholism and the Ile125 allele frequencies were 0.05 in controls vs. 0.06 in alcohol-dependent subjects. A CCK, receptor marker, Val365Ile, was uninformative in this Finnish dataset; all subjects were Val365/Val365 homozygous. The results suggest that CCK -45C > T and CCKBR Val125Ile polymorphisms do not have a major rule in alcohol dependence in the population studied. The role of the CCK, the receptor in alcohol dependence remains open until additional DNA sequence variants for this gene become available. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved, C1 Univ Helsinki, Dept Pharmacol & Toxicol, Inst Biomed, FIN-00014 Helsinki, Finland. NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Dept Psychiat, FIN-00014 Helsinki, Finland. RP Vanakoski, J (reprint author), Univ Helsinki, Dept Pharmacol & Toxicol, Inst Biomed, POB 8, FIN-00014 Helsinki, Finland. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 22 TC 9 Z9 12 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAY 10 PY 2001 VL 102 IS 1 BP 1 EP 7 DI 10.1016/S0165-1781(01)00246-3 PG 7 WC Psychiatry SC Psychiatry GA 438QL UT WOS:000169064500001 PM 11368834 ER PT J AU Bienvenu, OJ Brown, C Samuels, JF Liang, KY Costa, PT Eaton, WW Nestadt, G AF Bienvenu, OJ Brown, C Samuels, JF Liang, KY Costa, PT Eaton, WW Nestadt, G TI Normal personality traits and comorbidity among phobic, panic and major depressive disorders SO PSYCHIATRY RESEARCH LA English DT Article DE anxiety disorders; unipolar depression; quantitative trait; epidemiology ID DIAGNOSTIC-INTERVIEW-SCHEDULE; COMMON MENTAL-DISORDERS; AREA FOLLOW-UP; DSM-III-R; ANXIETY DISORDERS; 5-FACTOR MODEL; NATURAL-HISTORY; SOCIAL PHOBIA; PSYCHOPATHOLOGY; PREVALENCE AB High comorbidity among anxiety and depressive conditions is a consistent but not well-understood finding. The current study examines how normal personality traits relate to this comorbidity. In the Baltimore Epidemiologic Catchment Area Follow-up Study, psychiatrists administered the full Schedules for Clinical Assessment in Neuropsychiatry to 320 subjects, all of whom completed the Revised NEO Personality Inventory. The disorders of interest were simple phobia, social phobia, agoraphobia, panic disorder. and major depression. Analyses were carried out with second-order generalized estimating equations. The unadjusted summary odds ratio (SOR - or weighted mean odds ratio) for all five disorders was 1.72 (95% confidence interval = 1.21-2.-16). Neuroticism, introversion, younger age, and female gender were all significant predictors of prevalence of disorders. After adjustment for the relationships between these personality and demographic predictors and prevalence, the association among disorders was much with high extraversion had a SOR 213% as high (95% CI = 102-444%) as those with low extraversion (1.60 vs. 0.75). Therefore, neuroticism and introversion are associated with increased comorbidity due to relationships in common with the prevalence of the different disorders. In contrast. extraversion is associated with increased comorbidity per se. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD 21287 USA. NIA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mental Hyg, Baltimore, MD 21205 USA. RP Bienvenu, OJ (reprint author), 600 N Wolfe St,Meyer 125, Baltimore, MD 21287 USA. RI Liang, Kung-Yee/F-8299-2011; OI Samuels, Jack/0000-0002-6715-7905; Costa, Paul/0000-0003-4375-1712 FU NIMH NIH HHS [R01-MH47447, R01-MH50616, T32-MH14592] NR 46 TC 86 Z9 87 U1 5 U2 13 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAY 10 PY 2001 VL 102 IS 1 BP 73 EP 85 DI 10.1016/S0165-1781(01)00228-1 PG 13 WC Psychiatry SC Psychiatry GA 438QL UT WOS:000169064500009 PM 11368842 ER PT J AU Gower, TL Peeples, ME Collins, PL Graham, BS AF Gower, TL Peeples, ME Collins, PL Graham, BS TI RhoA is activated during respiratory syncytial virus infection SO VIROLOGY LA English DT Article DE RSV; RhoA; C3 toxin; p130(cas); Rho kinase; Y-27632; lovastatin; GGTI-298; FTI-277 ID FACTOR-KAPPA-B; SMOOTH-MUSCLE CONTRACTION; GENE-EXPRESSION; TYROSINE PHOSPHORYLATION; HEPTAD REPEAT; CELL ENTRY; PROTEIN; FUSION; INTEGRINS; GTPASE AB Respiratory syncytial virus (RSV) is an important human pathogen that can cause severe and life-threatening respiratory infections in infants and immunocompromised adults. We have recently shown the RSV F glycoprotein, which mediates viral fusion and entry, interacts with the cellular protein RhoA in two-hybrid and in vitro binding assays. Whether this interaction occurs in living cells remains an open question. However, because RhoA signaling is associated with many cellular functions relevant to RSV pathogenesis such as actin cytoskeleton organization, expression of proinflammatory cytokines, and smooth muscle contraction, we asked whether RhoA activation occurred during RSV infection of HEp-2 cells. We found that the amount of isoprenylated and membrane-bound RhoA in RSV-infected cultures was increased. Further evidence of RhoA activation was demonstrated by downstream signaling activity mediated by RhoA. There was an increase in p130(cas) phosphorylation during RSV infection, which was prevented by Y-27632, a specific inhibitor of Rho kinase, or lovastatin, an HMG-CoA reductase inhibitor that reduces the synthesis of groups needed for isoprenylation. In addition, RSV infection of HEp-2 cells resulted in an increase in the formation of actin stress fibers. Pretreatment of HEp-2 cells with Clostridium botulinum C3 exotoxin, an enzyme that specifically ADP-ribosylates and inactivates RhoA, prevented RSV-induced stress fiber formation. These observations indicate that RhoA and subsequent downstream signaling events are activated during RSV infection, which has implications for RSV pathogenesis, (C) 2001 Academic Press. C1 Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. Rush Med Coll, Dept Immunol & Microbiol, Chicago, IL 60612 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, A-4103 MCN,1161 21st Ave S, Nashville, TN 37232 USA. FU NIAID NIH HHS [R01-AI-33933] NR 54 TC 34 Z9 37 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2001 VL 283 IS 2 BP 188 EP 196 DI 10.1006/viro.2001.0891 PG 9 WC Virology SC Virology GA 431NF UT WOS:000168636900004 PM 11336544 ER PT J AU Reist, C Mazzanti, C Vu, R Tran, D Goldman, D AF Reist, C Mazzanti, C Vu, R Tran, D Goldman, D TI Rapid publication - Serotonin transporter promoter polymorphism is associated with attenuated prolactin response to fenfluramine SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE 5-HT; HTTLPR; impulsivity; aggression; alcoholism ID MAJOR DEPRESSIVE DISORDER; ANXIETY-RELATED TRAITS; IMPULSIVE AGGRESSION; REGULATORY REGION; EUROPEAN-AMERICAN; GENE POLYMORPHISM; AFRICAN-AMERICAN; VIOLENT BEHAVIOR; PROTEIN GENE; ALCOHOL AB Disturbances in central serotonin (5-HT) function may have a role in impulsive aggression in patients with a wide range of psychiatric diagnoses. The underlying mechanism, however, remains unknown. There are several naturally occurring mutations in the 5-HT signaling pathway that may underlie differences in 5-HT function and responsivity to drugs that affect 5-HT functioning. In the present study, we examined the relationship between polymorphisms in the promoter region of the gene coding for the neuronal 5-HT transporter, fenfluramine-induced prolactin release, and aggressive impulsivity las measured by Barratt Impulsivity Scale, Buss-Durkee Hostility Inventory, and Brown-Goodwin Aggression Scale scores), in a group of abstinent alcoholic patients and healthy volunteers, We report here that possession of the short variant of the 5-HT transporter promoter polymorphism was associated with a blunting of overall central 5-HT function, as measured by fenfluramine-induced prolactin release. We found no relationship between aggressive, hostile, or impulsive traits and fenfluramine-induced prolactin release or between these traits and polymorphisms in the 5-HT transporter promoter. Thus, we have shown that a 5-HT transporter promoter genotype, which has previously been associated with anxiety-based behaviors, alters an in vivo measure of central 5-HT function (fenfluramine-induced prolactin release), providing an important mechanism for linkage between a gene, physiological function, and behavior. Published 2001 Wiley-Liss, Inc. C1 Long Beach Vet Affairs Med Ctr, Dept Psychiat, Long Beach, CA 90822 USA. Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Reist, C (reprint author), Long Beach Vet Affairs Med Ctr, Dept Psychiat, 5901 E 7th St, Long Beach, CA 90822 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 36 TC 70 Z9 70 U1 3 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 MAY 8 PY 2001 VL 105 IS 4 BP 363 EP 368 DI 10.1002/ajmg.1360 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 439KN UT WOS:000169116200011 PM 11378851 ER PT J AU Feng, JN Yan, J Michaud, S Craddock, N Jones, IR Cook, EH Goldman, D Heston, LL Peltonen, L Delisi, LE Sommer, SS AF Feng, JN Yan, J Michaud, S Craddock, N Jones, IR Cook, EH Goldman, D Heston, LL Peltonen, L Delisi, LE Sommer, SS TI Scanning of estrogen receptor alpha (ER alpha) and thyroid hormone receptor alpha (TR alpha) genes in patients with psychiatric diseases: Four missense mutations identified in ER alpha gene SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE ER alpha; TR alpha; schizophrenia; psychiatric diseases; DOVAM-S; mutation detection ID DEFICIT HYPERACTIVITY DISORDER; BREAST-CANCER; GENERALIZED RESISTANCE; PUERPERAL PSYCHOSIS; DOVAM-S; SCHIZOPHRENIA; SEQUENCE; LINKAGE; WOMEN; ASSOCIATION AB Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ER alpha) and the thyroid hormone receptor alpha (TR alpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance tall coding exons and flanking splice junctions) of the ERa and TR alpha. genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ER alpha. gene and 1.16 megabases of the TR alpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ER alpha gene, while only four silent mutations were present in the TRa gene. Two of the missense mutations in ER alpha. are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ER alpha and TR alpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases. (C) 2001 Wiley-Liss, Inc. C1 City Hope Natl Med Ctr, Dept Mol Genet, Duarte, CA 91010 USA. Univ Birmingham, Queen Elizabeth Hosp, Div Neurosci, Birmingham B15 2TH, W Midlands, England. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIAAA, Dept Psychiat, NIH, Bethesda, MD USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. SUNY Stony Brook, Hlth Sci Ctr, Dept Psychiat, Stony Brook, NY 11794 USA. RP Sommer, SS (reprint author), City Hope Natl Med Ctr, Dept Mol Genet, 1500 E Duarte Rd, Duarte, CA 91010 USA. RI Jones, Ian/B-4925-2009; turton, miranda/F-4682-2011; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 40 TC 25 Z9 25 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 MAY 8 PY 2001 VL 105 IS 4 BP 369 EP 374 DI 10.1002/ajmg.1364 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 439KN UT WOS:000169116200012 PM 11378852 ER PT J AU Liu, CY Badner, JA Christian, SL Guroff, JJ Detera-Wadleigh, SD Gershon, ES AF Liu, CY Badner, JA Christian, SL Guroff, JJ Detera-Wadleigh, SD Gershon, ES TI Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32 SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE bipolar disorder; linkage; association; 13q; map ID COMPLEX TRAITS; SCHIZOPHRENIA; SCORES; TESTS AB A region between D13S71 and D13S274 on 13q32 showed linkage to bipolar disorder (BP) based on a genome scan using markers with an average spacing of similar to6 cM and an average heterozygosity of similar to 60% [Detera-Wadleigh et al., 1999: Proc Natl Acad Sci USA 96:5604-5609]. In an attempt to confirm this finding and achieve fine mapping of the susceptibility region, nine additional microsatellite markers with average heterozygosity of similar to 86%, located between D13S71 and D13S274, were typed in the same sample. The strongest linkage evidence was detected by multipoint linkage analysis (ASPEX program) around D13S779-D13S225 with maximum LOD score of 3.25 under Affection Status Model II (ASM II; P = 0.0000546). Data from additional nine markers resulted in a decrease of the 95% confidence interval of the Linkage region. Association analyses with GASSOC TDT and ASPEX/sib_tdt detect potential linkage disequilibrium with several markers, including D13S280 (ASPEX TDT P = 0.0033, ASM I). These data generated using a higher marker density within the proposed susceptibility region strengthen the validity of our previous findings and suggest a finer localization of the susceptibility gene(s) on 13q32. (C) 2001 Wiley-Liss, Inc. C1 Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Cent S Univ, Natl Lab Med Gene, Changsha, Hunan, Peoples R China. NIMH, NIH, Bethesda, MD 20892 USA. RP Liu, CY (reprint author), R-022,BSLC,924 E 57th St, Chicago, IL 60637 USA. EM cliu@yoda.bsd.uchicago.edu RI Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 NR 12 TC 30 Z9 30 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD MAY 8 PY 2001 VL 105 IS 4 BP 375 EP 380 DI 10.1002/ajmg.1358 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 439KN UT WOS:000169116200013 PM 11378853 ER PT J AU Heldman, AW Cheng, L Jenkins, GM Heller, PF Kim, DW Ware, M Nater, C Hruban, RH Rezai, B Abella, BS Bunge, KE Kinsella, JL Sollott, SJ Lakatta, EG Brinker, JA Hunter, WL Froehlich, JP AF Heldman, AW Cheng, L Jenkins, GM Heller, PF Kim, DW Ware, M Nater, C Hruban, RH Rezai, B Abella, BS Bunge, KE Kinsella, JL Sollott, SJ Lakatta, EG Brinker, JA Hunter, WL Froehlich, JP TI Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis SO CIRCULATION LA English DT Article DE paclitaxel; stents; angioplasty; restenosis ID LOCAL-DRUG DELIVERY; MUSCLE CELL-PROLIFERATION; ARTERIAL INJURY; EMITTING STENT; IN-VIVO; TAXOL; IMPLANTATION; ANGIOPLASTY; PREVENTION; DISEASE AB Background-Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis. Methods and Results-Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 mug/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P<0.05) at the highest level tested (187 mug/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P<0.05) with increasing dose (P<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P<0.05) with escalating dose (P<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis. Conclusions-Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis. C1 Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. NIA, NIH, Baltimore, MD 21224 USA. Angiotech Pharmaceut Inc, Vancouver, BC, Canada. RP Heldman, AW (reprint author), Johns Hopkins Hosp, Div Cardiol, Carnegie 565,600 N Wolfe St, Baltimore, MD 21287 USA. RI Abella, Benjamin/G-3579-2010; Heldman, Alan/K-8784-2012 NR 21 TC 266 Z9 284 U1 2 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 8 PY 2001 VL 103 IS 18 BP 2289 EP 2295 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 431RN UT WOS:000168644500021 PM 11342479 ER PT J AU Jacobson, S Cross, A AF Jacobson, S Cross, A TI Association of Chlamydia pneumoniae and multiple sclerosis: Stage two? SO NEUROLOGY LA English DT Editorial Material ID CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; INFECTION; DISEASES; BANDS C1 NIH, Viral Immunol Sect, Bethesda, MD 20892 USA. Washington Univ, Dept Neurol & Neurosurg, St Louis, MO USA. RP Jacobson, S (reprint author), NIH, Viral Immunol Sect, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. NR 20 TC 8 Z9 8 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 MAY 8 PY 2001 VL 56 IS 9 BP 1128 EP 1129 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 428ZU UT WOS:000168492200002 PM 11342674 ER PT J AU Monni, O Barlund, M Mousses, S Kononen, J Sauter, G Heiskanen, M Paavola, P Avela, K Chen, YD Bittner, ML Kallioniemi, A AF Monni, O Barlund, M Mousses, S Kononen, J Sauter, G Heiskanen, M Paavola, P Avela, K Chen, YD Bittner, ML Kallioniemi, A TI Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; CELL LUNG CARCINOMAS; CHROMOSOMAL-ABNORMALITIES; CDNA MICROARRAYS; DNA GAINS; IN-SITU; AMPLIFICATION; PROGRESSION; PROTEIN; KINASE AB The biological significance of DNA amplification in cancer is thought to be due to the selection of increased expression of a single or few important genes. However, systematic surveys of the copy number and expression of all genes within an amplified region of the genome have not been performed. Here we have used a combination of molecular, genomic, and microarray technologies to identify target genes for 17q23, a common region of amplification in breast cancers with poor prognosis. Construction of a 4-Mb genomic contig made it possible to define two common regions of amplification in breast cancer cell lines. Analysis of 184 primary breast tumors by fluorescence in situ hybridization on tissue microarrays validated these results with the highest amplification frequency (12.5%) observed for the distal region. Based on GeneMap'99 information, 17 known genes and 26 expressed sequence tags were localized to the contig. Analysis of genomic sequence identified 77 additional transcripts. A comprehensive analysis of expression levels of these transcripts in six breast cancer cell lines was carried out by using complementary DNA microarrays. The expression patterns varied from one cell line to another, and several overexpressed genes were identified. Of these, RPS6KB1, MUL, APPBP2, and TRAP240 as well as one uncharacterized expressed sequence tag were located in the two common amplified regions. In summary, comprehensive analysis of the 17q23 amplicon revealed a limited number of highly expressed genes that may contribute to the more aggressive clinical course observed in breast cancer patients with 17q23-amplified tumors. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Tampere Univ, Inst Med Technol, Canc Genet Lab, Tampere 33520, Finland. Tampere Univ Hosp, Tampere 33520, Finland. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Natl Publ Hlth Inst, Dept Human Mol Genet, Helsinki 00300, Finland. Univ Helsinki, Haartman Inst, Dept Med Genet, Helsinki 00280, Finland. Folkhalsan Inst Genet, Helsinki 00280, Finland. RP Kallioniemi, A (reprint author), NHGRI, Canc Genet Branch, NIH, 49 Convent Dr,Room 4B24, Bethesda, MD 20892 USA. OI Kallioniemi, Anne/0000-0003-3552-8158 NR 37 TC 181 Z9 184 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 8 PY 2001 VL 98 IS 10 BP 5711 EP 5716 DI 10.1073/pnas.091582298 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 431GK UT WOS:000168623300062 PM 11331760 ER PT J AU Manca, C Tsenova, L Bergtold, A Freeman, S Tovey, M Musser, JM Barry, CE Freedman, VH Kaplan, G AF Manca, C Tsenova, L Bergtold, A Freeman, S Tovey, M Musser, JM Barry, CE Freedman, VH Kaplan, G TI Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CD8(+) T-CELLS; INTERFERON-GAMMA; VIRUS-INFECTION; VIRAL-INFECTION; HUMAN MONOCYTES; RECEPTOR GENE; IN-VITRO; INTERLEUKIN-12; SUSCEPTIBILITY; AFRICANS AB To understand how Virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with various human outbreak Mycobacterium tuberculosis clinical isolates. One clinical isolate, HN878, was found to be hypervirulent, as demonstrated by unusually early death of infected immune-competent mice, compared with infection with other clinical isolates. The differential effect on survival required lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tubercolosis-specific proliferation and lFN-gamma production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tumor necrosis factor-cu (TNF-alpha), IL-6, IL-12, and IFN-gamma mRNAs were observed in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contrast, IFN-a mRNA levels were significantly higher in lungs of these mice. To further investigate the role of Type 1 IFNs, mice infected with HN878 were treated intranasally with purified IFN-alpha/beta. The treatment resulted in increased lung bacillary loads and even further reduced survival. These results suggest that the hypervirulence of HN878 may be due to failure of this strain to stimulate Th1 type immunity. In addition, the lack of development of Th1 immunity in response to HN878 appears to be associated with increased induction of Type 1 IFNs. C1 Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. CNRS, Lab Viral Oncol, F-94801 Villejuif, France. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. NIAID, TB Res Sect, Rockville, MD 20852 USA. RP Kaplan, G (reprint author), Rockefeller Univ, Cellular Physiol & Immunol Lab, 1230 York Ave, New York, NY 10021 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI 22616, AI 42056] NR 32 TC 338 Z9 349 U1 2 U2 10 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 MAY 8 PY 2001 VL 98 IS 10 BP 5752 EP 5757 DI 10.1073/pnas.091096998 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 431GK UT WOS:000168623300069 PM 11320211 ER PT J AU Hellstrom, A Perruzzi, C Ju, MH Engstrom, E Hard, AL Liu, JL Albertsson-Wikland, K Carlsson, B Niklasson, A Sjodell, L LeRoith, D Senger, DR Smith, LEH AF Hellstrom, A Perruzzi, C Ju, MH Engstrom, E Hard, AL Liu, JL Albertsson-Wikland, K Carlsson, B Niklasson, A Sjodell, L LeRoith, D Senger, DR Smith, LEH TI Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR-I; PROLIFERATIVE DIABETIC-RETINOPATHY; RETROLENTAL FIBROPLASIA; DEPENDENT MANNER; HUMAN FETUS; NEOVASCULARIZATION; RECEPTOR; HORMONE; INFANTS; OXYGEN AB Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low revels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As ICF-I increases to a critical lever, retinal neovascularization is triggered. These data indicate that serum LCF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levers could prevent this disease. C1 Harvard Univ, Dept Ophthalmol, Sch Med, Childrens Hosp, Boston, MA 02115 USA. Queen Silvia Childrens Hosp, Sect Opthalmol, Dept Clin Neurosci, S-41685 Gothenburg, Sweden. Queen Silvia Childrens Hosp, Dept Pediat, Int Pediat Growth Res Ctr, S-41685 Gothenburg, Sweden. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. NIH, Endocrine Branch, Bethesda, MD 20892 USA. Univ Goteborg, Dept Internal Med, Res Ctr Endocrinol & Metab, S-41345 Gothenburg, Sweden. RP Smith, LEH (reprint author), Harvard Univ, Dept Ophthalmol, Sch Med, Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. RI Albertsson-Wikland, Kerstin/D-3843-2012; OI Hellstrom, Ann/0000-0002-9259-1244 FU NEI NIH HHS [R01 EY008670] NR 35 TC 291 Z9 313 U1 0 U2 10 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 MAY 8 PY 2001 VL 98 IS 10 BP 5804 EP 5808 DI 10.1073/pnas.101113998 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 431GK UT WOS:000168623300078 PM 11331770 ER PT J AU Xia, Y Yang, ZY Hour, MJ Kuo, SC Xia, P Bastow, KF Nakanishi, Y Nampoothiri, P Hackl, T Hamel, E Lee, KH AF Xia, Y Yang, ZY Hour, MJ Kuo, SC Xia, P Bastow, KF Nakanishi, Y Nampoothiri, P Hackl, T Hamel, E Lee, KH TI Antitumor agents. Part 204: Synthesis and biological evaluation of substituted 2-aryl quinazolinones SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID TUBULIN POLYMERIZATION; CYTOTOXICITY; 2-PHENYL-4-QUINOLONES; INHIBITION AB A series of 2 ' ,3 ' ,4 ' ,6,7-substituted 2-aryl quinazolinones were synthesized and evaluated for biological activity. Among them, 17 displayed significant growth inhibitory action against a panel of tumor cell lines. Compound 17 was also a potent inhibitor of tubulin polymerization. Compounds 8-10 displayed selective activity against P-gp-expressing epidermoid carcinoma of the nasopharynx. (C) 2001 Elsevier Science Ltd. all rights reserved. C1 Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. China Med Coll, Taichung, Taiwan. NCI, Frederick Canc Res & Dev Ctr, Screening Technol Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Nat Prod Lab, Chapel Hill, NC 27599 USA. FU NCI NIH HHS [CA-17625]; NIAID NIH HHS [AI-33066] NR 11 TC 141 Z9 143 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 MAY 7 PY 2001 VL 11 IS 9 BP 1193 EP 1196 DI 10.1016/S0960-894X(01)00190-1 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 430DF UT WOS:000168557700023 PM 11354375 ER PT J AU Peschel, A Jack, RW Otto, M Collins, LV Staubitz, P Nicholson, G Kalbacher, H Nieuwenhuizen, WF Jung, G Tarkowski, A van Kessel, KPM van Strijp, JAG AF Peschel, A Jack, RW Otto, M Collins, LV Staubitz, P Nicholson, G Kalbacher, H Nieuwenhuizen, WF Jung, G Tarkowski, A van Kessel, KPM van Strijp, JAG TI Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with L-lysine SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE host defense peptides; oxygen-independent killing; Staphylococcus aureus virulence; phospholipids; innate immunity ID GRAM-POSITIVE BACTERIA; ANTIMICROBIAL PEPTIDES; HUMAN BETA-DEFENSIN-1; HOST-DEFENSE; GENE; EXPRESSION; ACIDS; TRANSFORMATION; PROTEGRINS; VANCOMYCIN AB Defensins, antimicrobial peptides of the innate immune system, protect human mucosal epithelia and skin against microbial infections and are produced in large amounts by neutrophils. The bacterial pathogen Staphylococcus aureus is insensitive to defensins by virtue of an unknown resistance mechanism. We describe a novel staphylococcal gene, mprF, which determines resistance to several host defense peptides such as defensins and protegrins. An mprF mutant strain was killed considerably faster by human neutrophils and exhibited attenuated virulence in mice, indicating a key role for defensin resistance in the pathogenicity of S. aureus. Analysis of membrane lipids demonstrated that the mprF mutant no longer modifies phosphatidylglycerol with L-lysine. As this unusual modification leads to a reduced negative charge of the membrane surface, MprF-mediated peptide resistance is most likely based on repulsion of the cationic peptides. Accordingly, inactivation of mprF led to increased binding of antimicrobial peptides by the bacteria. MprF has no similarity with genes of known function, but related genes were identified in the genomes of several pathogens including Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Enterococcus faecalis. MprF thus constitutes a novel virulence factor, which may be of general relevance for bacterial pathogens and represents a new targe for attacking multidrug resistant bacteria. C1 Univ Tuebingen, D-72076 Tuebingen, Germany. Univ Med Ctr Utrecht, Eijkman Winkler Inst, NL-3584 CX Utrecht, Netherlands. EMC Microcollect, D-72070 Tuebingen, Germany. Gothenburg Univ, Dept Rheumatol, S-41346 Gothenburg, Sweden. Univ Tuebingen, Med & Nat Sci Res Ctr, D-72074 Tuebingen, Germany. TNO, NL-3700 AJ Zeist, Netherlands. RP Peschel, A (reprint author), NIAID, Lab Human Bacterial Pathogensis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI van Strijp, Jos/J-9549-2014; OI van Strijp, Jos/0000-0001-6253-0830; Otto, Michael/0000-0002-2222-4115 NR 42 TC 423 Z9 432 U1 8 U2 42 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 7 PY 2001 VL 193 IS 9 BP 1067 EP 1076 DI 10.1084/jem.193.9.1067 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 432DX UT WOS:000168677900009 PM 11342591 ER PT J AU Ma, Y Lang, LX Kiesewetter, DO Jagoda, E Sassaman, MB Der, M Eckelman, WC AF Ma, Y Lang, LX Kiesewetter, DO Jagoda, E Sassaman, MB Der, M Eckelman, WC TI Liquid chromatography-tandem mass spectrometry identification of metabolites of two 5-HT1A antagonists, N-{2-[4-(2-methoxylphenyl)piperazino]ethyl}-N-(2-pyridyl) trans- and cis-4-fluorocyclohexanecarboxamide, produced by human and rat hepatocytes SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE 5-HT1A antagonists ID RADIOACTIVE METABOLITES; RECEPTOR RADIOLIGAND; HUMAN PLASMA; MONKEY; PET AB Two 5-HT1A antagonists, t-FCWAY and c-FCWAY, were developed as imaging agents for positron emission tomography (PET). In order to evaluate these compounds, hepatocytes from both human and rat were utilized to produce metabolites and LC-MS-MS was used to identify metabolites. These in vitro metabolism studies indicate that hydrolysis of the amide linkage is the major metabolism pathway for humans, whereas aromatic ring-oxidation is the major metabolism pathway for rat. The rat hepatocyte results correlate well with in vivo rat metabolism studies. Based on the structures of the metabolites, we have developed an extraction procedure to determine the concentration of the parent compound in plasma. Published by Elsevier Science B.V. C1 NIH, PET Dept, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Ma, Y (reprint author), NIH, PET Dept, Warren G Magnuson Clin Ctr, 10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. NR 10 TC 22 Z9 22 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4347 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 5 PY 2001 VL 755 IS 1-2 BP 47 EP 56 DI 10.1016/S0378-4347(00)00610-1 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 427UJ UT WOS:000168423600006 PM 11393732 ER PT J AU Agnew, EB Wilson, RH Grem, JL Neckers, L Bi, DQ Takimoto, CH AF Agnew, EB Wilson, RH Grem, JL Neckers, L Bi, DQ Takimoto, CH TI Measurement of the novel antitumor agent 17-(allylamino)-17-demethoxygeldanamycin in human plasma by high-performance liquid chromatography SO JOURNAL OF CHROMATOGRAPHY B LA English DT Article DE 17-(allylamino)-17-demethoxygeldanamycin ID GELDANAMYCIN AB A sensitive HPLC assay has been developed to determine the concentration of 17-(allylamino)-17-demethoxygel-danamycin (AAG) in human plasma over the concentration range of 12.5 to 2500 nM (7.33 to 1465 ng/mL). After the addition of 1000 nM geldanamycin as the internal standard, 1 mL samples of human plasma were subjected to solid-phase extraction, via Bond-Elut C-18 cartridges, followed by analysis using an isocratic reversed-phase HPLC assay with UV detection. A Phenomenex Kingsorb, 3 micron, C18, 150X4.60 mm column and a Phenomenex Security Guard pre-column, C-18 (ODS, Octadecyl), were used to achieve separation. AAG and GM were monitored at 334 and 308 nm, respectively, on a Hewlett-Packard 1050 Diode-Array Detector. The mobile phase, run at a flow-rate of 1 mL/min, was composed of 50% (v/v) 25 mM sodium phosphate (pH 3.00) with 10 mM triethylamine and 50% acetonitrile. HPLC effectively resolved AAG with retention times of 14.60 +/- 0.54 min and the internal standard geldanamycin at 10.72+/-0.38 min (n = 15). This assay was able to measure plasma concentrations of AAG, the lower limit of quantitation being 12.5 nM, at a starting dose of 10 mg/m(2) infused intravenously over 1 h in a Phase I clinical trial in adult patients with solid tumors. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Dev Therapeut Dept, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), USN, Natl Med Ctr, Med Branch, NCI, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 7 TC 17 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4347 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 5 PY 2001 VL 755 IS 1-2 BP 237 EP 243 DI 10.1016/S0378-4347(01)00113-X PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 427UJ UT WOS:000168423600027 PM 11393709 ER PT J AU Hildesheim, A Herrero, R Castle, PE Wacholder, S Bratti, MC Sherman, ME Lorincz, AT Burk, RD Morales, J Rodriguez, AC Helgesen, K Alfaro, M Hutchinson, M Balmaceda, I Greenberg, M Schiffman, M AF Hildesheim, A Herrero, R Castle, PE Wacholder, S Bratti, MC Sherman, ME Lorincz, AT Burk, RD Morales, J Rodriguez, AC Helgesen, K Alfaro, M Hutchinson, M Balmaceda, I Greenberg, M Schiffman, M TI HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica SO BRITISH JOURNAL OF CANCER LA English DT Article DE cervix; human papillomavirus; cancer; smoking; parity ID HUMAN-PAPILLOMAVIRUS INFECTION; INTRAEPITHELIAL NEOPLASIA; RISK-FACTORS; HIGH-GRADE; DEOXYRIBONUCLEIC-ACID; CIGARETTE-SMOKING; WOMEN; PREGNANCY; CARCINOGENESIS; PREVALENCE AB We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case-control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (P-trend = 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1-6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16-0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women. (C) 2001 Cancer Research Campaign. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Caja Costarricense Seguro Social, San Jose, Costa Rica. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Digene Corp, Silver Spring, MD USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Informat Management Serv, Silver Spring, MD USA. Women & Infants Hosp, Providence, RI USA. OMNIA, Blue Bell, PA USA. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 41 TC 131 Z9 141 U1 0 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 4 PY 2001 VL 84 IS 9 BP 1219 EP 1226 DI 10.1054/bjoc.2001.1779 PG 8 WC Oncology SC Oncology GA 433UQ UT WOS:000168779100015 PM 11336474 ER PT J AU Tsujishita, Y Guo, SL Stolz, LE York, JD Hurley, JH AF Tsujishita, Y Guo, SL Stolz, LE York, JD Hurley, JH TI Specificity determinants in phosphoinositide dephosphorylation: Crystal structure of an archetypal inositol polyphosphate 5-phosphatase SO CELL LA English DT Article ID MULTIPLE ISOMORPHOUS REPLACEMENT; SACCHAROMYCES-CEREVISIAE; DNA-REPAIR; LOWE-SYNDROME; YEAST; PROTEINS; DOMAINS; SYSTEM; FAMILY; IDENTIFICATION AB Inositol polyphosphate 5-phosphatases are central to intracellular processes ranging from membrane trafficking to Ca2+ signaling, and defects in this activity result in the human disease Lowe syndrome. The 1.8 Angstrom resolution structure of the inositol polyphosphate 5-phosphatase domain of SPsynaptojanin bound to Ca2+ and inositol (1,4)-bisphosphate reveals a fold and an active site His and Asp pair resembling those of several Mg2+-dependent nucleases. Additional loops mediate specific inositol polyphosphate contacts. The 4-phosphate of inositol (1,4)-bisphosphate is misoriented by 4.6 Angstrom compared to the reactive geometry observed in the apurinic/apyrimidinic endonuclease 1, explaining the dephosphorylation site selectivity of the 5-phosphatases. Based on the structure, a series of mutants are described that exhibit altered substrate specificity providing general determinants for substrate recognition. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Howard Hughes Med Inst, Durham, NC 27710 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 53 TC 88 Z9 89 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 4 PY 2001 VL 105 IS 3 BP 379 EP 389 DI 10.1016/S0092-8674(01)00326-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 429KL UT WOS:000168515900007 PM 11348594 ER PT J AU Park, GT Denning, MF Morasso, MI AF Park, GT Denning, MF Morasso, MI TI Phosphorylation of murine homeodomain protein Dlx3 by protein kinase C SO FEBS LETTERS LA English DT Article DE Dlx3; homeodomain; protein kinase C; phosphorylation; nuclear localization signal; epidermis ID DIFFERENTIATING MOUSE KERATINOCYTES; EPIDERMAL DIFFERENTIATION; ESTER RECEPTORS; HOMEOBOX GENE; DNA-BINDING; ISOZYMES; IDENTIFICATION; EXPRESSION; ACTIVATION; INDUCTION AB The D1x3 homeodomain gene is expressed in terminally differentiated murine epidermal cells. As demonstrated for differentiation-specific granular markers, D1x3 is activated in primary mouse keratinocytes cultured in vitro by increasing the level of the extracellular Ca2+ This activation is mediated through a protein kinase C-dependent (PKC) pathway. In this study we investigated whether PKC can modulate the activity of murine D1x3 protein. Using in vitro kinase assays, we show that PKC enzymes phosphorylate the D1x3 protein. Using keratinocyte nuclear extracts for the kinase reaction, we determined that D1x3 protein is phosphorylated, and the phosphorylation is inhibited by the PKC-specific inhibitor GF109203X, suggesting that D1x3 is phosphorylated by PKC in vivo. Of the PKC isoforms present in the epidermis, we tested alpha, delta, epsilon and zeta, D1x3 is primarily phosphorylated by PKC alpha, By deletion and mutational analysis, we show that the serine residue S-138, located in the homeodomain of D1x3 protein, was specifically phosphorylated by PKC, The phosphorylation of purified D1x3 proteins by PKC partially inhibited formation of complexes between D1x3 protein and DNA, These results suggest that D1x3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of D1x3. (C) 2001 Published by Elsevier Science B,V, on behalf of the Federation of European Biochemical Societies. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Loyola Univ, Med Ctr, Dept Pathol, Maywood, IL 60153 USA. RP Morasso, MI (reprint author), NIAMS, Skin Biol Lab, NIH, Bldg 6,Room 134, Bethesda, MD 20892 USA. FU NIAMS NIH HHS [Z01 AR041124-06] NR 25 TC 17 Z9 17 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 MAY 4 PY 2001 VL 496 IS 1 BP 60 EP 65 DI 10.1016/S0014-5793(01)02398-5 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 433EA UT WOS:000168741300012 PM 11343707 ER PT J AU Mizuguchi, G Vassilev, A Tsukiyama, T Nakatani, Y Wu, C AF Mizuguchi, G Vassilev, A Tsukiyama, T Nakatani, Y Wu, C TI ATP-dependent nucleosome remodeling and histone hyperacetylation synergistically facilitate transcription of chromatin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID RNA-POLYMERASE-II; SOLUBLE NUCLEAR FRACTION; SWI-SNF COMPLEX; IN-VITRO; ACETYLTRANSFERASE COMPLEXES; DROSOPHILA EMBRYOS; SACCHAROMYCES-CEREVISIAE; ACTIVATION DOMAIN; SWI/SNF COMPLEX; GENE-EXPRESSION AB Drosophila nucleosome remodeling factor (NURF) is an ISWI-containing protein complex that facilitates nucleosome mobility and transcriptional activation in an ATP-dependent manner. Numerous studies have implicated histone acetylation in transcriptional activation. We investigated the relative contributions of these two chromatin modifications to transcription in vitro of a chromatinized adenovirus E4 minimal promoter that contains binding sites for the GAL4-VP16 activator. We found that NURF could remodel chromatin and stimulate transcription irrespective of the acetylation status of histones, In contrast, hyperacetylation of histones in the absence of NURF was unable to stimulate transcription, suggesting that NURF-dependent chromatin remodeling is an obligatory step in E4 promoter activation. When chromatin templates were first hyperacetylated and then incubated with NURF, significantly greater transcription stimulation was observed. The results suggest that changes in chromatin induced by acetylation of histones and the mobilization of nucleosomes by NURF combine synergistically to facilitate transcription. Experiments using single and multiple rounds of transcription indicate that these chromatin modifications stimulate transcription preinitiation as well as reinitiation. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068502, Japan. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 104 TC 48 Z9 48 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 14773 EP 14783 DI 10.1074/jbc.M100125200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800034 PM 11279013 ER PT J AU Leonidas, DD Boix, E Prill, R Suzuki, M Turton, R Minson, K Swaminathan, GJ Youle, RJ Acharya, KR AF Leonidas, DD Boix, E Prill, R Suzuki, M Turton, R Minson, K Swaminathan, GJ Youle, RJ Acharya, KR TI Mapping the ribonucleolytic active site of eosinophil-derived neurotoxin (EDN) - High resolution crystal structures of EDN complexes with adenylic nucleotide inhibitors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID X-RAY-DIFFRACTION; CATIONIC PROTEIN; 5'-DIPHOSPHOADENOSINE 3'-PHOSPHATE; CATALYTIC PROPERTIES; MOLECULAR-DYNAMICS; RIBONUCLEASES; BINDING; RECOGNITION; HYDRATION; SUBSTRATE AB Eosinophil-derived neurotoxin (EDN), a basic ribonuclease found in the large specific granules of eosinophils, belongs to the pancreatic RNase A family. Although its physiological function is still unclear, it has been shown that EDN is a neurotoxin capable of inducing the Gordon phenomenon in rabbits. EDN is also a potent helminthotoxin and can mediate antiviral activity of eosinophils against isolated virions of the respiratory syncytial virus. EDN is a catalytically efficient RNase sharing similar substrate specificity with pancreatic RNase A with its ribonucleolytic activity being absolutely essential for its neurotoxic, helminthotoxic, and antiviral activities. The crystal structure of recombinant human EDN in the unliganded form has been determined previously (Mosimann, S. C., Newton, D. L., Youle, R. J., and James, M. N. G. (1996) J. Mol. Biol. 260, 540-552). We have now determined high resolution (1.8 Angstrom) crystal structures for EDN in complex with adenosine-3',5'-diphosphate (3',5'-ADP), adenosine-2',5'-diphosphate (2',5'-ADP), adenosine-5'-diphosphate (5'-ADP) as well as for a native structure in the presence of sulfate refined at 1.6 Angstrom. The inhibition constant of these mononucleotides for EDN has been determined. The structures present the first detailed picture of differences between EDN and RNase A in substrate recognition at the ribonucleolytic active site. They also provide a starting point for the design of tight-binding inhibitors, which may be used to restrain the RNase activity of EDN. C1 Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Acharya, KR (reprint author), Univ Bath, Dept Biol & Biochem, Claverton Down, Bath BA2 7AY, Avon, England. RI Boix, Ester/B-9038-2012; Leonidas, Demetres/F-7228-2013; OI Boix, Ester/0000-0003-1790-2142; Swaminathan, Jawahar/0000-0002-0215-4084; Leonidas, Demetres/0000-0002-3874-2523 NR 61 TC 33 Z9 35 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15009 EP 15017 DI 10.1074/jbc.M010585200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800066 PM 11154698 ER PT J AU Feng, X Jiang, Y Meltzer, P Yen, PM AF Feng, X Jiang, Y Meltzer, P Yen, PM TI Transgenic targeting of a dominant negative corepressor to liver blocks basal repression by thyroid hormone receptor and increases cell proliferation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETINOIC ACID RECEPTOR; CANDIDATE PROTOONCOGENE BCL-3; TUMOR-NECROSIS-FACTOR; KAPPA-B PROTEIN; N-COR; TRANSCRIPTIONAL REPRESSION; HISTONE DEACETYLASE; CYCLE CONTROL; PARTIAL-HEPATECTOMY; REGENERATING LIVER AB Unliganded thyroid hormone receptors (TRs) interact with corepressors and repress basal transcription of target genes in cotransfection and in vitro studies. Currently, little is known about the function of corepressors in vivo. We thus used a mouse albumin promoter to generate several transgenic mouse lines that overexpressed a dominant negative mutant corepressor, NCoRi, in liver. The transgenic mice had normal liver weight, appearance, and minimal changes in enzyme activity. To study the effects of NCoRi on transcription of hepatic target genes, we examined T-3-regulated gene expression of hypo- and hyperthyroid transgenic mice. In hypothyroid mice, hepatic expression of Spot 14, Bcl-3, glucose 6-phosphatase, and 5'-deiodinase mRNA was higher in transgenic mice than littermate controls whereas these genes were induced to similar levels in T-3-treated mice. Derepression was not observed for malic enzyme mRNA expression in hypothyroid mice. Thus, NCoRi selectively blocked basal transcription of several thyroid hormone-responsive genes but had no effect on ligand-mediated transcription. Additionally, compensatory increases in endogenous SMRT and NCoR mRNA were observed in hypothyroid transgenic mice, Interestingly, hepatocyte proliferation as detected by BrdUrd incorporation was increased in transgenic mice. The gene profile in transgenic mouse livers was studied by cDNA microarray, and several genes related to cell proliferation were induced, In summary, our studies show that NCoR plays important roles in mediating basal repression by TRs and may prevent cellular proliferation in vivo. C1 NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NHRGI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Yen, PM (reprint author), NIDDK, Mol Regulat & Neuroendocrinol Sect, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NR 60 TC 33 Z9 35 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15066 EP 15072 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800073 PM 11328825 ER PT J AU Lambert, G Sakai, N Vaisman, BL Neufeld, EB Marteyn, B Chan, CC Paigen, B Lupia, E Thomas, A Striker, LJ Blanchette-Mackie, J Csako, G Brady, JN Costello, R Striker, GE Remaley, AT Brewer, HB Santamarina-Fojo, S AF Lambert, G Sakai, N Vaisman, BL Neufeld, EB Marteyn, B Chan, CC Paigen, B Lupia, E Thomas, A Striker, LJ Blanchette-Mackie, J Csako, G Brady, JN Costello, R Striker, GE Remaley, AT Brewer, HB Santamarina-Fojo, S TI Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOLIPOPROTEIN-A-I; FISH-EYE DISEASE; CORONARY-ARTERY DISEASE; CELL MEMBRANE-LIPIDS; LCAT GENE; TRANSGENIC MICE; CORNEAL OPACITIES; MOLECULAR DEFECT; PLASMA LECITHIN AB To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice, LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential. etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Renal Cell Biol Lab, Miami, FL 33101 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NIDDK, Lipid Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Ctr Clin, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Lambert, G (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Rm 7N115,10 Ctr Dr, Bethesda, MD 20892 USA. NR 71 TC 70 Z9 71 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15090 EP 15098 DI 10.1074/jbc.M008466200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800076 PM 11278414 ER PT J AU Oshima, Y Puri, RK AF Oshima, Y Puri, RK TI Characterization of a powerful high affinity antagonist that inhibits biological activities of human interleukin-13 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLONY-STIMULATING FACTOR; CELL CARCINOMA-CELLS; RECEPTOR-ALPHA CHAIN; COMMON GAMMA-CHAIN; HUMAN GLIOMA-CELLS; HUMAN B-CELLS; PSEUDOMONAS EXOTOXIN; SIGNAL-TRANSDUCTION; IL-13 RECEPTOR; ATOPIC-DERMATITIS AB Interleukin-13 (IL-13), a predominantly Th2-derived cytokine, appears to play a central pathological role in asthma, atopic dermatitis, allergic rhinitis, some parasitic infections, and cancer. We hypothesized that an IL-13 antagonist may have profound therapeutic utility in these conditions. We, therefore, mutagenized human IL-13 in which Glu at position 13 was substituted by a Lys residue. This highly purified recombinant IL-13 variant, IL-13E13K, bound with 4-fold higher affinity to the IL-13 receptor than wild-type IL-13 but retained no detectable proliferative activity on the TF-1 hematopoietic cell line. IL-13E13K competitively inhibited IL-13- and IL-4-dependent TF-1 proliferation. It also inhibited IL13-induced STAT-B (signal transduction and activator of transducer-6) activation in immune cells and cancer cells and reversed IL-13-induced inhibition of CD14 expression on human primary monocytes. These results demonstrate that high affinity binding and signal generation can be uncoupled efficiently in a ligand receptor interaction. These results also suggest that IL-13E13K may be a useful antagonist for the treatment of allergic, inflammatory, and parasitic diseases or even malignancies in which IL-13 plays a central role. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, 29 Lincoln Dr,NIH Bldg 29B,Rm 2NN10, Bethesda, MD 20892 USA. NR 61 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15185 EP 15191 DI 10.1074/jbc.M010159200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800088 PM 11278629 ER PT J AU Ivanova, AV Ivanov, SV Danilkovitch-Miagkova, A Lerman, MI AF Ivanova, AV Ivanov, SV Danilkovitch-Miagkova, A Lerman, MI TI Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UBIQUITIN-CONJUGATING ENZYME; NUCLEAR-PORE COMPLEX; TRANSFORMING-GROWTH-FACTOR; GTPASE-ACTIVATING PROTEIN; RENAL-CELL CARCINOMA; MOLECULAR CHARACTERIZATION; HUMAN HOMOLOG; C-JUN; GENE; UBC9 AB In this study, we focus on different modes of regulation of STRA13, a human ortholog of the mouse basic helix-loop-helix transcriptional factor, previously identified by us as a new von Hippel-Lindau tumor suppressor gene (VHL) target. The gene was overexpressed in VHL-deficient cell lines and tumors, specifically clear cell renal carcinomas and hemangioblastomas, Introduction of wild type VHL transgene into clear cell renal carcinoma restored low level expression of STRA13, Overexpression was also detected in many common malignancies with an intact VHL gene, suggesting the existence of another, VHL-independent pathway of STRA13 regulation, Similar to many other von Hippel-Lindau tumor-suppressor protein (pVHL) targets, the expression of STRA13 on the mRNA level was hypoxia-sensitive, indicating oxygen-dependent regulation of the gene, presumably through the pVHL/hypoxia-inducible factor 1 (HIF-1) pathway. The yeast two-hybrid screening revealed interaction of the STRA13 protein with the human ubiquitin-conjugating enzyme (UBC9) protein, the specificity of which was confirmed in mammalian cells. By adding the proteasome inhibitor acetyl-leucinyl-leucinyl-norleucinal, we demonstrated that the 26 S proteasome pathway regulates the stability of pSTRA13, Go-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13, Hypoxia treatment of mammalian cells transiently expressing STRA13 protein showed that stability of pSTRA13 is not affected by hypoxia or VHL, Thus, STRA13, a new pVHL target, is regulated in cells on multiple levels. We propose that STRA13 may play a critical role in carcinogenesis, since it is a potent transcriptional regulator, abundant in a variety of common tumors. C1 NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Intamural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr,Lab Immunobiol, Ft Detrick, MD 21702 USA. RP Ivanova, AV (reprint author), NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 53 TC 86 Z9 91 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15306 EP 15315 DI 10.1074/jbc.M010516200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800104 PM 11278694 ER PT J AU Korotkov, KV Kumaraswamy, E Zhou, Y Hatfield, DL Gladyshev, VN AF Korotkov, KV Kumaraswamy, E Zhou, Y Hatfield, DL Gladyshev, VN TI Association between the 15-kDa selenoprotein and UDP-glucose : glycoprotein glucosyltransferase in the endoplasmic reticulum of mammalian cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SELENOCYSTEINE-CONTAINING PROTEINS; GOLGI-APPARATUS; PURIFICATION; EXPRESSION; SEQUENCE; CHAPERONES; INSERTION; ELEMENTS; CERAMIDE; ENZYME AB Mammalian selenocysteine-containing proteins characterized with respect to function are involved in redox processes and exhibit distinct expression patterns and cellular locations. A recently identified 15-kDa selenoprotein (Sep15) has no homology to previously characterized proteins, and its function is not known. Here we report the intracellular localization and identification of a binding partner for this selenoprotein which implicate Sep15 in the regulation of protein folding. The native Sep15 isolated from rat prostate and mouse liver occurred in a complex with a 150-kDa protein. The latter protein was identified as UDP-glucose:glycoprotein glucosyltransferase (UGTR), the endoplasmic reticulum (ER)-resident protein, which was previously shown to be involved in the quality control of protein folding. UGTR functions by glucosylating misfolded proteins, retaining them in the ER until they are correctly folded or transferring them to degradation pathways. To determine the intracellular localization of Sep15, we expressed a green fluorescent protein-Sep15 fusion protein in CV-1 cells, and this protein was localized to the ER and possibly other perinuclear compartments. We determined that Sep15 contained the N-terminal signal peptide that was essential for translocation and that it was cleaved in the mature protein. However, C-terminal sequences of Sep15 were not involved in trafficking and retention of Sep15. The data suggest that the association between Sep15 and UGTR is responsible for maintaining the selenoprotein in the ER This report provides the first example of the ER-resident selenoprotein and suggests a possible role of the trace element selenium in the quality control of protein folding. C1 Univ Nebraska, Dept Biochem, Beadle Ctr N151, Lincoln, NE 68588 USA. Univ Nebraska, Ctr Biotechnol, Lincoln, NE 68588 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Beadle Ctr N151, Lincoln, NE 68588 USA. RI Gladyshev, Vadim/A-9894-2013 NR 26 TC 80 Z9 88 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15330 EP 15336 DI 10.1074/jbc.M009861200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800107 PM 11278576 ER PT J AU van der Wal, J Habets, R Varnai, P Balla, T Jalink, K AF van der Wal, J Habets, R Varnai, P Balla, T Jalink, K TI Monitoring agonist-induced phospholipase C activation in live cells by fluorescence resonance energy transfer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAINS; ADRENAL GLOMERULOSA CELLS; INOSITOL 1,4,5-TRISPHOSPHATE; LYSOPHOSPHATIDIC ACID; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; NEUROKININ RECEPTORS; NEURITE RETRACTION; CA2+ OSCILLATIONS; PLASMA-MEMBRANE; LIVING CELLS AB Agonist-induced intracellular Ca2+ signals following phospholipase C (PLC) activation display a variety of patterns, including transient, sustained, and oscillatory behavior. These Ca2+ changes have been well characterized, but detailed kinetic analyses of PLC activation in single living cells is lacking, due to the absence of suitable indicators for use in vivo. Recently, green fluorescent protein-tagged pleckstrin homology domains have been employed to monitor PLC activation in single cells, based on (confocal) imaging of their fluorescence translocation from the membrane to the cytosol that occurs upon hydrolysis of phosphatidylinositol bisphosphate, Here we describe fluorescence resonance energy transfer between pleckstrin homology domains of PLC delta1 tagged with cyan and yellow fluorescent proteins as a sensitive readout of phosphatidylinositol bisphosphate metabolism for use both in cell populations and in single cells. Fluorescence resonance energy transfer requires significantly less excitation intensity, enabling prolonged and fast data acquisition without the cell damage that limits confocal experiments. It also allows experiments on motile or extremely flat cells, and can be scaled to record from cell populations as well as single neurites, Characterization of responses to various agonists by this method reveals that stimuli that elicit very similar Ca2+ mobilization responses can exhibit widely different kinetics of PLC activation, and that the latter appears to follow receptor activation more faithfully than the cytosolic Ca2+ transient. C1 Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands. NIH, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Jalink, K (reprint author), Netherlands Canc Inst, Div Cell Biol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. OI Balla, Tamas/0000-0002-9077-3335 NR 37 TC 173 Z9 177 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15337 EP 15344 DI 10.1074/jbc.M007194200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800108 PM 11152673 ER PT J AU Horiuchi, M Baron, GS Xiong, LW Caughey, B AF Horiuchi, M Baron, GS Xiong, LW Caughey, B TI Inhibition of interactions and interconversions of prion protein isoforms by peptide fragments from the C-terminal folded domain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; CELL-FREE CONVERSION; SYNTHETIC PEPTIDES; TRANSGENIC MICE; NEUROBLASTOMA-CELLS; SECONDARY STRUCTURE; RESISTANT STATE; SCRAPIE ISOFORM; SPECIES BARRIER; PRP AB The formation of protease-resistant prion protein (PrP-res or PrPSc) involves selective interactions between PrP-res and its normal protease-sensitive counterpart, PrP-sen or PrPC. Previous studies have shown that synthetic peptide fragments of the PrP sequence corresponding to residues 119-136 of hamster PrP (Ha119-136) can selectively block PrP-res formation in cell-free systems and scrapie-infected tissue culture cells. Here we show that two other peptides corresponding to residues 166-179 (Ha166-179) and 200-223 (Ha200-223) also potently inhibit the PrP-res induced cell-free conversion of PrP-sen to the protease-resistant state. In contrast, Ha121-141, Ha180-199, and Ha218-232 were much less effective as inhibitors. Mechanistic analyses indicated that Ha166-179, Ha200-223, and peptides containing residues 119-136 inhibit primarily by binding to PrP-sen and blocking its binding to PrP-res, Circular dichroism analyses indicated that Ha117-141 and Ha200-223, but not non-inhibitory peptides, readily formed high beta -sheet structures when placed under the conditions of the conversion reaction, We conclude that these inhibitory peptides may mimic contact surfaces between PrP-res and PrP-sen and thereby serve as models of potential therapeutic agents for transmissible spongiform encephalopathies. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Obihiro Univ Agr & Vet Med, Dept Vet Publ Hlth, Obihiro, Hokkaido 0808555, Japan. Obihiro Univ Agr & Vet Med, Natl Res Ctr Protozoan Dis, Obihiro, Hokkaido 0808555, Japan. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 42 TC 62 Z9 66 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2001 VL 276 IS 18 BP 15489 EP 15497 DI 10.1074/jbc.M100288200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429QQ UT WOS:000168528800127 PM 11279046 ER PT J AU Saavedra, JE Srinivasan, A Bonifant, CL Chu, JX Shanklin, AP Flippen-Anderson, JL Rice, WG Turpin, JA Davies, KM Keefer, LK AF Saavedra, JE Srinivasan, A Bonifant, CL Chu, JX Shanklin, AP Flippen-Anderson, JL Rice, WG Turpin, JA Davies, KM Keefer, LK TI The secondary amine/nitric oxide complex ion R2N[N(O)NO](-) as nucleophile and leaving group in SNAr reactions SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID NITRIC-OXIDE; ZINC FINGERS; INHIBITORS; RELEASE; AGENTS; DONORS; CONVERSION; AIDS; NO AB Ions of structure R2N[N(O)NO](-) and their alkylation products have seen increasing use as nitric oxide (NO)-generating agents for biomedical research applications. Were we show that such diazeniumdiolate anions can readily displace halide from a variety of electrophilic aza- or nitroaromatic substrates to form O-2-arylated derivatives of structure R2N-N(O)=N=OAr. The site of arylation and the cis arrangement of the oxygens were confirmed by X-ray crystallography. Displacement by various nucleophiles showed R2N[N(O)NO](-) to be a reasonably good leaving group, with rate constants for displacement by hydroxide, methoxide, and isopropylamine that were between those of chloride and fluoride in the SNAr reactions we surveyed. The Meisenheimer intermediate could be spectrally observed. These O-2-aryl diazeniumdiolates proved capable of reacting with the nucleophilic sulfur of the HIV-1 p7 nucleocapsid protein's zinc finger assembly to eject the zinc, disrupting a structural motif critical to viral replication and suggesting possible utility in the drug discovery realm. C1 NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. So Res Inst, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. RP Saavedra, JE (reprint author), NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO-56000] NR 29 TC 68 Z9 69 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAY 4 PY 2001 VL 66 IS 9 BP 3090 EP 3098 DI 10.1021/jo0016529 PG 9 WC Chemistry, Organic SC Chemistry GA 428KY UT WOS:000168461900025 PM 11325274 ER PT J AU Gomez-Flores, R Rice, KC Zhang, XY Weber, RJ AF Gomez-Flores, R Rice, KC Zhang, XY Weber, RJ TI Increased tumor necrosis factor-alpha and nitric oxide production by rat macrophages following in vitro stimulation and intravenous administration of the delta-opioid agonist SNC 80 SO LIFE SCIENCES LA English DT Article DE SNC 80; non-peptide opioids; delta-opioid agonist; macrophages; nitric oxide; tumor necrosis factor-alpha ID MURINE PERITONEAL-MACROPHAGES; MYCOBACTERIUM-AVIUM COMPLEX; NATURAL-KILLER; PERIAQUEDUCTAL GRAY; RECEPTOR AGONIST; IMMUNE FUNCTIONS; IFN-GAMMA; TNF-ALPHA; IN-VITRO; T-CELLS AB Opioids alter immune function by binding to opioid receptors on cells of the immune system, or indirectly by acting on receptors within the central nervous system. Mu-selective opioid agonists are generally associated with immunosuppression, whereas delta -opioid receptor-selective agonists are commonly associated with immunopotentiation. We have previously shown that intracerebroventricular administration of the nonpeptide delta -opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) did not alter certain parameters of immunocompetence. In the present study, we studied the in vitro and ex vivo effects of SNC 80 on rat macrophage and lymphocyte functions. We showed that SNC 80 at concentrations of 10(-7) M and 10(-6) M, significantly (P < 0.01) stimulated the in vitro production of tumor necrosis factor-alpha (TNF-alpha) (60-100% increase) and nitric oxide (34-67% increase) by resident and LPS-stimulated peritoneal macrophages. Similarly, intravenous administration of SNC 80 (6.8 mg/kg) significantly (P < 0.01) increased the production of TNF- and nitric oxide (2- and 15-fold increases respectively, compared with saline-injected control) by LPS-stimulated splenic macrophages. In addition, intravenous injection of SNC 80 plus Con A potentiated ex vivo LPS-stimulated macrophage functions. SNC 80 could potentially be utilized in various clinical situations where immunosuppression is undesirable. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Univ Illinois, Coll Med, Dept Biomed & Therapeut Sci, Sect Med Sci, Peoria, IL 61656 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Autonoma Nuevo Leon, Fac Ciencias Biol, Dept Microbiol & Inmunol, San Nicolas De Los Garza 66451, NL, Mexico. RP Weber, RJ (reprint author), Univ Illinois, Coll Med, Dept Biomed & Therapeut Sci, Sect Med Sci, 1 Illini Dr,Box 1649, Peoria, IL 61656 USA. FU NIDA NIH HHS [DA/AI08988, DA12095, F32-DA05865] NR 43 TC 20 Z9 20 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 4 PY 2001 VL 68 IS 24 BP 2675 EP 2684 DI 10.1016/S0024-3205(01)01082-7 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 432RK UT WOS:000168709300004 PM 11400911 ER PT J AU Gallo, V Chittajallu, R AF Gallo, V Chittajallu, R TI Neuroscience - Unwrapping glial cells from the synapse: What lies inside? SO SCIENCE LA English DT Editorial Material ID KAINATE RECEPTORS; GLUTAMATE; CLEARANCE; EFFICACY C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Gallo, V (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. NR 12 TC 22 Z9 23 U1 1 U2 1 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 MAY 4 PY 2001 VL 292 IS 5518 BP 872 EP 873 DI 10.1126/science.1060854 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 429KB UT WOS:000168514900032 PM 11341285 ER PT J AU Geiman, TM Tessarollo, L Anver, MR Kopp, JB Ward, JM Muegge, K AF Geiman, TM Tessarollo, L Anver, MR Kopp, JB Ward, JM Muegge, K TI Lsh, a SNF2 family member, is required for normal murine development SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE lymphoid specific helicase; SNF2; transcription; chromatin; transgenics; development ID CHROMATIN REMODELING COMPLEX; TRANSCRIPTIONAL ACTIVATION; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; HISTONE OCTAMER; DNA METHYLATION; SWI/SNF COMPLEX; MICE LACKING; PROTEIN; MAINTENANCE AB Lsh is a member of the SNF2 family of chromatin remodelers, that regulate diverse biological processes such as replication, repair and transcription. Although expression of Lsh is highly tissue specific in adult animals, Lsh mRNA is detectable in multiple tissues during embryogenesis. In order to determine the physiologic role of Lsh during murine development and to assess its unique function in adult mice, we performed targeted deletion of the Lsh gene using homologous recombination in murine embryonic stem cells. Lsh-/- embryos occurred with the expected Mendelian frequency after implantation and during embryogenesis. However, Lsh-/- mice died within a few hours after birth. Furthermore, newborn mice were 22% lower in weight in comparison with their littermates and showed renal lesions. Thus Lsh is a non-redundant member of the SNF2 family and is essential for normal murine development and survival. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, SAIC, Frederick, MD 21702 USA. NCI, Mammalian Genet Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Pathol Histotechnol Lab, SAIC, Frederick, MD 21702 USA. NIDDKD, Kidney Dis Sect, Bethesda, MD 21702 USA. NCI, Vet & Tumor Pathol Sect, Off Lab Anim Resources, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, SAIC, Bldg 469,Rm 239, Frederick, MD 21702 USA. OI Kopp, Jeffrey/0000-0001-9052-186X FU PHS HHS [N01-C0-56000] NR 35 TC 49 Z9 54 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD MAY 3 PY 2001 VL 1526 IS 2 BP 211 EP 220 DI 10.1016/S0304-4165(01)00129-5 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 429LU UT WOS:000168519300012 PM 11325543 ER PT J AU Bulavin, DV Higashimoto, Y Popoff, IJ Gaarde, WA Basrur, V Potapova, O Appella, E Fornace, AJ AF Bulavin, DV Higashimoto, Y Popoff, IJ Gaarde, WA Basrur, V Potapova, O Appella, E Fornace, AJ TI Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase SO NATURE LA English DT Article ID DNA-DAMAGE CHECKPOINT; CELL-CYCLE; CDC25 PHOSPHATASE; PROTEIN-KINASE; PHOSPHORYLATION; CHK1; MITOSIS; P53 AB Response to genotoxic stress can be considered as a multistage process involving initiation of cell-cycle arrest and maintenance of arrest during DNA repair(1). Although maintenance of G2/M checkpoints is known to involve Chk1, Chk2/Rad53 and upstream components, the mechanisms involved in its initiation are less well defined(1-4). Here we report that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. In vivo, inhibition of p38 prevents both phosphorylation of Cdc25B at serine 309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo Cdc25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. ISIS Pharmaceut, Carlsbad, CA 92008 USA. NIA, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. RP Fornace, AJ (reprint author), NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 23 TC 387 Z9 409 U1 2 U2 16 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 3 PY 2001 VL 411 IS 6833 BP 102 EP 107 DI 10.1038/35075107 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427XY UT WOS:000168432800052 PM 11333986 ER PT J AU Exner, DV Dries, DL Domanski, MJ Cohn, JN AF Exner, DV Dries, DL Domanski, MJ Cohn, JN TI Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGESTIVE-HEART-FAILURE; INDIVIDUAL-RESPONSES; RACIAL-DIFFERENCES; MORTALITY; ENALAPRIL; MORBIDITY; BLOCKER; TERM AB Background: Black patients with heart failure have a poorer prognosis than white patients, a difference that has not been adequately explained. Whether racial differences in the response to drug treatment contribute to differences in outcome is unclear. To address this issue, we pooled and analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, two large, randomized trials comparing enalapril with placebo in patients with left ventricular dysfunction. Methods: We used a matched-cohort design in which up to four white patients were matched with each black patient according to trial, treatment assignment, sex, left ventricular ejection fraction, and age. A total of 1196 white patients (580 from the prevention trial and 616 from the treatment trial) were matched with 800 black patients (404 from the prevention trial and 396 from the treatment trial). The average duration of follow-up was 35 months in the prevention trial and 33 months in the treatment trial. Results: The black patients and the matched white patients had similar demographic and clinical characteristics, but the black patients had higher rates of death from any cause (12.2 vs. 9.7 per 100 person-years) and of hospitalization for heart failure (13.2 vs. 7.7 per 100 person-years). Despite similar doses of drug in the two groups, enalapril therapy, as compared with placebo, was associated with a 44 percent reduction (95 percent confidence interval, 27 to 57 percent) in the risk of hospitalization for heart failure among the white patients (P<0.001) but with no significant reduction among black patients (P=0.74). At one year, enalapril therapy was associated with significant reductions from base line in systolic blood pressure (by a mean [+/-SD] of 5.0+/-17.1 mm Hg) and diastolic blood pressure (3.6+/-10.6 mm Hg) among the white patients, but not among the black patients. No significant change in the risk of death was observed in association with enalapril therapy in either group. Conclusions: Enalapril therapy is associated with a significant reduction in the risk of hospitalization for heart failure among white patients with left ventricular dysfunction, but not among similar black patients. This finding underscores the need for additional research on the efficacy of therapies for heart failure in black patients. (N Engl J Med 2001;344:1351-7.) Copyright (C) 2001 Massachusetts Medical Society. C1 Univ Calgary, Cardiovasc Res Grp, Calgary, AB T2N 4N1, Canada. Univ Texas, SW Med Sch, CArdiovasc Res Grp, Dallas, TX USA. NHLBI, Clin Trials Res Grp, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA. RP Exner, DV (reprint author), Univ Calgary, Cardiovasc Res Grp, 3330 Hosp Dr NW,Rm G208, Calgary, AB T2N 4N1, Canada. NR 30 TC 323 Z9 332 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 3 PY 2001 VL 344 IS 18 BP 1351 EP 1357 DI 10.1056/NEJM200105033441802 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 427NY UT WOS:000168413500002 PM 11333991 ER PT J AU Tataranni, PA Bogardus, C AF Tataranni, PA Bogardus, C TI Changing habits to delay diabetes. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID IMPAIRED GLUCOSE-TOLERANCE; DIET; EXERCISE; NIDDM C1 NIH, Phoenix, AZ 85016 USA. RP Tataranni, PA (reprint author), NIH, Phoenix, AZ 85016 USA. NR 12 TC 16 Z9 16 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 3 PY 2001 VL 344 IS 18 BP 1390 EP 1392 DI 10.1056/NEJM200105033441809 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 427NY UT WOS:000168413500009 PM 11333998 ER PT J AU Hohenstein, P Kielman, MF Breukel, C Bennett, LM Wiseman, R Krimpenfort, P Cornelisse, G van Ommen, GJ Devilee, P Fodde, R AF Hohenstein, P Kielman, MF Breukel, C Bennett, LM Wiseman, R Krimpenfort, P Cornelisse, G van Ommen, GJ Devilee, P Fodde, R TI A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage SO ONCOGENE LA English DT Article DE Brca1(1700T); mouse model; hereditary breast cancer; p53; genotype-phenotype correlation; DNA damage ID DNA-DAMAGE; BREAST-CANCER; TRANSCRIPTIONAL ACTIVATION; GENETIC INSTABILITY; TUMOR SPECTRUM; MEIOTIC CELLS; MODEL; EXPRESSION; REPAIR; MICE AB A mouse model with a targeted mutation in the 3' end of the endogenous Brca1 gene, Brca1(1700T), was generated to compare the phenotypic consequences of truncated SI cal proteins with other mutant Brca1 models reported in the literature to date. Mice heterozygous for the Brca1(1700T) mutation do not show any predisposition to tumorigenesis, Treatment of these mice with ionizing radiation or breeding with Ape, Msh-2 or Tp53 mutant mouse models did not show any change in the tumor phenotype, Like other Brca1 mouse models, the Brca1(1700T) mutation is embryonic lethal in homozygous state, However, homozygous Brca1(1700T) embryos reach the headfold stage but are delayed in their development and fail to turn. Thus, in contrast to Brca1(null) models, the mutant embryos do not undergo growth arrest leading to a developmental block at 6.5 dpc, but continue to proliferate and differentiate until 9.5 dpc. Homozygous embryos die between 9.5-10.5 dpc due to massive apoptosis throughout the embryo. These results indicate that a C-terminal truncating Brca1 mutation removing the last BRCT repeat has a different effect on normal cell function than does the complete absence of Brca1. C1 Leiden Univ, Med Ctr, Dept Human & Clin Genet, NL-2300 RA Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RA Leiden, Netherlands. NIEHS, Res Triangle Pk, NC 27709 USA. Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. RP Fodde, R (reprint author), Leiden Univ, Med Ctr, Dept Human & Clin Genet, POB 9503, NL-2300 RA Leiden, Netherlands. OI Fodde, Riccardo/0000-0001-9839-4324; Hohenstein, Peter/0000-0001-8548-4734 NR 43 TC 41 Z9 42 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 3 PY 2001 VL 20 IS 20 BP 2544 EP 2550 DI 10.1038/sj.onc.1204363 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 431VM UT WOS:000168652500005 PM 11420664 ER PT J AU Ebina, M Martinez, A Birrer, MJ Linnoila, RI AF Ebina, M Martinez, A Birrer, MJ Linnoila, RI TI In situ detection of unexpected patterns of mutant p53 gene expression in non-small cell lung cancers SO ONCOGENE LA English DT Article DE p53; lung cancer; immunohistochemistry; in situ PCR; in situ RT-PCR ID TRANSFORMED-CELLS; MUTATIONS; RAS; ABNORMALITIES; ANTIGEN AB Many solid tumors, including non-small cell lung cancers (NSCLCs), are characterized by heterogenous expression of p53 protein in the neoplastic cells. To analyse the molecular implications of this finding, we examined topographic distribution of p53 mutations using in situ polymerase chain reaction (PCR) in primary NSCLCs, showing distinct patterns of variable p53 overexpression by immunohistochemistry, Unique sets of primers for each mutation were designed, and optimal PCR conditions were determined by standard PCR using DNA from cloned mutants or cell lines established from these tumors. Ail tumor cell nuclei, regardless of the status of p53 overexpression, demonstrated homogeneous distribution of mutant p53 with specific primers, indicating that only subgroups of the mutated cells overexpressed p53 protein. In situ reverse transcription (RT)-PCR was applied to detect mutant mRNA in the individual tumor cells using specific primers. We found that in each case the distribution of mutant p53 mRNA coincided with that of immunohistochemical overexpression of p53 protein. Our results suggest that the regulation of mutant p53 expression, but not the genotype, is heterogeneous in the neoplastic cells, The topographic genomapping of p53 in NSCLC using in situ PCR provides a novel approach to view molecular mechanisms of lung carcinogenesis. C1 Tohoku Univ, Inst Dev Aging & Canc, Div Canc Control, Sendai, Miyagi 9808575, Japan. NCI, Dept Cell & Canc Biol, Med Branch, NIH, Bethesda, MD 20892 USA. RP Ebina, M (reprint author), Tohoku Univ, Inst Dev Aging & Canc, Div Canc Control, Sendai, Miyagi 9808575, Japan. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 21 TC 11 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 3 PY 2001 VL 20 IS 20 BP 2579 EP 2586 DI 10.1038/sj.onc.1204351 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 431VM UT WOS:000168652500009 PM 11420668 ER PT J AU Grajkowski, A Wilk, A Chmielewski, MK Phillips, LR Beaucage, SL AF Grajkowski, A Wilk, A Chmielewski, MK Phillips, LR Beaucage, SL TI The 2-(N-formyl-N-methyl)aminoethyl group as a potential phosphate/thiophosphate protecting group in solid-phase oligodeoxyribonucleotide synthesis SO ORGANIC LETTERS LA English DT Article ID PHOSPHATE PROTECTION; CHLORIDE AB [GRAPHICS] The 2-(N-formyl-N-methyl)aminoethyl deoxyribonucleoside phosphoramidite 1 has been synthesized and used in the solid-phase synthesis of an octadecathymidylic acid as a cost-efficient monomer for potential application in the preparation of therapeutic oligonucleotides, The 2-(N-formyl-N-methyl)aminoethyl group can be cleaved from oligonucleotides according to a unique thermolytic cyclodeesterification process at pH 7.0. In addition to being cost-effective, the use of 1 simplifies oligonucleotide postsynthesis processing by eliminating the utilization of concentrated ammonium hydroxide in oligonucleotide deprotection. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. NCI, Biol Tresting Branch, Dev Therapeut Program, Frederick, MD 21701 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. NR 10 TC 23 Z9 23 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD MAY 3 PY 2001 VL 3 IS 9 BP 1287 EP 1290 DI 10.1021/ol0156852 PG 4 WC Chemistry, Organic SC Chemistry GA 427GA UT WOS:000168395400011 PM 11348216 ER PT J AU Ramanathan, R Corwin, MJ Hunt, CE Lister, G Tinsley, LR Baird, T Silvestri, JM Crowell, DH Hufford, D Martin, RJ Neuman, MR Weese-Mayer, DE Cupples, LA Peucker, M Willinger, M Keens, TG AF Ramanathan, R Corwin, MJ Hunt, CE Lister, G Tinsley, LR Baird, T Silvestri, JM Crowell, DH Hufford, D Martin, RJ Neuman, MR Weese-Mayer, DE Cupples, LA Peucker, M Willinger, M Keens, TG CA Collaborative Home Infant Monitori TI Cardiorespiratory events recorded on home monitors - Comparison of healthy infants with those at increased risk for SIDS SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DEATH-SYNDROME; APNEA; PLETHYSMOGRAPHY; SIBLINGS; PATTERN; AGE AB Context Home monitors designed to identify cardiorespiratory events are frequently used in infants at increased risk for sudden infant death syndrome (SIDS), but the efficacy of such devices for this use is unproven. Objective To test the hypothesis that preterm infants, siblings of infants who died of SIDS, and infants who have experienced an idiopathic, apparent life-threatening event have a greater risk of cardiorespiratory events than healthy term infants. Design Longitudinal cohort study conducted from May 1994 through February 1998. Setting Five metropolitan medical centers in the United States. Participants A total of 1079 infants (classified as healthy term infants and 6 groups of those at risk for SIDS) who, during the first 6 months after birth, were observed with home cardiorespiratory monitors using respiratory inductance plethysmography to detect apnea and obstructed breathing. Main Outcome Measures Occurrence of cardiorespiratory events that exceeded predefined conventional and extreme thresholds as recorded by the monitors. Results During 718 358 hours of home monitoring, 6993 events exceeding conventional alarm thresholds occurred in 445 infants (41%), Of these, 653 were extreme events in 116 infants (10%), and of those events with apnea, 70% included at least 3 obstructed breaths. The frequency of at least 1 extreme event was similar in term infants in all groups, but preterm infants were at increased risk of extreme events until 43 weeks' postconceptional age. Conclusions In this study, conventional events are quite common, even in healthy term infants. Extreme events were common only in preterm infants, and their timing suggests that they are not likely to be immediate precursors to SIDS. The high frequency of obstructed breathing in study participants would likely preclude detection of many events by conventional techniques. These data should be important for designing future monitors and determining if an infant is likely to be at risk for a cardiorespiratory event. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. Univ So Calif, Sch Med, Dept Pediat & Neonatol, Los Angeles, CA USA. Womens & Childrens Hosp, Los Angeles, CA USA. Good Samaritan Hosp, Los Angeles, CA USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Pediat, Boston, MA 02118 USA. Med Coll Ohio, Dept Pediat, Toledo, OH 43699 USA. Univ Hawaii Manoa, Kapiolani Med Ctr Women & Children, Dept Pediat, Honolulu, HI 96822 USA. Case Western Reserve Univ, Sch Med, Metrohlth Med Ctr, Dept Pediat, Cleveland, OH USA. Rush Univ, Rush Med Coll, Rush Childrens Hosp, Dept Pediat, Chicago, IL 60612 USA. Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. NICHHD, Ctr Res Mothers & Children, Pregnancy & Perinatol Branch, NIH, Bethesda, MD 20892 USA. RP Lister, G (reprint author), Yale Univ, Sch Med, Dept Pediat, Box 208064, New Haven, CT 06520 USA. FU NICHD NIH HHS [HD 29073, HD 28791, HD 29056, HD 29060, HD 29067, HD 29071, HD 34625] NR 23 TC 141 Z9 148 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 2 PY 2001 VL 285 IS 17 BP 2199 EP 2207 DI 10.1001/jama.285.17.2199 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 424WC UT WOS:000168256100022 PM 11325321 ER PT J AU Biesecker, LG AF Biesecker, LG TI The multifaceted challenges of Proteus syndrome SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PULMONARY THROMBOEMBOLISM; MOSAICISM AB Proteus syndrome is a rare and sporadic disorder that causes postnatal overgrowth of multiple tissues in a mosaic pattern. The overgrowth can involve skin, subcutaneous tissue, connective tissue (including bone), the central nervous system, and viscera, Complications of Proteus syndrome include, among others, progressive skeletal deformities, invasive lipomas, benign and malignant tumors, and deep venous thrombosis with pulmonary embolism. Care of patients with Proteus syndrome presents significant challenges to both physicians and parents because of the various medical as well as psychosocial consequences of the disease, Herein, the case of a 5-year-otd patient who manifested a number of these complications is presented. Current knowledge about the diagnosis, natural history, etiology, and management of the disorder is reviewed. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. NR 15 TC 50 Z9 52 U1 1 U2 3 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 MAY 2 PY 2001 VL 285 IS 17 BP 2240 EP 2243 DI 10.1001/jama.285.17.2240 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 424WC UT WOS:000168256100027 PM 11325326 ER PT J AU Bewley, CA Otero-Quintero, S AF Bewley, CA Otero-Quintero, S TI The potent anti-HIV protein cyanovirin-N contains two novel carbohydrate binding sites that selectively bind to man(8) D1D3 and Man(9) with nanomolar affinity: Implications for binding to the HIV envelope protein gp120 SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INACTIVATING PROTEIN; CONCANAVALIN-A; GLYCOPROTEIN GP120; VACCINIA VIRUS; TYPE-1; CD4; INHIBITION; COMPLEX; FUSION AB Cyanovirin-N (CVN) is a monomeric II kDa cyanobacterial protein that potently inactivates diverse strains of human immunodeficiency virus (HIV) at the level of cell fusion by virtue of high affinity interactions with the surface envelope glycoprotein gp120. Several lines of evidence have suggested that CVN-gp120 interactions are in part mediated by N-linked complex carbohydrates present on gp120, but experimental evidence has been lacking. To this end we screened a comprehensive panel of carbohydrates which represent structurally the N-linked carbohydrates found on gp120 for their ability to inhibit the fusion-blocking activity of CVN in a quantitative HIV-1 envelope-mediated cell fusion assay. Our results show that CVN specifically recognizes with nanomolar affinity Man(9)GlcNAc(2) and the D1D3 isomer of ManpGlcNAc(2). Nonlinear least squares best fitting of titration data generated using the cell fusion assay show that CVN binds to gp120 with an equilibrium association constant (K-a) of 2.4 (+/- 0.1) x 10(7) M-1 and an apparent stoichiometry of 2 equiv of CVN per gp120, Man(8)GlcNAc(2) DID3 acts as a divalent ligand (2 CVN:I Man(8)) with a K-a of 5.4 (+/- 0.5) x 10(7) M-1, and Man(9)GlcNAc(2) functions as a trivalent ligand (3 CVN:1 Man(9)) with a K-a of 1.3 (+/- 0.3) x 10(8) M-1 Isothermal titration calorimetry experiments of CVN binding to Man(9)GlcNAc(2) at micromolar concentrations confirmed the nanomolar affinity (K-a = 1.5 (+/- 0.9) x 10(8) M-1), and the fitted data indicated a stoichiometry equal to approximately one (1 Man(9):1 CVN). The 1:1 stoichiometry at micromolar concentrations suggested that CVN has not only a high affinity binding site-relevant to the studies at nM concentrations-but a lower affinity site as well that facilitates cross-linking of CVN-oligomannose at micromolar concentrations or higher. The specificity of CVN for Man(8) D1D3 and Mans over the D1D2 isomer of Man(8) indicated that the minimum structure required for high affinity binding comprises Man alpha1 --> 2Man alpha. By following the H-1-N-15 correlation spectrum of N-15-Iabeled CVN upon titration with this disaccharide, we unambiguously demonstrate that CVN recognizes and binds to the disaccharide Man alpha1 --> 2Mana via two distinct binding sites of differing affinities located on opposite ends of the protein. The high affinity site has a K, of 7.2 (+/- 4) x 10(6) M(-)1 and the low affinity site a kj of 6.8 (+/- 4) x 10(5) RI-l as determined by isothermal titration calorimetry. Mapped surfaces of the carbohydrate binding sites are presented, and implications for binding to gp120 are discussed. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 44 TC 106 Z9 110 U1 0 U2 5 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 MAY 2 PY 2001 VL 123 IS 17 BP 3892 EP 3902 DI 10.1021/ja004040e PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 428CC UT WOS:000168442700006 PM 11457139 ER PT J AU Kuszewski, J Schwieters, C Clore, GM AF Kuszewski, J Schwieters, C Clore, GM TI Improving the accuracy of NMR structures of DNA by means of a database potential of mean force describing base-base positional interactions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; MOLECULAR-DYNAMICS SIMULATIONS; PHOSPHORYL TRANSFER COMPLEX; LIQUID-CRYSTALLINE MEDIUM; X-RAY STRUCTURES; NUCLEIC-ACIDS; 3-DIMENSIONAL STRUCTURES; B-DNA; MACROMOLECULAR STRUCTURES; ORIENTED MACROMOLECULES AB NMR structure determination of nucleic acids presents an intrinsically difficult problem since the density of short interproton distance contacts is relatively low and limited to adjacent base pairs. Although residual dipolar couplings provide orientational information that is clearly helpful, they do not provide translational information of either a short-range (with the exception of proton-proton dipolar couplings) or long-range nature. As a consequence, the description of the nonbonded contacts has a major impact on the structures of nucleic acids generated from NMR data. In this paper, we describe the derivation of a potential of mean force derived from all high-resolution (2 Angstrom or better) DNA crystal structures available in the Nucleic Acid Database (NDB) as of May 2000 that provides a statistical description, in simple geometric terms, of the relative positions of pairs of neighboring bases (both intra- and interstrand) in Cartesian space. The purpose of this pseudopotential, which we term a DELPHIC base-base positioning potential, is to bias sampling during simulated annealing refinement to physically reasonable regions of conformational space within the range of possibilities that are consistent with the experimental NMR restraints. We illustrate the application of the DELPHIC base-base positioning potential to the structure refinement of a DNA dodecamer, d(CGCCAATTCGCG)(2), for which NOE and dipolar coupling data have been measured in solution and for which crystal structures have been determined. We demonstrate by cross-validation against independent NMR observables (that is, both residual dipolar couplings and NOE-derived intereproton distance restraints) that the DELPHIC base-base positioning potential results in a significant increase in accuracy and obviates artifactual distortions in the structures arising from the Limitations of conventional descriptions of the nonbonded contacts in terms of either Lennard-Jones van der Waals and electrostatic potentials or a simple van der Waals repulsion potential. We also demonstrate, using experimental NMR data for a complex of the male sex determining factor SRY with a duplex DNA 14mer, which includes a region of highly unusual and distorted DNA, that the DELPHIC base-base positioning potential does not in any way hinder unusual interactions and conformations from being satisfactorily sampled and reproduced. We expect that the methodology described in this paper for DNA can be equally applied to RNA, as well as side chain-side chain interactions in proteins and protein-protein complexes, and side chain-nucleic acid interactions in protein-nucleic acid complexes. Further, this approach should be useful not only for NMR structure determination but also for refinement of low-resolution (3-3.5 Angstrom) X-ray data. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Computat Biosci & Engn Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 88 TC 52 Z9 52 U1 2 U2 7 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 MAY 2 PY 2001 VL 123 IS 17 BP 3903 EP 3918 DI 10.1021/ja010033u PG 16 WC Chemistry, Multidisciplinary SC Chemistry GA 428CC UT WOS:000168442700007 PM 11457140 ER PT J AU Baber, JL Szabo, A Tjandra, N AF Baber, JL Szabo, A Tjandra, N TI Analysis of slow interdomain motion of macromolecules using NMR relaxation data SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; CHEMICAL-SHIFT ANISOTROPY; MULTIDIMENSIONAL NMR; ROTATIONAL DIFFUSION; BACKBONE DYNAMICS; CALMODULIN; PROTEINS; SPECTROSCOPY; SPECTRA AB The interpretation of NMR relaxation data for macromolecules possessing slow interdomain motions is considered. It is shown how the "extended model-free approach" can be used to analyze N-15 backbone relaxation data acquired at three different field strengths for Xenopus Ca2+-ligated calmodulin. This protein is comprised of two domains connected by two rigid helices joined by a flexible segment. It is possible to uniquely determine all "extended model-free" parameters without any a priori assumptions regarding their magnitudes by simultaneously least-squares fitting the relaxation data measured at two different magnetic fields. It is found that the two connecting helices (and consequently the domains) undergo slow motions relative to the conformation in which the two helices are parallel. The time scales and amplitudes of these "wobbling" motions are characterized by effective correlation times and squared-order parameters of approximately 3 ns and 0.7, respectively. These values are consistent with independent estimates indicating that this procedure provides a useful first-order description of complex internal motions in macromolecules despite neglecting the coupling of overall and interdomain motions. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. RI Szabo, Attila/H-3867-2012 NR 36 TC 104 Z9 104 U1 0 U2 6 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 MAY 2 PY 2001 VL 123 IS 17 BP 3953 EP 3959 DI 10.1021/ja0041876 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 428CC UT WOS:000168442700012 PM 11457145 ER PT J AU Abrams, JA AF Abrams, JA TI Tamoxifen: Five versus ten years - Is the end in sight? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID SURGICAL ADJUVANT BREAST; RECEPTOR-POSITIVE TUMORS; CANCER PATIENTS; CLINICAL-TRIAL; BOWEL PROJECT; THERAPY; B-14 C1 NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Abrams, JA (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, 6130 Execut Blvd,EPN 7040, Bethesda, MD 20892 USA. NR 22 TC 8 Z9 8 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 2 PY 2001 VL 93 IS 9 BP 662 EP 664 DI 10.1093/jnci/93.9.662 PG 3 WC Oncology SC Oncology GA 428KJ UT WOS:000168460600001 PM 11333277 ER PT J AU Jemal, A Devesa, SS Hartge, P Tucker, MA AF Jemal, A Devesa, SS Hartge, P Tucker, MA TI Recent trends in cutaneous melanoma incidence among whites in the United States SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID MALIGNANT-MELANOMA; SKIN-CANCER; ULTRAVIOLET-RADIATION; RATES; MORTALITY; EPIDEMIC; EXPOSURE; SURVEILLANCE; APPARENT; PATTERNS AB Background: It is not pet clear whether increasing melanoma incidence is real or whether recent incidence trends mainly reflect improved diagnosis. To address this question, we examined the most recent melanoma incidence patterns among the white population stratified by ses, age, tumor stage, and tumor thickness by use of data from the Surveillance, Epidemiology, and End Results Program. Methods: We examined log-transformed age-specific rates for melanoma by 5-year age groups and time periods by year of diagnosis and birth cohort. Melanoma trends were further examined among broader age groups (<40 pears, 40-59 pears, and 60 years) by tumor stage and tumor thickness. Rates were age-adjusted to the 1970 U.S. standard population, and trends were tested by use of a two-sided Student's t test. Results: Melanoma incidence increased in females horn since the 1960s, From 1974-1975 through 1988-1989, upward trends for the incidence of localized tumors and downward trends for the incidence of distant-stage tumors occurred in the age group under 40 Sears. In the more recent time period, 1990-1991 through 1996-1997, age-specific rates among females compared with males generally remained stable or declined more for distant-stage tumors and increased less for local-stage tumors. Thin tumors <1 mm) increased statistically significantly in all age groups (P<.01 for all), except in men under age 40 years, In contrast, rates for thick tumors (greater than or equal to4 mm) increased statistically significantly (P = .003) only in males aged 60 years and older. Conclusion: Melanoma incidence may well continue to rise in the United States, at least until the majority of the current population in the middle-age groups becomes the oldest population. The recent trends may reflect increased sunlight exposure. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Jemal, A (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8049, Bethesda, MD 20892 USA. RI Tucker, Margaret/B-4297-2015 NR 33 TC 305 Z9 310 U1 0 U2 2 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 2 PY 2001 VL 93 IS 9 BP 678 EP 683 DI 10.1093/jnci/93.9.678 PG 6 WC Oncology SC Oncology GA 428KJ UT WOS:000168460600010 PM 11333289 ER PT J AU Fisher, B Dignam, J Bryant, J Wolmark, N AF Fisher, B Dignam, J Bryant, J Wolmark, N TI Five versus more than five years of tamoxifen for lymph node-negative breast cancer: Updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RECEPTOR-POSITIVE TUMORS; CLINICAL-TRIAL; THERAPY; LONG; DURATION AB Background: Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy, When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate. Methods: Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free sere rerandomized to receive placebo (n = 579) or tamoxifen (n = 593), Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals! were determined by the Cox proportional hazards model. P values were two-sided. Results: Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. Conclusion: Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes. C1 Univ Pittsburgh, NSABP, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15212 USA. Univ Pittsburgh, NSABP Biostat Ctr, Pittsburgh, PA 15212 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. RP Fisher, B (reprint author), Univ Pittsburgh, NSABP, 4 Allegheny Ctr,Suite 602, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U10CA12027, U10CA37377, U10CA69651, U10CA69974] NR 27 TC 381 Z9 393 U1 1 U2 12 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 2 PY 2001 VL 93 IS 9 BP 684 EP 690 DI 10.1093/jnci/93.9.684 PG 7 WC Oncology SC Oncology GA 428KJ UT WOS:000168460600011 PM 11333290 ER PT J AU Burbee, DG Forgacs, E Zochbauer-Muller, S Shivakumar, L Fong, K Gao, BN Randle, D Kondo, M Virmani, A Bader, S Sekido, Y Latif, F Milchgrub, S Toyooka, S Gazdar, AF Lerman, MI Zabarovsky, E White, M Minna, JD AF Burbee, DG Forgacs, E Zochbauer-Muller, S Shivakumar, L Fong, K Gao, BN Randle, D Kondo, M Virmani, A Bader, S Sekido, Y Latif, F Milchgrub, S Toyooka, S Gazdar, AF Lerman, MI Zabarovsky, E White, M Minna, JD TI Epigenetic inactivation of RASSF14 in lung and breast cancers and malignant phenotype suppression SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN-CHROMOSOME 3P21.3; BRONCHIAL EPITHELIUM; ALLELE LOSS; CELL-LINES; TUMOR; GENE; IDENTIFICATION; ABNORMALITIES; METHYLATION; DNA AB Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell Lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures, We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. Ail statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 63% of breast cancer lines, in 30% of primary NSCLCs, and in 39% of primary breast tumors but in none of the nonmalignant lung tissues, RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P =.046), Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region. C1 Univ Texas, SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. Prince Charles Hosp, Dept Thorac Med, Brisbane, Qld 4032, Australia. Univ Birmingham, Dept Reprod & Child Hlth, Birmingham B15 2TT, W Midlands, England. NCI, Immunobiol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Karolinska Inst, Stockholm, Sweden. RP Minna, JD (reprint author), Univ Texas, SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, 6000 Harry Hines Blvd, Dallas, TX 75390 USA. RI Zabarovsky, Eugene/A-6645-2010; Fong, Kwun/G-6369-2010; Zochbauer-Muller, Sabine/B-8399-2012; KONDO, Masashi/I-7378-2014; Sekido, Yoshitaka/P-9756-2015 OI Zochbauer-Muller, Sabine/0000-0002-6777-1729; FU NCI NIH HHS [R01 CA071443, CA71443, CA71618, N01CO56000, P50 CA070907, P50CA70907, R01 CA071443-14, R01 CA071618] NR 36 TC 566 Z9 620 U1 0 U2 18 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 2 PY 2001 VL 93 IS 9 BP 691 EP 699 DI 10.1093/jnci/93.9.691 PG 9 WC Oncology SC Oncology GA 428KJ UT WOS:000168460600012 PM 11333291 ER PT J AU Dorgan, JF Baer, DJ Albert, PS Judd, JT Brown, ED Corle, DK Campbell, WS Hartman, TJ Tejpar, AA Clevidence, BA Giffen, CA Chandler, DW Stanczyk, FZ Taylor, PR AF Dorgan, JF Baer, DJ Albert, PS Judd, JT Brown, ED Corle, DK Campbell, WS Hartman, TJ Tejpar, AA Clevidence, BA Giffen, CA Chandler, DW Stanczyk, FZ Taylor, PR TI Serum hormones and the alcohol-breast cancer association in postmenopausal women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROGESTERONE-RECEPTOR STATUS; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; BEVERAGE CONSUMPTION; PREMENOPAUSAL WOMEN; SEX-HORMONES; RISK-FACTORS; ESTROGEN; TESTOSTERONE; PLASMA; ESTRADIOL AB Background: Alcohol ingestion is associated with an increased risk of breast cancer in most epidemiologic studies. Results, however, are heterogeneous at lon er levels of alcohol intake, and a biologic mechanism for the association has not been clearly identified. To determine whether alcohol consumption by postmenopausal women elevates serum levels of hormones associated with an increased risk of breast cancer, we performed a controlled feeding study, Methods: Participants were 51 healthy postmenopausal women not using hormone replacement therapy. Each participant rotated through three 8-week dietary periods in which she consumed 15 or 30 g of alcohol per day or an alcohol-free placebo beverage. The order of assignment to the three alcohol levels was random. During the dietary periods, all food and beverages were supplied by the study, and energy intake mas adjusted to keep body weight constant. Levels of estradiol, estrone. estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol were measured by radioimmunoassays in serum collected at the end of each dietary period. AII statistical tests are two-sided. Results: When women consumed 15 or 30 g of alcohol per day, respectively, estrone sulfate concentrations increased by 7.5% (95% confidence interval [CI] = -0.3% to 15.9%; P =.06) and 10.7% (95% CI = 2.7% to 19.3%; P =.009) and DHEAS: concentrations increased by: 5.1% (95% CI = 1.4% to 9.0%; P =.008) and 7.5% (95% CI = 3.7% to 11.5%; P<.001) relative to levels when women consumed placebo, None of the other hormones measured changed statistically significantly when women consumed alcohol. Conclusions: Results suggest a possible mechanism by which consumption of one or two alcoholic drinks per day by postmenopausal women could increase their risk of breast cancer. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. ARS, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. NCI, Div Canc Treatment, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. Informat Management Serv Inc, Silver Spring, MD USA. Esoterix Endocrinol Inc, Calabasas Hills, CA USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. RP Dorgan, JF (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. NR 61 TC 159 Z9 163 U1 0 U2 5 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 2 PY 2001 VL 93 IS 9 BP 710 EP 715 DI 10.1093/jnci/93.9.710 PG 6 WC Oncology SC Oncology GA 428KJ UT WOS:000168460600015 PM 11333294 ER PT J AU Clarke, LP Croft, BY Staab, E Baker, H Sullivan, DC AF Clarke, LP Croft, BY Staab, E Baker, H Sullivan, DC TI National Cancer Institute Initiative: Lung image database resource for imaging research SO ACADEMIC RADIOLOGY LA English DT Article AB Preliminary clinical studies suggest that spiral computed tomography (CT) of the lungs can improve early detection of lung cancer in high-risk individuals. More clinical studies are needed, however, before public health recommendations can be proposed for population-based screening. Spiral CT generates large-volume data sets and thus poses problems in terms of implementation of efficient and cost-effective screening methods. Image processing algorithms such as computer assisted diagnostic (CAD) methods have the potential to assist in lesion leg, nodule) detection on spiral CT studies. CAD methods may also be used to characterize nodules by either assessing the stability or change in size of lesions based on evaluation of serial CT studies, or quantitatively measuring the temporal parameters related to contrast dynamics when using contrast material-enhanced CT studies. CAD methods therefore have the potential to enhance the sensitivity and specificity of spiral CT lung screening studies. Lung cancer screening studies now under investigation create an opportunity to develop an image database that will allow comparison and optimization of CAD algorithms. This database could serve as an important national resource for the academic and industrial research community that is currently involved in the development of CAD methods, The National Cancer Institute request for applications (RFA) (CA-01-001) has already been announced (April 2000) to establish and support a consortium of academic centers to develop this database, the consortium to be referred to as the Lung Image Database Consortium (LIDC). This RFA is now closed. Five academic sites have been selected to be members of the LIDC, the first meeting of this consortium is planned for spring of 2001, and a public meeting is to be held in 2002, This report is abstracted from the previously published RFA to serve as an example of how an initiative is developed by the National Cancer Institute to support a research resource. For specific details of the RFA, please access the following Internet site: http://www.nci.nih.gov/bip/NCI-DIPinisumm.htm#a11. C1 NCI, Div Canc Treatment & Diag, Biomed Imaging Program, Rockville, MD 20852 USA. RP Clarke, LP (reprint author), NCI, Div Canc Treatment & Diag, Biomed Imaging Program, Execut Plaza N,Suite 6000,6130 Execut Blvd, Rockville, MD 20852 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 0 TC 43 Z9 43 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 MAY PY 2001 VL 8 IS 5 BP 447 EP 450 DI 10.1016/S1076-6332(03)80555-X PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 427EE UT WOS:000168391200013 PM 11345275 ER PT J AU Enoch, MA Harris, CR Goldman, D AF Enoch, MA Harris, CR Goldman, D TI Does a reduced sensitivity to bitter taste increase the risk of becoming nicotine addicted? SO ADDICTIVE BEHAVIORS LA English DT Article DE phenylthiocarbamide; taste; nicotine; smoking; alcohol; addiction ID SMOKING; 6-N-PROPYLTHIOURACIL; AGE AB Cigarette smoking appears to be on the increase in adolescents. The initiation of regular smoking nearly always begins before adulthood. It is therefore crucial to find ways of identifying those children most vulnerable to nicotine addiction and prioritizing them for preventive measures. We hypothesized that individuals who, in a simple taste test, perceive phenylthiocarbamide (PTC) as bitter may find the taste of cigarettes aversively bitter and could therefore have a reduced vulnerability to nicotine addiction compared to nontasters, who would be the group at greater risk of addiction. We studied 242 Plains American Indians, 136 women and 106 men aged 18-59 years, and found that (allowing for gender differences and the possible direct effects of smoking on taste) the proportion of PTC nontasters to tasters in smokers, even light smokers, was significantly greater than in both nonsmokers and social smokers (chi (2) = 15.875, 4 df, P=.003), suggesting that nontasters, who are not aversive to the bitter taste of cigarettes, may be more at risk for heavy smoking and therefore more vulnerable to nicotine addiction. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, Room 451,Pk 5 Bldg,MSC 8110,12420 Parklawn Dr, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 19 TC 43 Z9 44 U1 4 U2 20 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 MAY-JUN PY 2001 VL 26 IS 3 BP 399 EP 404 DI 10.1016/S0306-4603(00)00117-9 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 439JR UT WOS:000169114100008 PM 11436931 ER PT J AU Bautista, AP Wang, EZ AF Bautista, AP Wang, EZ TI Chronic ethanol intoxication enhances the production of cytokine-induced neutrophil chemoattractant and macrophage inflammatory protein-2 by hepatocytes after human immunodeficiency virus-1 glycoprotein 120 vaccination SO ALCOHOL LA English DT Article DE immunosuppression; inflammation; chemokines; transcription; gene expression; liver injury; rat ID ALCOHOL-INTOXICATION; CHEMOTACTIC FACTOR; ENDOTOXIC RATS; KUPFFER CELLS; INTERLEUKIN-8; LIVER; CHEMOKINES; HEPATITIS; EXPRESSION; RELEASE AB Chemokines are implicated in the pathogenesis of alcoholic liver disease and human immunodeficiency virus-1 (HIV-1) infection. Thus, this work examined the regulation of chemokines - i.e.. cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) - produced by hepatocytes after HIV-1 glycoprotein 120 (gp 120) vaccination in Wistar rats fed with ethanol for 30 weeks. HIV-1 gp120 in complete Freund's adjuvant was given by intrainguinal route at a dose of 5 mug/kg, followed by two booster shots in incomplete Freund's adjuvant at a weekly interval. Samples were taken I week after the last injection was given. Results show that anti-HIV-1 gp120 antibody titer was suppressed by 40% in the ethanol-fed rats, compared with findings in the parallel controls. However, serum CINIC and MIP-2 levels were more elevated in the ethanol-fed rats than in the pair-fed group. The likely sources of these chemokines are the hepatocytes. After HIV-1 gp120 treatment, isolated hepatocytes obtained from the ethanol-fed group produced more CINC and MIP-2 than did those of pair-fed rats. Concomitantly, mRNA expression for these two chemokines and hepatic sequestration of neutrophils were upregulated. Ethanol feeding alone suppressed chemokine release, but it did not alter mRNA expression in isolated hepatocytes. Administration of Freund's adjuvant (without HIV-1 gp120) did not induce chemokine release in vivo and did not prime isolated hepatocytes for enhanced chemokine production in vitro. These results show that chronic ethanol intoxication affects the ability of the host to respond to HIV-1 gp120 vaccination. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, New Orleans, LA 70112 USA. Louisiana State Univ, Hlth Sci Ctr, NIAAA, Sponsored Alcohol Res Ctr, New Orleans, LA 70112 USA. RP Bautista, AP (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Physiol, 1901 Perdido St, New Orleans, LA 70112 USA. FU NIAAA NIH HHS [P50 AA09803, R01 AA08846, R01 AA10746] NR 23 TC 11 Z9 11 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD MAY PY 2001 VL 24 IS 1 BP 35 EP 44 DI 10.1016/S0741-8329(01)00140-9 PG 10 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 464ZZ UT WOS:000170564400007 PM 11524180 ER PT J AU Mann, K Agartz, I Harper, C Shoaf, S Rawlings, RR Momenan, R Hommer, DW Pfefferbaum, A Sullivan, EV Anton, RF Drobes, DJ George, MS Bares, R Machulla, HJ Mundle, G Reimold, M Heinz, A AF Mann, K Agartz, I Harper, C Shoaf, S Rawlings, RR Momenan, R Hommer, DW Pfefferbaum, A Sullivan, EV Anton, RF Drobes, DJ George, MS Bares, R Machulla, HJ Mundle, G Reimold, M Heinz, A TI Neuroimaging in alcoholism: Ethanol and brain damage SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Japanese-Medical-Society-of-Alcohol-and-Drug-Studie/10th International-Society-for-Biomedical-Research-on-Alcoholism CY JUL 02-08, 2000 CL YOKOHAMA, JAPAN SP Japanese Med Soc Alcohol & Drug Studies, Int Soc Biomed Res Alcoholism DE brain damage; white matter abnormalities; function magnetic resonance imaging; mu-opiate receptor ID WHITE-MATTER; BINDING; COCAINE; DRINKING; LESIONS; NEURONS; CORTEX; SCALE AB This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoal, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu -Opiate: receptor availability in alcoholism First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz. C1 Univ Heidelberg, Dept Addict Behav & Addict Med, Cent Inst Mental Hlth Mannheim, D-68159 Mannheim J5, Germany. Univ Sydney, Dept Pathol, Sydney, NSW 2006, Australia. Royal Prince Alfred Hosp, Camperdown, NSW, Australia. NIAAA, Clin Studies Lab, Sect Electrophysiol & Brain Imaging, NIH, Bethesda, MD 20892 USA. SRI Int, Neuropsychiat Program, Menlo Park, CA 94025 USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Med Univ S Carolina, Alcohol Res Ctr, Charleston, SC 29425 USA. Univ Heidelberg, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, D-6800 Mannheim, Germany. Univ Tubingen, Dept Nucl Med, D-72074 Tubingen, Germany. RP Mann, K (reprint author), Univ Heidelberg, Dept Addict Behav & Addict Med, Cent Inst Mental Hlth Mannheim, D-68159 Mannheim J5, Germany. NR 32 TC 58 Z9 60 U1 4 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2001 VL 25 IS 5 SU 1 BP 104S EP 109S DI 10.1111/j.1530-0277.2001.tb02383.x PG 6 WC Substance Abuse SC Substance Abuse GA 434ZP UT WOS:000168846000019 PM 11391058 ER PT J AU Warren, KR Calhoun, FJ May, PA Viljoen, DL Li, TK Tanaka, H Marinicheva, GS Robinson, LK Mundle, G AF Warren, KR Calhoun, FJ May, PA Viljoen, DL Li, TK Tanaka, H Marinicheva, GS Robinson, LK Mundle, G TI Fetal alcohol syndrome: An international perspective SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Japanese-Medical-Society-of-Alcohol-and-Drug-Studie/10th International-Society-for-Biomedical-Research-on-Alcoholism CY JUL 02-08, 2000 CL YOKOHAMA, JAPAN SP Japanese Med Soc Alcohol & Drug Studies, Int Soc Biomed Res Alcoholism DE fetal alcohol syndrome; fetal tobacco syndrome; epidemiology ID CHILDREN; EXPOSURE AB This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Kenneth R. Warren and Faye J. Calhoun. The presentations were (I) Epidemiological research on fetal alcohol syndrome (FAS) in the United States, by Philip A. May; (2) An overview of fetal alcohol syndrome in the Western Cape Province of South Africa, by Denis L. Viljoen and Ting-Kai Li; (3) Diagnostic perspectives of fetal alcohol and tobacco syndromes, by Harumi Tanaka; (4) FAS among pupils of special boarding schools and orphanages in Moscow, Russia, by Galina S. Marinicheva and Luther K. Robinson; and (5) Research on FAS and FAE in Germany: Update and perspectives, by Goetz Mundle. C1 NIAAA, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. Univ Witwatersrand, Dept Human Genet, S African Inst Med Res, Johannesburg, South Africa. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. Natl Inst Neurosci, Dept Mental Retardat & Birth Defects Res, Kodaira, Tokyo 187, Japan. Moscow Res Inst Psychiat, Moscow, Russia. SUNY Buffalo, Buffalo, NY 14260 USA. Univ Tubingen, Dept Psychiat, Addict Res Ctr, D-7400 Tubingen, Germany. RP Warren, KR (reprint author), NIAAA, NIH, 6000 Execut Blvd,Suite 409, Bethesda, MD 20892 USA. NR 18 TC 27 Z9 27 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2001 VL 25 IS 5 SU 1 BP 202S EP 206S DI 10.1111/j.1530-0277.2001.tb02397.x PG 5 WC Substance Abuse SC Substance Abuse GA 434ZP UT WOS:000168846000033 ER PT J AU Neuman, MG Brenner, DA Rehermann, B Taieb, J Chollet-Martin, S Cohard, M Garaud, JJ Poynard, T Katz, GG Cameron, RG Shear, NH Gao, B Takamatsu, M Yamauchi, M Ohata, M Saito, S Maeyama, S Uchikoshi, T Toda, G Kumagi, T Akbar, SMF Abe, M Michitaka, K Horlike, N Onji, M AF Neuman, MG Brenner, DA Rehermann, B Taieb, J Chollet-Martin, S Cohard, M Garaud, JJ Poynard, T Katz, GG Cameron, RG Shear, NH Gao, B Takamatsu, M Yamauchi, M Ohata, M Saito, S Maeyama, S Uchikoshi, T Toda, G Kumagi, T Akbar, SMF Abe, M Michitaka, K Horlike, N Onji, M TI Mechanisms of alcoholic liver disease: Cytokines SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Japanese-Medical-Society-of-Alcohol-and-Drug-Studie/10th International-Society-for-Biomedical-Research-on-Alcoholism CY JUL 02-08, 2000 CL YOKOHAMA, JAPAN SP Japanese Med Soc Alcohol & Drug Studies, Int Soc Biomed Res Alcoholism DE hepatic fibrosis; hepatitis C; interleukin-10; protein kinase C; alcoholic liver disease ID HEPATITIS-C VIRUS; INDUCED APOPTOSIS; MESSENGER-RNA; GENE; CELL AB This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Manuela G. Neuman. The presentations were (1) New aspects of hepatic fibrosis, by D. A. Brenner; (2) Cellular immune response in hepatitis C models, by B. Rehermann; (3) The role of interleukin-10 in acute alcoholic hepatitis, by J. Taieb, S. Ghollet-Martin, M. Cohard, J. J. Garaud, and T. Poynard; (4) Cytokine-mediated apoptosis in vitro, by M. Ci. Neuman; (5) Signaling for apoptosis and repair in vitro, by G. G. Katz, R. G. Cameron, N.H. Shear, and M. G. Neuman; (6) Interferons activate the P42/44 mitogen-activated protein kinase and Janus Kinase signal transducers and activation of transcription (JAK-STAT) signaling pathways in hepatocytes: Differential regulation by acute ethanol via a protein kinase C-dependent mechanism, by B. Gao; (7) Genetic polymorphisms of interleukin-1 in association with the development of Japanese alcoholic liver disease, by M. Takamatsu, M. Yamauchi, M. Ohata, S. Saito, S. Maeyama, T. Uchikoshi, and G. Toda; and (8) Increased levels of macrophage migration inhibitory factor in sera from patients with alcoholic liver diseases, by T. Kumagi, S. M. F. Akbar, M. Abe, K. Michitaka, N. Horiike, and M. Onji. C1 Univ Toronto, Sunybrook & Womens Coll, Hlth Sci Ctr, Div Clin Pharmacol,Vitro Toxicol Lab, Toronto, ON M4N 3M5, Canada. Univ N Carolina, Dept Med, Chapel Hill, NC USA. NIH, Liver Dis Sect, Bethesda, MD USA. Hop La Pitie Salpetriere, Hepatogastroenterol Dept, Paris, France. INSERM, Immunol Lab, U294, Paris, France. Schering Plough Res Inst, Kenilworth, NJ USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Jikei Univ, Sch Med, Dept Internal Med, Tokyo, Japan. Jikei Univ, Sch Med, Div Mol Immunol, Tokyo, Japan. St Marianna Univ, Sch Med, Dept Pathol, Kanagawa, Japan. Ehime Univ, Sch Med, Dept Internal Med 3, Shigenobu, Ehime 79102, Japan. RP Neuman, MG (reprint author), Univ Toronto, Sunybrook & Womens Coll, Hlth Sci Ctr, Div Clin Pharmacol,Vitro Toxicol Lab, Room E242,2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. NR 17 TC 24 Z9 24 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2001 VL 25 IS 5 SU 1 BP 251S EP 253S DI 10.1111/j.1530-0277.2001.tb02404.x PG 3 WC Substance Abuse SC Substance Abuse GA 434ZP UT WOS:000168846000040 PM 11391079 ER PT J AU Umhau, JC Petrulis, SG Diaz, R Biddison, JR George, DT AF Umhau, JC Petrulis, SG Diaz, R Biddison, JR George, DT TI Hypothalamic function in response to 2-deoxy-D-glucose in long-term abstinent alcoholics SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE 2-deoxy-D-glucose; cortisol; corticotrophin; alcoholism; hypothalamus ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING FACTOR; CORTISOL RESPONSE; INSULIN-HYPOGLYCEMIA; SOBER ALCOHOLICS; STRESS-RESPONSE; MEN; ADRENOCORTICOTROPIN; WITHDRAWAL; ENDOCRINE AB Background: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. Methods: To characterize PIPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-D-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. Results: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. Conclusions: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved. C1 NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. RP Umhau, JC (reprint author), NIAAA, Clin Studies Lab, 10 Ctr Dr,MSC-1610,Bldg 10,Room 6S-240, Bethesda, MD 20892 USA. NR 32 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2001 VL 25 IS 5 BP 781 EP 786 DI 10.1111/j.1530-0277.2001.tb02279.x PG 6 WC Substance Abuse SC Substance Abuse GA 433RL UT WOS:000168773500020 PM 11371728 ER PT J AU Taylor, ML Metcalfe, DD AF Taylor, ML Metcalfe, DD TI Mast cells in allergy and host defense SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID DEPENDENT MECHANISM; HISTAMINE-RELEASE; TNF-ALPHA; IMMUNITY; IGE; MICE; PHAGOCYTOSIS; MODULATION; ACTIVATION; INFECTION AB Mast cells have been implicated in the pathogenesis of allergic diseases and in inflammatory responses associated with pathological immune and disease-related processes including fibrosis, autoimmune pathology, and neoplasia. Recent findings in animal models of bacterial infection also suggest that mast cells may have a protective role in host defense against pathogens in innate immunity along with the probable role of mast cells in acquired immunity against parasitic infections. Mast cells are strategically located at the host-environment interface and may provide an early defense against an invading pathogen. Mast cells express an array of adhesion and immune receptors that may assist in the recognition of invading pathogens. When activated, these cells then synthesize and release key immunoregulatory cytokines, one consequence of which is to mobilize a rapid and vigorous inflammatory response. However, although it has been demonstrated that mast cells may have a role in innate immunity in defined in vitro and animal models, it remains to be determined whether mast cells are protective in innate immune responses in humans. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Taylor, ML (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C207,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 40 TC 28 Z9 29 U1 0 U2 2 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD MAY-JUN PY 2001 VL 22 IS 3 BP 115 EP 119 DI 10.2500/108854101778148764 PG 5 WC Allergy SC Allergy GA 443WD UT WOS:000169364400001 PM 11424870 ER PT J AU Knight, JR AF Knight, JR TI The role of the primary care provider in preventing and treating alcohol problems in adolescents SO AMBULATORY PEDIATRICS LA English DT Editorial Material DE adolescence; adolescent behavior; alcohol drinking; health behavior; primary health care; substance-related disorders ID DISORDERS IDENTIFICATION TEST; ORIENTED SCREENING INSTRUMENT; 12 PROBLEM BEHAVIORS; TEST AUDIT; SUBSTANCE-ABUSE; BRIEF INTERVENTIONS; DRUG-USE; COLLEGE-FRESHMEN; PROBLEM DRINKING; CONSUMPTION QUESTIONS AB Adolescents use alcohol more frequently and heavily than all other illicit drugs combined.(1) Given the myriad health, developmental, and social problems associated with alcohol use, it is not surprising that the American Medical Association's Guidelines for Adolescent Preventive Services recommends that adolescents be asked annually about their use of alcohol, and those who report any use during the past year should be assessed further. However, routine alcohol screening of adolescents in primary care and emergency medical settings is not universally applied. In March 2000, the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health and the Agency for Health care Research and Quality jointly sponsored a meeting entitled The Expanding Role of Primary Care in the Prevention and Treatment of Alcohol-Use Disorders. The purpose of the meeting was to bring together researchers, policymakers, clinicians, insurance providers, and medical education specialists to determine the best approaches to increase the involvement of primary care physicians and other health care professionals in screening and intervening for alcohol problems in their patients. The National Institute on Alcohol Abuse and Alcoholism and Agency for Health care Research and Quality believe that the evidence of efficacy for primary care involvement is compelling and are working together to promote the translation of these findings into clinical practice. The following article summarizes what is currently known about adolescent alcohol use and how it can be addressed in primary care settings. It provided the background for the meeting's focus on adolescent issues. C1 Childrens Hosp, Ctr Adolescent Subst Abuse Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Addict, Boston, MA 02115 USA. NIAAA, Off Collaborat Res, NIH, Bethesda, MD USA. Agcy Healthcare Res & Qual, Ctr Primary Care Res, Rockville, MD USA. RP Knight, JR (reprint author), Childrens Hosp, Ctr Adolescent Subst Abuse Res, JB 372,300 Longwood Ave, Boston, MA 02115 USA. NR 116 TC 12 Z9 12 U1 3 U2 5 PU AMBULATORY PEDIATRIC ASSOC PI MCLEAN PA 6728 OLD MCLEAN VILLAGE DR, MCLEAN, VA 22101-3906 USA SN 1530-1567 J9 AMBUL PEDIATR JI Ambul. Pediatr. PD MAY-JUN PY 2001 VL 1 IS 3 BP 150 EP 161 DI 10.1367/1539-4409(2001)001<0150:TROTPC>2.0.CO;2 PG 12 WC Pediatrics SC Pediatrics GA 473YJ UT WOS:000171076700006 PM 11888392 ER PT J AU Reis, SE Holubkov, R Smith, AJC Kelsey, SF Sharaf, BL Reichek, N Rogers, WJ Merz, CNB Sopko, G Pepine, CJ AF Reis, SE Holubkov, R Smith, AJC Kelsey, SF Sharaf, BL Reichek, N Rogers, WJ Merz, CNB Sopko, G Pepine, CJ CA WISE Investigators TI Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE study SO AMERICAN HEART JOURNAL LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; POSTMENOPAUSAL WOMEN; FLOW RESERVE; SMOOTH-MUSCLE; YOUNG MEN; ESTROGEN; ANGINA; ANGIOGRAMS; ESTRADIOL; THERAPY AB Background Chest pain in the absence of obstructive coronary artery disease (CAD) is common in women; it is Frequently associated with debilitating symptoms and repeated evaluations and may be caused by coronary microvascular dysfunction. However, the prevalence and determinants of microvascular dysfunction in these women are uncertain. Methods We measured coronary flow velocity reserve (coronary velocity response to intracoronary adenosine) to evaluate the coronary microvasculature and risk factors for atherosclerosis in 159 women (mean age, 52.9 years) with chest pain and no obstructive CAD. All women were referred for coronary angiography to evaluate their chest pain as part of the Women's Ischemia Syndrome Evaluation (WISE) study. Results Seventy-four (47%) women had subnormal (<2.5) coronary flow velocity reserve suggestive of microvascular dysfunction (mean, 2.02 +/- 0.38): 85 (53%) had normal reserve (mean, 3.13 +/- 0.64). Demographic characteristics, blood pressure, ventricular function, lipid levels, and reproductive hormone levels were not significantly different between women with normal and those with abnormal microvascular function. Postmenopausal hormone use within 3 months was significantly less prevalent among those with microvascular dysfunction (40% vs 60%, P = .032). Age and number of years past menopause correlated with flow velocity reserve (r = -0.18, P = .02, and r = -0.30, P < .001, respectively). No significant associations were identified between flow velocity reserve and lipid and hormone levels, blood pressure, and left ventricular ejection fraction. Conclusions Coronary microvascular dysfunction is present in approximately one half of women with chest pain in the absence of obstructive CAD and cannot be predicted by risk factors for atherosclerosis and hormone levels. Therefore, the diagnosis of coronary microvascular dysfunction should be considered in women with chest pain not attributable to obstructive CAD. C1 Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Rhode Isl Hosp, Dept Med, Div Cardiol, Providence, RI 02903 USA. Allegheny Gen Hosp, Dept Med, Div Cardiol, Pittsburgh, PA 15212 USA. Univ Alabama, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. Cedars Sinai Med Ctr, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. RP Reis, SE (reprint author), WISE Coordinating Ctr, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164] NR 28 TC 200 Z9 213 U1 2 U2 6 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 MAY PY 2001 VL 141 IS 5 BP 735 EP 741 DI 10.1067/mhj.2001.114198 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 427YC UT WOS:000168433500007 PM 11320360 ER PT J AU Backinger, CL Leischow, SJ AF Backinger, CL Leischow, SJ TI Advancing the science of adolescent tobacco use cessation SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Health-Behavior-Reseach CY SEP 24, 2000 CL SANTA FE, NEW MEXICO SP Amer Acad Hlth Behavior Res ID SMOKING CESSATION; NICOTINE DEPENDENCE; SMOKERS; PREDICTORS; YOUTH AB Objective: To examine how science is advancing in order to address adolescent tobacco use cessation. Methods: Review of the published scientific literature from 1995 to September 2000 and National Cancer Institute youth tobacco cessation, research portfolio. Results: Because of methodological limitations, results of behavioral interventions are inconclusive. Two studies have been published evaluating the nicotine patch for adolescent smoking cessation, though neither employed a randomized, placebo-control design. Both of these studies found the nicotine patch to be ineffective. Conclusions: Although much is known about youth tobacco use, additional research is needed to find answers to best help youth to quit smoking. C1 NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, Bethesda, MD 20892 USA. RP Backinger, CL (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, 6130 Execut Blvd,EPN 4044, Bethesda, MD 20892 USA. NR 38 TC 21 Z9 22 U1 0 U2 1 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD MAY-JUN PY 2001 VL 25 IS 3 BP 183 EP 190 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 414QF UT WOS:000167677100003 PM 11322616 ER PT J AU Rudek, MA Horne, M Figg, WD Dahut, W Dyer, V Pluda, JM Reed, E AF Rudek, MA Horne, M Figg, WD Dahut, W Dyer, V Pluda, JM Reed, E TI Reversible sideroblastic anemia associated with the tetracycline analogue COL-3 SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE anemia; COL-3; tetracycline; sideroblast; cancer; phase I AB Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute, Three of these patients had bone marrow examinations that revealed ringed sideroblasts, This paper describes these cases. Am. J. Hematol, 87:51-53, 2001. Published 2001 Wiley-Liss, Inc. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. WG Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diagnosis,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 13 TC 10 Z9 10 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2001 VL 67 IS 1 BP 51 EP 53 DI 10.1002/ajh.1076 PG 3 WC Hematology SC Hematology GA 419JM UT WOS:000167945600010 PM 11279658 ER PT J AU Cavanaugh, J AF Cavanaugh, J CA IBD Int Genetics Consortium TI International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; DEPENDENT DIABETES-MELLITUS; LARGE EUROPEAN COHORT; SUSCEPTIBILITY LOCUS; ULCERATIVE-COLITIS; SUPPORTS LINKAGE; GENETIC-ANALYSIS; HETEROGENEITY; FAMILIES; GENOME AB Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits. C1 Canberra Hosp, Gastroenterol Unit, Canberra, ACT, Australia. UZ Gasthuisberg, Gastroenterol Unit, Louvain, Belgium. UZ Gasthuisberg, Ctr Human Genet, Louvain, Belgium. MIT, Whitehead Inst, Ctr Genome Res, Cambridge, MA 02139 USA. Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Fdn Jean Dausset, CEPH, Paris, France. Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. CNR Mol Genet, S Maria La Palma, Italy. Univ Penn, Childrens Hosp, Philadelphia, PA 19104 USA. CSS IRCCS Hosp, S Giovanni Rotondo, Italy. Radcliffe Infirm, Gastroenterol Unit, Oxford OX2 6HE, England. Wellcome Trust Ctr Human Genet, Oxford, England. Oxagen Ltd, Oxford, England. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NHGRI, NIH, Baltimore, MD USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Chicago Hosp, Dept Med, Gastroenterol Sect, Martin Boyer Genet Res Labs, Chicago, IL 60637 USA. Univ Chicago Hosp, Dept Pediat, Gastroenterol Sect, Martin Boyer Genet Res Labs, Chicago, IL 60637 USA. Univ Chicago Hosp, Dept Med, Gastroenterol Sect, Martin Boyer Genet Res Labs, Chicago, IL 60637 USA. Cedars Sinai Med Ctr, Div Med Genet, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, IBD Ctr, Los Angeles, CA 90048 USA. NYU, Sch Med, N Shore Univ Hosp, Dept Med,Div Mol Med, Manhasset, NY USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Ctr Genom Sci, Pittsburgh, PA USA. Cleveland Clin Fdn, Dept Gastroenterol, Cleveland, OH 44195 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. RP Cavanaugh, J (reprint author), Canberra Hosp, Gastroenterol Res Unit, Woden, ACT 2606, Australia. RI Cavanaugh, Juleen/C-9413-2009; Siminovitch, Katherine/K-1475-2013; Rioux, John D./A-9599-2015; OI Duerr, Richard/0000-0001-6586-3905; Bailey-Wilson, Joan/0000-0002-9153-2920; Rioux, John D./0000-0001-7560-8326; Vermeire, Severine/0000-0001-9942-3019; Latiano, Anna/0000-0003-3719-2061 NR 21 TC 154 Z9 159 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 2001 VL 68 IS 5 BP 1165 EP 1171 DI 10.1086/320119 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 423HZ UT WOS:000168171200010 PM 11309682 ER PT J AU Sutton-Tyrrell, K Mackey, RH Holubkov, R Vaitkevicius, PV Spurgeon, HA Lakatta, EG AF Sutton-Tyrrell, K Mackey, RH Holubkov, R Vaitkevicius, PV Spurgeon, HA Lakatta, EG TI Measurement variation of aortic pulse wave velocity in the elderly SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE pulse wave velocity; Doppler ultrasound; aged; reproducibility ID ARTERIAL DISTENSIBILITY; DOPPLER ULTRASOUND; STIFFNESS; ATHEROSCLEROSIS; REPRODUCIBILITY; HYPERTENSION; HYPERTROPHY AB Accurate and reproducible measures are required to study arterial stiffness in human populations. The reproducibility of aortic pulse wave velocity was evaluated in 14 participants from a population-based study of cardiovascular disease in the elderly. Three data files were collected per participant by each of two sonographers and files were read by two readers. Seven of the 14 participants returned for a second visit I week later to assess between-visit variability. Reproducibility was evaluated with Pearson and intraclass correlations and by the absolute value of the difference between replicate values. The overall reliability coefficient was r(I) = 0,77, Between-sonographer, between-reader, and between-visit correlations were r(p) = 0.80 to 0.87, r(p) = 0.73 to 0.89 and r(p) = 0.63. The mean absolute value of the difference between replicates was 59.4 to 94.0 cm/sec and 88.7 to 112.8 cm/sec for sonographers and readers, respectively. These results indicate that the mean PWV measure is reproducible even when sonographers and readers are newly trained. (C) 2001 American Journal of Hypertension, Ltd. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Johns Hopkins Bayview Med Ctr, Johns Hopkins Geriat Ctr, Baltimore, MD USA. NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, 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 NR 20 TC 57 Z9 63 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2001 VL 14 IS 5 BP 463 EP 468 DI 10.1016/S0895-7061(00)01289-9 PN 1 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 429ZW UT WOS:000168549500013 PM 11368468 ER PT J AU Baris, D Garrity, TJ Telles, JL Heineman, EF Olshan, A Zahm, SH AF Baris, D Garrity, TJ Telles, JL Heineman, EF Olshan, A Zahm, SH TI Cohort mortality study of Philadelphia firefighters SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE firefighters; mortality; cohort study ID FIRE-FIGHTERS; CANCER INCIDENCE; OCCUPATIONAL MORTALITY; PHYSICAL-ACTIVITY; HEALTHY WORKER; UNITED-STATES; EXPOSURE; TORONTO; HAZARDS; SEATTLE AB Background Fire fighters are exposed to a wide variety of toxic chemicals. Previous studies have reported excess risk of some cancers but have been limited by small numbers or little information on employment characteristics. Methods We conducted a retrospective cohort mortality study among 7,789 Philadelphia firefighters employed between 1925 and 1986. For each cause of death, the standardized mortality ratios (SMRs) and 95% confidence intervals were estimated. We also compared mortality among groups of firefighters defined by the estimated number of career runs and potential for diesel exposure. Results In comparison with U.S. white men, the firefighters had similar mortality from all causes of death combined (SMR = 0.96) and all cancers (SMR = 1.10). There were statistically significant deficits of deaths from nervous system diseases (SMR = 0.47), cerebrovascular diseases (SMR = 0.83), respiratory diseases (SMR = 0.67), genitourinary diseases (SMR = 0.54), all accidents (SMR = 0.72), and suicide (SMR = 0.66). Statistically significant excess risks were observed for colon cancer (SMR = 1.51) and ischemic heart disease (SMR = 1.09). The risks of mortality from colon cancer (SMR = 1.68), kidney cancer (SMR = 2.20), non-Hodgkin's lymphoma (SMR = 1.72), multiple myeloma (SMR = 2.31), and benign neoplasms (SMR = 2.54) were increased among firefighters with at least 20 years of service. Conclusions Our study found no significant increase in overall mortality among Philadelphia firefighters. However, we observed increased mortality for cancers of the colon and kidney, non-Hodgkin's lymphoma and multiple myeloma. There was insufficient follow-up since the introduction of diesel equipment to adequately assess risk. Am. J. Ind. Med. 39:463-476, 2001. Published 2001 Wiley-Liss, Inc(dagger). C1 NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. Delaware Valley Healthcare Council HAP, Philadelphia, PA USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, 6120 Execut Blvd,EPS 8122, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 40 TC 51 Z9 51 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2001 VL 39 IS 5 BP 463 EP 476 DI 10.1002/ajim.1040 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 428FF UT WOS:000168450500003 PM 11333408 ER PT J AU De Roos, AJ Poole, C Teschke, K Olshan, AF AF De Roos, AJ Poole, C Teschke, K Olshan, AF TI An application of hierarchical regression in the investigation of multiple paternal occupational exposures and neuroblastoma in offspring SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE hierarchical regression; occupation; neuroblastoma; childhood cancer; multiple comparisons ID EPIDEMIOLOGIC ANALYSES; EMPIRICAL-BAYES; LIKELIHOOD; CANCER AB Background We used hierarchical regression to study the effects of 46 paternal occupational exposures on the incidence of neuroblastoma in offspring. Methods The study population included 405 cases and 302 controls. The effect of each exposure was estimated using both conventional maximum likelihood and hierarchical regression. Results Using hierarchical regression, overall precision was greatly enhanced compared to the conventional analysis. In addition, adjustment of effect estimates based on prespecified prior distributions of the true effect parameters allowed a more consistent interpretation across the entire panel of exposures. Estimates for several metals and solvents were shrunk close to the null value, whereas estimates for several thinner solvents, diesel fuel, solders, wood dust, and grain dust remained moderately elevated. Conclusions Hierarchical regression may mitigate some of the problems of the conventional approach by controlling for correlated exposures, enhancing the precision of estimates, and providing some adjustments of estimates based on prior knowledge. Am. J. Ind. Med. 39:477-486, 2001. (C) 2001 Wiley-Liss, Inc. C1 NCI, Occupat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ British Columbia, Dept Hlth Care Epidemiol, Vancouver, BC V5Z 1M9, Canada. RP De Roos, AJ (reprint author), NCI, Occupat Epidemiol Branch, NIH, 6120 Execut Blvd,EPS 8091,MSC 7240, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA57004]; NIEHS NIH HHS [T32-ES-07018] NR 13 TC 18 Z9 18 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2001 VL 39 IS 5 BP 477 EP 486 DI 10.1002/ajim.1041 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 428FF UT WOS:000168450500004 PM 11333409 ER PT J AU Gennaro, V Montanaro, F Ceppi, M Fontana, V Perrotta, A Puntoni, R AF Gennaro, V Montanaro, F Ceppi, M Fontana, V Perrotta, A Puntoni, R TI RE: Mesothelioma and lung tumors attributable to asbestos among petroleum workers. Am. J. Ind. Med. 2000. 37 : 275-282. I. Reply to Tsai et al.'s letter to the editor and new evidence SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Letter DE maintenance workers; occupational epidemiology; refinery workers; oil refinery; lung cancer; mesothelioma; pleural tumor; smoking; asbestos ID REFINERY; MORTALITY C1 Natl Canc Inst, Genoa, Italy. Ontario Minist Labour, Toronto, ON, Canada. AUSL, Occupat Hyg & Safety Dept, La Spezia, Italy. RP Gennaro, V (reprint author), Natl Canc Inst, Genoa, Italy. NR 9 TC 3 Z9 3 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 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2001 VL 39 IS 5 BP 517 EP 521 DI 10.1002/ajim.1049 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 428FF UT WOS:000168450500012 ER PT J AU Horne, MK AF Horne, MK TI The dark side of deep venous thrombosis: The failure of anticoagulation SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID RECOMBINANT HIRUDIN; VEIN THROMBOSIS; HEPARIN; THROMBOLYSIS; ARGATROBAN; THERAPY; DISEASE; SAFETY C1 NIH, Dept Lab Med, Hematol Serv, Bethesda, MD 20892 USA. RP Horne, MK (reprint author), NIH, Dept Lab Med, Hematol Serv, Bldg 10,Rm 2C 306, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAY PY 2001 VL 110 IS 7 BP 589 EP 590 DI 10.1016/S0002-9343(01)00690-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 430CM UT WOS:000168556000012 PM 11343675 ER PT J AU Lancaster, JM Risinger, JI Carney, ME Barrett, JC Berchuck, A AF Lancaster, JM Risinger, JI Carney, ME Barrett, JC Berchuck, A TI Mutational analysis of the PTEN gene in human uterine sarcomas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE human uterine sarcoma; PTEN gene; SKUT-1B cell line ID ENDOMETRIAL CANCERS; OVEREXPRESSION; DISEASE; BREAST AB OBJECTIVE: Uterine sarcomas are rare, lethal cancers, and little is known about their molecular etiology. The PTEN gene is located on chromosome 10q23.3, a region that displays frequent loss of heterozygosity in human uterine sarcomas. PTEN mutations have been described in 40% to 60% of uterine adenocarcinomas. To determine whether the PTEN gene is involved in the pathogenesis of uterine sarcoma, we analyzed deoxyribonucleic acid from uterine sarcomas and cell lines. STUDY DESIGN: Single-strand conformation analysis and direct sequencing of deoxyribonucleic acid were used to screen for PTEN mutations. RESULTS: Silent polymorphisms were detected in 2 of 36 primary uterine sarcomas. A 4-base pair deletion and a point mutation producing a stop codon were identified in 1 cell line. CONCLUSIONS: Mutational inactivation of PTEN does not play a major role in uterine sarcoma tumorigenesis, and another gene or genes on chromosome 10q may be implicated as a cause of these cancers. Differences in the molecular alterations underlying the development of uterine sarcomas and adenocarcinomas are significant. C1 Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Durham, NC 27710 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Berchuck, A (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Box 3079, Durham, NC 27710 USA. NR 10 TC 10 Z9 12 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2001 VL 184 IS 6 BP 1051 EP 1053 DI 10.1067/mob.2001.114508 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 433KJ UT WOS:000168758300001 PM 11349153 ER PT J AU Lin, FYC Brenner, RA Johnson, YR Azimi, PH Philips, JB Regan, JA Clark, P Weisman, LE Rhoads, GG Kong, FH Clemens, JD AF Lin, FYC Brenner, RA Johnson, YR Azimi, PH Philips, JB Regan, JA Clark, P Weisman, LE Rhoads, GG Kong, FH Clemens, JD TI The effectiveness of risk-based intrapartum chemoprophylaxis for the prevention of early-onset neonatal group B streptococcal disease SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE group B Streptococcus; early-onset disease; intrapartum antibiotic prophylaxis; effectiveness ID INFECTIONS; TRANSMISSION AB OBJECTIVE: Our purpose was to evaluate the effectiveness of a risk-based intrapartum antibiotic prophylaxis strategy for the prevention of early-onset neonatal group B streptococcal disease. STUDY DESIGN: Cases and controls were selected from infants born to women with one or more risk factors: preterm labor or rupture of membranes, prolonged rupture of membranes (>18 hours), fever during labor, or previous child with group B streptococcal disease. Cases were matched with controls by birth hospital and gestational age. Data abstracted from medical records were analyzed to estimate the effectiveness of intrapartum antibiotic prophylaxis. RESULTS: We analyzed data from 109 cases and 207 controls. Nineteen (17%) case Versus 69 (33%) control mothers received an acceptable regimen of intrapartum antibiotic prophylaxis. In adjusted analyses, the effectiveness of intrapartum antibiotic prophylaxis was 86% (95% confidence interval, 66%-94%). When the first dose of antibiotics was given greater than or equal to2 hours before delivery, the effectiveness increased to 89% (95% confidence interval, 70%-96%); when it was given within 2 hours of delivery, the effectiveness was 71% (95% confidence interval, -8%-92%). Effectiveness was lowest in mothers with intrapartum fever (72%, 95% confidence interval, -9%-93%). On the basis of a 70% prevalence of maternal risk factors expected among cases in the absence of intrapartum antibiotic prophylaxis, we estimate that the risk-based strategy could reduce early-onset group B streptococcal disease by 60%. CONCLUSIONS: The risk-based approach to intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease. To achieve the maximum preventive effect, the first dose of antibiotics should be administered at least 2 hours before delivery. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. NICHHD, Rockville, MD USA. Childrens Hosp Med Ctr No Calif, Oakland, CA USA. Univ Alabama, Birmingham, AL USA. Columbia Univ Hlth Sci, New York, NY USA. Univ Florida, Gainesville, FL USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Med & Dent New Jersey, Piscataway, NJ 08854 USA. Westat Inc, Piscataway, NJ USA. RP Lin, FYC (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bldg 61E Rm 7B03,9000 Rockville Pike,MSC 7510, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-4-3215, N01-HD-4-3219, N01-HD-4-3217, N01-HD-4-3218, N01-HD-5-3233, N01-HD-4-3214, N01-HD-4-3220] NR 19 TC 48 Z9 51 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2001 VL 184 IS 6 BP 1204 EP 1210 DI 10.1067/mob.2001.113875 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 433KJ UT WOS:000168758300037 PM 11349189 ER PT J AU Minkoff, H Ahdieh, L Watts, H Greenblatt, RM Schmidt, J Schneider, M Stek, A AF Minkoff, H Ahdieh, L Watts, H Greenblatt, RM Schmidt, J Schneider, M Stek, A TI The relationship of pregnancy to the use of highly active antiretroviral therapy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE CD4(+) cell count; highly active antiretroviral therapy; human immunodeficiency virus; human immunodeficiency virus type 1ribonucleic acid; pregnancy; women ID IMMUNODEFICIENCY-VIRUS INFECTION; PERINATAL TRANSMISSION; NUCLEOSIDE ANALOGS; HIV-INFECTION; ZIDOVUDINE; TYPE-1; WOMEN; INDINAVIR; PLASMA; AIDS AB OBJECTIVE: Public health agencies have recommended that the criteria for the use of highly active antiretroviral therapy should not be modified because of pregnancy. However, little information has been published with regard to the degree to which these recommendations are being followed. We report here the frequency of highly active antiretroviral therapy use among pregnant women in the Women's Interagency HIV Study and compare the frequencies of its use by pregnant women meeting published criteria for implementing highly active antiretroviral therapy and its use by nonpregnant women meeting the same criteria. STUDY DESIGN: From October 1994 through November 1995, a total of 2059 human immunodeficiency virus type 1-seropositive women were enrolled in a cohort study. Participants were evaluated at baseline and at 6-month intervals with standardized interview instruments. In addition to a general physical examination at each visit, patients had a urine pregnancy test performed and were asked about current pregnancies, pregnancies since the last visit. and which antiretroviral medications they had used since the last visit. Highly active antiretroviral therapy was defined according to 1997 National institutes of Health guidelines. RESULT: At each calendar interval after October 1996, a greater proportion of nonpregnant women than pregnant women reported the use of highly active antiretroviral therapy. The use of monotherapy declined for both groups during the course of multiple calendar periods (P <.01), although the use of monotherapy remained higher among the pregnant women. In any given calendar period, pregnant women meeting published criteria for highly active antiretroviral therapy use were slightly less likely than similar nonpregnant women to receive highly active antiretroviral therapy (odds ratio, 0.28-0.98). Because of the sample size these differences reached significance in only one calendar period (P=.02). With time pregnant women did demonstrate an increase in the percentage receiving highly active antiretroviral therapy In nearly all calendar periods a larger percentage of pregnant than nonpregnant women were receiving a regimen that included zidovudine. CONCLUSIONS: Highly active antiretroviral therapy is being received by an increasing percentage of women who meet published criteria for its use, and pregnancy is a relatively small impediment to its use. Further efforts are needed to bolster the use of highly active antiretroviral therapy by all appropriate candidates and to ensure equal access to this therapy for pregnant women. Because of the increasingly frequent use of highly active antiretroviral therapy during pregnancy, ongoing efforts are needed to monitor any long-term effects of in utero exposure to multiple antiretroviral agents. C1 Maimonides Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. Suny Hlth Sci, Brooklyn, NY USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. NICHHD, Pediat & Maternal AIDS Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA. Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Cook Cty Hosp, Dept Obstet & Gynecol, Chicago, IL 60612 USA. RP Minkoff, H (reprint author), Maimonides Med Ctr, Dept Obstet & Gynecol, 4802 10th Ave, Brooklyn, NY 11219 USA. FU NIAID NIH HHS [AI-34989, U01-AI-34993, U01-AI-42590, U01-AI-31834, U01-AI-34994, U01-AI-35004, N01-AI-35161]; NICHD NIH HHS [U01-HD-32632] NR 25 TC 23 Z9 24 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2001 VL 184 IS 6 BP 1221 EP 1227 DI 10.1067/mob.2001.113871 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 433KJ UT WOS:000168758300040 PM 11349192 ER PT J AU Kono, H Rusyn, I Uesugi, T Yamashina, S Connor, HD Dikalova, A Mason, RP Thurman, RG AF Kono, H Rusyn, I Uesugi, T Yamashina, S Connor, HD Dikalova, A Mason, RP Thurman, RG TI Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE nuclear factor-kappa B; tumor necrosis factor-alpha; enteral feeding ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; INTRAGASTRIC ETHANOL INFUSION; FACTOR-ALPHA; RADICAL ADDUCTS; KUPFFER CELLS; INFLAMMATION; MACROPHAGES; INDUCTION; REDUCTASE AB The oxidant source in alcohol-induced liver disease remains unclear. NADPH oxidase (mainly in liver Kupffer cells and infiltrating neutrophils) could be a potential free radical source. We aimed to determine if NADPH oxidase inhibitor diphenyleneiodonium sulfate (DPI) affects nuclear factor-kappaB (NF-kappaB) activation, liver tumor necrosis factor-alpha (TNF-alpha) mRNA expression, and early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g.kg(-1).day(-1)) continuously for up to 4 wk, using the Tsukamoto-French intragastric enteral feeding protocol. DPI or saline vehicle was administered by subcutaneous injection for 4 wk. Mean urine ethanol concentrations were similar between the ethanol-and ethanol plus DPI-treated groups. Enteral ethanol feeding caused severe fat accumulation, mild inflammation, and necrosis in the liver (pathology score, 4.3 +/- 0.3). In contrast, DPI significantly blunted these changes (pathology score, 0.8 +/- 0.4). Enteral ethanol administration for 4 wk also significantly increased free radical adduct formation, NF-kappaB activity, and TNF-alpha expression in the liver. DPI almost completely blunted these parameters. These results indicate that DPI prevents early alcohol-induced liver injury, most likely by inhibiting free radical formation via NADPH oxidase, thereby preventing NF-kappaB activation and TNF-alpha mRNA expression in the liver. C1 Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Pharmacol, Hepatobiol & Toxicol Lab, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. RI Rusyn, Ivan/S-2426-2016 NR 43 TC 107 Z9 109 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD MAY PY 2001 VL 280 IS 5 BP G1005 EP G1012 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 424CK UT WOS:000168214400027 PM 11292610 ER PT J AU Gabel, SA London, RE Funk, CD Steenbergen, C Murphy, E AF Gabel, SA London, RE Funk, CD Steenbergen, C Murphy, E TI Leukocyte-type 12-lipoxygenase-deficient mice show impaired ischemic preconditioning-induced cardioprotection SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE myocardial ischemia; infarction; prostaglandins; nuclear magnetic resonance ID PROTEIN-KINASE-C; SENSITIVE K+ CHANNELS; ARACHIDONIC-ACID; RAT-HEART; LIPOXYGENASE METABOLITES; RABBIT CARDIOMYOCYTES; POTASSIUM CHANNELS; INFARCT SIZE; EXPRESSION; PROTECTION AB To investigate the role of 12-lipoxygenase in preconditioning, we examined whether hearts lacking the "leukocyte-type" 12-lipoxygenase (12-LOKO) would be protected by preconditioning. In hearts from wild-type (WT) and 12-LOKO mice, left ventricular developed pressure (LVDP) and P-31 NMR were monitored during treatment (+/-preconditioning) and during global ischemia and reperfusion. Postischemic function (rate-pressure product, percentage of initial value) measured after 20 min of ischemia and 40 min of reperfusion was significantly improved by preconditioning in WT hearts (78 +/- 12% in preconditioned vs. 44 +/- 7% in nonpreconditioned hearts) but not in 12-LOKO hearts (47 +/- 7% in preconditioned vs. 33 +/- 10% in nonpreconditioned hearts). Postischemic recovery of phosphocreatine was significantly better in WT preconditioned hearts than in 12-LOKO preconditioned hearts. Preconditioning significantly reduced the fall in intracellular pH during sustained ischemia in both WT and 12-LOKO hearts, suggesting that attenuation of the fall in pH during ischemia can be dissociated from preconditioning-induced protection. Necrosis was assessed after 25 min of ischemia and 2 h of reperfusion using 2,3,5- triphenyltetrazolium chloride. In WT hearts, preconditioning significantly reduced the area of necrosis (26 +/- 4%) compared with nonpreconditioned hearts (62 +/- 10%) but not in 12-LOKO hearts (85 +/- 3% in preconditioned vs. 63 +/- 11% in nonpreconditioned hearts). Preconditioning resulted in a significant increase in 12(S)-hydroxyeicosatetraenoic acid in WT but not in 12-LOKO hearts. These data demonstrate that 12- lipoxygenase is important in preconditioning. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Univ Penn, Ctr Expt Therapeut, Philadelphia, PA 19104 USA. RP Murphy, E (reprint author), Maildrop D2-03,Box 12233, Res Triangle Pk, NC 27709 USA. RI Funk, Colin/A-9518-2010 FU NHLBI NIH HHS [HL-39752, HL-53558, R01 HL039752] NR 29 TC 27 Z9 28 U1 0 U2 2 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 MAY PY 2001 VL 280 IS 5 BP H1963 EP H1969 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 420WE UT WOS:000168027600005 PM 11299195 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI "Salus populi suprema lex": The health of the people is the supreme law SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. RP Theerman, P (reprint author), Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2001 VL 91 IS 5 BP 689 EP 689 DI 10.2105/AJPH.91.5.689 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BP UT WOS:000170345300001 PM 11344868 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Preemptive biopreparedness: Can we learn anything from history? SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID UNITED-STATES; PUBLIC-HEALTH; BIOTERRORISM PREPAREDNESS; BIOLOGICAL-WARFARE; PREVENTION AB The threat of bioterrorism is in the public eye again, and major public health agencies are urging preparedness efforts and special federal funding. In a sense, we have seen this all before. The Centers for Disease Control and Prevention grew substantially during the Cold War era in large part because Alexander Langmuir, Chief Epidemiologist of the CDC, used an earlier generation's anxieties to revitalize the CDC, create an Epidemic Intelligence Service, and promote epidemiologic "surveillance" as part of the nation's defense. Retrospective investigation suggests that, while Langmuir contributed to efforts promoted by the Department of Defense and the Federal Civil Defense Administration, the United States did not have real cause to fear Communist biological warfare aggression. Given clear historical parallels, it is appropriate to ask, What was gained and what was lost by Langmuir's central role in that first instance of American biopreparedness? Among the conclusions drawn is that biopreparedness efforts fed the Cold War climate, narrowed the scope of public health activities, and failed to achieve sustained benefits for public health programs across the country. C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. Univ Rochester, Rochester, NY USA. RP Fee, E (reprint author), Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 39 TC 24 Z9 25 U1 0 U2 3 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 MAY PY 2001 VL 91 IS 5 BP 721 EP 726 DI 10.2105/AJPH.91.5.721 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BP UT WOS:000170345300012 PM 11344879 ER PT J AU Miller, HG Baldwin, WH AF Miller, HG Baldwin, WH TI A terse amendment produces broad change in data access SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 NIH, Off Director, Off Extramural Res, Bethesda, MD 20892 USA. RP Miller, HG (reprint author), NIH, Off Director, Off Extramural Res, 1 Ctr Dr,MSC 0152,Bldg 1,Room 150, Bethesda, MD 20892 USA. NR 3 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 MAY PY 2001 VL 91 IS 5 BP 824 EP 825 DI 10.2105/AJPH.91.5.824 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 461BP UT WOS:000170345300032 PM 11344898 ER PT J AU Fahy, JV Boushey, HA Lazarus, SC Mauger, EA Cherniack, RM Chinchilli, VM Craig, TJ Drazen, JM Ford, JG Fish, JE Israel, E Kraft, M Lemanske, RF Martin, RJ McLean, D Peters, SP Sorkness, C Szefler, SJ AF Fahy, JV Boushey, HA Lazarus, SC Mauger, EA Cherniack, RM Chinchilli, VM Craig, TJ Drazen, JM Ford, JG Fish, JE Israel, E Kraft, M Lemanske, RF Martin, RJ McLean, D Peters, SP Sorkness, C Szefler, SJ CA Natl Heart Lung Blood Inst Asthma TI Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID AIRWAY INFLAMMATION; SEVERITY; INDEXES; CELL AB The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV1 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV1 and the methacholine PC20. The FEV1 decreased greater than or equal to 20% from the post-bronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC20 were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC20 and should prove useful in the assessment of airway inflammation in multicenter clinical trials. C1 Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Columbia Univ, Harlem Hosp Ctr, New York, NY USA. Milton S Hershey Med Ctr, Hershey, PA USA. Univ Wisconsin, Madison, WI USA. Natl Jewish Med & Res Ctr, Denver, CO USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. NHLBI, Bethesda, MD 20892 USA. RP Fahy, JV (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, Box 0111, San Francisco, CA 94143 USA. RI Drazen, Jeffrey/E-5841-2012 NR 22 TC 102 Z9 106 U1 0 U2 2 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 MAY PY 2001 VL 163 IS 6 BP 1470 EP 1475 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 436YE UT WOS:000168962800040 PM 11371420 ER PT J AU Eissa, NT Haggerty, CM Palmer, CD Patton, W Moss, J AF Eissa, NT Haggerty, CM Palmer, CD Patton, W Moss, J TI Identification of residues critical for enzymatic activity in the domain encoded by exons 8 and 9 of the human inducible nitric oxide synthase SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID MOLECULAR-CLONING; OXYGENASE DOMAIN; REVEALS; NO; TETRAHYDROBIOPTERIN; LOCALIZATION; DIMERIZATION; MACROPHAGES; MUTAGENESIS; CALMODULIN AB Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathogenesis of several diseases including airway inflammation of asthma. iNOS is active only as a homodimer. We previously demonstrated that the region encoded by exons 8 and 9 is critical for dimerization. In this study, alanine-scanning mutagenesis was used to identify critical amino acids in that region by expression of mutant proteins in human embryonic kidney 293 cells. All iNOS mutants yielded iNOS protein as detected by Western analysis. Four iNOS mutants with alanine replacing Trp(260), Asn(261), Tyr(267), or Asp(280) did not generate NO. Dimer formation was tested by sodium dodecyl sulfate polyacrylamide gel electrophoresis at 4 degreesC, followed by immunoblotting. Wild-type iNOS migrated both as monomers and dimers. iNOS mutants with alanine replacing Trp(260), Asn(261) Or Tyr(267) however, migrated only as monomers, suggesting that their inability to produce NO is related to a defect in dimer formation. Interestingly, the Asp(280) mutant retained the ability to dimerize, indicating that it represents an inactive form of an iNOS dimer. These data identify four amino acids in exons 8 and 9 critical for iNOS activity, three of which also influence dimerization. These residues are strictly conserved among all NOS isforms and across species. Thus all NOS isoforms share general structural similarities, including specific amino acids critical for dimerization and catalytic activity. These data increase our understanding of the structural elements critical for NO synthesis and lay the groundwork for future studies aimed at downregulation of iNOS activity. C1 Baylor Coll Med, Dept Med, Pulm & Crit Care Med Sect, Houston, TX 77030 USA. NHLBI, Pulm Crit Care Med Branch, Bethesda, MD USA. RP Eissa, NT (reprint author), Baylor Coll Med, Dept Med, Pulm & Crit Care Med Sect, 6565 Fannin St,FBRN-B567, Houston, TX 77030 USA. EM teissa@bcm.tmc.edu NR 28 TC 17 Z9 17 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAY PY 2001 VL 24 IS 5 BP 616 EP 620 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 436AA UT WOS:000168913300015 PM 11350832 ER PT J AU Plowe, CV Doumbo, OK Djimde, A Kayentao, K Diourte, Y Doumbo, SN Coulibaly, D Thera, M Wellems, TE Diallo, DA AF Plowe, CV Doumbo, OK Djimde, A Kayentao, K Diourte, Y Doumbo, SN Coulibaly, D Thera, M Wellems, TE Diallo, DA TI Chloroquine treatment of uncomplicated Plasmodium falciparum malaria in Mali: Parasitologic resistance versus therapeutic efficacy SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID TREATMENT POLICY; AFRICA AB Whether and when to replace chloroquine with other antimalarial drugs is an urgent public health question in much of Africa, where Plasmodium falciparum, which is increasingly resistant to chloroquine, continues to kill millions each year. Antimalarial drug efficacy has traditionally been measured as parasitologic resistance, but recent guidelines use both clinical and parasitologic criteria to monitor therapeutic efficacy. To assess the new efficacy protocol, we measured parasitologic and therapeutic outcomes in 514 patients treated with chloroquine for uncomplicated P. falciparum malaria in Mall. There was a general agreement between parasitologic and therapeutic outcomes at two sites, with 13-17% parasitologic resistance rates and 10-15% treatment failure rates. However, the new protocol overestimated early treatment failure rates (21-71% of cases classified as early treatment failure had sensitive or RI parasitologic responses), particularly where resistance was rare, and missed low-level parasitologic resistance. Modifications of the protocol for monitoring antimalarial therapeutic efficacy are recommended. C1 Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Med,Malaria Sect, Baltimore, MD 21201 USA. Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Bamako, Mali. Fac Med Pharm & Odontostomatol, Dept Hematol, Bamako, Mali. NIAID, Parasit Dis Lab, Malaria Genet Sect, NIH, Bethesda, MD 20892 USA. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Med,Malaria Sect, 685 W Baltimore St,HSF 480, Baltimore, MD 21201 USA. NR 9 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAY-JUN PY 2001 VL 64 IS 5-6 BP 242 EP 246 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 453NH UT WOS:000169921600004 PM 11463110 ER PT J AU Gastwirth, JL Freidlin, B AF Gastwirth, JL Freidlin, B TI Freidlin, B., and Gastwirth, J. L. (2000), "should the median test be retired from general use?" The American Statistician 54, 161-164: Comment by Gartside and reply - Reply SO AMERICAN STATISTICIAN LA English DT Letter C1 George Washington Univ, Washington, DC 20052 USA. NCI, Bethesda, MD 20892 USA. RP Gastwirth, JL (reprint author), George Washington Univ, Washington, DC 20052 USA. NR 2 TC 0 Z9 0 U1 1 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD MAY PY 2001 VL 55 IS 2 BP 171 EP 171 PG 1 WC Statistics & Probability SC Mathematics GA 427RN UT WOS:000168419400016 ER PT J AU Crotti, LB Drgon, T Cabib, E AF Crotti, LB Drgon, T Cabib, E TI Yeast cell permeabilization by osmotic shock allows determination of enzymatic activities in situ SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CHITIN SYNTHASE-3; SHUTTLE VECTORS; SYNTHETASE; GENE; PURIFICATION; BIOSYNTHESIS; GROWTH; SYSTEM; CAL1 AB Yeast cells were permeabilized by incubation in 0.8 M sorbitol followed by suspension in dilute buffer. A preincubation with 2-mercaptoethanol was also included for optimal permeabilization, More than 90% of the treated cells were stainable with methylene blue, Determinations of cell wall-synthesizing enzymes (beta (1 --> 3)glucan and chitin synthases) and cytosolic enzymes in permeabilized cells yielded similar or higher activities than those in cell extracts. With chitin synthase III, the activity obtained with cells was 4- to 6-fold higher than in membrane preparations. Little protein leaks from the cells during permeabilization; Set the cells appear to be readily permeable to substrates and even proteins. Thus, these preparations may be of wide use for the study of enzymes and of biological processes in situ, (C) 2001 Academic Press. C1 NIDDKD, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP NIDDKD, Lab Biochem & Genet, Bldg 8,Room 403, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov NR 35 TC 31 Z9 31 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 1 PY 2001 VL 292 IS 1 BP 8 EP 16 DI 10.1006/abio.2001.5051 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 428YH UT WOS:000168488900002 PM 11319811 ER PT J AU Kevala, JH Kim, HY AF Kevala, JH Kim, HY TI Determination of substrate preference in phosphatidylserine decarboxylation by liquid chromatography-electrospray ionization mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE phosphatidylserine decarboxylase; electrospray mass spectrometry; mitochondria; phosphatidylethanolamine; liposomes; docosahexaenoic acid; brain cortex; liver ID RAT-BRAIN; MITOCHONDRIAL-MEMBRANE; PHOSPHATIDYLETHANOLAMINE; PROTEIN; ACID; TRANSLOCATION; MECHANISM; CELLS; LIVER AB A method has been developed to determine the substrate preference in phosphatidylserine decarboxylation (PSD), the process by which phosphatidylserine is converted to phosphatidylethanolamine (PE) in the mitochondria, The in vitro assay utilized liposomes containing deuterium-labeled PS molecular species incubated with liver and brain cortex mitochondria, and the conversion of PS to the corresponding PE species wets monitored by electrospray ionization mass spectrometry in conjunction with reversed-phase liquid chromatography, Employing this approach we were able to establish for the first time that there exists a substrate preference in PSD in liver (18:0,18:1 greater than or equal to 18:0,22:6 > 18:0,20:4-PS) and brain cortex (18:0,22:6 > 18:0,18:1 > 18:0,20:4-PS). The observed PSD molecular species preference, however, did not reflect the mitochondrial PE profile, suggesting that selectivity in other processes such as de novo PE synthesis, intracellular transport of phospholipid molecules, or remodeling by deacylation-reacylation may be important contributors in maintaining a specific lipid profile-in mitochondria. (C) 2001 Academic Press. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. NR 32 TC 24 Z9 24 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 1 PY 2001 VL 292 IS 1 BP 130 EP 138 DI 10.1006/abio.2001.5076 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 428YH UT WOS:000168488900018 PM 11319827 ER PT J AU Buzas, Z Li, T Chrambach, A AF Buzas, Z Li, T Chrambach, A TI Horizontal gel electrophoresis of SDS-proteins on the PhastSystem with an at least 25-fold increased protein load volume SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID APPARATUS; DISPERSION; BUFFER; SYSTEM; DNA C1 NIH, Macromol Anal Sect, Lab Cellular & Mol Biophys, Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. Agr Biotechnol Ctr, H-2101 Godollo, Hungary. RP Chrambach, A (reprint author), NIH, Macromol Anal Sect, Lab Cellular & Mol Biophys, Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. NR 8 TC 1 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 1 PY 2001 VL 292 IS 1 BP 161 EP 163 DI 10.1006/abio.2001.5070 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 428YH UT WOS:000168488900022 PM 11319831 ER PT J AU Sarno, RJ Franklin, WL O'Brien, SJ Johnson, WE AF Sarno, RJ Franklin, WL O'Brien, SJ Johnson, WE TI Patterns of mtDNA and microsatellite variation in an island and mainland population of guanacos in southern Chile SO ANIMAL CONSERVATION LA English DT Article ID MITOCHONDRIAL-DNA; GENETIC DIFFERENTIATION; EVOLUTION; AMPLIFICATION; ALLELES; POLYMORPHISMS; CONSERVATION; SEQUENCES AB The archaeological record indicates that guanacos inhabited the Patagonia of Chile and Argentina about 13,600 years ago, but were unable to migrate further south owing to the presence of glacial and water barriers that covered much of southern South America including the island of Tierra del Fuego. As environmental and ecological conditions improved, guanacos, along with other large mammals including horses, colonized the area. As a result of continued world-wide glacial melting, ocean levels rose and Tierra del Fuego became isolated from the mainland approximately 8000 years ago. Although island populations generally exhibit lower levels of genetic variation than their counterpart mainland populations, it is difficult to predict how much less variation island populations will exhibit. An analysis of mitochondrial cytochrome b and ATPase-8 sequences and 15 nuclear microsatellite loci revealed that both populations retained appreciable genetic diversity. The island population, however, exhibited much less variation than the mainland population. Measures of genetic variation revealed modest, but significant genetic differentiation, consistent with separation of the two populations approximately 8000 years ago. The assessment of levels of genetic diversity and population differentiation among populations of the wild South American camelids is becoming increasingly important as interest mounts in their utilization as a renewable resource. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. Iowa State Univ Sci & Technol, Dept Anim Ecol, Ames, IA 50011 USA. RP Sarno, RJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. RI Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X NR 59 TC 21 Z9 21 U1 1 U2 12 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 1367-9430 J9 ANIM CONSERV JI Anim. Conserv. PD MAY PY 2001 VL 4 BP 93 EP 101 DI 10.1017/S1367943001001123 PN 2 PG 9 WC Biodiversity Conservation; Ecology SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 435ZZ UT WOS:000168913200001 ER PT J AU Ornato, JP Selker, HP Zalenski, RJ AF Ornato, JP Selker, HP Zalenski, RJ TI Overview: Diagnosing acute cardiac ischemia in the emergency department. A report from the National Heart Attack Alert Program SO ANNALS OF EMERGENCY MEDICINE LA English DT Article C1 NHLBI, Natl Heart Attack Alert Program Coordinating Comm, Sci Bas Subcomm, NIH, Bethesda, MD 20892 USA. RP Ornato, JP (reprint author), NHLBI, Natl Heart Attack Alert Program Coordinating Comm, Sci Bas Subcomm, NIH, 31 Ctr Dr,MSC 2480, Bethesda, MD 20892 USA. NR 9 TC 9 Z9 9 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD MAY PY 2001 VL 37 IS 5 BP 450 EP 452 DI 10.1067/mem.2001.114760 PG 3 WC Emergency Medicine SC Emergency Medicine GA 429BC UT WOS:000168495300004 PM 11326180 ER PT J AU Brinton, LA Lubin, JH Burich, MC Colton, T Brown, SL Hoover, RN AF Brinton, LA Lubin, JH Burich, MC Colton, T Brown, SL Hoover, RN TI Cancer risk at sites other than the breast following augmentation mammoplasty SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE breast implants; cancer; incidence; epidemiology ID GENETICALLY SUSCEPTIBLE STRAINS; SILICONE GEL; MULTIPLE-MYELOMA; UNITED-STATES; LOS-ANGELES; IMPLANTS; WOMEN; MAMMAPLASTY; ASSOCIATION; PLASMACYTOMAS AB PURPOSE: There has been limited investigation of cancer risk other than breast cancer among patients with breast implants, despite some clinical and laboratory evidence suggesting links with certain cancer sites, including hematopoietic and connective tissue malignancies. METHODS: A retrospective cohort study of 13,488 patients who received cosmetic breast implants at 18 plastic surgery practices in six geographic areas was conducted to assess long-term health effects. After an average of 12 years of follow-up, questionnaires were administered to subjects located and alive (78% of eligible population). Attempts were made to obtain death certificates for deceased subjects and medical verification for all reported cancers. Expected numbers of cancers were derived using general population cancer incidence rates and an internal comparison series of 3936 patients who received other types of plastic surgery at the same practices as the implant patients. RESULTS: A total of 359 malignancies was observed versus 295.95 expected based on general population rates, resulting in a standardized incidence ratio (SIR) of 1.21 [95% confidence interval (CI) 1.1-1.4]. Individual malignancies for which incidence was significantly elevated inducted cancers of the stomach (SIR = 2.65), cervix (SIR = 3.18), vulva (SIR = 2.51), brain (SIR = 2.16), and leukemia (SIR = 2.19). No excess risks were observed for other hematopoietic malignancies, including multiple myeloma. The internal analyses, however, based on cancer rates derived among the comparison patients, showed no increased cancer risk among the implant patients [relative risk (RR) = 1.00, 95% CI 0.8-1.2], as well as no statistically significant elevations for most individual sites. Cervical cancer continued to be elevated (RR = 1.78), although to a lesser extent than in the external analyses, while the risk for respiratory cancers was higher (RR = 2.40). Non-significant elevations in risk persisted in this analysis for liver cancer (RR = 2.65), brain cancer (RR = 2.83), and leukemia (RR = 1.83). Many of the cancers showing excesses were defined on the basis of death certificates, requiring caution in interpretation. The histologies of the leukemias were quite varied, which makes a biologic relationship appear unlikely. However, respiratory cancers showed some evidence of increasing risk with follow-up time and both respiratory and brain cancers were elevated in the mortality analyses. CONCLUSIONS: Although excesses of cervical and vulvar cancer among implant patients might he attributable to lifestyle factors, reasons for excesses of respiratory and brain cancers were less apparent. Ann Epidemiol 2001;11:248-256. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NCI, Environm Epidemiol Branch, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. Boston Univ, Dept Epidemiol & Biostat, Boston, MA 02215 USA. ABT Associates Inc, Chicago, IL USA. US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. RP Brinton, LA (reprint author), NCI, Environm Epidemiol Branch, Epidemiol & Biostat Program, 6120 Execut Blvd,Room 7068, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 43 TC 42 Z9 42 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAY PY 2001 VL 11 IS 4 BP 248 EP 256 DI 10.1016/S1047-2797(00)00223-4 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 422FD UT WOS:000168107100005 PM 11306343 ER PT J AU Detera-Wadleigh, SD AF Detera-Wadleigh, SD TI Lithium-related genetics of bipolar disorder SO ANNALS OF MEDICINE LA English DT Review DE Akt; association; expression profiling; glycogen synthase kinase-3 beta; IMPA2; linkage; protein kinase C; single-nucleotide polymorphisms; susceptibility; Wnt ID PROTEIN-KINASE-C; GLYCOGEN-SYNTHASE KINASE-3; INOSITOL-POLYPHOSPHATE 1-PHOSPHATASE; MANIC-DEPRESSIVE ILLNESS; MYOINOSITOL MONOPHOSPHATASE GENE; SINGLE-NUCLEOTIDE POLYMORPHISMS; MAGNETIC-RESONANCE-SPECTROSCOPY; RESPONSIVE AFFECTIVE-DISORDERS; LONG-TERM LITHIUM; GENOMIC STRUCTURE AB Lithium is a potent prophylactic medication and mood stabilizer in bipolar disorder. However, clinical outcome is variable. and its therapeutic effect manifests after a period of chronic treatment, implying a progressive and complex biological response process, Signal transduction systems known to be perturbed by lithium involve phosphoinositide (PI) turnover, activation of the Wnt pathway via inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), and a growth factor-induced, Akt-mediated signalling that promotes cell survival. These pathways, acting in synergy. probably prompt the amplification of lithium signal causing such immense impact on the neuronal network. The sequencing of the human genome presents an unparallelled opportunity to uncover the full molecular repertoire involved in lithium action. Interrogation of high-resolution expression micro-arrays and protein profiles represents a strategy that should help accomplish this goal. A recent microarray analysis on lithium-treated versus untreated PC12 cells identified multiple differentially altered transcripts. Lithium-perturbed genes, particularly those that map to susceptibility regions, could be candidate risk-conferring factors for mood disorders. Transcript and protein profiling in patients could reveal a lithium fingerprint for responsiveness or nonresponsiveness, and a signature motif that may be diagnostic of a specific phenotype. Similarly, lithium-sensitive gene products could provide a new generation of pharmacological targets. C1 NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Detera-Wadleigh, SD (reprint author), NIMH, Intramural Res Program, NIH, Bldg 36 Room 3D16, Bethesda, MD 20892 USA. EM sevilla@helix.nih.gov NR 121 TC 35 Z9 37 U1 1 U2 6 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0785-3890 J9 ANN MED JI Ann. Med. PD MAY PY 2001 VL 33 IS 4 BP 272 EP 285 DI 10.3109/07853890108998756 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 437WU UT WOS:000169023000009 PM 11405549 ER PT J AU Nelson, KB Grether, JK Croen, LA Dambrosia, JM Dickens, BF Jelliffe, LL Hansen, RL Phillips, TM AF Nelson, KB Grether, JK Croen, LA Dambrosia, JM Dickens, BF Jelliffe, LL Hansen, RL Phillips, TM TI Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation SO ANNALS OF NEUROLOGY LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; LONG-TERM POTENTIATION; CULTURED MOUSE EMBRYOS; HIPPOCAMPAL-FORMATION; SPECTRUM DISORDERS; CORTICAL-NEURONS; POLYPEPTIDE VIP; RAT-BRAIN; GROWTH; BDNF AB There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5), Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life. C1 NINDS, NIH, Bethesda, MD 20892 USA. Calif Dept Hlth Serv, March Dimes Birth Defect Fdn, Calif Birth Defects Monitoring Program, Emeryville, CA USA. George Washington Univ, Sch Med, Washington, DC 20052 USA. Univ Calif Davis, Davis, CA 95616 USA. NIH, Off Res Serv, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NINDS, NIH, Bldg 10,Room 5S221, Bethesda, MD 20892 USA. NR 71 TC 270 Z9 279 U1 6 U2 24 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 MAY PY 2001 VL 49 IS 5 BP 597 EP 606 DI 10.1002/ana.1024.abs PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 427YE UT WOS:000168433700008 PM 11357950 ER PT J AU Bielamowicz, S Squire, S Bidus, K Ludlow, CL AF Bielamowicz, S Squire, S Bidus, K Ludlow, CL TI Assessment of posterior cricoarytenoid botulinum toxin injections in patients with abductor spasmodic dysphonia SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT Meeting of the American-Laryngological-Association CY MAY 13-14, 2000 CL ORLANDO, FLORIDA SP Amer Laryngol Assoc DE botox; botulinum toxin; electromyography; larynx; posterior cricoarytenoid muscle; spasmodic dysphonia; voice ID SPASTIC DYSPHONIA; LARYNGEAL DYSTONIA; ADDUCTOR AB In this study, we compared 2 techniques for injection of botulinum toxin type A (Botox) into the posterior cricoarytenoid (PCA) muscle for the treatment of abductor spasmodic dysphonia (ABSD). Fifteen patients with ABSD were enrolled in a prospective randomized crossover treatment trial comparing the 2 injection techniques. The PCA muscle was injected with 5 units on each side, with the injections staged 2 weeks apart, via either a percutaneous posterior-lateral approach or a transnasal fiberoptic approach. Eleven patients reported some benefit with the injections: however, the patient-perceived benefits were not related to changes in symptoms on blinded counts by speech pathologists. No significant reductions in the numbers of breathy breaks occurred with either technique, and no differences were found between techniques. Although patients perceived a benefit, blinded symptom counts did not substantiate these benefits. Thus, PCA muscle injections of Botox provided limited benefits to patients with ABSD, demonstrating the need for a more effective therapy for these patients. C1 NINDS, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. RP Bielamowicz, S (reprint author), George Washington Univ, Med Ctr, Div Otolaryngol Head & Neck Surg, 2150 Penn Ave NW, Washington, DC 20037 USA. OI Ludlow, Christy/0000-0002-2015-6171 FU NIDCD NIH HHS [Z01 DC 00004] NR 20 TC 32 Z9 33 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD MAY PY 2001 VL 110 IS 5 BP 406 EP 412 PN 1 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 432QQ UT WOS:000168707500003 PM 11372922 ER PT J AU Saif, MW Bilgrami, A Greenberg, B AF Saif, MW Bilgrami, A Greenberg, B TI Second cancer risk in hairy cell leukemia SO ANNALS OF SAUDI MEDICINE LA English DT Letter C1 Natl Canc Inst, NIH, Bethesda, MD 20892 USA. RP Saif, MW (reprint author), Natl Canc Inst, NIH, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU K FAISAL SPEC HOSP RES CENTRE PI RIYADH PA PUBLICATIONS OFFICE PO BOX 3354, RIYADH 11211, SAUDI ARABIA SN 0256-4947 J9 ANN SAUDI MED JI Ann. Saudi Med. PD MAY-JUL PY 2001 VL 21 IS 3-4 BP 260 EP 262 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 520MW UT WOS:000173786500034 PM 17264575 ER PT J AU Johanning, GL Cope, MB Wilborn, T Grubbs, CJ Lubet, RA AF Johanning, GL Cope, MB Wilborn, T Grubbs, CJ Lubet, RA TI Effect of high retinoid doses on RAR-beta mRNA expression in female B6D2F1 mice SO ANTICANCER RESEARCH LA English DT Article DE RAR-beta expression; retinoids; retinoid receptors; 13-cis-retinoic acid; 4-hydroxyphenylretinamide; mice ID ACID RECEPTOR-BETA; URINARY-BLADDER CARCINOGENESIS; CARCINOMA CELL-LINES; HUMAN LUNG-CANCER; BREAST-CANCER; 13-CIS-RETINOIC ACID; MESSENGER-RNA; UP-REGULATION; IN-SITU; NUCLEAR AB The expression of retinoid receptors is altered during the development of several types of cancer: In the present study, we determined the influence of high dietary concentrations of 4-hydroxyphenylretinamide (4-HPR) and w13-cis-retinoic acid (13-cis-RA) on RAR-beta mRNA expression in female mice. Expression of liver and lung RAR-beta RNA increased with increasing levels of dietary retinoid (both 4-HPR and 13-cis RA). Bladder RAR-beta mRNA levels, however; were significantly decreased in mice fed 13-cis RA or 4-HPR. These results suggest that feeding high levels of retinoids to mice results in tissue-specific elfects on expression of RAR-beta mRNA. C1 Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. Univ Alabama, Chemoprevent Ctr, Birmingham, AL 35294 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Johanning, GL (reprint author), Univ Alabama, Dept Nutr Sci, 340 Webb Bldg, Birmingham, AL 35294 USA. RI Johanning, Gary/A-9671-2008 FU NCI NIH HHS [N01-CN-65025-MAO] NR 40 TC 2 Z9 2 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2001 VL 21 IS 3B BP 1691 EP 1695 PG 5 WC Oncology SC Oncology GA 459XK UT WOS:000170276600004 PM 11497248 ER PT J AU Moody, TW Leyton, J Zakowicz, H Hida, T Kang, Y Jakowlew, S You, L Ozbun, L Zia, H Youngberg, J Malkinson, A AF Moody, TW Leyton, J Zakowicz, H Hida, T Kang, Y Jakowlew, S You, L Ozbun, L Zia, H Youngberg, J Malkinson, A TI Indomethacin reduces lung adenoma number in A/J mice SO ANTICANCER RESEARCH LA English DT Article DE cyclooxygenase; indomethacin; A/J mice; apoptosis; lung adenomas ID PROSTAGLANDIN-G/H SYNTHASE; SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SMALL CELL CARCINOMAS; COLON-CANCER CELLS; ENDOPEROXIDE SYNTHASES; ASPIRIN USE; GROWTH; EXPRESSION; TUMORIGENESIS AB The effects of indomethacin on A/J mice were investigated. The non-steroidal antiinflammatory drug (NSAID) indomethacin reduced significantly the number of lung adenomas 3, 4 or 8 months after urethane injection by 28, 30 and 29% respectively. The density of apoptotic cell bodies increased 2.9-fold in the lung adenomas of A/J mice treated with indomethacin. By immunocytochemistry, COX-2 immunoreactivity was present in the cytosol of lung adenomas, and in epithelial cells lining the bronchioli and bronchus as well as type 2 alveolar cells. COX-1 immunostaining was similar to that of COX-2 in the lungs of urethane-injected mice treated with or without indomethacin. By RT-PCR, COX-1 and COX-2 PCR products were present in mouse hung adenomas; alveoli and bronchioli. These results suggest that indomethacin may inhibit COX-1 and COX-2 in the A/J mouse lung resulting in reduced adenoma formation. C1 NCI, Cell & Canc Biol Dept Med Branch, Rockville, MD 20850 USA. Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA. RP Moody, TW (reprint author), Med Branch, Bldg KWC,Rm 300,9610 Med Ctr Dr, Rockville, MD 20850 USA. NR 47 TC 41 Z9 44 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2001 VL 21 IS 3B BP 1749 EP 1755 PG 7 WC Oncology SC Oncology GA 459XK UT WOS:000170276600011 PM 11497255 ER PT J AU Ratnasinghe, D Daschner, PJ Anver, MR Kasprzak, BH Taylor, PR Yeh, GC Tangrea, JA AF Ratnasinghe, D Daschner, PJ Anver, MR Kasprzak, BH Taylor, PR Yeh, GC Tangrea, JA TI Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; Is chemoprevention against multidrug resistance possible? SO ANTICANCER RESEARCH LA English DT Article DE multi-drug resistance; breast cancer; cyclooxygenase-2; NSAIDs ID CANCER MCF-7 CELLS; PROTEIN-KINASE-C; BREAST-CANCER; GENE-EXPRESSION; P-GLYCOPROTEIN; ADRIAMYCIN; LINE; DOXORUBICIN; EFFLUX; MDR1 AB Background: It is generally accepted that P-glycoprotein 170 (MDR1/Pgp170) expression in breast tumors results in poor response to chemotherapy due to its ability to export chemotherapeutic agents. Studies indicate that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may enhance the anti-tumor activity of cancer chemotherapeutic agents and reduce the risk of many cancers. The best known function of NSAIDs is to block the enzyme cyclooxygenase (Cox), the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated whether expression of the inducible isoform of Cox (Cox-2) is linked with the multidrug resistance phenotype in breast cancer. Methods: Expression of Cox-2 and MDR1/Pgp170 was investigated in tumor specimens along with normal epithelium in breast cancer patients using immunohistochemistry. Expression of Cox-2, MDR1/Pgp170, Protein Kinase C (PKC), and Activator Protein I (API) were investigated in a series of increasingly resistant human MCF-7 breast cancer cells compared to wild type using immunohistochemistry, Western blots, Northern blots, RT-PCR, and Southern blots. Results: Immunohistochemical analyses of human breast tumor specimens revealed a strong correlation between expression of Cox-2 and MDR1/Pgp170. In drug resistant cell lines that over-express MDR1/Pgp170 there was also significant up-regulation of Cox-2 expression. In addition, PKC and API subunits c-Jun and c-Fos were also upregulated. We hypothesized that increased prostaglandin production by Cox-2 induces PKC and the expression of transcriptional factor c-Jun, which in turn, induces the expression of MDR1/Pgp170, Conclusion: We propose that pretreatment with selective Cox-2 inhibitors may be useful in the prevention of multidrug resistance in response to cancer chemotherapy and should he further evaluated. C1 NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Frederick, MD 21701 USA. NCI, Frederick Canc Res & Dev Ctr, Pathol Histotechnol Lab, SAIC, Frederick, MD USA. RP Ratnasinghe, D (reprint author), NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, 6006 Execut Blvd,Suite 321, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CO-56000] NR 23 TC 70 Z9 80 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDNTIOU-KALAMOU RD KAPANDRITI, POB 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2001 VL 21 IS 3C BP 2141 EP 2147 PG 7 WC Oncology SC Oncology GA 459XL UT WOS:000170276700008 PM 11501838 ER PT J AU Ball, MD Bartlett, MS Shaw, M Smith, JW Nasr, M Meshnick, SR AF Ball, MD Bartlett, MS Shaw, M Smith, JW Nasr, M Meshnick, SR TI Activities and conformational fitting of 1,4-naphthoquinone derivatives and other cyclic 1,4-diones tested in vitro against Pneumocystis carinii SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; CYTOCHROME-B; IN-VITRO; ATOVAQUONE; PROPHYLAXIS; 8-AMINOQUINOLINES; PNEUMONIA; INFECTION; CHILDREN; EFFICACY AB Atovaquone is a chemotherapeutic agent used to treat pneumonia caused by Pneumocystis carinii in some immunocompromised patients. A set of cyclic l, l-diones were tested in vitro for ability to inhibit growth of P. carinii, including 22 variously substituted 1,4-naphthoquinones one bis-1,4-naphthoquinone, and three other quinones, For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethy1 metabolite were also tested. At 1.0 mug/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 mug/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 A from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 Angstrom from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents. C1 Rose Hulman Inst Technol, Dept Chem, Terre Haute, IN 47803 USA. Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Ball, MD (reprint author), Rose Hulman Inst Technol, Dept Chem, Terre Haute, IN 47803 USA. FU NIAID NIH HHS [R01 AI38078] NR 22 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2001 VL 45 IS 5 BP 1473 EP 1479 DI 10.1128/AAC.45.5.1473-1479.2001 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 424PH UT WOS:000168240300024 PM 11302813 ER PT J AU Kodama, EI Kohgo, S Kitano, K Machida, H Gatanaga, H Shigeta, S Matsuoka, M Ohrui, H Mitsuya, H AF Kodama, EI Kohgo, S Kitano, K Machida, H Gatanaga, H Shigeta, S Matsuoka, M Ohrui, H Mitsuya, H TI 4 '-ethynyl nucleoside analogs: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; ANTIRETROVIRAL THERAPY; SELECTIVE-INHIBITION; DRUG-SENSITIVITY; ANTIVIRAL AGENT; TYPE-1 VARIANTS; PLUS INDINAVIR; CELL-LINE; IN-VITRO; REPLICATION AB A series of 4 ' -ethynyl (4 ' -E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4 ' -E-2 ' -deoxycytidine (4 ' -E-dC), 4 ' -E-2 ' -deoxyadenosine (4 ' -E-dA), 4 ' -E-2 ' -deoxyribofuranosyl-2,6-diamifiopurine and 4 ' -E-2 ' -deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 muM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4 ' -E analogs also suppressed replication of various drug-resistant HIV-I clones, including HIV-I,,,,,, HIV-1K(65R), HIV-1(L74V), HIV-1(M41/T69S-S-G/T215Y), and HIV-1(A62V/V75I/F77L/F116Y/Q151M). Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4 ' -E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1(Y181C), and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4 ' -E-thymidine and 4 ' -E-dC was blocked by the addition of thymidine and 2 ' -deoxycytidine, respectively, while that of 4 ' -E-dA was not affected by 2 ' -deoxyadenosine, similar to the antiviral activity reversion feature of 2 ' ,3 ' -dideoxynucleosides, strongly suggesting that 4 ' -E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4 ' -E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted. C1 NCI, Med Branch, Dept Dev Therapeut, Expt Retrovirol Sect, Bethesda, MD 20892 USA. Kyoto Univ, Inst Virus Res, Lab Virus Immunol, Kyoto 6068507, Japan. Tohoku Univ, Fac Agr, Dept Appl Biol Chem, Sendai, Miyagi 9818555, Japan. Yamasa Corp, Div Biochem, Chiba 2880056, Japan. Fukushima Med Univ, Sch Med, Dept Microbiol, Fukushima 9601295, Japan. Kumamoto Univ, Sch Med, Dept Immunopathophysiol & Internal Med 2, Kumamoto 8600811, Japan. NCI, Expt Retrovirol Sect, Dept Dev Therapeut, Med Branch, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), NCI, Med Branch, Dept Dev Therapeut, Expt Retrovirol Sect, Bldg 10,Room 5A11,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Matsuoka, Masao/0000-0002-0473-754X NR 42 TC 91 Z9 98 U1 0 U2 8 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 MAY PY 2001 VL 45 IS 5 BP 1539 EP 1546 DI 10.1128/AAC.45.5.1539-1546.2001 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 424PH UT WOS:000168240300035 PM 11302824 ER PT J AU Hafner, R Bethel, J Standiford, HC Follansbee, S Cohn, DL Polk, RE Mole, L Raasch, R Kumar, P Mushatt, D Drusano, G AF Hafner, R Bethel, J Standiford, HC Follansbee, S Cohn, DL Polk, RE Mole, L Raasch, R Kumar, P Mushatt, D Drusano, G CA DATRI 001B Study Grp TI Tolerance and pharmacokinetic interactions of rifabutin and azithromycin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MYCOBACTERIUM-AVIUM COMPLEX; AIDS PATIENTS; INFECTION; DISEASE; SERUM; CLARITHROMYCIN; PROPHYLAXIS; VOLUNTEERS; SURVIVAL; TISSUES AB This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs. C1 NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. Vet Adm Med Ctr, Baltimore, MD 21218 USA. Davies Med Ctr, San Francisco, CA 94114 USA. Denver Publ Hlth, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80206 USA. Virginia Commonwealth Univ, Richmond, VA 23298 USA. Vet Adm Palo Alto Hlth Care Syst, AIDS Res Ctr, Palo Alto, CA USA. Univ N Carolina, Chapel Hill, NC 27514 USA. Georgetown Univ, Washington, DC 20007 USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Albany Med Coll, Albany, NY 12208 USA. RP Hafner, R (reprint author), NIAID, Div Aids, NIH, 6700-B Rockledge Dr,MSC 7624, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-15123] NR 18 TC 15 Z9 16 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 MAY PY 2001 VL 45 IS 5 BP 1572 EP 1577 DI 10.1128/AAC.45.5.1572-1577.2001 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 424PH UT WOS:000168240300043 PM 11302832 ER PT J AU Hershkowitz, I Orbach, Y Lamb, ME Sternberg, KJ Horowitz, D AF Hershkowitz, I Orbach, Y Lamb, ME Sternberg, KJ Horowitz, D TI The effects of mental context reinstatement on children's accounts of sexual abuse SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID COGNITIVE INTERVIEW; EYEWITNESS IDENTIFICATION; MEMORY; EVENT; WITNESSES; RECALL; RESPONSES; CUES; PERFORMANCE; VICTIMS AB Forensic interviewers guided 46.4- to 13-year-old alleged victims of sexual abuse to recall the context in which the reported incidents had taken place. A comparable group of 50 alleged victims were interviewed using an interview protocol that was identical except that the mental context reinstatement (MCR) techniques were not included. MCR did not increase the total number of event-related details reported, but it did lead children to reported proportionally more details (55% versus 46%) in response to invitations rather than focused prompts. Such information is more likely to be accurate. MCR had an especially powerful effect on the youngest children (4- to 6-year-olds) studied. The results suggest that non-suggestive contextual cues may indeed be useful in forensic interviews, published in 2001 by John Wiley & Sons, Ltd. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20892 USA. Univ Haifa, IL-31999 Haifa, Israel. Minist Labor & Social Affairs, Jerusalem, Israel. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, 9190 Rockville Pike, Bethesda, MD 20892 USA. EM Michael_Lamb@nih.gov NR 72 TC 24 Z9 25 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD MAY PY 2001 VL 15 IS 3 BP 235 EP 248 DI 10.1002/acp.699 PG 14 WC Psychology, Experimental SC Psychology GA 441VU UT WOS:000169250900001 ER PT J AU McGuinness, BM Buck, GM Mendola, P Sever, LE Vena, JE AF McGuinness, BM Buck, GM Mendola, P Sever, LE Vena, JE TI Infecundity and consumption of polychlorinated biphenyl-contaminated fish SO ARCHIVES OF ENVIRONMENTAL HEALTH LA English DT Article DE fecundability; polychlorinated biphenyls; reproduction; sportfish; time to pregnancy ID TIME-TO-PREGNANCY; STATE-ANGLER-COHORT; LAKE ONTARIO; PESTICIDE EXPOSURE AB Biologic capacity for reproduction, or fecundity, may be threatened by environmental contaminants, especially compounds capable of disrupting endocrine pathways. Telephone interviews that focused on reproductive events were conducted with female members of the New York State Angler Cohort Study who became pregnant between 1991 and 1993 and who reported known time to pregnancy (N = 895; 73%). Consumption of polychlorinated biphenyl-contaminated Lake Ontario sportfish and other factors were ascertained in 1991. The authors classified the women as follows: (a) fecund (time to pregnancy less than or equal to 12 cycles; n = 723); (b) having resolved infecundity (time to pregnancy > 12 cycles; n = 81); or (C) having unresolved infecundity (time to pregnancy > 12 cycles without pregnancy; n = 94). Adjusted odds ratios for duration of fish consumption for both resolved and unresolved infecundity were elevated (1.46 and 1.19, respectively), although confidence intervals included unity. Frequency of recent fish consumption was associated with an increased risk for select categories, although confidence intervals included one. C1 SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. NICHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. RP McGuinness, BM (reprint author), SUNY Buffalo, Dept Social & Prevent Med, 270 Farber Hall,3435 Main St, Buffalo, NY 14214 USA. OI Mendola, Pauline/0000-0001-5330-2844; Buck Louis, Germaine/0000-0002-1774-4490 NR 18 TC 15 Z9 15 U1 0 U2 1 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0003-9896 J9 ARCH ENVIRON HEALTH JI Arch. Environ. Health PD MAY-JUN PY 2001 VL 56 IS 3 BP 250 EP 253 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 455DX UT WOS:000170013200007 PM 11480501 ER PT J AU Giedd, JN AF Giedd, JN TI Neuroimaging of pediatric neuropsychiatric disorders - Is a picture really worth a thousand words? SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Editorial Material ID BRAIN-DEVELOPMENT C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 4C110,10 Ctr Dr,MSC 1367, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 6 TC 3 Z9 3 U1 3 U2 3 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 MAY PY 2001 VL 58 IS 5 BP 443 EP 444 DI 10.1001/archpsyc.58.5.443 PG 2 WC Psychiatry SC Psychiatry GA 428UE UT WOS:000168479100002 PM 11343522 ER PT J AU Hahn, H Trant, MR Brownstein, MJ Harper, RA Milstien, S Butler, IJ AF Hahn, H Trant, MR Brownstein, MJ Harper, RA Milstien, S Butler, IJ TI Neurologic and psychiatric manifestations in a family with a mutation in exon 2 of the guanosine triphosphate-cyclohydrolase gene SO ARCHIVES OF NEUROLOGY LA English DT Article ID DOPA-RESPONSIVE DYSTONIA; PARKINSONS-DISEASE; AFFECTIVE-DISORDERS; I DEFICIENCY; SEROTONIN; LEVODOPA; TETRAHYDROBIOPTERIN; SCHIZOPHRENIA; PENETRANCE; METABOLISM AB Objective: To investigate the range of clinical features to correlate genotypic and phenotypic manifestations in hereditary progressive and/or levodopa-responsive dystonia due to a defect in the guanosine triphosphate-cyclohydrolase (GCH1) gene. Design and Setting: A large family from Texas was studied in an ambulatory setting by clinicians in genetics, neurology, and psychiatry using structured interviews and examinations. Patients: The family was selected after neurometabolic investigations of a young boy (proband) with foot dystonia and fatigue and his father, who had a long history of anxiety and depression. Results of metabolic studies showed decreased levels of metabolites of biopterin and biogenic amines in cerebrospinal fluid. Subsequently, a novel mutation (37-base pair deletion) in exon 2 of the GCH1 gene was demonstrated in 11 family members. There was no observed female sex bias, but there was a wide variability of motor dysfunctions in family members. Approximately 50% had clinical deafness and a similar number had significant psychiatric dysfunction, including depression and anxiety. Conclusion: Study of additional families with hereditary progressive and/or levodopa-responsive dystonia using modern molecular methods will be necessary to confirm the neuropsychiatric spectrum of this disorder, in which important clinical features may be unrecognized and thus inappropriately managed. C1 GSF, Res Ctr Environm & Hlth, Inst Pathol, Neuherberg, Germany. Univ Texas, Hlth Sci Ctr, Dept Neurol, Div Child Neurol, Houston, TX 77225 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, Div Med Genet, Houston, TX 77225 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, Div Child Psychiat, Houston, TX 77225 USA. NIMH, Genet Lab, NHGRI, Bethesda, MD 20892 USA. NIMH, Dept Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Butler, IJ (reprint author), Univ Texas, Hlth Sci Ctr, Dept Neurol, Div Child Neurol, POB 20708, Houston, TX 77225 USA. RI Brownstein, Michael/B-8609-2009 FU NCRR NIH HHS [RR02588] NR 40 TC 24 Z9 25 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAY PY 2001 VL 58 IS 5 BP 749 EP 755 DI 10.1001/archneur.58.5.749 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 431AY UT WOS:000168610800007 PM 11346370 ER PT J AU Zhou, YX Qiao, WH Gu, WH Xie, H Tang, BS Zhou, LS Yang, BX Takiyama, Y Tsuji, S He, HY Deng, CX Goldfarb, LG Wang, GX AF Zhou, YX Qiao, WH Gu, WH Xie, H Tang, BS Zhou, LS Yang, BX Takiyama, Y Tsuji, S He, HY Deng, CX Goldfarb, LG Wang, GX TI Spinocerebellar ataxia type 1 in China - Molecular analysis and genotype-phenotype correlation in 5 families SO ARCHIVES OF NEUROLOGY LA English DT Article ID DOMINANT CEREBELLAR-ATAXIA; MACHADO-JOSEPH-DISEASE; DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; CAG-REPEAT; TRINUCLEOTIDE REPEAT; INTERGENERATIONAL INSTABILITY; CHROMOSOME 3P12-P21.1; CLINICAL CORRELATIONS; ITALIAN FAMILIES; LARGE KINDREDS AB Background: Twelve genetic types of autosomal dominant hereditary ataxia have been recently identified and the genes responsible for most of them cloned. Molecular identification of the type of ataxia is important to determine the disease prevalence and its natural history in various populations. Objectives: To perform molecular analysis of 75 Chinese families affected with spinocerebellar ataxia (SCA) and to evaluate the spectrum of mutations in these genes and the correlation between genotypes and phenotypes in Chinese patients. Setting: Neurogenetics Unit, China-Japan Friendship Hospital, Beijing, China. Methods: One hundred nine patients from 75 kindreds diagnosed as having autosomal dominant SCA, 16 patients with sporadic SCA or spastic paraplegia, 280 control chromosomes of the Chinese population, and 120 control chromosomes of the Sakha population were selected for this study. We conducted detailed mutational analysis by direct sequencing of polymerase chain reaction products amplified from genomic DNA. Results: Spinocerebellar ataxia type 1 (SCA1) was identified in 5 families with 12 studied patients. All affected family members were heterozygous for a CAG repeat expansion in the SCAI gene containing 51 to 64 trinucleotide repeats. Normal alleles had 26 to 35 repeats. Spinocerebellar ataxia type 1 accounted for 7% of the studied Chinese families with ataxia. In addition, we determined the frequency of a single vs double CAT interruption in 120 control chromosomes of the Siberian Sakha population, which has the highest known prevalence of SCA1, and compared this with 280 control chromosomes from the Chinese populations. The results show that 64.7% of the Siberian normal alleles contain a single CAT interruption whereas 92% of the Chinese had more than 1 interruption. Conclusions: Spinocerebellar ataxia type 1 is responsible for 7% of affected families in the Chinese population. A correlation between the prevalence of SCA1 and the number of CAT interruptions in the trinucleotide chain suggests that a CAT-to-GAG substitution may have been the initial event contributing to the generation of expanded alleles and influencing relative prevalence of SCA1. C1 China Japan Friendship Hosp, Dept Neurol, Neurogenet Unit, Beijing, Peoples R China. NINCDS, Clin Neurogenet Branch, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dvi Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Cent S Univ, Inst Neurol, Changsha, Peoples R China. First Peoples Hosp Xuzhou, Dept Neurol, Xuzhou, Peoples R China. Jichi Med Sch, Dept Neurol, Minami Kawachi, Tochigi 32904, Japan. Niigata Univ, Brain Res Inst, Dept Neurol, Niigata 951, Japan. RP Zhou, YX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10-9N104,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 64 TC 9 Z9 12 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAY PY 2001 VL 58 IS 5 BP 789 EP 794 DI 10.1001/archneur.58.5.789 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 431AY UT WOS:000168610800011 PM 11346374 ER PT J AU Caruso, RC Nussenblatt, RB Csaky, KG Valle, D Kaiser-Kupfer, MI AF Caruso, RC Nussenblatt, RB Csaky, KG Valle, D Kaiser-Kupfer, MI TI Assessment of visual function in patients with gyrate atrophy who are considered candidates for gene replacement SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID ORNITHINE-DELTA-AMINOTRANSFERASE; RETINAL DEGENERATION; HETEROGENEITY AB Objective: To assess the course of change of visual function outcome variables in 5 patients with gyrate atrophy before a gene replacement therapy clinical trial. Methods: The outcome variables selected were visual field sensitivity and electroretinogram amplitude. The course of change of these outcome variables was determined by calculation of their half-lives. Results: In the 4 to 6 years during which each patient was followed up for this study, median visual field half-lives were 17.0 years (static perimetry) and 11.4 years (kinetic perimetry). Median electroretinogram half-lives were 16.0 years (maximal response) and 10.7 years (flicker response). Conclusions: The course of the decline of visual function outcome variables is frequently slow. Thus, a longterm clinical trial would be required to assess the efficacy of the intervention in the preservation of visual function. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Res Labs, Baltimore, MD 21205 USA. RP Caruso, RC (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bldg 10,Room 10N226,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. NR 10 TC 7 Z9 7 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 MAY PY 2001 VL 119 IS 5 BP 667 EP 669 PG 3 WC Ophthalmology SC Ophthalmology GA 429KF UT WOS:000168515400003 PM 11346393 ER PT J AU Kennedy, RH Hogan, N Brown, P Holland, E Johnson, RT Stark, W Sugar, J AF Kennedy, RH Hogan, N Brown, P Holland, E Johnson, RT Stark, W Sugar, J TI Eye banking and screening for Creutzfeldt-Jakob disease SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Meeting of the US Food and Drug Administrations Transmissible Spongiform Encephalopathies Advisory Committee CY JAN 18, 2001 CL BETHESDA, MARYLAND ID SPONGIFORM ENCEPHALOPATHY; VARIANT; TRANSMISSION; HEALTH; RISK AB Objectives: To quantify the risk of Creutzfeldt-Jakob disease (CJD) among cornea donors, evaluate supplemental screening strategies, and address concerns about the adequacy of current methods of screening tissue donors in the United States. Methods: Reported data on deaths due to CJD and from all causes were used to estimate the rate of CJD among cornea donors. The impact of increased screening on risk of CJD and donor supply was evaluated. Results: Only 1.3 of the approximately 45000 cornea donors in the United States each year might be expected to have CJD. Most of the estimated risk (91%) is due to preclinical (asymptomatic) disease and therefore could not be eliminated by screening for signs or symptoms. If only the highest-risk age group (60 to 69 years) were screened and specificity were 90%, more than 21 000 otherwise acceptable donors would incorrectly be ex eluded over a period of 17.5 years to correctly exclude a single donor with symptomatic CJD. Conclusions: Currently, the risk of CJD transmission following cornea transplantation is remarkably low. Screening for symptoms of CJD would have minimal impact on safety, but would reduce donor supply and likely result in many patients not receiving needed treatment. C1 Exponent Inc, Hlth Grp, Menlo Park, CA 94025 USA. Univ Texas, SW Med Ctr, Dept Ophthalmol, Dallas, TX USA. NINDS, Cent Nervous Syst Studies Lab, Washington, DC USA. Univ Minnesota, Dept Ophthalmol, Minneapolis, MN 55455 USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. Univ Illinois, Dept Ophthalmol, Chicago, IL 60680 USA. RP Kennedy, RH (reprint author), Exponent Inc, Hlth Grp, 149 Commonwealth Dr, Menlo Park, CA 94025 USA. NR 20 TC 16 Z9 16 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 MAY PY 2001 VL 119 IS 5 BP 721 EP 726 PG 6 WC Ophthalmology SC Ophthalmology GA 429KF UT WOS:000168515400009 PM 11346399 ER PT J AU Fong, DS Gottlieb, J Ferris, FL Klein, R AF Fong, DS Gottlieb, J Ferris, FL Klein, R TI Understanding the value of diabetic retinopathy screening SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID NON-HISPANIC WHITES; MEXICAN-AMERICANS; RISK; PREVALENCE; DIAGNOSIS; CARE; AGE AB Regular dilated eye examinations are an effective approach to detecting and treating vision-threatening diabetic retinopathy.(1) They can help prevent blindness, and they are cost-effective.(2,3) Guidelines for systematic screening have been developed because patients with retinopathy are often asymptomatic, and photocoagulation treatment is more effective at reducing visual loss when applied at specific, frequently asymptomatic, stages of retinopathty.(4,5) However, despite the recommendations for regular screening and the availability of effective treatment, many patients at risk of visual loss due to severe retinopathy are not receiving dilated eye examinations and needed photocoagulation treatments.(6,7) C1 Kaiser Permanente Med Ctr, Dept Ophthalmol, So Calif Permanente Med Grp, Baldwin Pk, CA 91706 USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. NEI, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Fong, DS (reprint author), Kaiser Permanente Med Ctr, Dept Ophthalmol, So Calif Permanente Med Grp, 1011 Baldwin Pk Blvd, Baldwin Pk, CA 91706 USA. EM donald.s.fong@kp.org NR 16 TC 10 Z9 10 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9950 EI 1538-3601 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 2001 VL 119 IS 5 BP 758 EP 760 PG 3 WC Ophthalmology SC Ophthalmology GA 429KF UT WOS:000168515400016 PM 11346406 ER PT J AU Murata, T Sugatani, T Manganiello, VC Shimizu, K Tagawa, T AF Murata, T Sugatani, T Manganiello, VC Shimizu, K Tagawa, T TI Expression of phosphodiesterase 3 in rat submandibular gland cell lines SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE rat submandibular gland cell lines; phosphodiesterase 3 or PDE 3; phosphodiesterase 4 or PDE 4 ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; INHIBITED CAMP-PHOSPHODIESTERASE; SMOOTH-MUSCLE CELLS; MOLECULAR-CLONING; DIFFERENTIAL EXPRESSION; PURIFICATION; ISOFORMS; FAMILIES; PROTEIN; ISOZYME AB A recent preliminary (unpublished) study showed that phosphodiesterase (PDE) 3A and 3B are expressed in rat submandibular glands, Here, PDE3 activity was detected in homogenates of rat submandibular gland acinar epithelial (SMIE) cells, but not rat A5 (epithelial duct) cells. Most of the PDE3 activity in SMIE cells was recovered in the particulate fraction. Only PDE3B mRNA was detected by reverse transcription-polymerase chain reaction in RNA from SMIE cells. The nucleotide sequence of the fragment was identical to the sequence of rat PDE3B. The PDE3 specific inhibitor, OPC3689 (10 and 50 muM), inhibited the growth of SMIE cells (19 and 63%), but not A5 cells. As the submandibular gland contains many types of cells, these results indicate that PDE3B may regulate a cAMP pool that is important in submandibular gland acinar epithelial cell function. Published by Elsevier Science Ltd. C1 Mie Univ, Fac Med, Dept Oral & Maxillofacial Surg, Tsu, Mie 5148507, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Murata, T (reprint author), Mie Univ, Fac Med, Dept Oral & Maxillofacial Surg, 2-174 Edobashi, Tsu, Mie 5148507, Japan. NR 28 TC 2 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD MAY PY 2001 VL 46 IS 5 BP 453 EP 457 DI 10.1016/S0003-9969(00)00119-9 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 422GX UT WOS:000168111100007 PM 11286810 ER PT J AU Katsetos, CD Del Valle, L Geddes, JF Assimakopoulou, M Legido, A Boyd, JC Balin, B Parikh, NA Maraziotis, T de Chadarevian, JP Varakis, JN Matsas, R Spano, A Frankfurter, A Herman, MM Khalili, K AF Katsetos, CD Del Valle, L Geddes, JF Assimakopoulou, M Legido, A Boyd, JC Balin, B Parikh, NA Maraziotis, T de Chadarevian, JP Varakis, JN Matsas, R Spano, A Frankfurter, A Herman, MM Khalili, K TI Aberrant localization of the neuronal class III beta-tubulin in astrocytomas - A marker for anaplastic potential SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID PROSTATE CARCINOMA-CELLS; MICROTUBULE-ASSOCIATED PROTEIN-2; RECURRENT MALIGNANT GLIOMA; IMMUNOHISTOCHEMICAL CHARACTERIZATION; COMPARATIVE IMMUNOBLOT; POSTTRANSLATIONAL MODIFICATION; PLEOMORPHIC XANTHOASTROCYTOMA; CEREBRAL HEMISPHERES; SUBVENTRICULAR ZONE; BETA(III) ISOTYPE AB Background.-The class III beta -tubulin isotype (beta III) is widely regarded as a neuronal marker in development and neoplasia. In previous work, we have shown that the expression of beta III in neuronal/neuroblastic tumors is differentiation dependent. In contrast, the aberrant localization of this isotype in certain nonneuronal neoplasms, such as epithelial neuroendocrine lung tumors, is associated with anaplastic potential. Objective.-To test the generality of this observation, we investigated the immunoreactivity profile of beta III in astrocytomas. Design,Sixty archival, surgically excised astrocytomas (8 pilocytic astrocytomas, WHO grade 1; 18 diffuse fibrillary astrocytomas, WHO grade 2; 4 anaplastic astrocytomas, WHO grade 3; and 30 glioblastomas, WHO grade 4), were studied by immunohistochemistry using anti-pill monoclonal (TuJ1) and polyclonal antibodies. A monoclonal antibody to Ki-67 nuclear antigen (NC-MM1) was used as a marker For cell proliferation. Antibodies to glial fibrillary acidic protein (GFAP) and BM89 synaptic vesicle antigen/synaptophysin were used as glial and neuronal markers, respectively. Results.-The beta III immunoreactivity was significantly greater in high-grade astrocytomas (anaplastic astrocytomas and glioblastomas; median labeling index [MLI], 35%; interquartile range [IQR], 20%-47%) as compared with diffuse fibrillary astrocytomas (MLI, 4%; IQR, 0.2%-21%) (P < .0001) and was rarely detectable in pilocytic astrocytomas (MLI, 0%; IQR, 0%-0.5%) (P < .0001 vs high-grade astrocytomas; P < .01 vs diffuse fibrillary astrocytomas). A highly significant, grade-dependent relationship was observed between III and Ki-67 labeling and malignancy, but this association was stronger for Ki-67 than for beta III (beta III, P < .006; Ki-67, P < .0001). There was co-localization of beta III and GFAP in neoplastic astrocytes, but no BM89 synaptic vesicle antigen/synaptophysin staining was detected. Conclusions.-In the context of astrocytic gliomas, beta III immunoreactivity is associated with an ascending gradient of malignancy and thus may be a useful ancillary diagnostic marker. However, the significance of pill-positive phenotypes in diffuse fibrillary astrocytomas with respect to prognostic and predictive value requires further evaluation. Under certain neoplastic conditions, pill expression is not neuron specific, calling For a cautious interpretation of pill-positive phenotypes in brain tumors. C1 St Christophers Hosp Children, Dept Pediat, Philadelphia, PA 19134 USA. St Christophers Hosp Children, Dept Pathol & Lab Med, Philadelphia, PA 19134 USA. Med Coll Penn & Hahnemann Univ, Sch Med, Dept Pediat, Philadelphia, PA 19102 USA. Temple Univ, Coll Sci & Technol, Ctr Neurovirol & Canc Biol, Philadelphia, PA 19122 USA. Univ London, Dept Histopathol & Morbid Anat, London, England. Univ Patras, Sch Med, Dept Anat, GR-26110 Patras, Greece. Univ Patras, Sch Med, Dept Neurosurg, GR-26110 Patras, Greece. Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. Univ Virginia, Dept Biol, Charlottesville, VA 22903 USA. Philadelphia Coll Osteopath Med, Philadelphia, PA USA. Hellenic Pasteur Inst, Dept Biochem, Athens, Greece. NIMH, Clin Brain Disorders Branch, Neuropathol Sect, NIH, Bethesda, MD 20892 USA. RP Katsetos, CD (reprint author), St Christophers Hosp Children, Neurol Sect, Res Labs, Eire Ave & Front St, Philadelphia, PA 19134 USA. RI Del Valle, Luis/J-4085-2015 OI Del Valle, Luis/0000-0003-3894-9206 FU NINDS NIH HHS [3 PO1 NS36466, 3 PO1 NS36466-03 S1] NR 78 TC 67 Z9 68 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAY PY 2001 VL 125 IS 5 BP 613 EP 624 PG 12 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 428YF UT WOS:000168488700006 PM 11300931 ER PT J AU Bild, DE Folsom, AR Lowe, LP Sidney, S Kiefe, C Westfall, AO Zheng, ZJ Rumberger, J AF Bild, DE Folsom, AR Lowe, LP Sidney, S Kiefe, C Westfall, AO Zheng, ZJ Rumberger, J TI Prevalence and correlates of coronary calcification in black and white young adults - The coronary artery risk development in young adults - (CARDIA) study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary heart disease; risk factors; race; coronary artery calcification ID BEAM COMPUTED-TOMOGRAPHY; DENSITY-LIPOPROTEIN CHOLESTEROL; HEART-DISEASE; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; FOLLOW-UP; ATHEROSCLEROSIS; CALCIUM; ASSOCIATION; POPULATION AB Whereas cardiovascular risk factor levels are substantially different in black and white Americans, the relative rates of cardiovascular disease in the 2 groups are not always consistent with these differences. To compare the prevalence of coronary calcification, an indicator of coronary atherosclerosis, in young adult blacks and whites, we performed electron-beam computed tomography of the heart in 443 men and women aged 28 to 40 years recruited from a population-based cohort. The presence of calcium. defined as at least 1 focus of at least 2.05 mm(2) in area and >130 Hounsfield units in density within the coronary arteries, was identified in 16.1% of black men, 11.8% of black women, 17.1% of white men, and 4.6% of white women (P=0.04 for comparison across groups). Coronary calcium was associated with age and male sex, and after adjustment for age, race, and sex, coronary calcium was positively associated with body mass index, weight, systolic blood pressure. total cholesterol, low density lipoprotein cholesterol, triglycerides, and fasting insulin and negatively associated with education (all P<0.05). Independent risk factors included male sex, body mass index, and low density lipoprotein cholesterol. Race was not significantly associated with coronary calcium in men or women, before or after adjustment for risk factors. Coronary calcification is associated with increased levels of cardiovascular risk factors in young adults, and its prevalence is not significantly different in blacks and whites. C1 NHLBI, DECA, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Dept Epidemiol, Minneapolis, MN USA. Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Alabama, Dept Prevent Med, Birmingham, AL USA. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL USA. Ctr Dis Control, Atlanta, GA 30333 USA. Diagnost Cardiovasc Consultants, Columbus, OH USA. RP Bild, DE (reprint author), NHLBI, DECA, NIH, 2 Rockledge Ctr,6701 Rockledge Dr,MSC 7934, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095] NR 43 TC 101 Z9 103 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAY PY 2001 VL 21 IS 5 BP 852 EP 857 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 431VG UT WOS:000168652000025 PM 11348886 ER PT J AU Jacobsson, LTH Turesson, C Hanson, RL Pillemer, S Sievers, ML Pettitt, DJ Bennett, PH Knowler, WC AF Jacobsson, LTH Turesson, C Hanson, RL Pillemer, S Sievers, ML Pettitt, DJ Bennett, PH Knowler, WC TI Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians SO ARTHRITIS AND RHEUMATISM LA English DT Article ID C-REACTIVE PROTEIN; APPARENTLY HEALTHY-MEN; RHEUMATOID-ARTHRITIS; MYOCARDIAL-INFARCTION; UNSTABLE ANGINA; RISK-FACTORS; FOLLOW-UP; ATHEROSCLEROTIC PLAQUES; CORONARY RISK; MORTALITY AB Objective. Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. Methods. Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. Results. During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (P-trend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). Conclusion. Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD. C1 Malmo Univ Hosp, Dept Rheumatol, S-20502 Malmo, Sweden. NIDDKD, Phoenix, AZ USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Sansum Med Res Inst, Santa Barbara, CA USA. RP Jacobsson, LTH (reprint author), Malmo Univ Hosp, Dept Rheumatol, S-20502 Malmo, Sweden. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 65 TC 50 Z9 53 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 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2001 VL 44 IS 5 BP 1170 EP 1176 DI 10.1002/1529-0131(200105)44:5<1170::AID-ANR200>3.0.CO;2-T PG 7 WC Rheumatology SC Rheumatology GA 485JJ UT WOS:000171751000025 PM 11352251 ER PT J AU Didisheim, P Rose, EA Long, JW Holman, WL Burns, G Shive, MS AF Didisheim, P Rose, EA Long, JW Holman, WL Burns, G Shive, MS TI Infection with clinical ventricular assist devices: Clinical therapy SO ASAIO JOURNAL LA English DT Article C1 Columbia Med Ctr, New York, NY 10032 USA. NHLBI, NIH, Washington, DC USA. LDS Hosp, Utah Artificial Heart Program, Salt Lake City, UT USA. Artificial Heart Inst, Salt Lake City, UT USA. Univ Alabama, Med Ctr, Birmingham, AL 35294 USA. Biosyntech, Montreal, PQ, Canada. RP Rose, EA (reprint author), Columbia Med Ctr, 177 Fort Washington Ave, New York, NY 10032 USA. NR 10 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1058-2916 J9 ASAIO J JI Asaio J. PD MAY-JUN PY 2001 VL 47 IS 3 BP 195 EP 196 DI 10.1097/00002480-200105000-00004 PG 2 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 431HQ UT WOS:000168626100003 PM 11374755 ER PT J AU Hsich, E Zhou, YF Paigen, B Johnson, TM Burnett, MS Epstein, SE AF Hsich, E Zhou, YF Paigen, B Johnson, TM Burnett, MS Epstein, SE TI Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice SO ATHEROSCLEROSIS LA English DT Article DE murine cytomegalovirus; atherosclerosis; hypercholesterolemia; ApoE -/- mice ID SMOOTH-MUSCLE CELLS; VIRUS-INDUCED ATHEROSCLEROSIS; CORONARY-ARTERY DISEASE; CHLAMYDIA-PNEUMONIAE; INTERLEUKIN-8 GENE; RISK FACTOR; EXPRESSION; LESIONS; RESTENOSIS; STRAINS AB Cytomegalovirus (CMV) infection has been associated with coronary artery disease. but it is unknown whether the virus can causally contribute to atherogenesis. To determine whether the virus has this capacity. we infected an atherosclerotic-prone mouse strain (C57BL/6J apoE-/-) with murine CMV. At 14 days of age, 30 mice received CMV (30 000 pfu) ip and 30 received virus free media. At 13 and 16 weeks atherosclerotic lesion size was measured from aortic sinus cross-sections. Infection did not alter plasma levels of cholesterol, triglycerides, and high density lipoprotein (HDL), however, 4 weeks after infection IFN gamma levels were elevated (infection vs control: 156 +/- 49 vs 50 +/- 22 pg/ml, P = 0.04). No differences in lesion size were present at 13 weeks post infection. However. by 16 weeks mean aortic sinus lesion area (mm(2) x 10(3) +/- SEM; N = 75) in the CMV-infected mice was significantly greater than in uninfected mice (74 +/- 6 vs 57 +/- 6, P = 0.04). CMV caused the greatest increase (34%) in lesion size in females (103 +/- 9 vs 77 +/- 10; P = 0.05, N = 35). These results provide additional evidence implicating CMV as a causal agent of atherosclerosis, at least in an animal model. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Washington Hosp Ctr, Inst Cardiovasc Res, Washington, DC 20010 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Epstein, SE (reprint author), Washington Hosp Ctr, Inst Cardiovasc Res, 110 Irving St NW,Suite 4B-1, Washington, DC 20010 USA. NR 54 TC 94 Z9 99 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAY PY 2001 VL 156 IS 1 BP 23 EP 28 DI 10.1016/S0021-9150(00)00608-0 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 438BU UT WOS:000169034500003 PM 11368993 ER PT J AU Lee, GH Um, PY Park, MH AF Lee, GH Um, PY Park, MH TI Structure-function studies of human deoxyhypusine synthase: identification of amino acid residues critical for the binding of spermidine and NAD SO BIOCHEMICAL JOURNAL LA English DT Article DE eIF5A; hypusine; site-directed mutagenesis ID INITIATION-FACTOR 5A; YEAST SACCHAROMYCES-CEREVISIAE; ENZYME-SUBSTRATE INTERMEDIATE; EUKARYOTIC CELL-PROLIFERATION; ANGSTROM RESOLUTION; HYPUSINE DEPLETION; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; RAT TESTIS; INHIBITION AB Deoxyhypusine synthase catalyses the first step in the biosynthesis of hypusine [N-epsilon-(4-amino-2-hydroxybutyl)lysine]. The crystal structure of human deoxyhypusine synthase in complex with NAD revealed four NAD-binding sites per enzyme tetramer, and led to a prediction of the spermidine-binding pocket. We have replaced each of the seven amino acid residues at the predicted spermidine-binding site, and eleven residues that contact NAD, on an individual basis with alanine. Of the amino acid residues at the spermidine site, substitution of Asp-243, Trp-327, His-288, Asp-316 or Glu-323 with alanine caused an almost complete loss of spermidine binding and enzyme activity; only the mutation Tyr-305 --> Ala showed partial binding and activity. His-288 --> Ala was also deficient in terms of binding NAD. NAD binding was significantly reduced in all of the NAD-site mutant enzymes, except for Glu-137 --> Ala. which showed a normal binding of NAD, but was totally lacking in spermidine binding. Of the NAD-site mutant enzymes, Asp-342 --> Ala, Asp-313 --> Ala and Asp-238 --> Ala displayed the lowest binding of NAD. These enzymes and His-288Ala also showed a reduced binding of spermidine. presumably because spermidine binding is dependent on NAD. These findings permit the positive identification of amino acid residues critical for binding of spermidine and NAD, and provide a nem insight into the complex molecular interactions involved in the deoxyhypusine synthase reaction. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Park, MH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NR 34 TC 6 Z9 6 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 1 PY 2001 VL 355 BP 841 EP 849 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431MY UT WOS:000168636200035 ER PT J AU Reitman, ML Bi, S Marcus-Samuels, B Gavrilova, O AF Reitman, ML Bi, S Marcus-Samuels, B Gavrilova, O TI Leptin and its role in pregnancy and fetal development - an overview SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Cytokines and Cytokin Receptors in Fetal Growth and Development CY DEC 19-21, 2000 CL UNIV SUSSEX, BRIGHTON, ENGLAND HO UNIV SUSSEX DE energy homoeostasis; paracrine effects; placenta ID MESSENGER-RIBONUCLEIC-ACID; CORD-BLOOD LEPTIN; BODY-MASS INDEX; SERUM LEPTIN; GESTATIONAL PROFILE; ADIPOSE-TISSUE; FEMALE MICE; RNA LEVELS; RECEPTOR; PLACENTA AB Leptin is a hormone that is secreted by adipose cells in proportion to adipose mass, and therefore a low leptin level signifies depletion of energy stores. It has been proposed that leptin is one of the signals controlling sexual maturation. For example, humans and rodents lacking leptin fail to undergo complete puberty, while overexpression of leptin in mice causes early puberty. The placenta also produces leptin in human pregnancy, increasing the amount in the maternal circulation. The effects of the increased leptin levels during pregnancy are not clear. In contrast, the mouse placenta does not produce endocrinologically significant amounts of leptin. The mouse placenta does secrete a leptin-binding protein, the production of which correlates with a large increase in maternal leptin levels. The physiology of leptin during pregnancy and fetal development differs significantly between species, and is not well understood in any. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 8N-250, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 NR 40 TC 45 Z9 47 U1 0 U2 4 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD MAY PY 2001 VL 29 BP 68 EP 72 DI 10.1042/0300-5127:0290068 PN 2 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 444TN UT WOS:000169416300011 PM 11356129 ER PT J AU Tissier, A Frank, EG McDonald, JP Vaisman, A de Henestrosa, ARF Boudsocq, F McLenigan, MP Woodgate, R AF Tissier, A Frank, EG McDonald, JP Vaisman, A de Henestrosa, ARF Boudsocq, F McLenigan, MP Woodgate, R TI Biochemical characterization of human DNA polymerase iota provides clues to its biological function SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on New Frontiers in DNA Repair CY DEC 19-21, 2000 CL UNIV SUSSEX, BRIGHTON, ENGLAND HO UNIV SUSSEX DE DNA polymerase eta; Rad30; Rad30B; Xeroderma pigmentosum variant ID XERODERMA-PIGMENTOSUM VARIANT; THYMINE-THYMINE DIMER; ESCHERICHIA-COLI DINB; ERROR-PRONE BYPASS; GENE ENCODES; ETA; HOMOLOG; MUTAGENESIS; MUTATIONS; REPAIR AB The human RAD30B gene has recently been shown to encode a novel DNA polymerase, DNA polymerase i (poli). The role of poll within the cell is presently unknown, and the only clues to its cellular function come from its biochemical characterization in vitro. The aim of this short review is, therefore, to summarize the known enzymic activities of poll and to speculate as to how these biochemical properties might relate to its in vivo function. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), Bldg 6,Room 1A13,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 NR 35 TC 16 Z9 17 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD MAY PY 2001 VL 29 BP 183 EP 187 DI 10.1042/0300-5127:0290183 PN 2 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 444TN UT WOS:000169416300032 PM 11356150 ER PT J AU Hebert, AM Strohmaier, J Whitman, MC Chen, T Gubina, E Hill, DM Lewis, MS Kozlowski, S AF Hebert, AM Strohmaier, J Whitman, MC Chen, T Gubina, E Hill, DM Lewis, MS Kozlowski, S TI Kinetics and thermodynamics of beta 2-microglobulin binding to the alpha 3 domain of major histocompatibility complex class I heavy chain SO BIOCHEMISTRY LA English DT Article ID MHC CLASS-I; INDUCED CONFORMATIONAL CHANGE; PROTEIN-PROTEIN INTERACTIONS; CELL-SURFACE EXPRESSION; PEPTIDE BINDING; HUMAN BETA(2)-MICROGLOBULIN; T-CELLS; MOLECULES; ANTIGEN; RECOGNITION AB The major histocompatibility complex (MHC) class I molecule plays a crucial role in cytotoxic lymphocyte function. Functional class I MHC exists as a heterotrimer consisting of the MHC class I heavy chain, an antigenic peptide fragment, and beta2-microglobulin (beta 2m). beta 2m has been previously shown to play an important role in the folding of the MHC heavy chain without continued beta 2m association with the MHC complex. Therefore, beta 2m is both a structural component of the MHC complex and a chaperone-like molecule for MHC folding. In this study we provide data supporting a model in which the chaperone-like role of beta 2m is dependent on initial binding to only one of the two beta 2m interfaces with class 1 heavy chain. beta2-Microglobulin binding to an isolated alpha3 domain of the class I MHC heavy chain accurately models the biochemistry and thermodynamics of beta 2m-driven refolding. Our results explain a 1000-fold discrepancy between beta 2m binding and refolding of MHC1. The biochemical study of the individual domains of complex molecules is an important strategy for understanding their dynamic structure and multiple functions. C1 US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Ab, Bethesda, MD 20892 USA. NIH, Mol Interact Resource, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Kozlowski, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Ab, 8800 Rockville Pike,Bldg 29B-3NN08,HFM-561, Bethesda, MD 20892 USA. NR 59 TC 17 Z9 17 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 1 PY 2001 VL 40 IS 17 BP 5233 EP 5242 DI 10.1021/bi002392s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 427YV UT WOS:000168435100015 PM 11318646 ER PT J AU Chen, YD Yan, B Chalovich, JM Brenner, B AF Chen, YD Yan, B Chalovich, JM Brenner, B TI Theoretical kinetic studies of models for binding myosin subfragment-1 to regulated actin: Hill model versus Geeves model SO BIOPHYSICAL JOURNAL LA English DT Article ID TROPONIN-TROPOMYOSIN COMPLEX; ACTOMYOSIN ATPASE ACTIVITY; MUSCLE THIN-FILAMENTS; COOPERATIVE BINDING; CONTRACTION; ACTIVATION; INHIBITION; STATES AB It was previously shown that a one-dimensional Ising model could successfully simulate the equilibrium binding of myosin S1 to regulated actin filaments (T. L. Hill, E. Eisenberg and L, Greene, Proc. Natl. Acad. Sci. U.S.A. 77:3186-3190, 1980). However, the time course of myosin S1 binding to regulated actin was thought to be incompatible with this model, and a three-state model was subsequently developed (D. F. McKillop and M. A. Geeves, Biophys. J. 65:693-701, 1993). A quantitative analysis of the predicted time course of myosin S1 binding to regulated actin, however, was never done for either model. Here we present the procedure for the theoretical evaluation of the time course of myosin S1 binding for both models and then show that 1) the Hill model can predict the "lag" in the binding of myosin S1 to regulated actin that is observed in the absence of Ca++ when S1 is in excess of actin, and 2) both models generate very similar families of binding curves when [S1]/[actin] is varied. This result shows that, just based on the equilibrium and pre-steady-state kinetic binding data alone, it is not possible to differentiate between the two models. Thus, the model of Hill et at. cannot be ruled out on the basis of existing pre-steady-state and equilibrium binding data. Physical mechanisms underlying the generation of the lag in the Hill model are discussed. C1 NIDDK, Math Res Branch, NIH, Bethesda, MD 20892 USA. E Carolina Univ, Sch Med, Dept Biochem, Greenville, NC 27858 USA. Hannover Med Sch, Dept Mol & Cell Physiol, D-30623 Hannover, Germany. RP Chen, YD (reprint author), NIDDK, Math Res Branch, NIH, 9190 Rockville Pike, Bethesda, MD 20892 USA. OI Chalovich, Joseph/0000-0002-1243-4055 FU NIAMS NIH HHS [R01 AR035216] NR 27 TC 28 Z9 28 U1 0 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 2001 VL 80 IS 5 BP 2338 EP 2349 PG 12 WC Biophysics SC Biophysics GA 428WZ UT WOS:000168485800028 PM 11325734 ER PT J AU Kumar, S Sham, YY Tsai, CJ Nussinov, R AF Kumar, S Sham, YY Tsai, CJ Nussinov, R TI Protein folding and function: The N-terminal fragment in adenylate kinase SO BIOPHYSICAL JOURNAL LA English DT Article ID ACTIVE-SITE RESIDUES; ESCHERICHIA-COLI; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURES; DOMAIN CLOSURE; BINDING LOOP; RESOLUTION; ENERGY; UNITS; MECHANISM AB Three-dimensional protein folds range from simple to highly complex architectures. in complex folds, some building block fragments are more important for correct protein folding than others. Such fragments are typically buried in the protein core and mediate interactions between other fragments. Here we present an automated, surface area-based algorithm that is able to indicate which, among all local elements of the structure, is critical for the formation of the native fold, and apply it to structurally well-characterized proteins. In particular, we focus on adenylate kinase. The fragment containing the phosphate binding, P-loop (the "giant anion hole") flanked by a beta -strand and an alpha -helix near the N-terminus, is identified as a critical building block. This building block shows a high degree of sequence and structural conservation in all adenylate kinases. The results of our molecular dynamics simulations are consistent with this identification. In its absence, the protein flips to a stable, non-native state. In this misfolded conformation, the other local elements of the structure are in their native-like conformations; however, their association is non-native. Furthermore, this element is critically important for the function of the enzyme, coupling folding, and function. C1 NCI, SAIC Frederick, FCRDC, Intramural Res Support Program, Ft Detrick, MD 21702 USA. NCI, Lab Expt & Computat Biol, SAIC Frederick, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, SAIC Frederick, FCRDC, Intramural Res Support Program, Bldg 469,Rm 151, Ft Detrick, MD 21702 USA. RI Sham, Yuk/A-6472-2011 FU NCI NIH HHS [N01-CO-56000] NR 47 TC 33 Z9 33 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 2001 VL 80 IS 5 BP 2439 EP 2454 PG 16 WC Biophysics SC Biophysics GA 428WZ UT WOS:000168485800037 PM 11325743 ER PT J AU Hawley, TS Telford, WG Ramezani, A Hawley, RG AF Hawley, TS Telford, WG Ramezani, A Hawley, RG TI Four-color flow cytometric detection of retrovirally expressed red, yellow, green, and cyan fluorescent proteins SO BIOTECHNIQUES LA English DT Article ID GENE-TRANSFER; LIVING CELLS; VARIANTS; GFP; EXCITATION; VECTORS; MARKER AB Flow cytometric procedures are described to detect a "humanized" version of a new red fluorescent protein (DsRed) from the coral Discosoma sp. in conjunction with various combinations of three Aequorea victoria green fluorescent protein (GFP) variants-EYFP, EGFP, and ECFP. In spite of overlapping emission spectra, the combination of DsRed with EYFP, EGFP, and ECFP generated fluorescence signals that could be electronically compensated in real time using dual-laser excitation at 458 and 568 nm. Resolution of fluorescence signals from DsRed, EYFP, and EGFP was also readily achieved by single-laser excitation at 488 nm. Since many flow cytometers are equipped with an argon-ion laser that can be tuned to 488 nm, the DsRed/EYFP/EGFP combination is expected to have broad utility for facile monitoring of gene transfer and expression in mammalian cells. The dual-laser technique is applicable for use on flow cytometers equipped with tunable multiline argon-ion and krypton-ion lasers, providing the framework for studies requiring simultaneous analysis of four fluorescent gene products within living cells. C1 Amer Red Cross, Jerome H Holland Lab, Hematopoiesis Dept, Rockville, MD 20855 USA. NCI, NIH, Bethesda, MD 20892 USA. George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. RP Hawley, TS (reprint author), Amer Red Cross, Jerome H Holland Lab, Hematopoiesis Dept, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. NR 25 TC 35 Z9 37 U1 0 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD MAY PY 2001 VL 30 IS 5 BP 1028 EP + PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431NB UT WOS:000168636500025 PM 11355338 ER PT J AU Longo, DL AF Longo, DL TI A hole you can drive a MAC through SO BLOOD LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 MAY 1 PY 2001 VL 97 IS 9 BP 2533 EP 2533 PG 1 WC Hematology SC Hematology GA 429KP UT WOS:000168516200002 ER PT J AU Lyons, SE Shue, BXC Oates, AC Zon, LI Liu, PP AF Lyons, SE Shue, BXC Oates, AC Zon, LI Liu, PP TI A novel myeloid-restricted zebrafish CCAAT/enhancer-binding protein with a potent transcriptional activation domain SO BLOOD LA English DT Article ID C/EBP-EPSILON; DEFICIENT MICE; C-MYB; HEMATOPOIESIS; ALPHA; GENE; GENOME; CLOCHE; DIFFERENTIATION; FAMILY AB The CCAAT/enhancer-binding protein (C/ EBP) family consists of transcription factors essential for hematopoiesis. The defining feature of the C/EBPs is a highly conserved carboxy-terminal bZIP domain that is necessary and sufficient for dimerization and DNA binding, whereas their amino-terminal domains are unique. This study reports a novel c/ebp gene (c/ebp1) from zebrafish that encodes a protein homologous to mammalian C/EBPs within the bZIP domain, but with an amino terminus lacking homology to any C/EBP or to any known sequence. In zebrafish embryos, c/ebp1 expression was initially observed in cells within the yolk sac circulation valley at approximately the 16-to 18-somite stage, and at 24 hours postfertilization (hpf), also in circulating cells. Most c/ebp1(+) cells also expressed a known early macrophage marker, leukocyte-specific plastin (l-plastin). Expression of both markers was lost in cloche, a mutant affecting hematopoiesis at the level of the hemangioblast. Expression of both markers was retained in m683 and spadetail, mutants affecting erythropoiesis, but not myelopoiesis. Further, c/ebp1 expression was lost in a mutant with defective myelopoiesis, but intact erythropoiesis. These data suggest that c/ebp1 is expressed exclusively in myeloid cells. In electrophoretic mobility shift assays, c/ebp1 was able to bind a C/EBP consensus DNA site. Further, a chimeric protein containing the amino-terminal domain of c/ebp1 fused to the DNA-binding domain of GAL4 induced a GAL4 reporter 4000-fold in NIH3T3 cells. These results suggest that c/ebp1 is a novel member of the C/EBP family that may function as a potent transcriptional activator in myeloid cells. (Blood.2001;97:2611-2617) (C) 2001 by The American Society of Hematology. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Liu, PP (reprint author), NHGRI, NIH, 49 Convent Dr,Rm 3A18, Bethesda, MD 20892 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 46 TC 38 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 MAY 1 PY 2001 VL 97 IS 9 BP 2611 EP 2617 DI 10.1182/blood.V97.9.2611 PG 7 WC Hematology SC Hematology GA 429KP UT WOS:000168516200015 PM 11313249 ER PT J AU Kawakami, K Taguchi, J Murata, T Puri, RK AF Kawakami, K Taguchi, J Murata, T Puri, RK TI The interleukin-13 receptor alpha 2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway SO BLOOD LA English DT Article ID CARCINOMA CELL-LINES; COMMON GAMMA-CHAIN; PSEUDOMONAS EXOTOXIN; FUNCTIONAL COMPONENT; (IL)-13 BINDING; TYROSINE KINASE; IL-13 RECEPTOR; B-CELLS; T-CELLS; PROTEIN AB The interleukin-13 receptor (IL-13R) complex is composed of 2 different chains, IL-13R alpha1 (also known as IL-13R alpha') and IL-13R alpha2 (also known as IL-13R alpha). For a functional IL-13 receptor, the IL-13R alpha1 chain forms a productive complex with the primary IL-4 binding protein (IL-4R alpha also known as IL-4R beta). However, the function of the IL-13R alpha2 chain is not clear even though this chain binds IL-13 with high affinity. This study demonstrates that IL-13R alpha2 can undergo internalization after binding to ligand without causing activation of its signaling pathways. These conclusions were drawn on the basis of (1) internalization of I-125-IL-13 in Chinese hamster ovarian (CHO-K1) and T98G glioblastoma cells transiently transfected with the IL-13Ra2 chain; (2) a recombinant chimeric fusion protein comprising IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin) is specifically cytotoxic to IL-13R alpha2-transfected CHO-K1 cells in a gene dose-dependent manner, whereas cells transfected with vector alone were not sensitive; and (3) IL-13 did not cause activation of signal transduction and activation of transcription 6 (STAT6) in IL-13R alpha2-transfected cells. IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13R alpha1 and IL-4R alpha chains, and IL-13R alpha2 inhibited this activation. Taken together, these observations indicate that internalization of IL-13R alpha2 is signal independent and that this property of IL-13R alpha2 can be exploited for receptor-directed cancer therapy. (Blood, 2001;97:2673-2679) (C) 2001 by The American Society of Hematology. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,NIH, Bldg 29B,Rm 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. NR 39 TC 162 Z9 174 U1 0 U2 4 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 MAY 1 PY 2001 VL 97 IS 9 BP 2673 EP 2679 DI 10.1182/blood.V97.9.2673 PG 7 WC Hematology SC Hematology GA 429KP UT WOS:000168516200023 PM 11313257 ER PT J AU Sakai, T Matsuoka, M Aoki, M Nosaka, K Mitsuya, H AF Sakai, T Matsuoka, M Aoki, M Nosaka, K Mitsuya, H TI Missense mutation of the interleukin-12 receptor beta 1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection SO BLOOD LA English DT Article ID CALMETTE-GUERIN INFECTION; CELL LEUKEMIA-CELLS; INTERFERON-GAMMA; T-CELLS; EXPRESSION; DEFICIENCY; TUBERCULOSIS; COMPONENT; TYPE-1; CHILD AB Interleukin-12 (IL-12) plays an important role in the production of interferon gamma (IFN-gamma) and is essential for protection against intracellular pathogens such as Mycobacterium and Salmonella. A 31-year-old man had disseminated Mycobacterium avium complex (MAC) infection. The production of IFN-gamma by peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMCs) was found severely impaired (40.7 pg/mL compared with 833 +/- 289 pg/mL for the patient's and healthy subjects' (n = 3) PHA-PBMCs, respectively), and the patient's PHA-PBMCs completely lacked surface IL-12 receptor beta1 (IL-12R beta1) chain. The IL-12R beta1 gene transcript in his PHA-PBMCs had an R213W substitution in each allele, Family history showed that both parents were heterozygotes in the R213W substitution. Transfection of a human embryonal kidney cell line 293 (HEKC293) with wild-type IL-12R beta 1wt gene led to cell surface IL-12R beta1 expression; however, no expression was seen in HEKC293 transfected with the mutated IL-12R beta 1R213W gene. The IL-12R beta1 gene transcript, but no IL-12RB1 protein, was detected in PHA-PBMCs and T cells, suggesting a post-translational event(s), most likely a shortened turnover of the protein. The R213W substitution was not detected in the cells of 32 healthy persons or of 25 patients with tuberculosis or MAC infection. Six amino acid substitutions (Q214R, M365T, G378R, H438Y, A525T, and G594E) were identified, but the incidences of such substitutions were not significantly different between the groups. The Q214R substitution is reportedly linked to IL-12R beta1 deficiency; however, the study showed that 19 and 10 of 57 Japanese and 6 and 4 of 33 healthy white persons were heterozygous and homozygous for Arg-214, respectively, suggesting that the Q214R substitution represents a polymorphism and is not related to IL-12R beta1 deficiency but that the R213W substitution is responsible for IL-12R beta1 deficiency. (Blood, 2001;97:2688-2694) (C) 2001 by The American Society of Hematology. C1 Kyoto Univ, Inst Virus Res, AIDS Res Ctr, Lab Virus Immunol, Kyoto 6068506, Japan. Kumamoto Univ, Sch Med, Dept Immunopathophysiol & Internal Med 2, Kumamoto 860, Japan. NCI, Div Clin Sci, Med Branch, Expt Retrovirol Sect, Bethesda, MD 20892 USA. RP Matsuoka, M (reprint author), Kyoto Univ, Inst Virus Res, AIDS Res Ctr, Lab Virus Immunol, Kyoto 6068506, Japan. OI Matsuoka, Masao/0000-0002-0473-754X NR 29 TC 71 Z9 72 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2001 VL 97 IS 9 BP 2688 EP 2694 DI 10.1182/blood.V97.9.2688 PG 7 WC Hematology SC Hematology GA 429KP UT WOS:000168516200025 PM 11313259 ER PT J AU Moulds, JM Zimmerman, PA Doumbo, OK Kassambara, L Sagara, I Diallo, DA Atkinson, JP Krych-Goldberg, M Hauhart, RE Hourcade, DE McNamara, DT Birmingham, DJ Rowe, JA Moulds, JJ Miller, LH AF Moulds, JM Zimmerman, PA Doumbo, OK Kassambara, L Sagara, I Diallo, DA Atkinson, JP Krych-Goldberg, M Hauhart, RE Hourcade, DE McNamara, DT Birmingham, DJ Rowe, JA Moulds, JJ Miller, LH TI Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1 SO BLOOD LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; PLASMODIUM-FALCIPARUM; C3B/C4B RECEPTOR; GROUP ANTIGENS; SWAIN-LANGLEY; CR-1; ERYTHROCYTES; ANTIBODIES; MALARIA; NUMBER AB Complement receptor 1 (CR1) has been implicated in resetting of uninfected red blood cells to Plasmodium falciparum-infected cells, and rosette formation is associated with severe malaria. The Knops blood group (KN) is located on CR1 and some of these antigens, ie, McCoy (McC) and Swain-Langley (Sl(a)), show marked frequency differences between Caucasians and Africans. Thus, defining the molecular basis of these antigens may provide new insight into the mechanisms of P falciparum malaria. Monoclonal antibody epitope mapping and serologic inhibition studies using CR1 deletion constructs localized McC and Sl(a) to long homologous repeat D of CR1. Direct DNA sequencing of selected donors identified several single nucleotide polymorphisms in exon 29 coding for complement control protein modules 24 and 25. Two of these appeared to be blood group specific: McC associated with K1590E and Sl(a) with R1601G. These associations were confirmed by inhibition studies using allele-specific mutants. A sequence-specific oligonucleotide probe hybridization assay was developed to genotype several African populations and perform family inheritance studies. Concordance between the 1590 mutation and McC was 94%; that between Sl(a) and 1601 was 88%. All but samples exhibiting discrepancies between the genotype and phenotype were found to be due to low red cell CR1 copy numbers, low or absent expression of some alleles, or heterozygosity combined with low normal levels of CR1. These data further explain the variability observed in previous serologic studies of CR1 and show that DNA and protein-based genetic studies will be needed to clarify the role of the KN antigens in malaria. (Blood.2001;97:2879-2885) (C) 2001 by The American Society of Hematology. C1 Univ Texas, Sch Med, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Mali, Bamako, Mali. Washington Univ, Sch Med, St Louis, MO USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. Ortho Clin Diagnost, Raritan, NJ USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Moulds, JJ (reprint author), MCP Hahnemann Univ, Sch Med, Dept Microbiol & Immunol, 2900 Queen Lane,G44, Philadelphia, PA 19129 USA. FU NIAID NIH HHS [R01 AI 41592, R01 AI 41729, R01 AI 42367] NR 30 TC 48 Z9 51 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 MAY 1 PY 2001 VL 97 IS 9 BP 2879 EP 2885 DI 10.1182/blood.V97.9.2879 PG 7 WC Hematology SC Hematology GA 429KP UT WOS:000168516200050 PM 11313284 ER PT J AU Ameye, L Aria, D Miller, G Chen, XD Robey, PG Chakravarti, S Oldberg, A Xu, T Young, MF AF Ameye, L Aria, D Miller, G Chen, XD Robey, PG Chakravarti, S Oldberg, A Xu, T Young, MF TI Biglycan and fibromodulin double knockout mice exhibit gait impairment and develop ectopic sesamoid bones and premature osteoarthritis in their joints. SO BONE LA English DT Meeting Abstract C1 NIH, NIDCR, CSDB, Bethesda, MD USA. NIH, Vet Resources Program, Bethesda, MD USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Univ Lund, Dept Cell & Mol Biol, Lund, Sweden. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S83 EP S83 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000072 ER PT J AU Balemans, W Ebeling, M Patel, N Van Hul, E Olson, P Dioszegi, M Lacza, C Wuyts, W Van Den Ende, J Willems, P Paes-Alves, AF Hill, S Bueno, M Ramos, FJ Tacconi, P Dikkers, FG Lindpaintner, K Vickery, B Foernzler, D Van Hul, W AF Balemans, W Ebeling, M Patel, N Van Hul, E Olson, P Dioszegi, M Lacza, C Wuyts, W Van Den Ende, J Willems, P Paes-Alves, AF Hill, S Bueno, M Ramos, FJ Tacconi, P Dikkers, FG Lindpaintner, K Vickery, B Foernzler, D Van Hul, W TI Mutations in SOST, a novel secreted protein, cause increased bone formation in sclerosteosis SO BONE LA English DT Meeting Abstract C1 Dept Med Genet, Antwerp, Belgium. F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. Roche Biosci, Palo Alto, CA USA. Dept Clin Genet, Rotterdam, Netherlands. Dept Ginecol, Salvador, BA, Brazil. NIH, Bethesda, MD 20892 USA. Univ Zaragoza, Zaragoza, Spain. Inst Neurol, Cagliari, Italy. Univ Groningen Hosp, Groningen, Netherlands. Roche Genet, Basel, Switzerland. RI Dikkers, Frederik/M-1212-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S88 EP S89 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000095 ER PT J AU Barsony, J Prufer, K Segovis, C AF Barsony, J Prufer, K Segovis, C TI Regulation and functions of vitamin D receptor shuttling SO BONE LA English DT Meeting Abstract C1 NIDDK, NIH, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S79 EP S79 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000057 ER PT J AU Bianco, P Kuznetsov, SA Riminucci, M Cherman, N Fisher, LW Collins, MT Wientroub, S Robey, PG AF Bianco, P Kuznetsov, SA Riminucci, M Cherman, N Fisher, LW Collins, MT Wientroub, S Robey, PG TI Age dependent demise of mutated stem cells and "normalization" of fibrous dysplasia of bone SO BONE LA English DT Meeting Abstract C1 Univ La Sapienza, Rome, Italy. NIH, NIDCR, CSDB, Bethesda, MD 20892 USA. Univ Aquila, Laquila, Italy. Tel Aviv Med Ctr, Tel Aviv, Israel. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S125 EP S125 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000251 ER PT J AU Bianco, P Kuznetuov, SA Riminucci, M Ziran, N Calvi, L Kronenberg, HM Robey, PG Schipani, E AF Bianco, P Kuznetuov, SA Riminucci, M Ziran, N Calvi, L Kronenberg, HM Robey, PG Schipani, E TI Signaling via the PTH/PTHrP receptor negatively regulates the formation of hematopoietic marrow SO BONE LA English DT Meeting Abstract C1 Univ La Sapienza, Rome, Italy. NIH, NIDCR, CSDB, Bethesda, MD USA. Univ Aquila, I-67100 Laquila, Italy. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S83 EP S83 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000074 ER PT J AU Corsi, A Riminucci, M Collins, MT Wientroub, S Robey, PG Bianco, P AF Corsi, A Riminucci, M Collins, MT Wientroub, S Robey, PG Bianco, P TI Gnatho-diaphyseal dysplasia: A new syndrome of fibro-osseous lesions in cranio-gnathic bones. Undermodeling of long bones, and bone fragility SO BONE LA English DT Meeting Abstract C1 Univ Aquila, I-67100 Laquila, Italy. NIH, NIDR, CSDB, Bethesda, MD 20892 USA. Souraski Med Ctr, Tel Aviv, Israel. Univ La Sapienza, Rome, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S124 EP S124 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000249 ER PT J AU Fohr, B Young, MF Fisher, LW AF Fohr, B Young, MF Fisher, LW TI Bone sialoprotein expression in cell lines of human breast and prostate cancer SO BONE LA English DT Meeting Abstract C1 Univ Heidelberg, Dept Med 1, Heidelberg, Germany. NIH, NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S137 EP S137 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000305 ER PT J AU Marini, JC Bergwitz, C Forlino, A Frankenburg, EP Kozloff, KM Goldstein, SA Nahounou, M Gronowicz, G AF Marini, JC Bergwitz, C Forlino, A Frankenburg, EP Kozloff, KM Goldstein, SA Nahounou, M Gronowicz, G TI The brittle mouse model for non-lethal osteogenesis imperfecta has decreased bone density, bone formation rate and femur strength SO BONE LA English DT Meeting Abstract C1 NICHD, NIH, Heritable Disorders Branch, Bethesda, MD USA. Univ Michigan, Sch Med, Orthoped Res Labs, Ann Arbor, MI 48109 USA. Univ Connecticut, Ctr Hlth, Dept Orthoped, Storrs, CT 06269 USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S115 EP S115 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000208 ER PT J AU Mora, S Proverbio, MC Bolzoni, L Colussi, G Hu, J Jones, K Spiegel, AM AF Mora, S Proverbio, MC Bolzoni, L Colussi, G Hu, J Jones, K Spiegel, AM TI A new mutation in the extracellular aminoterminal domain of the calcium-sensing receptor causing familial hypercalciuric hypocalcemia SO BONE LA English DT Meeting Abstract C1 Univ Milan, IRCCS S Raffaele, Lab Pediat Endocrinol, Milan, Italy. Niguarda Granda Hosp, Renal Unit, Milan, Italy. NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. RI Mora, Sefano/B-2143-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S134 EP S134 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000289 ER PT J AU Riminucci, M Corsi, A Kuznetsov, S Licci, S Robey, PG Bianco, P AF Riminucci, M Corsi, A Kuznetsov, S Licci, S Robey, PG Bianco, P TI Angiogenesis and expression of alpha-SM actin in fibrous dysplasia of bone SO BONE LA English DT Meeting Abstract C1 Univ Aquila, I-67100 Laquila, Italy. NIH, NIDR, CSDB, Bethesda, MD 20892 USA. Univ La Sapienza, Rome, Italy. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2001 VL 28 IS 5 SU S BP S124 EP S124 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 434PL UT WOS:000168825000250 ER PT J AU Heyes, MP Ellis, RJ Ryan, L Childers, ME Grant, I Wolfson, T Archibald, S Jernigan, TL AF Heyes, MP Ellis, RJ Ryan, L Childers, ME Grant, I Wolfson, T Archibald, S Jernigan, TL CA HNRC Grp TI Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection SO BRAIN LA English DT Article DE excitotoxin; neurodegeneration; magnetic resonance imaging; human immunodeficiency virus (HIV) ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; NEUROACTIVE KYNURENINES; HIV-1-INFECTED PATIENTS; NEUROLOGICAL DISEASE; IMMUNE ACTIVATION; COAT PROTEIN; L-TRYPTOPHAN; BRAIN; NEUROTOXICITY AB Neuronal injury, dendritic loss and brain atrophy are frequent complications of infection with human immunodeficiency virus (HIV) type 1, Activated brain macrophages and microglia can release quinolinic acid, a neurotoxin and NMDA (N-methyl-D-aspartate) receptor agonist, which we hypothesize contributes to neuronal injury and cerebral volume loss. In the present cross-sectional study of 94 HIV-1-infected patients, elevated CSF quinolinic acid concentrations correlated with worsening brain atrophy, quantified by MRI, in regions vulnerable to excitotoxic injury (the striatum and limbic cortex) but not in regions relatively resistant to excitotoxicity (the non-limbic cortex, thalamus and white matter). Increased CSF quinolinic acid concentrations also correlated with higher CSF HIV-1 RNA levels. In support of the specificity of these associations, blood levels of quinolinic acid were unrelated to striatal and limbic volumes, and CSF levels of beta (2-)microglobulin, a non-specific and non-excitotoxic marker of immune activation, were unrelated to regional brain volume loss. These results are consistent with the hypothesis that quinolinic acid accumulation in brain tissue contributes to atrophy in vulnerable brain regions in HIV infection and that virus replication is a significant driver of local quinolinic acid biosynthesis. C1 Univ Calif San Diego, HNRC, Brain Image Anal Lab, San Diego, CA 92103 USA. NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. Univ Arizona, Dept Psychiat, Tucson, AZ USA. RP Ellis, RJ (reprint author), Univ Calif San Diego, HNRC, Brain Image Anal Lab, 150 W Washington St,2nd Floor, San Diego, CA 92103 USA. RI Ellis, Ronald/K-3543-2015 OI Ellis, Ronald/0000-0003-4931-752X FU NIMH NIH HHS [P50-MH 45294] NR 61 TC 69 Z9 70 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2001 VL 124 BP 1033 EP 1042 DI 10.1093/brain/124.5.1033 PN 5 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 436GD UT WOS:000168927400017 PM 11335705 ER PT J AU Hilgenfeld, E Padilla-Nash, H McNeil, N Knutsen, T Montagna, C Tchinda, J Horst, J Ludwig, WD Serve, H Buchner, T Berdel, WE Schrock, E Ried, T AF Hilgenfeld, E Padilla-Nash, H McNeil, N Knutsen, T Montagna, C Tchinda, J Horst, J Ludwig, WD Serve, H Buchner, T Berdel, WE Schrock, E Ried, T TI Spectral karyotyping and fluorescence in situ hybridization detect novel chromosomal aberrations, a recurring involvement of chromosome 21 and amplification of the MYC oncogene in acute myeloid leukaemia M2 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE chromosomal aberrations; SKY; trisomy 21; AML-M2 ID ACUTE MYELOGENOUS LEUKEMIA; DOUBLE-MINUTE CHROMOSOMES; MYELODYSPLASTIC SYNDROME; MLL GENE; TRANSLOCATION; T(8-21)(Q22-Q22); IDENTIFICATION; LEUKEMOGENESIS; ABNORMALITIES; CYTOGENETICS AB Recurring chromosomal aberrations are of aetiological, diagnostic, prognostic and therapeutic importance in acute myeloid leukaemia (AML). However, aberrations are detected in only two thirds of AML cases at diagnosis and recurrent balanced translocations in only 50%. Spectral karyotyping (SKY) enables simultaneous visualization of all human chromosomes in different colours, facilitating the comprehensive evaluation of chromosomal abnormalities. Therefore, SKY was used to characterize 37 cases of newly diagnosed AML-M2, previously analysed using G-banding. In 15/23 patients it was possible to obtain metaphases from viably frozen cells; in 22 additional cases, fixed-cell suspensions were used. Of the 70 chromosomal aberrations identified by SKY, 30 aberrations were detected for the first time, 18 aberrations were redefined and 22 were confirmed. SKY detected two reciprocal translocations, t(X;3) and t(11;19). In five cases, eight structural aberrations resulted in partial gains of chromosome 21, six of which were undetected by G-banding. In 4/5 cases, these resulted in copy number increases for AML1. Amplification of MYC was detected in three cases. Using SKY and FISH, clonal aberrations were identified in 5/18 cases with a presumed normal karyotype; 3/5 aberrations were of known unfavourable prognostic significance. Karyotypes were entered into a custom-designed SKY database, which will be integrated with other cytogenetic and genomic databases. C1 NCI, Dept Genet, Div Clin Sci, NIH, Bethesda, MD 20205 USA. Univ Munster, Dept Human Genet, D-4400 Munster, Germany. Humboldt Univ, Univ Klinikum Charite, Robert Rossle Klin, Berlin, Germany. Univ Munster, Dept Haematol & Med Oncol, D-4400 Munster, Germany. RP Hilgenfeld, E (reprint author), NCI, Dept Genet, Div Clin Sci, NIH, Bldg 9,Room 1N-105,9 Mem Dr, Bethesda, MD 20205 USA. NR 44 TC 33 Z9 34 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2001 VL 113 IS 2 BP 305 EP 317 DI 10.1046/j.1365-2141.2001.02723.x PG 13 WC Hematology SC Hematology GA 439AG UT WOS:000169086100007 PM 11380393 ER PT J AU Miao, FJP Benowitz, NL Levine, JD AF Miao, FJP Benowitz, NL Levine, JD TI Endogenous opioids suppress activation of nociceptors by sub-nanomolar nicotine SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE sub-nanomolar nicotine; opioids; nociceptors; adrenal medulla; plasma extravasation; knee joint ID ENVIRONMENTAL TOBACCO-SMOKE; PLASMA EXTRAVASATION; SENSORY NEURONS; KNEE-JOINT; RAT; BRADYKININ; RESPONSES; AGONISTS; RELEASE; HYPERTENSION AB 1 Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of subnanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta -opioid receptor agonists. 2 While neurogenic plasma extravasation in the knee joint of the rat was not increased by intraarticular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta -opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intraarticular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3 Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4 Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist. RP-87,580 abolished the pro-inflammatory effect of nicotine. 5 The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids. C1 Univ Calif San Francisco, NIH Pain Ctr, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, Div Clin Immunol & Rheumatol, San Francisco, CA 94143 USA. RP Miao, FJP (reprint author), Univ Calif San Francisco, NIH Pain Ctr, Dept Oral & Maxillofacial Surg, Box 0440, San Francisco, CA 94143 USA. FU NIAMS NIH HHS [R01 AR032634, AR32634] NR 35 TC 11 Z9 11 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2001 VL 133 IS 1 BP 23 EP 28 DI 10.1038/sj.bjp.0704031 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 428TJ UT WOS:000168476500004 PM 11325790 ER PT J AU Perretti, M Wheller, SK Getting, SJ Gao, JL AF Perretti, M Wheller, SK Getting, SJ Gao, JL TI Involvement of FPR in the anti-inflammatory action of annexin-1 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Meeting Abstract ID NEUTROPHIL; RECEPTOR C1 William Harvey Res Inst, London, England. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2001 VL 133 SU S MA 203P BP U105 EP U105 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 421FT UT WOS:000168054700204 ER PT J AU Kiel, DP Kauppila, LI Cupples, LA Hannan, MT O'Donnell, CJ Wilson, PWF AF Kiel, DP Kauppila, LI Cupples, LA Hannan, MT O'Donnell, CJ Wilson, PWF TI Bone loss and the progression of abdominal aortic calcification over a 25 year period: The Framingham Heart Study SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE osteoporosis; pathologic calcification; vascular disease; cohort study; aged ID POSTMENOPAUSAL WOMEN; ATHEROSCLEROTIC PLAQUES; ARTERIAL CALCIFICATION; MINERAL DENSITY; DEFICIENT MICE; MESSENGER-RNA; OSTEOPOROSIS; EXPRESSION; OSTEOPONTIN; PROTEIN AB Vascular calcification and osteoporosis are common age-related processes that are prominently displayed on routine lateral lumbar spine radiographs as dense calcium mineral deposits of the aorta that lie adjacent to osteopenic vertebrae. Using a population-based cohort of older men and women, we tested the hypothesis that the progression of vascular calcification of the abdominal aorta should be greatest in those individuals with the greatest amount of bone loss. From the original population-based Framingham Heart Study cohort, 364 women and 190 men had lateral lumbar spine and hand radiographs performed between 1966 and 1970 and repeated between 1992 and 1993. The lateral lumbar films were read for the presence of aortic calcification using a semiquantitative method, and the hand films were read for second metacarpal relative cortical area (MCA). Using multivariate regression techniques, the 25-year progression of the abdominal aortic calcification index was examined in relation to the change in the MCA, while adjusting for recognized risk factors for atherosclerotic cardiovascular disease. During the 25 years of followup, the MCA decreased by 22.4% in women (from 79.6 +/- 7.8 (SD) to 61.8 +/- 10.3) and by 13.3% in men (from 80.6 +/- 6.9 to 69.9 +/- 8.3), The aortic calcification score increased over eightfold in women (from 1.2 +/- 2.7 (SD) to 9.9 +/- 6.7) and sixfold in men (from 1.6 +/- 2.8 to 9.6 +/- 6.3). There was a significant association between percent change in MCA and change in aortic calcification index (P = 0.01) in women after controlling for all potential confounders. No association was observed in men (P = 0.50), including the 50% of men with the greatest bone loss. This is the first longitudinal study to show that women with the greatest magnitude of bone loss also demonstrate the most severe progression of abdominal aortic calcification, suggesting that the two processes may be related. C1 Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Harvard Univ, Sch Med, Div Aging, Boston, MA 02115 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Kiel, DP (reprint author), Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. OI Kiel, Douglas/0000-0001-8474-0310 FU NHLBI NIH HHS [N01-HC-38038]; NIAMS NIH HHS [R01 AR/AG 41398] NR 37 TC 274 Z9 288 U1 0 U2 8 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD MAY PY 2001 VL 68 IS 5 BP 271 EP 276 DI 10.1007/BF02390833 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 439CN UT WOS:000169093400002 PM 11683533 ER PT J AU McEntyre, J Lipman, D AF McEntyre, J Lipman, D TI PubMed: bridging the information gap SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Review C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. RP McEntyre, J (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 45,Off 5C,45 Ctr Dr, Bethesda, MD 20892 USA. NR 2 TC 54 Z9 56 U1 0 U2 3 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD MAY 1 PY 2001 VL 164 IS 9 BP 1317 EP 1319 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 426WH UT WOS:000168371100025 PM 11341144 ER PT J AU Chokkalingam, AP Pollak, M Fillmore, CM Gao, YT Stanczyk, FZ Deng, J Sesterhenn, IA Mostofi, FK Fears, TR Madigan, MP Ziegler, RG Fraumeni, JF Hsing, AW AF Chokkalingam, AP Pollak, M Fillmore, CM Gao, YT Stanczyk, FZ Deng, J Sesterhenn, IA Mostofi, FK Fears, TR Madigan, MP Ziegler, RG Fraumeni, JF Hsing, AW TI Insulin-like growth factors and prostate cancer: A population-based case-control study in China SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FACTOR-BINDING-PROTEINS; FACTOR-I; INCREASED EXPRESSION; RECEPTOR GENE; IGF-I; RISK; INSULIN-LIKE-GROWTH-FACTOR-1; CARCINOMA; APOPTOSIS; PROTEASE AB Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate epithelial cells, Through modulation of IGF bioactivity and other mechanisms, IGF-binding proteins (IGFBPs) also have growth-regulatory effects on prostate cells. Recently, IGF-I and IGFBP-3 have been implicated in prostate cancer risk among Western populations. To assess whether IGF-I, IGF-II, IGFBP-1, or IGFBP3 are also associated with prostate cancer in a tow-risk population, we measured plasma levels of these factors among 128 newly diagnosed prostate cancer cases and 306 randomly selected population controls in Shanghai, China. Relative to the lowest quartile of IGF-I levels, men in the highest quartile had a 2.6-fold higher prostate cancer risk, with a significant trend [odds ratio (OR) = 2.63; 95% confidence interval (95% CI) = 1.19-5.79; P-trend = 0.01], In contrast, men in the highest quartile of IGFBP-3 levels had a 46% decreased risk relative to the lowest quartile (OR = 0.54; 95% CI = 0.26-1.15; P-trend = 0.08), A similar but less distinct result was observed for IGFBP-1 (OR = 0.60; 95% CI = 0.31-1.17; P-trend = 0.25), Men in the highest quartile for the IGF-I:IGFBP-3 molar ratio (an indirect measure of free IGF-I) had a 2.5-fold higher risk compared with the lowest quartile (OR = 2.51; 95% CI = 1.32-4.75, P-trend < 0.001), These associations were more pronounced after adjustment for serum 5 alpha -androstane-3 alpha ,17 beta -diol glucuronide and sex hormone-binding globulin levels. There was no significant association with IGF-II levels, Our findings in a low-risk population provide evidence that IGF-I, IGFBP-3, and IGFBP-1 are determinants of prostate cancer and indicate that additional studies are needed to evaluate their effects on ethnic and geographic incidence differentials and to elucidate carcinogenic mechanisms. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. McGill Univ, Canc Prevent Res Unit, Lady Davis Res Inst, Montreal, PQ H3T 1E2, Canada. Shanghai Canc Inst, Shanghai 200032, Peoples R China. Univ So Calif, Dept Obstet & Gynecol, Sch Med, Los Angeles, CA 90033 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, EPS-MSC-7234,6120 Execut Blvd, Rockville, MD 20852 USA. RI Pollak, Michael/G-9094-2011 OI Pollak, Michael/0000-0003-3047-0604 NR 27 TC 133 Z9 135 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 421 EP 427 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800001 PM 11352850 ER PT J AU Michaud, DS Giovannucci, E Willett, WC Colditz, GA Fuchs, CS AF Michaud, DS Giovannucci, E Willett, WC Colditz, GA Fuchs, CS TI Coffee and alcohol consumption and the risk of pancreatic cancer in two prospective United States cohorts SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DIABETES-MELLITUS; TEA CONSUMPTION; QUESTIONNAIRE; CAFFEINE; EPIDEMIOLOGY; SMOKING; HISTORY; MEN AB Although most prospective cohort studies do not support an association between coffee consumption and pancreatic cancer, the findings for alcohol are inconsistent. Recently, a large prospective cohort study of women reported statistically significant elevations in risk of pancreatic cancer for both coffee and alcoholic beverage consumption. We obtained data on coffee, alcohol, and other dietary factors using semiquantitative food frequency questionnaires administered at baseline (1986 in the Health Professionals Follow-Up Study and 1980 in the Nurses' Health Study) and in subsequent follow-up questionnaires. Data on other risk factors for pancreatic cancer, including cigarette smoking, were also available. Individuals with a history of cancer at study initiation were excluded from all of the analyses. During the 1,907,222 person years of follow-up, 288 incident cases of pancreatic cancer were diagnosed. The data were analyzed separately for each cohort, and results were pooled to compute overall relative risks (RR), Neither coffee nor alcohol intakes were associated with an increased risk of pancreatic cancer in either cohort or after pooling the results (pooled RR, 0.62; 95% confidence interval, 0.27-1.43, for >3 cups of coffee/day versus none; and pooled RR, 1.00; 95% confidence interval, 0.57-1.76, for greater than or equal to 30 grams of alcohol/day versus none). The associations did not change with analyses examining different latency periods for coffee and alcohol. Similarly, no statistically significant associations were observed for intakes of tea, decaffeinated coffee, total caffeine, or alcoholic beverages. Data from these two large cohorts do not support any overall association between coffee intake or alcohol intake and risk of pancreatic cancer. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Michaud, DS (reprint author), NCI, 6120 Execut Blvd,EPS Room 7026, Rockville, MD 20852 USA. RI Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 40356, CA 55075, CA 86102] NR 34 TC 80 Z9 84 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 429 EP 437 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800002 PM 11352851 ER PT J AU Satagopan, JM Offit, K Foulkes, W Robson, ME Wacholder, S Eng, CM Karp, SE Begg, CB AF Satagopan, JM Offit, K Foulkes, W Robson, ME Wacholder, S Eng, CM Karp, SE Begg, CB TI The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID OVARIAN-CANCER; WOMEN; PENETRANCE; GENE; PREVALENCE; FAMILIES; FREQUENCY; COHORT AB Several studies using families with multiple occurrences of breast cancer have provided evidence for a very high lifetime penetrance in carriers of BRCA1 or BRCA2 mutations. However, there are reasons to suspect that the estimates of penetrance from studies of cancer families may be inflated, Access to the genotypes of incident cases of breast cancer in three hospitals and from a large series of unaffected survey participants provided the basis for direct estimation of the age-specific relative risks attributable to these mutations, and the resulting lifetime penetrance, without any reference to familial aggregation of cancer. Cases were identified from incident series of Jewish patients treated for primary breast cancer at the three hospitals. Control data were obtained from the large series of Jewish women recruited in the Washington, D.C., area by investigators at the National Cancer Institute and limited to 3434 women with no previous history of breast or ovarian canter. All subjects were genotyped for the three mutations that are relatively common in Ashkenazi Jews, namely 185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2, For BRCA1, the relative risks of breast cancer were estimated to be 21.6 in women under 40 years of age, 9.6 in women 40-39 years of age, and 7.6 in women greater than or equal to 50 years of age. On the basis of these estimates, the penetrance of breast canter at age 70 among BRCA1 mutation carriers is estimated to be 46% (95% confidence, 31%-80%) rising to 59% (95% confidence, 40%-93%) at age 80, For BRCA2, the relative risks in the same three age categories were estimated to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance at age 70 of 26% (95% confidence, 14%-50%) rising to 38% (95% confidence, 20%-68%) at age 80. The lifetime risk of breast cancer in Jewish women who are mutation carriers estimated via this approach is substantially lower than the reported lifetime risks estimated using multiple-case families. The risks appear to be different for carriers of BRCA1 and BRCA2 mutations. C1 Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. McGill Univ, Sir Mortimer B Davis Jewish Gen Hosp, Montreal, PQ H3A 2T5, Canada. NCI, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23284 USA. RP Begg, CB (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. OI Robson, Mark/0000-0002-3109-1692 NR 35 TC 142 Z9 145 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 467 EP 473 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800007 PM 11352856 ER PT J AU Strickler, HD Goedert, JJ Butel, JS Daniel, R Freymuth, F Gibbs, A Griffiths, DJ Jablons, D Jasani, B Jones, C Lednicky, JA Miller, CW Radu, C Richards, WG Shah, KV You, L Corson, JM Gerwin, B Harris, C Sugarbaker, DJ Egan, W Lewis, AM Krause, PR Peden, K Levine, AS Melnick, S Cosentino, M da Costa, M Devairrakam, V Ji, J Palefsky, J Rasmussen, L Shea, K Wacholder, S Waters, D Wright, T AF Strickler, HD Goedert, JJ Butel, JS Daniel, R Freymuth, F Gibbs, A Griffiths, DJ Jablons, D Jasani, B Jones, C Lednicky, JA Miller, CW Radu, C Richards, WG Shah, KV You, L Corson, JM Gerwin, B Harris, C Sugarbaker, DJ Egan, W Lewis, AM Krause, PR Peden, K Levine, AS Melnick, S Cosentino, M da Costa, M Devairrakam, V Ji, J Palefsky, J Rasmussen, L Shea, K Wacholder, S Waters, D Wright, T CA Int SV40 Working Grp TI A multicenter evaluation of assays for detection of SV40 DNA and results in masked mesothelioma specimens SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-BRAIN-TUMORS; LARGE-T-ANTIGEN; HUMAN PLEURAL MESOTHELIOMA; POLYMERASE-CHAIN-REACTION; SIMIAN VIRUS 40; SV40-LIKE SEQUENCES; POLIO VACCINES; CHOROID-PLEXUS; SIMIAN-VIRUS-40; EXTRACTION AB This nine-laboratory multicenter investigation was designed to assess the sensitivity, specificity, and reproducibility of previously described assays for detection of SV40 DNA with three goals, i.e., (a) to compare methods for testing human tissues, (b) to examine the ability of these methods to detect SV40 in human mesotheliomas, and (c) to uncover assay differences that could explain conflicting findings in some past investigations. Each laboratory received, in a masked fashion, paired replicate DNA samples extracted from 25 fresh frozen mesotheliomas (50 samples) and one from each of 25 normal human lungs. Interspersed were masked positive (titrations of the SV40 genome) and negative control samples. Preliminary studies confirmed the adequacy of the samples for testing high molecular weight double-stranded linear DNA targets. All 15 PCR-based assays detected 5,000 copies or less of the SV40 genome spiked into 2 mug of WI-38 DNA. A high level of specificity and reproducibility was found among the PCR assays performed in most laboratories. However, none of the selected normal human lung tissue or the 25 mesothelioma tumor specimens obtained from archival samples at a single center was reproducibly positive for the presence of SV40 DNA. Further studies are needed to reconcile these results with previous reports of detection of SV40 DNA in tumor specimens. C1 Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. NCI, Viral Epidemiol Branch, NIH, Bethesda, MD USA. Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Hosp Univ Caen, Lab Virol Humaine & Mol, Caen, France. Univ Wales Coll Cardiff, Coll Med, Dept Pathol, Cardiff, S Glam, Wales. UCL, Windeyer Inst Med Sci, Wohl Vir Ctr, London, England. Univ Calif San Francisco, Thorac Oncol Lab, San Francisco, CA 94143 USA. Univ Calif Los Angeles, Cedars Sinai Res Inst, Dept Med, Los Angeles, CA USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. US FDA, Off Vaccines Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. BBI Biotech Res Labs, Gaithersburg, MD USA. Res Triangle Inst, Rockville, MD USA. Sci Applicat Int Corp, Frederick, MD USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. RP Strickler, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Social Med, 1300 Morris Pk Ave,Belfer Bldg 1308-B, Bronx, NY 10461 USA. NR 52 TC 68 Z9 70 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 523 EP 532 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800015 PM 11352864 ER PT J AU Sinha, R Kulldorff, M Chow, WH Denobile, J Rothman, N AF Sinha, R Kulldorff, M Chow, WH Denobile, J Rothman, N TI Dietary intake of heterocyclic amines, meat-derived mutagenic activity, and risk of colorectal adenomas SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID WELL-DONE; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; VARYING DEGREES; BREAST-CANCER; RED MEAT; FOOD; COLON; CARCINOGEN; PRODUCTS; RATS AB Meats cooked well-done by high temperature techniques produce mutagenic compounds such as heterocyclic amines (HCAs), but the amounts of these compounds vary by cooking techniques, temperature, time, and type of meat. We investigated the role of KCAs in the etiology of colorectal adenomas and the extent to which they may explain the previously observed risk for red meat and meat cooking methods. In a case-control study of colorectal adenomas, cases (n = 146) were diagnosed with colorectal adenomas at sigmoidoscopy or colonoscopy, and controls (n = 228) were found not to have colorectal adenomas at sigmoidoscopy. Using a meat-derived HCA and mutagen database and responses from a meat-cooking questionnaire module, we estimated intake of 2-amino-3,4,8-trimethylimidazo[45-f]quinoxaline (DiMeIQx), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]p (PhIP) and mutagenic activity. We calculated odds ratios and 95% confidence intervals using logistic regression adjusting for several established risk factors for colorectal adenomas or cancer. The odds ratios (95% confidence interval; P for trend test) fifth versus first quintiles are: 2.2 (1.2-4.1; P = 0.02) for DiMeIQx; 2.1 (1.0-4.3; P = 0.002) for MeIQx; 2.5(1.1-5.5; P = 0.02) for PhIP; and 3.1 (1.4-6.8; P = 0.001) for mutagenic activity. When the three HCAs were adjusted for the other two, only the trend for MeIQx (P = 0.04) remained statistically significant, When we tried to disentangle the relative contribution of the three HCAs from the meat variables, we found that MeIQx: even when adjusted for red meat but not vice versa. When MeIQx and well-done meat were analyzed in the same model, the risks were attenuated for both. Mutagenic activity from meat remained significantly associated with increased risk even when adjusted for intake of red meat or well-done red meat, whereas the red meat and well-done red meat associations were no longer significant when adjusted for total mutagenic activity, In conclusion, we found an elevated risk of colorectal adenomas associated with high intake of certain HCAs, Further, mutagenic activity from cooked meat consumption, a measure that integrates all of the classes of mutagens, was strongly associated with risk and explained the excess risk with intake of well done red meat. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Sch Med, Dept Community Med & Hlth Care, Div Biostat, Farmington, CT 06030 USA. Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Sinha, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza N,Room 443,6130 Execut Blvd, Bethesda, MD 20892 USA. RI Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 NR 28 TC 130 Z9 131 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 559 EP 562 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800020 PM 11352869 ER PT J AU Ji, BT Chow, WH Yang, G Jin, F Gao, YG Fraumeni, JF AF Ji, BT Chow, WH Yang, G Jin, F Gao, YG Fraumeni, JF TI Correspondence re: A. H. Wu et al., A meta-analysis of soyfoods and risk of stomach cancer: The problem of potential confounders. Cancer Epidemiol. Biomark. Prev., 9 : 105-1058, 2000 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Vanderbilt Univ, Hlth Serv Res Ctr, Div Gen Internal Med, Dept Med, Nashville, TN 37232 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. RP Ji, BT (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8120, Rockville, MD 20852 USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2001 VL 10 IS 5 BP 570 EP 571 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 433CM UT WOS:000168737800026 PM 11352874 ER PT J AU McCarthy, NJ Swain, SM AF McCarthy, NJ Swain, SM TI Tumor markers: Should we or shouldn't we? SO CANCER JOURNAL LA English DT Editorial Material ID ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER PATIENTS; SERUM; DIAGNOSIS; C-ERBB-2; RECEPTOR; TISSUE; CA15.3; CEA C1 NCI, Med Branch, Bethesda, MD 20892 USA. RP Swain, SM (reprint author), NCI, Med Branch, Bldg 10,Rm 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. RI McCarthy, Nicole/A-3468-2013 NR 22 TC 9 Z9 9 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PONE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. Sci. Am. PD MAY-JUN PY 2001 VL 7 IS 3 BP 175 EP 177 PG 3 WC Oncology SC Oncology GA 444AG UT WOS:000169375300002 PM 11419024 ER PT J AU Stanley, KJ Irick, N Holdsworth, MT Rech, H Berger, A Hedlund, SC AF Stanley, KJ Irick, N Holdsworth, MT Rech, H Berger, A Hedlund, SC TI A patient with renal cell carcinoma, myoclonus, and unrelieved pain SO CANCER PRACTICE LA English DT Article C1 Pain Management & Palliat Care, Claremont, CA USA. Pain Med Consultants, Indianapolis, IN USA. Univ New Mexico, Albuquerque, NM 87131 USA. NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Sch Med, Div Hematol, Oncol Fac, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Grad Sch Social Work, Div Hematol, Oncol Fac, Portland, OR 97201 USA. RP Stanley, KJ (reprint author), Pain Management & Palliat Care, Claremont, CA USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD MAY-JUN PY 2001 VL 9 IS 3 BP 114 EP 118 DI 10.1046/j.1523-5394.2001.009003114.x PG 5 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 427AD UT WOS:000168381800002 PM 11879291 ER PT J AU Shen, J Glaspy, J AF Shen, J Glaspy, J TI Acupuncture: Evidence and implications for cancer supportive care SO CANCER PRACTICE LA English DT Editorial Material ID CHRONIC PAIN; ADVERSE EVENTS; ANALGESIA; BRAIN; ELECTROACUPUNCTURE; METAANALYSIS; ENDORPHIN; MEDICINE; PATHWAY C1 NIAAA, Clin Sci Lab, Brain Electrophysiol & Imaging Sect, NIH, Bethesda, MD USA. Univ Calif Los Angeles, Bowyer Oncol Clin, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. RP Shen, J (reprint author), NIAAA, Clin Sci Lab, Brain Electrophysiol & Imaging Sect, NIH, Bethesda, MD USA. NR 28 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1065-4704 J9 CANCER PRACT JI Cancer Pract. PD MAY-JUN PY 2001 VL 9 IS 3 BP 147 EP 150 DI 10.1046/j.1523-5394.2001.009003147.x PG 4 WC Oncology; Health Care Sciences & Services; Nursing SC Oncology; Health Care Sciences & Services; Nursing GA 427AD UT WOS:000168381800007 PM 11879300 ER PT J AU Chansky, HA Hu, M Hickstein, DD Yang, L AF Chansky, HA Hu, M Hickstein, DD Yang, L TI Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein SO CANCER RESEARCH LA English DT Article ID BINDING-PROTEIN; POLYMERASE-II; EWINGS-SARCOMA; GENE; TRANSCRIPTION; TRANSLOCATION; INTERACTS; LIPOSARCOMA; EXPRESSION; TLS/FUS AB The translocation liposarcoma protein TLS has recently been shown to function as an adapter molecule coupling gene transcription to RNA splicing. Here we demonstrate that YB-1, a protein known to play important roles in transcription and translation, interacts with the COOH-terminal domains of TLS and the structurally related Ewing's sarcoma protein EWS. Through this interaction, YB-1 is recruited to RNA polymerase II and promotes splicing of E1A pre-mRNA to the 13S isoform, This splicing function of YB-1 is inhibited by exogenous TLS/ERG or EWS/ Fli-1 fusion proteins, which bind to RNA polymerase II but fail to recruit the YB-1 protein. In Ewing's sarcoma cells that express endogenous EWS/Fli-1, this linkage between YB-1 and RNA pol II via EWS (or TLS) was found to be defective. Together, these results suggest that TLS and EWS fusion proteins may contribute to malignant transformation through disruption of RNA splicing mediated by TLS- and EWS-binding proteins such as YB-1. C1 Univ Washington, Sch Med, Dept Orthoped, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA 98108 USA. NCI, Bethesda, MD 20892 USA. RP Yang, L (reprint author), Univ Washington, Sch Med, Dept Orthoped, GMR-151,1660 S Columbian Way, Seattle, WA 98108 USA. NR 20 TC 114 Z9 124 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2001 VL 61 IS 9 BP 3586 EP 3590 PG 5 WC Oncology SC Oncology GA 428WV UT WOS:000168485400012 PM 11325824 ER PT J AU Zhu, MZ Terasawa, H Gulley, J Panicali, D Arlen, P Schlom, J Tsang, KY AF Zhu, MZ Terasawa, H Gulley, J Panicali, D Arlen, P Schlom, J Tsang, KY TI Enhanced activation of human T cells via avipox vector-mediated hyperexpression of a triad of costimulatory molecules in human dendritic cells SO CANCER RESEARCH LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; RECOMBINANT VACCINIA VIRUS; COLONY-STIMULATING FACTOR; IN-VITRO; ADAPTIVE IMMUNITY; CEA VACCINE; PHASE-I; LYMPHOCYTES; PEPTIDE; EXPRESSION AB T-cell activation usually requires at least two signals. The first signal is antigen-specific, and the second signal(s) involves the interaction of a T-cell costimulatory molecule(s) on the antigen-presenting cell (APC) with its ligand on the T cell. Dendritic cells (DCs) are the most potent APCs, attributable, in part, to their expression of several T-cell costimulatory molecules. Human DCs generated in vitro, however, will vary in methods of generation and maturation and in terms of expression of different phenotypic markers-including costimulatory molecules-among different donors. We report here that a recombinant avipox (fowlpox, rF) vector has been constructed that can efficiently express the transgenes for three human T-cell costimulatory molecules (B7-1, ICAM-1, and LFA-3) as a result of individual early avipox promoters driving the expression of each transgene. This triad of costimulatory molecules (designated TRICOM I) was selected because each has an individual ligand on T cells and each has been shown previously to prime a unique signaling pathway in T cells. We report here that rF-TRICOM can efficiently infect human DCs of different states of maturity and hyperexpress each of the three costimulatory molecules on the DC surface without affecting other DC phenotypic markers. Infection of influenza or human papilloma virus 9-mer peptide-pulsed DCs from different individuals, or at different stages of maturity with rF-TRICOM, resulted in enhanced activation of T cells from peripheral blood mononuclear cells of autologous donors after 24 h of incubation with DCs. This enhanced activation was analyzed by both titrating the peptide and differing the DC:effector cell ratios. No effect was observed using the control wild-type avipox vector. No increase in apoptosis was observed in T cells hyperstimulated with the TRICOM vector, and no decrease in interleukin-12 production was seen in lipopolysaccharide-stimulated DCs infected with rF-TRICOM. Antibody-blocking experiments demonstrated that enhanced T-cell activation by TRICOM was attributed to each of the three costimulatory molecules. Peptide-pulsed, rF-TRICOM-infected DCs were also shown to be more effective than peptide-pulsed DCs in activating T cells to 9-mer peptides derived from two relatively weak "self" immunogens, i.e., human prostate-specific antigen and human carcinoembryonic antigen. These studies thus demonstrate for the first time that a vector that ran simultaneously hyperexpress three costimulatory molecules can be used to efficiently infect human DCs, leading to enhanced peptide-specific T-cell activation, The use of this approach for in vitro studies and clinical applications in immunotherapy is discussed. C1 NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MA 02142 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 62 TC 62 Z9 62 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2001 VL 61 IS 9 BP 3725 EP 3734 PG 10 WC Oncology SC Oncology GA 428WV UT WOS:000168485400033 PM 11325845 ER PT J AU Ju, DW Tao, Q Lou, GL Bai, M He, L Yang, YL Cao, XT AF Ju, DW Tao, Q Lou, GL Bai, M He, L Yang, YL Cao, XT TI Interleukin-18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates SO CANCER RESEARCH LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; IN-VIVO; CANCER-IMMUNOTHERAPY; GAMMA PRODUCTION; ANTIGEN; VITRO; THERAPY; VACCINATION; INDUCTION; RESPONSES AB Dendritic cell (DC)-based tumor vaccine represents a promising approach to the immunotherapy of malignant tumors. We prepared a novel type of DC-based vaccine, stable conjugates of DCs and EL4 cells transduced with cDNA of OVA (E.G7). Immunization with DC-E.G7 conjugates led to generation of T helper (Th) 1 cytokine-producing cells, antigen-specific CD8(+) T cells, and strong antitumor immunity that is dependent on both CB4(+) T cells and CD8(+) T cells. To further increase the potency of the vaccine, interleukin 18-transfected DCs were used to prepare the IL18DC-E.G7 conjugates. Immunization with such conjugates significantly increased the production of Th1 cytokine-producing cells and the number of antigen-specific CD8(+) T cells, as well as stronger antitumor Immunity, Furthermore, the increased Th1 cytokine production and stronger antitumor effect were not observed in mice depleted of IFN-gamma. These data indicated that DC-tumor cell conjugates are a potent tumor vaccine. Interleukin 18 can be administrated using gene-transfected cells and enhances antitumor Immunity, which is mainly mediated by IFN-gamma. C1 Second Mil Med Univ, Dept Immunol, Shanghai 200433, Peoples R China. NCI, Lab Immune Cell Biol, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Cao, XT (reprint author), Second Mil Med Univ, Dept Immunol, 800 Xiang Yin Rd, Shanghai 200433, Peoples R China. NR 46 TC 38 Z9 44 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2001 VL 61 IS 9 BP 3735 EP 3740 PG 6 WC Oncology SC Oncology GA 428WV UT WOS:000168485400034 PM 11325846 ER PT J AU Khanna, C Khan, J Nguyen, P Prehn, J Caylor, J Yeung, C Trepel, J Meltzer, P Helman, L AF Khanna, C Khan, J Nguyen, P Prehn, J Caylor, J Yeung, C Trepel, J Meltzer, P Helman, L TI Metastasis-associated differences in gene expression in a murine model of osteosarcoma SO CANCER RESEARCH LA English DT Article ID HUMAN-MELANOMA CELLS; MATRIX METALLOPROTEINASES; CDNA MICROARRAYS; COLON-CANCER; IN-VITRO; EZRIN; MEMBRANE; PROTEIN; ADHESION; INVOLVEMENT AB Despite advances in the management of osteosarcoma (OSA) and other solid tumors, the development of metastasis continues to be the most significant problem and cause of death for cancer patients. To define genetic determinants of pulmonary metastasis, we have applied cDNA microarrays to a recently described murine model of OSA that is characterized by orthotopic tumor growth, a period of minimal residual disease, spontaneous pulmonary metastasis, and cell line variants that differ in metastatic potential. Microarray analysis defined 53 genes (of 3166 unique cDNAs) that were differentially expressed between the primary tumors of the more aggressive (K7M2) and less aggressive (K12) OSA models. By review of the literature, these differentially expressed genes a ere assigned to six nonmutually exclusive metastasis-associated categories (proliferation and apoptosis, motility and cytoskeleton, invasion, immune surveillance, adherence, and angiogenesis). Functional studies to evaluate K7M2 and K12 for differences in each of these metastasis-associated processes revealed enhanced motility, adherence, and angiogenesis in the more aggressive K7M2 model. For this reason, 10 of the 53 differentially expressed genes that were assigned to the motility and cytoskeleton, adherence, and angiogenesis categories mere considered as most likely to define differences in the metastatic behavior of the two models. Ezrin, a gene not described previously in OSA, with functions in motility, invasion, and adherence, was 3-fold overexpressed in K7M2 compared with K12 by microarray. Differential expression for RNA was confirmed by Northern analysis and for protein by immunostaining. Alterations in ezrin protein levels and concomitant cytoskeletal changes in our model confirmed predictions from the arrays. The potential relevance of ezrin in OSA was suggested by its expression in five of five human OSA cell lines. This work represents a rationale approach to the evaluation of microarray data and will be useful to identify genes that may be causally associated with metastasis. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Branch, Bethesda, MD 20892 USA. NIH, Human Genome Res Inst, Canc Genet Branch, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 35 TC 207 Z9 228 U1 2 U2 7 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 MAY 1 PY 2001 VL 61 IS 9 BP 3750 EP 3759 PG 10 WC Oncology SC Oncology GA 428WV UT WOS:000168485400036 PM 11325848 ER PT J AU Matrisian, LM Cunha, GR Mohla, S AF Matrisian, LM Cunha, GR Mohla, S TI Epithelial-stromal interactions and tumor progression: Meeting summary and future directions SO CANCER RESEARCH LA English DT Article ID CANCER; CARCINOGENESIS AB The Epithelial-Stromal Interactions Workshop was organized with the purpose of accelerating progress in understanding the interrelationship between tumor cells and their microenvironment and applying this knowledge to the control of tumor progression. The format of the meeting was the presentation of brief reports that focused on concepts rather than specifics, with extensive discussion periods to identify the issues and barriers hindering progress in this area. This report summarizes the findings of this meeting, highlighting the intimate relationship between tumor cells and their environment and addressing the opportunities that manipulation of host-tumor interactions has for therapeutic intervention. Several specific recommendations are made to advance knowledge and progress in this field. C1 Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. NCI, Tumor Biol & Metastasis Branch, Div Canc Biol, NIH, Rockville, MD 20852 USA. RP Matrisian, LM (reprint author), Vanderbilt Univ, Sch Med, Dept Canc Biol, C-2310 Med Ctr N, Nashville, TN 37232 USA. NR 18 TC 64 Z9 65 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2001 VL 61 IS 9 BP 3844 EP 3846 PG 3 WC Oncology SC Oncology GA 428WV UT WOS:000168485400049 PM 11325861 ER PT J AU Spooner, PM Priori, SG Myerburg, RJ AF Spooner, PM Priori, SG Myerburg, RJ TI Spotlight on sudden cardiac death SO CARDIOVASCULAR RESEARCH LA English DT Editorial Material C1 NHLBI, Arrhythmia Res Grp, DHVD, Bethesda, MD 20892 USA. Fondaz Salvatore Maugeri, I-27100 Pavia, Italy. Univ Miami, Sch Med, Div Cardiol, Miami, FL USA. RP Spooner, PM (reprint author), NHLBI, Arrhythmia Res Grp, DHVD, 2 Rockledge Ctr,MSC-7940,6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAY PY 2001 VL 50 IS 2 BP 173 EP 176 DI 10.1016/S0008-6363(01)00270-X PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432GU UT WOS:000168684500001 ER PT J AU Myerburg, RJ Spooner, PM AF Myerburg, RJ Spooner, PM TI Opportunities for sudden death prevention: Directions for new clinical and basic research SO CARDIOVASCULAR RESEARCH LA English DT Review DE epidemiology; sudden death ID FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; CARDIAC DEATH; MYOCARDIAL-INFARCTION; HIGH-RISK; CARDIOVASCULAR MEDICINE; VENTRICULAR ARRHYTHMIA; DEFIBRILLATOR; IMPACT; POPULATION; DISEASE AB Sudden cardiac death (SCD) represents an enormous public health problem in all developed countries of the world, yet its magnitude and precise incidence in different populations and disease subgroups remains unclear. There also remain major questions and research challenges in establishing the sensitive and specific markers of SCD risk needed for optimizing therapeutic strategies and allocation of resources, such as implantable defibrillators. In the past, risk factors for coronary artery disease (CAD) have been heavily relied on to identify risk for SCD. However, although a majority of SCD events continue to occur in the context of this disease etiology, risk factors for CAD appear to have relatively limited ability to predict risk in specific individuals and subgroups with enhanced progressive or inherited susceptibility to lethal arrhythmias. This commentary is intended to assess potentials for progress in developing improved approaches to SCD prediction and prevention through new clinical and basic research on the fundamental causes of ventricular arrhythmias, the development of new markers of electrical instability, and better understanding of the role of genetic variability in their origin. (C) 2001 Published by Elsevier Science BN. C1 NHLBI, Arrhythmia Res Grp, DHVD, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Div Cardiol, Miami, FL USA. RP Spooner, PM (reprint author), NHLBI, Arrhythmia Res Grp, DHVD, 2 Rockledge Ctr,MSC-7940,6071 Rockledge Dr, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL21735] NR 39 TC 42 Z9 44 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAY PY 2001 VL 50 IS 2 BP 177 EP 185 DI 10.1016/S0008-6363(01)00253-X PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432GU UT WOS:000168684500002 PM 11334821 ER PT J AU Kontny, HU Hammerle, K Klein, R Shayan, P Mackall, CL Niemeyer, CM AF Kontny, HU Hammerle, K Klein, R Shayan, P Mackall, CL Niemeyer, CM TI Sensitivity of Ewing's sarcoma to TRAIL-induced apoptosis SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE Ewing's sarcoma; TRAIL; interferon-gamma; caspase 8; apoptosis ID CYTOTOXIC LIGAND TRAIL; FAS-MEDIATED APOPTOSIS; BREAST CELL-LINES; DEATH DOMAIN; NEUROECTODERMAL TUMORS; MELANOMA-CELLS; RECEPTOR; EXPRESSION; CASPASE-8; FAMILY AB Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill transformed cells. We have studied the expression and functionality of the TRAIL apoptotic pathway in Ewing's sarcoma. We demonstrate that tumors from patients with Ewing's sarcoma express receptors TRAIL-R1 and -R2, Using a panel of nine Ewing's sarcoma cell lines TRAIL could induce apoptosis in seven cell lines. Preincubation with interferon-gamma rendered the two resistant cell lines sensitive. TRAIL was the most potent inducer of apoptosis when compared to Fas ligand or TNF. TRAIL-mediated apoptosis could be inhibited by various caspase-inhibitors. No difference in the surface expression of TRAIL receptors was observed between sensitive and resistant cell lines. Also, all cell lines had similar levels of expression of Flice-like inhibitory protein (FLIP) on immunoblot. However, the two resistant cell lines had only very low level expression of caspase 8 on RNA and protein level. In summary, we show that Ewing's sarcoma expresses receptors for TRAIL, and that cells are exquisitely sensitive to TRAIL-mediated apoptosis. These results may warrant clinical trials with TRAIL in Ewing's sarcoma once the safety of TRAIL for humans has been established. C1 Univ Freiburg, Childrens Hosp, D-79106 Freiburg, Germany. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Kontny, HU (reprint author), Univ Freiburg, Childrens Hosp, Mathildenstr 1, D-79106 Freiburg, Germany. NR 51 TC 56 Z9 56 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2001 VL 8 IS 5 BP 506 EP 514 DI 10.1038/sj.cdd.4400836 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 429UF UT WOS:000168534800008 PM 11423911 ER PT J AU Paruszewski, R Strupinska, M Stables, JP Swiader, M Czuczwar, S Kleinrok, Z Turski, W AF Paruszewski, R Strupinska, M Stables, JP Swiader, M Czuczwar, S Kleinrok, Z Turski, W TI Amino acid derivatives with anticonvulsant activity SO CHEMICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE anticonvulsants; cyclic amino acid derivative ID MICE; ALA AB A series of benzylamides of N-alkylated, N-acylated or free nine cyclic and one linear amino acids as potential anticonvulsants have been synthesized. The structures of the obtained compounds were designed on the basis of the previously determined structure and physicochemical properties/anticvonvulsant activity relationship of the formerly synthesized compounds of this type. The obtained compounds were evaluated in mice after intraperitoneal (ip) administration, by maximal electroshock seizure test (MES test), subcutaneous (sc) pentylenetetrazol test (sc PTZ test) and by the rotarod neurotoxicity test (Tox test). The results were the basis for their classification into one of three classes of the Anticonvulsant Screening Project (ASP) of the Antiepileptic Drug Development Program (ADDP) of the NIH. Three selected compounds were tested quantitatively in rats after oral administration, The MES ED50, sc PTZ ED50, Tox TD50 were determined and their protective index (PI) values were calculated. Anticonvulsant activity of the most promising compound (15) was examined in different seizure models, The respective ED50 and PI values of this compound were as follows: against bicuculline, 73 and 1.4; against PTZ, 47 and 2.2; against strychnine, 73 and 1.4; against pilocarpine 156, and 0.7; against kainic acid (2-carboxy-4-isopropenyl-3-pyrrolidineac acid), 39 and 2.6; against AMPA (alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), 10 and 10.3 and against NMDA (N-methyl-D-Aspartic acid), 114 and 0.9. C1 Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. NIH, Neurol Inst, Bethesda, MD 20892 USA. Med Univ, Dept Pharmacol & Toxicol, PL-20090 Lublin, Poland. RP Paruszewski, R (reprint author), Med Univ, Dept Drug Chem, PL-02097 Warsaw, Poland. EM rpbw@farm.amwaw.edu.pl NR 14 TC 24 Z9 25 U1 1 U2 8 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0009-2363 J9 CHEM PHARM BULL JI Chem. Pharm. Bull. PD MAY PY 2001 VL 49 IS 5 BP 629 EP 631 DI 10.1248/cpb.49.629 PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 427KB UT WOS:000168402400022 PM 11383620 ER PT J AU Sternberg, KJ Lamb, ME Davies, GM Westcott, HL AF Sternberg, KJ Lamb, ME Davies, GM Westcott, HL TI The Memorandum of Good Practice: theory versus application SO CHILD ABUSE & NEGLECT LA English DT Article DE sexual abuse; investigative interviews; forensic interviews ID INVESTIGATIVE UTTERANCE TYPES; SEXUAL-ABUSE VICTIMS; CHILD WITNESSES; INTERVIEWS AB Objective: The goal of this study was to evaluate the quality of investigative interviews in England and Wales since implementation of the Memorandum of Good Practice (MC)GP), which specified how forensic interviews of alleged child abuse victims should be conducted. Method: Transcripts of 119 videotaped interviews of alleged victims between the ages of 4 and 13 years were obtained from 13 collaborating police forces. Trained raters then classified the types of prompts used by the investigators to elicit substantive information from the children, and tabulated the number of forensically relevant details provided by the children in each response. Results: Like their counterparts in the United States, Israel, and Sweden, forensic interviewers in England and Wales relied heavily on option-posing prompts, seldom using open-ended utterances to elicit information from the children. Nearly 40% of the information obtained was elicited using option-posing and suggestive prompts, which are known to elicit less reliable information than open-ended prompts do. Conclusion: Despite the clarity and specificity of the MOGP, its implementation appears to have had less effect on the practices of forensic interviewers in the field than was hoped. Further work should focus on ways of training interviewers to implement the superior practices endorsed by the MOGP and similar professional guidelines. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20892 USA. Univ Leicester, Dept Psychol, Leicester LE1 7RH, Leics, England. Open Univ, Dept Psychol, Milton Keynes MK7 6AA, Bucks, England. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, BSA Bldg,Suite 331,9190 Rockville Pike, Bethesda, MD 20892 USA. NR 44 TC 86 Z9 86 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD MAY PY 2001 VL 25 IS 5 BP 669 EP 681 DI 10.1016/S0145-2134(01)00232-0 PG 13 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 435LK UT WOS:000168882800006 PM 11428428 ER PT J AU Tamis-LeMonda, CS Bornstein, MH Baumwell, L AF Tamis-LeMonda, CS Bornstein, MH Baumwell, L TI Maternal responsiveness and children's achievement of language milestones SO CHILD DEVELOPMENT LA English DT Article ID 2ND YEAR; WORD; MOTHER; PLAY; GROWTH; SENSITIVITY; COMPETENCE; EMERGENCE; ATTENTION; BEHAVIOR AB This prospective longitudinal study examined the contribution of dimensions of maternal responsiveness (descriptions, play, imitations) to the timing of five milestones in children's (N = 40) early expressive language: first imitations, first words, 50 words in expressive language, combinatorial speech, and the use of language to talk about the past. Events-History Analysis, a statistical technique that estimates the extent to which predictors influence the timing of events, was used. At 9 and 13 months, maternal responsiveness and children's activities (e.g., vocalizations, play) were coded from videotaped interactions of mother-child free play; information about children's language acquisition was obtained through biweekly interviews with mothers from 9 through 21 months. Maternal responsiveness at both ages predicted the timing of children's achieving language milestones over and above children's observed behaviors. Responsiveness at 13 months was a stronger predictor of the timing of language milestones than was responsiveness at 9 months, and certain dimensions of responsiveness were more predictive than others. The multidimensional nature of maternal responsiveness and specificity in mother-child language relations are discussed. C1 NYU, Dept Appl Psychol, New York, NY 10003 USA. NICHHD, Bethesda, MD 20892 USA. RP Tamis-LeMonda, CS (reprint author), NYU, Dept Appl Psychol, 239 Greene St,5th Floor, New York, NY 10003 USA. EM ct1@is8.nyu.edu FU NICHD NIH HHS [HD20559, HD20807, HD48915] NR 67 TC 304 Z9 306 U1 4 U2 49 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD MAY-JUN PY 2001 VL 72 IS 3 BP 748 EP 767 DI 10.1111/1467-8624.00313 PG 20 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 438JA UT WOS:000169048800010 PM 11405580 ER PT J AU Chen, JP Clemens, DL Cederbaum, AI Gao, B AF Chen, JP Clemens, DL Cederbaum, AI Gao, B TI Ethanol inhibits the JAK-STAT signaling pathway in freshly isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism SO CLINICAL BIOCHEMISTRY LA English DT Article DE ethanol; acetaldehyde; 4-methlepyrazole; interleukin 6; interferon; Janus kinase-signal transducer and activator transcription factor (JAK-STAT); liver; hydrogen peroxide ID PROTEIN-KINASE-C; MITOGEN-ACTIVATED PROTEIN; CHRONIC HEPATITIS-C; LIVER-REGENERATION; DIFFERENTIAL REGULATION; INTERFERON THERAPY; GENE-EXPRESSION; MESSENGER-RNA; ALCOHOL; RECEPTORS AB Objectives: To understand the molecular mechanism underlying alcoholic liver injury, effects of acute ethanol on the Janus kinase-signal transducer and activator transcription factor (JAK-STAT) signaling in hepatic cells were studied. Designs and methods: Effects of acute ethanol on the JAK-STAT signaling in freshly isolated, cultured rat hepatocytes, and HepG2 cells were explored. Results: Acute ethanol exposure inhibited IL-6- or IFN-activated STAT in freshly isolated hepatocytes but not in cultured hepatocytes, HepG2 cells, or HepG2 cells transfected with alcohol dehydrogenase (ADH) or cytochrome P450(2E1). The inhibitory action of ethanol in freshly isolated hepatocytes was not antagonized by the ADH inhibitor 4-methylpyrazole (4-MP). Acute exposure of hepatocytes to acetaldehyde or hydrogen peroxide did not suppress STAT activation. Further studies indicated that the loss of response to the inhibitory effect of ethanol was not due to hepatocyte proliferation and collagen contact. Conclusions: Freshly isolated hepatocytes are more susceptible to the inhibitory action of ethanol on the JAK-STAT signaling than cultured hepatocytes or HepG2 cells, which may be implicated in pathogenesis and progression of alcoholic liver disease. (C) 2001 The Canadian Society of Clinical Chemists. All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Dept Vet Affairs Med Ctr, Liver Study Unit, Omaha, NE 68105 USA. Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE 68105 USA. Mt Sinai Sch Med, Dept Biochem, New York, NY 10029 USA. RP Gao, B (reprint author), NIAAA, NIH, Rockville, MD 20852 USA. FU NCI NIH HHS [R29 CA 72681]; NIAAA NIH HHS [R03 AA 11823, R01 AA 12637] NR 53 TC 22 Z9 22 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD MAY PY 2001 VL 34 IS 3 BP 203 EP 209 DI 10.1016/S0009-9120(01)00216-8 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 478EX UT WOS:000171330900007 PM 11408018 ER PT J AU Srivastava, S Verma, M Henson, DE AF Srivastava, S Verma, M Henson, DE TI Biomarkers for early detection of colon cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID FAMILIAL ADENOMATOUS POLYPOSIS; NONPOLYPOSIS COLORECTAL-CANCER; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TUMOR SUPPRESSOR GENES; K-RAS MUTATIONS; BCL-2 EXPRESSION; MOLECULAR-GENETICS; BREAST-CANCER; BETA-CATENIN; CYCLIN D1 AB There is an increasing demand for biomarkers in colon cancer for risk assessment, early detection, prognosis, and surrogate end points. A number of biomarkers have been identified for early detection of colon cancer, although the risk factors have not been identified extensively. The major advances in understanding colorectal cancer include the identification and the involvement of APC, p53, and Ki-ras in the development and progression of the disease, the identification of the aberrant crypt foci as an early preinvasive lesion, and its relation to the development of cancer. Detecting malignant neoplasms in the early stages offers clinical advantages; therefore, the National Cancer Institute has established an Early Detection Research Network. The emphasis of the network is on translational research and collaboration among scientists. C1 NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Rockville, MD 20852 USA. RP Srivastava, S (reprint author), NCI, Div Canc Prevent, Canc Biomarkers Res Grp, 6130 Execut Blvd,Room EPN-330F, Rockville, MD 20852 USA. NR 87 TC 115 Z9 121 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY PY 2001 VL 7 IS 5 BP 1118 EP 1126 PG 9 WC Oncology SC Oncology GA 433PG UT WOS:000168768500005 PM 11350874 ER PT J AU von Mehren, M Arlen, P Gulley, J Rogatko, A Cooper, HS Meropol, NJ Alpaugh, RK Davey, M McLaughlin, S Beard, MT Tsang, KY Schlom, J Weiner, LM AF von Mehren, M Arlen, P Gulley, J Rogatko, A Cooper, HS Meropol, NJ Alpaugh, RK Davey, M McLaughlin, S Beard, MT Tsang, KY Schlom, J Weiner, LM TI The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; ANTITUMOR IMMUNITY; CANCER-PATIENTS; DENDRITIC CELLS; PHASE-I; COSTIMULATORY MOLECULES; COLORECTAL-CANCER; ELISPOT ASSAY; GENE-TRANSFER; T-CELLS AB Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to be an effective vaccine adjuvant because it enhances antigen processing and presentation by dendritic cells, ALVAC-CEA B7.1 is a canarypox virus encoding the gene for the tumor-associated antigen carcinoembryonic antigen (CEA) and for a T-cell costimulatory molecule, B7.1, After an initial dose escalation phase, this study evaluated vaccination with 4.5 x 10(8) plaque-forming units ALVAC-CEA B7.1 alone (n = 30) or with GM-CSF (n = 30) in patients with advanced CEA-expressing tumors to determine whether the addition of the adjuvant GM-CSF enhances induction of CEA-specific T-cells, Patients were vaccinated with vaccine intradermally every other week for 8 weeks. GM-CSF was given s.c. for 5 days beginning 2 days before vaccination. Patients with stable or responding disease after four immunizations received monthly boost injections alone or with GM-CSF, Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression. Induction of peripheral blood CPA-specific T-cell precursors was assessed in HLA-AZ positive patients by an ELISPOT assay looking for the production of IFN-gamma, Therapy was well tolerated, All of the patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites. In the patients receiving GM-CSF, leukocytic infiltrates were greater in cell number but were less likely to have a predominant lymphocytic infiltrate compared with patients receiving vaccine in the absence of the cytokine adjuvant, After four vaccinations, CEA-specific T-cell precursors were statistically increased in HLA-A2 positive patients who received vaccine alone. However, the GM-CSF plus vaccine cohort of HLA-AZ positive did not demonstrate a statistically significant increase in their CEA-specific T-cell precursor frequencies compared with baseline results. The number of prior chemotherapy regimens was negatively correlated with the generation of a T-cell response, whereas there was a positive correlation between the number of months from the last chemotherapy regimen and the T-cell response, ALVAC-CEA B7.1 is safe in patients with advanced, recurrent adenocarcinomas that express CEA, is associated with the induction of a CEA-specific T-cell response in patients treated with vaccine alone but not with vaccine and GM-CSF, and can lead to disease stabilization for up to 13 months. C1 Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. NCI, Lab Tumor Immunol, NIH, Bethesda, MD 20892 USA. RP von Mehren, M (reprint author), Fox Chase Canc Ctr, Dept Med Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI Rogatko, Andre/A-8099-2008; Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU NCI NIH HHS [K12 CA01728, P30 P0 CA06927] NR 48 TC 134 Z9 135 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY PY 2001 VL 7 IS 5 BP 1181 EP 1191 PG 11 WC Oncology SC Oncology GA 433PG UT WOS:000168768500013 PM 11350882 ER PT J AU Logothetis, CJ Wu, KK Finn, LD Daliani, D Figg, W Ghaddar, H Gutterman, JU AF Logothetis, CJ Wu, KK Finn, LD Daliani, D Figg, W Ghaddar, H Gutterman, JU TI Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-GROWTH; PLASMA THROMBOMODULIN AB Clinical and laboratory observations support the view that angiogenesis is necessary for prostate cancer progression. The angiogenesis inhibitor TNP-470 has demonstrated irt vivo antitumor activity in a series of clinical models. To evaluate a possible therapeutic clinical value, we conducted a Phase I dose escalation trial of alternate-day i.v. TNP-470 in 33 patients with metastatic and androgen-independent prostate cancer. The patients were evaluated during therapy for evidence of neurological toxic effects. An assay of endothelial and vascular proliferation "markers'' and a sequential assay of serum prostate-specific antigen concentration were performed. The effects of TNP-470 could be evaluated in 32 of the 33 patients. The maximum tolerated dose was 70.88 mg/m(2) of body surface area. The dose-limiting toxic effect was a characteristic neuropsychiatric symptom complex (anesthesia, gait disturbance, and agitation) that resolved upon cessation of therapy. The times to clinical recovery of neurological side effects were 6, 8, and 14 weeks, No definite antitumor activity of TNP-470 was observed; however, transient stimulation of the serum prostate-specific antigen concentration occurred in some of the patients treated. Additional studies of TNP-470 should be conducted using an alternate-day i.v. injection of 47.25 mg/m(2) body surface area and should focus on understanding and overcoming the neurological toxic effects. In addition, valid intermediate end points that reflect the status of tumor-associtated neovascularity are needed to facilitate effective development of treatment strategies. C1 Univ Texas, MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Blood & Marrow Transplantat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Protocol Res, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Cellular Mol Growth Regulat, Houston, TX 77030 USA. NCI, Dept Clin Pharmacol, Bethesda, MD 20892 USA. RP Wu, KK (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Box 13,1515 Holcombe Blvd, Houston, TX 77030 USA. RI Wu, Kenneth Kun-Yu/B-1070-2010; Figg Sr, William/M-2411-2016 NR 13 TC 114 Z9 117 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY PY 2001 VL 7 IS 5 BP 1198 EP 1203 PG 6 WC Oncology SC Oncology GA 433PG UT WOS:000168768500015 PM 11350884 ER PT J AU Sunwoo, JB Chen, Z Dong, G Yeh, N Bancroft, CG Sausville, E Adams, J Elliott, P Van Waes, C AF Sunwoo, JB Chen, Z Dong, G Yeh, N Bancroft, CG Sausville, E Adams, J Elliott, P Van Waes, C TI Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID PROINFLAMMATORY CYTOKINE EXPRESSION; HOST ENVIRONMENT PROMOTES; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTOR; INDUCED APOPTOSIS; CANCER-THERAPY; BREAST-CANCER; HUMAN HEAD; IN-VIVO; LINES AB We have shown that activation of nuclear factor-kappaB (NF-kappaB) promotes cell survival and expression of cytokines such as growth-regulated oncogene-alpha, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC), Activation of NF-kappaB and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-kappaB, In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-kappaB and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-kappaB DNA binding and functional reporter activity at concentrations between 10(-8) and 10(-7) M. Cytotoxicity was observed at 10(-7) M in four murine and two human SCC lines, and followed early cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1-2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg, Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proangiogenic cytokines growth-regulated oncogene-alpha and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-kappaB, We conclude that PS-341 inhibits activation of NF-kappaB pathway components related to cell survival, tumor growth, and angiogenesis in SCC. C1 NIDOCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Rockville, MD 20850 USA. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. RP Van Waes, C (reprint author), NIDOCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5D55, Bethesda, MD 20892 USA. FU NIDCD NIH HHS [Z01-DC-00016] NR 34 TC 377 Z9 387 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY PY 2001 VL 7 IS 5 BP 1419 EP 1428 PG 10 WC Oncology SC Oncology GA 433PG UT WOS:000168768500044 PM 11350913 ER PT J AU Soini, H Musser, JM AF Soini, H Musser, JM TI Molecular diagnosis of mycobacteria SO CLINICAL CHEMISTRY LA English DT Review ID TUBERCULOSIS DIRECT TEST; POLYMERASE-CHAIN-REACTION; LINE PROBE ASSAY; LABELED DNA PROBES; RESPIRATORY SPECIMENS; SPECIES IDENTIFICATION; SEQUENCE DETERMINATION; RIFAMPICIN RESISTANCE; CLINICAL-EVALUATION; RAPID DIAGNOSIS AB Tuberculosis is one of the leading infectious diseases in the world and is responsible for more than 2 million deaths and 8 million new cases annually. Because of the slow growth rate of the causative agent Mycobacterium tuberculosis, isolation, identification, and drug susceptibility testing of this organism and other clinically important mycobacteria can take several weeks or longer. During the past several years, many molecular methods have been developed for direct detection, species identification, and drug susceptibility testing of mycobacteria. These methods can potentially reduce the diagnostic time from weeks to days. Currently two nucleic acid amplification methods, the Enhanced Mycobacterium tuberculosis Direct Test (Gen-Probe) and the Amylicor Mycobacterium tuberculosis Test (Roche Diagnostic Systems), have been approved by the Food and Drug Administration for direct detection of M. tuberculosis from clinical specimens. PCR-based sequencing has become commonly used to identify many mycobacterial species. DNA probes have been widely used for species determination of the most commonly encountered mycobacteria. High-density oligonucleotide arrays (DNA microarrays) also have been applied to simultaneous species identification and detection of mutations that confer rifampin resistance in mycobacteria. (C) 2001 American Association for Clinical Chemistry C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Natl Publ Hlth Inst, Mycobacterial Reference Lab, Turku 20530, Finland. RP Musser, JM (reprint author), NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 37 TC 135 Z9 142 U1 0 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2001 VL 47 IS 5 BP 809 EP 814 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 427AT UT WOS:000168383200005 PM 11325882 ER PT J AU Tkaczyk, C Gilfillan, AM AF Tkaczyk, C Gilfillan, AM TI Fc epsilon RI-dependent signaling pathways in human mast cells SO CLINICAL IMMUNOLOGY LA English DT Review ID AFFINITY IGE RECEPTOR; PROTEIN-KINASE-C; IMMUNOGLOBULIN-E RECEPTORS; BASOPHILIC LEUKEMIA-CELLS; N-TERMINAL KINASE; CORD BLOOD-CELLS; TYROSINE KINASE; MEDIATOR RELEASE; RBL-2H3 CELLS; RECOMBINANT HUMAN C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C213,MSC 1881,10 Ctr Dr, Bethesda, MD 20892 USA. NR 137 TC 35 Z9 38 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2001 VL 99 IS 2 BP 198 EP 210 DI 10.1006/clim.2001.4992 PG 13 WC Immunology SC Immunology GA 431QR UT WOS:000168642500002 PM 11318592 ER PT J AU Mermel, LA Farr, BM Sherertz, RJ Raad, II O'Grady, N Harris, JS Craven, DE AF Mermel, LA Farr, BM Sherertz, RJ Raad, II O'Grady, N Harris, JS Craven, DE TI Guidelines for the management of intravascular catheter-related infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; CENTRAL-VENOUS-CATHETER; ANTIBIOTIC-LOCK TECHNIQUE; BLOOD-STREAM INFECTION; DEVICE-RELATED INFECTIONS; CRITICALLY-ILL PATIENTS; LONG-TERM HEMODIALYSIS; SUPPURATIVE PERIPHERAL THROMBOPHLEBITIS; COAGULASE-NEGATIVE STAPHYLOCOCCI; PROSTHETIC VALVE ENDOCARDITIS C1 Lahey Clin Med Ctr, Burlington, MA 01806 USA. Brown Univ, Rhode Isl Hosp, Div Infect Dis, Sch Med, Providence, RI 02903 USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Wake Forest Univ, Sch Med, Sect Infect Dis, Winston Salem, NC USA. Univ Texas MD Anderson Canc Ctr, Dept Internal Med Specialties, Houston, TX 77030 USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. Boston Univ, Sect Pediat Infect Dis, Sch Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Boston Med Ctr, Boston, MA USA. RP Craven, DE (reprint author), Lahey Clin Med Ctr, Burlington, MA 01806 USA. EM Donald.E.Craven@Lahey.org NR 209 TC 735 Z9 785 U1 3 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2001 VL 32 IS 9 BP 1249 EP 1272 DI 10.1086/320001 PG 24 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 429LF UT WOS:000168517900021 PM 11303260 ER PT J AU Metman, LV Gillespie, M Farmer, C Bibbiani, F Konitsiotis, S Morris, M Shill, H Bara-Jimenez, W Mouradian, MM Chase, TN AF Metman, LV Gillespie, M Farmer, C Bibbiani, F Konitsiotis, S Morris, M Shill, H Bara-Jimenez, W Mouradian, MM Chase, TN TI Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease SO CLINICAL NEUROPHARMACOLOGY LA English DT Review DE skin patch; constant delivery system; rotigotine CDS; continuous dopaminergic stimulation; Parkinson's disease; dopamine agonist ID LEVODOPA; COMPLICATIONS; TRIAL AB The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm(2)). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1.400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Metman, LV (reprint author), Rush Presbyterian St Lukes Med Ctr, 1725 W Harrison St,Suite 755, Chicago, IL 60612 USA. OI Mouradian, M. Maral/0000-0002-9937-412X NR 10 TC 72 Z9 75 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-5664 J9 CLIN NEUROPHARMACOL JI Clin. Neuropharmacol. PD MAY-JUN PY 2001 VL 24 IS 3 BP 163 EP 169 DI 10.1097/00002826-200105000-00008 PG 7 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 440HP UT WOS:000169170100008 PM 11391128 ER PT J AU Leocani, L Toro, C Zhuang, P Gerloff, C Hallett, M AF Leocani, L Toro, C Zhuang, P Gerloff, C Hallett, M TI Event-related desynchronization in reaction time paradigms: a comparison with event-related potentials and corticospinal excitability SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE electroencephalography; event-related desynchronization/synchronization; reaction time; simple; choice; go/no go ID TRANSCRANIAL MAGNETIC STIMULATION; MOVEMENT-RELATED POTENTIALS; NO-GO REACTION; SELF-PACED MOVEMENTS; HAND MOVEMENT; COLOR DISCRIMINATION; CORTICAL POTENTIALS; VOLUNTARY MOVEMENT; EVOKED-POTENTIALS; PREFRONTAL CORTEX AB Objectives: To study cortical activity in different motor tasks, we compared event-related desynchronization (ERD) and event-related potentials (ERPs) in different reaction time (RT) paradigms with the time course of corticospinal excitability. Methods: Nine right-handed, normal subjects performed right or left thumb extensions in simple, choice and go/no go auditory RT paradigms. Eight subjects had participated in a previous study evaluating changes in corticospinal excitability during the same paradigms. Twenty-nine EEG channels with electrooculogram and bilateral EMG monitoring were collected. ERPs and ERD of 10 and 18-22 Hz bands were obtained with respect to tone administration and EMG onset. Results: Trials with movement showed lateralized ERP components, corresponding to the motor potential (MP), both in the averages on the tone and on EMG. The MP corresponded well in time and location to the rise in corticospinal excitability on the moving side observed in the previous study. Sensorimotor ERD, followed by event-related synchronization (ERS), was present for trials with movements and for the no go. ERD was present contralaterally during movement preparation and in no go trials, while it was bilateral during motor execution. No go ERD was followed more rapidly by ERS than in trials with movement. This finding suggests that in no go trials, there is a brief active process in the sensorimotor areas. ERD and ERS do not correspond, respectively, in time and location to increases and decreases in corticospinal excitability. In fact, ERD is bilateral during movement execution, when corticospinal inhibition of the side at rest is observed. Contralateral no go ERS occurs later than corticospinal inhibition, which is bilateral. Conclusions: These findings may suggest that ERD is compatible with both corticospinal activation and inhibition, ERS indicating the removal of either, resulting in cortical idling. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 Natl Inst Neurol Disorders & Stroke, Med Neurol Branch, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Milan, Hosp San Raffaele, Dept Neurophysiol, Milan, Italy. RP Hallett, M (reprint author), Natl Inst Neurol Disorders & Stroke, Med Neurol Branch, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. NR 47 TC 91 Z9 91 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAY PY 2001 VL 112 IS 5 BP 923 EP 930 DI 10.1016/S1388-2457(01)00530-2 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 439CQ UT WOS:000169093600027 PM 11336910 ER PT J AU Boroojerdi, B Battaglia, F Muellbacher, W Cohen, LG AF Boroojerdi, B Battaglia, F Muellbacher, W Cohen, LG TI Mechanisms influencing stimulus-response properties of the human corticospinal system SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE stimulus-response curve; transcranial magnetic stimulation; excitability; motor system ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; CORTICAL EXCITABILITY; HUMAN-BRAIN; ANTIEPILEPTIC DRUGS; AMPHETAMINE; MOTONEURONS; LAMOTRIGINE; MODULATION; INHIBITION AB Background: Stimulus-response (S-R) properties of the corticospinal system in humans depend on the interactions that take place at different sites along the corticospinal pathway. The mechanisms influencing stimulus-response curves elicited by transcranial magnetic stimulation (TMS) and their operation site along the human neuraxis are poorly understood. In this study, we investigated the effects of CNS-active drugs with distinct mechanisms of action on S-R curves. Effects of each of these drugs on S-R curves would point to the involvement of specific mechanisms. Additionally, relative sensitivity of S-R curves compared with other measures of corticospinal excitability was studied. Methods: We studied the effects of lorazepam, which is a positive allosteric modulator of GABAA receptors; lamotrigine, an inhibitor of voltage-gated Na+ and Ca2+ channels; and D-amphetamine, an indirect agonist of the dopaminergic-adrenergic system on S-R curves, motor thresholds (MT), and intracortical inhibition (ICI) and facilitation (ICF) with a double-pulse technique. Maximum peripheral M responses and F waves were investigated as measures of the total cr-motoneuron pool and its excitability. Results: F and M waves were unaffected by either the drugs or placebo. S-R curves were significantly depressed by lorazepam and lamotrigine without changes in ICI and ICF. Both S-R curves and ICF were enhanced by D-amphetamine. MT increased only with lamotrigine. Conclusions: S-R curves were influenced by changes in the GABAergic and monoaminergic system and Na+ and Ca2+ channel properties. Our results indicate that, out of different parameters of motor system excitability, S-R curves were the most sensitive. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Kliniken Aachen, Neurol Klin, D-52074 Aachen, Germany. RP Boroojerdi, B (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NR 48 TC 153 Z9 154 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAY PY 2001 VL 112 IS 5 BP 931 EP 937 DI 10.1016/S1388-2457(01)00523-5 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 439CQ UT WOS:000169093600028 PM 11336911 ER PT J AU McKay, R AF McKay, R TI Asymmetry, stem cells and the emergence of function SO CLINICAL NEUROSCIENCE RESEARCH LA English DT Article DE development; stem cells; embryonic stem cells; brain repair; cell division ID CENTRAL-NERVOUS-SYSTEM; ADULT-MOUSE BRAIN; IN-VIVO; HIPPOCAMPAL-NEURONS; HUMAN BLASTOCYSTS; PRECURSOR CELLS; DIFFERENTIATION; GENERATION; TRANSPLANTATION; PROLIFERATION AB How do cells become different from one another? A series of startling observations suggest that muscle, liver and blood may be obtained from the same stem cells. The nervous system also provides good evidence for the importance of stern cells. Recent discoveries open up the possibility of replacement of tissue in neurology and psychiatry and in understanding and even altering basic aspects of the developmental process. (C) 2001 Association for Research in Nervous and Mental Disease. Published by Elsevier Science B.V. All rights reserved. C1 NINCDS, LMB, NIH, Bethesda, MD 20892 USA. RP McKay, R (reprint author), NINCDS, LMB, NIH, Bldg 36,Room 5A29, Bethesda, MD 20892 USA. NR 40 TC 1 Z9 3 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1566-2772 J9 CLIN NEUROSCI RES JI Clin. Neurosci. Res. PD MAY PY 2001 VL 1 IS 3 BP 183 EP 186 AR PII S1566-2771(01)00004-4 DI 10.1016/S1566-2772(01)00004-4 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 529FB UT WOS:000174288400003 ER PT J AU James, LP Wilson, JT Simar, R Farrar, HC Kearns, GL Simpson, PM Hinson, JA Pumford, NR AF James, LP Wilson, JT Simar, R Farrar, HC Kearns, GL Simpson, PM Hinson, JA Pumford, NR CA Pediat Pharmacology Res Unit Netwo TI Evaluation of occult acetaminophen hepatotoxicity in hospitalized children receiving acetaminophen SO CLINICAL PEDIATRICS LA English DT Article ID PARACETAMOL HEPATOTOXICITY; GLUTATHIONE DEFICIENCY; PROTEIN ADDUCTS; TOXICITY; OVERDOSE; PATIENT AB The safety of repeated doses of acetaminophen in ill children with the potential of reduced glutathione stores has been questioned. This study measured hepatic transaminases in children and adolescents (n=100) who received greater than or equal to6 therapeutic doses of acetaminophen over a 48-hour period of hospitalization. Acetaminophen-protein adducts were measured in a cohort of subjects with hepatic transaminase elevation (n=8) and in those (n=10) receiving concurrent drug therapy with agents that induce the cytochrome P450 enzymes involved in acetanlinophen metabolism. Acetaminophen-protein adducts were not detected in this cohort of 18 subjects. Based on this Pilot study the routine use of acetaminophen at therapeutic doses in ill, hospitalized children and adolescents appears safe. C1 Arkansas Childrens Hosp, Little Rock, AR 72202 USA. Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Sect Pediat Clin Pharmacol & Toxicol, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Ctr Appl Res & Evaluat, Little Rock, AR 72205 USA. Louisiana State Univ, Sch Med, Dept Pediat, Clin Pharmacol Sect, Shreveport, LA USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Childrens Mercy Hosp, Sect Pediat Clin Pharmacol & Expt Therapeut, Kansas City, MO 64108 USA. Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. NICHHD, Bethesda, MD 20892 USA. RP James, LP (reprint author), Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA. FU NICHD NIH HHS [UOI HD31324-04] NR 28 TC 8 Z9 8 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD MAY PY 2001 VL 40 IS 5 BP 243 EP 248 DI 10.1177/000992280104000501 PG 6 WC Pediatrics SC Pediatrics GA 434HT UT WOS:000168809600001 PM 11388672 ER PT J AU McCray, AT Gallagher, ME AF McCray, AT Gallagher, ME TI Principles for digital library development SO COMMUNICATIONS OF THE ACM LA English DT Article C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP McCray, AT (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. NR 12 TC 8 Z9 8 U1 0 U2 1 PU ASSOC COMPUTING MACHINERY PI NEW YORK PA 1515 BROADWAY, NEW YORK, NY 10036 USA SN 0001-0782 J9 COMMUN ACM JI Commun. ACM PD MAY PY 2001 VL 44 IS 5 BP 48 EP 54 DI 10.1145/374308.374339 PG 7 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering; Computer Science, Theory & Methods SC Computer Science GA 428PH UT WOS:000168469700015 ER PT J AU Wilkinson, AC Thomas, ML Morse, BC AF Wilkinson, AC Thomas, ML Morse, BC TI Evaluation of a transdermal fentanyl system in yucatan miniature pigs SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID PAIN; MANAGEMENT; PATCH; DOGS AB Of 18 pigs used on a coronary stent experimental protocol, 6 each received a transdermal fentanyl patch to document the patterns of transdermal fentanyl absorption in swine. This approach was taken to reduce animal use and potentially refine the surgical regimen. The objective of the fentanyl portion of the study was to demonstrate that transdermal fentanyl may be useful in the management of postoperative analgesia in swine. This study sought to document that demonstrable levels of fentanyl are achievable in swine plasma via a transdermal system and to compare the magnitude of these levels to data in other species. This study does not directly correlate plasma fentanyl levels with analgesic efficacy. Plasma fentanyl concentration peaked within 42 h in five pigs and within 48 h in the remaining pig. All pigs had similar absorption patterns; the only difference was in magnitude, One pig reached 0.99 ng/ml at 42 h; the next highest concentration was 0.77 ng/ml at 48 h in a different animal. The peak concentration in the others ranged from 0.38 to 0.71 ng/ml. C1 Uniformed Serv Univ Hlth Sci, Dept Lab Anim Med, Bethesda, MD 20814 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Div Vet Med, Washington, DC 20307 USA. RP Wilkinson, AC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Lab Anim Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 16 TC 20 Z9 21 U1 0 U2 8 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD MAY PY 2001 VL 40 IS 3 BP 12 EP 16 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 435XC UT WOS:000168906600003 PM 11353518 ER PT J AU Vignes, S Newman, JD Roberts, RL AF Vignes, S Newman, JD Roberts, RL TI Mealworm feeders as environmental enrichment for common marmosets SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article AB The impact of a foraging enrichment device, the "mealworm feeder," on the behavior of the common marmoset was examined. In 3-h weekly exposures to the wormfeeder device, behavioral observations were conducted to compare the rates of feeder use, use of other enrichment devices, stereotyped behavior, and inactivity, to those of control sessions in which the enrichment device was not provided. Significantly decreased rates of pacing and time spent sitting still were observed in association with placement of the mealworm feeder. Feeder use declined over a period of 3 h, even if the feeders' contents were not fully depleted, and the effects of enrichment on activity waned in a like fashion. Use of other enrichment devices, comprised primarily of cage furniture, increased in the presence of the mealworm feeder. This effect did not change significantly over the 3 h of exposure even though use of the feeder declined. There was significant variation in feeder use among sex and housing condition, with females housed singly and in peer groups using the feeders significantly more than did males, whereas subadults used the feeder significantly more often than did either the dominant female or male in family groups. The results of this study suggest that the mealworm feeder is an effective form of environmental enrichment for the common marmoset, but interest wanes after approximately 3 h. C1 NICHHD, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. RP Roberts, RL (reprint author), POB 529, Poolesville, MD 20837 USA. NR 10 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD MAY PY 2001 VL 40 IS 3 BP 26 EP 29 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 435XC UT WOS:000168906600006 PM 11353521 ER PT J AU Fetters, MD Churchill, L Danis, M AF Fetters, MD Churchill, L Danis, M TI Conflict resolution at the end of life SO CRITICAL CARE MEDICINE LA English DT Article DE terminal care; decision making; resuscitation orders; life support care; ethics; medical; patient participation; physician-patient relations; competence; communication; palliation ID SUSTAINING TREATMENT; PATIENT-RELATIONSHIP; INFORMED CONSENT; PHYSICIANS; AUTONOMY; FUTILITY; MODELS; FAMILY; CARE; COST AB Objective: Limited empirical research has examined how decisions are made when the preferences of terminally ill patients conflict with physicians' recommendations. This study sought to investigate physicians' strategies for resolving conflicts with dying patients, Design: Cross-sectional, qualitative interviews, Subjects, Subjects were 158 physicians caring for at least one terminally ill patient. Setting: University medical center. Measurements and Main Results: We analyzed physicians' responses to the open-ended interview questions, "How do you handle a situation when a patient wants a treatment that you believe does not provide any benefit?" and "How do you handle a situation when a patient does not want a treatment you think would be beneficial?" For patient requests of nonbeneficial treatments, physicians reported the following as important: negotiating with and educating patients (71%), deferring to patient requests for benign or uncomplicated treatments (34%), convincing patients to forgo treatments (33%), refusing patient requests for nonbeneficial treatment (22%), using family influence (16%), not offering futile treatments (13%), and referring to other physicians for disputed care (9%), Potential harm (23%) and cost of treatment (18%) were reasons cited for withholding treatments, In response to patient refusals of beneficial treatments, physicians report the following as important: negotiating with patients (59%), convincing patients to receive treatment (41%), assessing patient competence (32%), using family influence (27%), and referring to other physicians (21%), Conclusions: Physicians vary in the communication and negotiation strategies they use when their medical judgment conflicts with dying patients' preferences. Medical ethicists could play a greater role in teaching ethically important communication skills. Physicians providing care at the end of life report strategies for respecting patients that reflect graduated degrees of accommodation tailored to the costliness and riskiness of requests; they are most accepting of patient requests for benign, technically easy, inexpensive, and medically effective treatments. C1 Univ Michigan Hlth Syst, Dept Family Med, Ann Arbor, MI 48109 USA. Univ Michigan Hlth Syst, Japanese Family Hlth Program, Ann Arbor, MI 48109 USA. Univ N Carolina, Chapel Hill, NC USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Fetters, MD (reprint author), Univ Michigan Hlth Syst, Dept Family Med, 1018 Fuller St, Ann Arbor, MI 48109 USA. FU AHRQ HHS [HS 06655] NR 45 TC 25 Z9 27 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2001 VL 29 IS 5 BP 921 EP 925 DI 10.1097/00003246-200105000-00001 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 431DB UT WOS:000168615700001 PM 11378597 ER PT J AU Buggage, RR Chan, CC Nussenblatt, RB AF Buggage, RR Chan, CC Nussenblatt, RB TI Ocular manifestations of central nervous system lymphoma SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID PRIMARY INTRAOCULAR LYMPHOMA; PRIMARY CNS LYMPHOMA; RETICULUM-CELL SARCOMA; POLYMERASE-CHAIN-REACTION; INTERLEUKIN-6 RATIO; GENE REARRANGEMENT; CLINICAL-FEATURES; CHEMOTHERAPY; DIAGNOSIS; METHOTREXATE AB Primary intraocular lymphoma (PIOL) is a Variant of primary central nervous system lymphoma in which lymphoma cells are initially present only in the eyes without evidence of disease in the brain or cerebrospinal fluid. Patients with PIOL are typically older adults who present with blurred vision and floaters. The ophthalmic examination characteristically shows a cellular infiltrate in the vitreous with or without the presence of subretinal infiltrates. Diagnostic evaluation for PIOL includes neuroimaging, cytologic examination of the cerebrospinal fluid, and a diagnostic vitrectomy with special handling of the Vitreous specimen, if the former is nondiagnostic. Molecular and cytokine analyses are useful adjuncts to cytology for the diagnosis of PIOL. Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest a role for infectious agents in the pathogenesis of PIOL. To date, the best mode for treatment of PIOL or recurrent primary central nervous system lymphoma involving only the eyes remains undefined. Curr Opin Oncol 2001. 13:137-142 (C) 2001 Lippincott Williams & Wilkins, Inc. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20982 USA. RP Buggage, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20982 USA. NR 52 TC 45 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2001 VL 13 IS 3 BP 137 EP 142 DI 10.1097/00001622-200105000-00001 PG 6 WC Oncology SC Oncology GA 427ZM UT WOS:000168436700001 PM 11307054 ER PT J AU Hoffman, JM AF Hoffman, JM TI New advances in brain tumor imaging SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; HIGH-GRADE GLIOMAS; F-18 FLUORODEOXYGLUCOSE; PET; CORTEX; TL-201; MOTOR; MRI AB During the period of this review, there has been continued use and development of neuroimaging techniques in brain tumor diagnosis and management. Although no monumental developments or improvements in neuroimaging techniques or technology have occurred, important studies continue to be published showing the clinical impact and utility of various neuroimaging techniques to improve the care of patients with brain tumors. Several studies have shown the power of functional neuroimaging techniques with both magnetic resonance imaging (MRI) and positron-emission tomography (PET) to map eloquent cortex and assist in the planning of surgical and radiation therapy. New nuclear imaging radiopharmaceuticals, including various PET ligands and single photon emission computed tomography (SPECT) agents. have also been developed and show their potential power in the evaluation of brain tumor patients. New MRI pulse sequences to improve image quality and shorten imaging time have also been developed. Several excellent reviews of the use of fluorodeoxyglucose (FDG)-PET and MRI techniques were also published. This article reviews the relevant and important neuroimaging literature related to brain tumor that was published during the defined time period of November 1, 1999 to October 31, 2000. Discussion is organized by modality, including nuclear imaging techniques (SPECT and PET) and MRI (pulse sequence development, contrast agent development, functional MRI developments, and general MRI-related information). Curr Opin Oncol 2001. 13:148-153 (C) 2001 Lippincott Williams & Wilkins. Inc. C1 NCI, Mol Imaging Branch, Biomed Imaging Program, Bethesda, MD 20892 USA. RP Hoffman, JM (reprint author), NCI, Mol Imaging Branch, Biomed Imaging Program, EPN-6066,6130 Execut Blvd,MSC 7412, Bethesda, MD 20892 USA. NR 19 TC 17 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2001 VL 13 IS 3 BP 148 EP 153 DI 10.1097/00001622-200105000-00003 PG 6 WC Oncology SC Oncology GA 427ZM UT WOS:000168436700003 PM 11307056 ER PT J AU Ernst, M Chefer, S AF Ernst, M Chefer, S TI Neuroimaging and substance abuse disorders in the year 2000 SO CURRENT OPINION IN PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DEPENDENT PATIENTS; MARIJUANA USE; LONG-TERM; ALCOHOL; BRAIN; ABSTINENT; RECEPTORS; ECSTASY; HEROIN AB This review summarizes the findings of substance abuse research published throughout the year 2000, which used noninvasive neuroimaging approaches. These findings encompass abnormalities in brain morphometry, integrated brain activity, cognitive activation and neurochemical systems associated with various aspects of substance abuse disorders. The methodological strengths and weaknesses of these studies are critically addressed, and future research directions are outlined. Curr Opin Psychiatry 14:179-185. (C) 2001 Lippincott Williams & Wilkins. C1 NIDA, Brain Imaging Ctr, NIH, Baltimore, MD 21224 USA. RP Ernst, M (reprint author), NIMH, Mood & Anxiety Disorders Program, 1-B3-10,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. NR 30 TC 2 Z9 2 U1 12 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAY PY 2001 VL 14 IS 3 BP 179 EP 185 DI 10.1097/00001504-200105000-00004 PG 7 WC Psychiatry SC Psychiatry GA 433CF UT WOS:000168737200004 ER PT J AU Hoare, SRJ Usdin, TB AF Hoare, SRJ Usdin, TB TI Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; TERMINALLY SUBSTITUTED ANALOG; FIRST EXTRACELLULAR LOOP; NMR SOLUTION STRUCTURE; TUBEROINFUNDIBULAR PEPTIDE; BINDING DOMAIN; 39 RESIDUES; H-1-NMR SPECTROSCOPY; PTH/PTHRP RECEPTOR; PROTEIN-RECEPTOR AB The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) and tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal a-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction), The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Hoare, SRJ (reprint author), NIMH, Genet Lab, Bldg 36,Rm 3D06,36 Convent Dr MSC4090, Bethesda, MD 20892 USA. NR 130 TC 42 Z9 42 U1 2 U2 5 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAY PY 2001 VL 7 IS 8 BP 689 EP 713 DI 10.2174/1381612013397825 PG 25 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 439CG UT WOS:000169092800006 PM 11375776 ER PT J AU von Stebut, E Udey, MC AF von Stebut, E Udey, MC TI Langerhans cells in cutaneous infections: Cellular bridges between innate and adaptive immunity SO CURRENT PROBLEMS IN DERMATOLOGY-US LA English DT Review ID DENDRITIC CELLS; BORRELIA-BURGDORFERI; OLIGODEOXYNUCLEOTIDES; INTERLEUKIN-12; LEISHMANIASIS; ACTIVATION; LEPROSY C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP von Stebut, E (reprint author), NCI, Dermatol Branch, Bldg 10, Bethesda, MD 20892 USA. NR 29 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1040-0486 J9 CURR PROBL DERM-US JI Curr. Probl. Dermatol. PD MAY-JUN PY 2001 VL 13 IS 3 BP 167 EP 172 DI 10.1016/S1040-0486(01)70010-5 PG 6 WC Dermatology SC Dermatology GA 439VP UT WOS:000169138500006 ER PT J AU Steinert, PM AF Steinert, PM TI Keratins: Dynamic, flexible structural proteins of epithelial cells SO CURRENT PROBLEMS IN DERMATOLOGY-US LA English DT Review ID INTERMEDIATE FILAMENT NETWORKS; PLECTIN; COMPONENTS; DISEASES; VIMENTIN; GENE C1 NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. RP Steinert, PM (reprint author), NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. NR 27 TC 5 Z9 5 U1 1 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1040-0486 J9 CURR PROBL DERM-US JI Curr. Probl. Dermatol. PD MAY-JUN PY 2001 VL 13 IS 3 BP 193 EP 198 DI 10.1016/S1040-0486(01)70013-0 PG 6 WC Dermatology SC Dermatology GA 439VP UT WOS:000169138500009 ER PT J AU Telford, WG Moss, MW Morseman, JP Allnutt, FCT AF Telford, WG Moss, MW Morseman, JP Allnutt, FCT TI Cryptomonad algal phycobiliproteins as fluorochromes for extracellular and intracellular antigen detection by flow cytometry SO CYTOMETRY LA English DT Article DE flow cytometry; cryptomonad algae; phycobiliprotein; phycocyanin; CryptoFluor (TM) ID IMMUNOFLUORESCENCE; PHYCOERYTHRIN; BILIPROTEINS AB Background: Phycobiliproteins play an important role in fluorescent labeling, particularly for flow cytometry. The spectral properties of R-phycoerythrin (R-PE) and allophy- cocyanin (APC) have made them the dominant reagents in this class of fluorochromes. In this study, we evaluate a lesser-known but potentially important series of low-molecular weight cryptomonad-derived phycobiliproteins (commercially termed the CryptoFluor (TM) dyes) for their applicability to now cytometry, both in extracellular and intracellular labeling applications. Methods: Several cell lines were labeled with biotin-conjugated antibodies against expressed extracellular surface proteins, followed by streptavidin conjugates of three cryptomonad phycobiliproteins (CryptoFluor-2, CryptoFluor-4, and CryptoFluor-5). Cells were then analyzed by flow cytometry using a variety of laser lines and emission filters to establish the optimal excitation/emission characteristics for each fluorochrome. Some cells mere permeabilized and labeled for intracellular antigens, also using the cryptomonad fluorochromes. Where appropriate, parallel samples were labeled with other fluorochromes (including R-PE, APC, the cyanin dyes Cy3 and Cy5, and others) to gauge the performance of the cryptomonad fluorochromes against fluorescent labels previously evaluated for flow cytometry. Results: CryptoFluor-2 possessed excitation/emission maxima similar to those of APC and Cy5, with good excitation in the red (HeNe laser 632 nm) and strong emission in the far red (660 nn). CryptoFluor-4 possessed excitation/emission maxima similar to those of Cy3, with optimal excitation in the green (Kr 530 nm) and strong emission in the yellow-orange (585 nm). CryptoFluor-5 possessed excitation/emission maxima similar to these of lissamine rhodamine, with optimal excitation in the yellow (Kr 568 nm) and emission in the orange (610 nm). AU cryptomonad fluorochromes gave satisfactory results for both intracellular and extracellular labeling, with detection sensitivities that were comparable or better than traditional phycobiliproteins and low- molecular weight synthetic fluorochromes such as the cyanin dyes. Conclusions: The CryptoFluor fluorochromes were applicable to flow cytometric immunodetection, with excitation and emission conditions commonly found on multilaser instruments. Performance of several of these dyes was at least comparable to existing fluorescent labels. The low molecular weights (30-60 kd) of phycobiliproteins may make them particularly useful in intracellular antigen detection. Cytometry 44:16-23, 2001. Published 2001 Wiley-Liss, Inc.dagger. C1 NCI, Med Branch, Div Clin Sci, Dept Expt Transplantat & Immunol,NIH, Bethesda, MD 20892 USA. Martek Biosci Corp, Columbia, MD USA. RP Telford, WG (reprint author), NCI, Med Branch, Div Clin Sci, Dept Expt Transplantat & Immunol,NIH, Bldg 10 Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 15 Z9 15 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 0196-4763 J9 CYTOMETRY JI Cytometry PD MAY 1 PY 2001 VL 44 IS 1 BP 16 EP 23 DI 10.1002/1097-0320(20010501)44:1<16::AID-CYTO1077>3.0.CO;2-H PG 8 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426JT UT WOS:000168346600003 PM 11309804 ER PT J AU Tjioe, I Legerton, T Wegstein, J Herzenberg, LA Roederer, M AF Tjioe, I Legerton, T Wegstein, J Herzenberg, LA Roederer, M TI Phycoerythrin-allophycocyanin: A resonance energy transfer fluorochrome for immunofluorescence SO CYTOMETRY LA English DT Article DE phycobiliproteins; immunophenotyping; fluorescent dyes; antibody conjugation AB Background: As immunofluorescence experiments become more complex, the demand for new dyes with different properties increases. Fluorescent dyes fifth large Stoke's shifts that are very bright and have low background binding to cells are especially desirable. We report on the properties of the resonance energy tandems of phycoerythrin and allophycocyanin (PE-APC). PE-APC is the original fluorescence resonance energy tandem dye described in the literature, but it has not been utilized because of the difficulty of synthesizing and preparing a consistent product. Methods: PE-APC complexes comprising different ratios of the two phycobiliproteins conjugated to streptavidin were synthesized using standard protein-protein conjugation chemistry. The PE-APC streptavidins were evaluated for flow cytometric analysis. They were compared directly to Cy5PE conjugates because Cy5PE is the fluorophore that is spectrally most like the PE-APC. Results: PE-APC complexes showed the expected fluorescence spectral properties of a tandem: excitation was excellent at 488 nm (and best at the PE excitation maximum) and emission was greatest at the APC emission maximum at about 660 nm. The efficiency of transfer of energy from PE to APC was about 90%. Conclusion: PE-APC can be considered an excellent substitute for Cy5PE. Compared with Cy5PE, PE-APC has similar brightness (in staining experiments), slightly greater compensation requirements with PE but much lower compensation with Cy5.5PE or Cy5.5PerCP, and lower nonspecific background binding. PE-APC is a useful alternative to Cy5PE, especially in applications in which the use of Cy5 is impractical. Cytometry 44:24 -29, 2001. Published 2001 Wiley-Liss, Inc.(dagger). C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Stanford Univ, Dept Genet, Stanford, CA 94305 USA. ProZyme Inc, San Leandro, CA USA. RP Roederer, M (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 FU NCI NIH HHS [CA-42509, CA-81543] NR 3 TC 13 Z9 13 U1 2 U2 8 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOMETRY JI Cytometry PD MAY 1 PY 2001 VL 44 IS 1 BP 24 EP 29 PG 6 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426JT UT WOS:000168346600004 PM 11309805 ER PT J AU Njoroge, JM Mitchell, LB Centola, M Kastner, D Raffeld, M Miller, JL AF Njoroge, JM Mitchell, LB Centola, M Kastner, D Raffeld, M Miller, JL TI Characterization of viable autofluorescent macrophages among cultured peripheral blood mononuclear cells SO CYTOMETRY LA English DT Article DE autofluorescence; flow cytometry; macrophages; IL-1 alpha; erythropoiesis; human blood ID HUMAN ALVEOLAR MACROPHAGES; DENDRITIC CELLS; CHRONIC DISEASE; IDENTIFICATION; EXPRESSION; PHENOTYPE; FLAVINS; SMOKERS; ANEMIA AB Background: Inflammatory macrophages that demonstrate intense autofluorescence have been isolated directly from alveolar and peritoneal tissues, but their generation in vitro remains vague. We use flow cytometry to identify a population of autofluorescent macrophages as they arise among nonadherent populations of cultured blood mononuclear cells. Methods: Cells R ere obtained from donated blood buffy coats and placed in culture for ii days. Unstained populations from the cells remaining in suspension were sampled daily using flow cytometry. During the first 5 culture days, a distinct population of autofluorescent cells arose and comprised an avenge of less than or equal to 14% of the total cell population. This population declined to less than 6% by culture day 8. Results: The cells were identified as viable macrophages expressing CD68, lysozyme, and HLA-DR. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) demonstrated a unique cytokine profile with IL-1 alpha expression levels 138-fold higher than those measured in uncultured monocytes. No significant elevation in the levels of other cytokines was identified. Upon replating, the sorted populations became readherent, were able to ingest plastic beads, and remained viable for G or more additional weeks in culture without evidence of proliferation or multinucleation. Conclusion: Viable autofluorescent macrophage populations arising among cultured peripheral blood may be easily identified and isolated for further study using flow cytometry. Cytometry 44:38-44, 2001. Published 2001 Wiley-Liss, Inc.(dagger). C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Oklahoma Med Res Fdn, Arthrit & Immunol Program, Oklahoma City, OK 73104 USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. NCI, Pathol Lab, NIH, Bethesda, MD USA. RP Miller, JL (reprint author), NIDDK, Biol Chem Lab, NIH, Bldg 10,Room 9B17, Bethesda, MD 20892 USA. NR 28 TC 12 Z9 12 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 0196-4763 J9 CYTOMETRY JI Cytometry PD MAY 1 PY 2001 VL 44 IS 1 BP 38 EP 44 DI 10.1002/1097-0320(20010501)44:1<38::AID-CYTO1080>3.0.CO;2-T PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426JT UT WOS:000168346600006 PM 11309807 ER PT J AU Lu, JI Oliver, B AF Lu, JI Oliver, B TI Drosophila OVO regulates ovarian tumor transcription by binding unusually near the transcription start site SO DEVELOPMENT LA English DT Article DE initiator; ovo; germ cell; ovarian tumor; transcription; sex determination; Drosophila ID LINE SEX DETERMINATION; RNA-POLYMERASE-II; FEMALE-STERILE MUTATIONS; TATA-BOX; GENE REGION; FUNCTIONAL INTERACTIONS; PROMOTER SPECIFICITY; BASAL TRANSCRIPTION; MOLECULAR ANALYSIS; STAND STILL AB Evolutionarily conserved ovo loci encode developmentally regulated, sequence-specific, DNA-binding, C2H2-zinc-finger proteins required in the germline and epidermal cells of flies and mice. The direct targets of OVO activity are not known. Genetic experiments suggest that ovo acts in the same regulatory network as ovarian tumor (otu), but the relative position of these genes in the pathway is controversial. Three OVO-binding sites exist in a compact regulatory region that controls germline expression of the otu gene. Interestingly, the strongest OVO-binding site is very near the otu transcription start, where basal transcriptional complexes must function. Loss-of-function, gain-of-function and promoter swapping constructs demonstrate that OVO binding near the transcription start site is required for OVO-dependent otu transcription in vivo, These data unambiguously identify otu as a direct OVO target gene and raise the tantalizing possibility that an OVO site, at the location normally occupied by basal components, functions as part of a specialized core promoter. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 76 TC 23 Z9 24 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY PY 2001 VL 128 IS 9 BP 1671 EP 1686 PG 16 WC Developmental Biology SC Developmental Biology GA 434EN UT WOS:000168802300017 PM 11290304 ER PT J AU Lowe, LA Yamada, S Kuehn, MR AF Lowe, LA Yamada, S Kuehn, MR TI Genetic dissection of nodal function in patterning the mouse embryo SO DEVELOPMENT LA English DT Article DE nodal; anteroposterior axis; left-right asymmetry; node; lateral plate mesoderm; mouse ID LEFT-RIGHT ASYMMETRY; ANTERIOR PRIMITIVE ENDODERM; RIGHT AXIS FORMATION; ONE-EYED PINHEAD; MESODERM INDUCTION; CRANIOFACIAL DEVELOPMENT; EXPRESSION PATTERN; SPEMANN ORGANIZER; SIGNALING PATHWAY; VISCERAL ENDODERM AB Loss-of-function analysis has shown that the transforming growth factor-like signaling molecule nodal is essential for mouse mesoderm development. However, definitive proof of nodal function in other developmental processes in the mouse embryo has been lacking because the null mutation blocks gastrulation. We describe the generation and analysis of a hypomorphic nodal allele, Mouse embryos heterozygous for the hypomorphic allele and a null allele undergo gastrulation but then display abnormalities that fall into three distinct mutant phenotypic classes, which may result from expression levels falling below critical thresholds in one or more domains of nodal expression. Our analysis of each of these classes provides conclusive evidence for nodal-mediated regulation of several developmental processes in the mouse embryo, beyond its role in mesoderm formation. We find that nodal signaling is required for correct positioning of the anteroposterior axis, normal anterior and midline patterning, and the left-right asymmetric development of the heart, vasculature, lungs and stomach. C1 NCI, Expt Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Kuehn, MR (reprint author), NCI, Expt Immunol Branch, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RI Kuehn, Michael/A-4573-2014 OI Kuehn, Michael/0000-0002-7703-9160 NR 78 TC 221 Z9 223 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY PY 2001 VL 128 IS 10 BP 1831 EP 1843 PG 13 WC Developmental Biology SC Developmental Biology GA 438MJ UT WOS:000169057400011 PM 11311163 ER PT J AU Damjanovski, S Amano, T Li, Q Pei, DQ Shi, YB AF Damjanovski, S Amano, T Li, Q Pei, DQ Shi, YB TI Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: Implications for tissue-dependent functions of matrix metalloproteinases during late embryonic development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE transgenesis; extracellular matrix (ECM); Xenopus laevis; morphogenesis; matrix metalloproteinase (MMP) ID EXTRACELLULAR-MATRIX; THYROID-HORMONE; STROMELYSIN-3 GENE; AMPHIBIAN METAMORPHOSIS; MOUSE STROMELYSIN-3; FIBROBLASTIC CELLS; FROG METAMORPHOSIS; DISTINCT FUNCTIONS; TAIL RESORPTION; BREAST-CANCER AB The extracellular matrix (ECM) functions as the structural support of cells and as a medium for cell-cell interactions. It is understood to play critical roles in development. ECM remodeling is mediated largely through the action of matrix metalloproteinases (MMPs), a family of Zn2+-dependent proteases capable of degrading various proteinaceous components of the ECM, MMPs are expressed in many developmental and pathologic processes. However, few studies have been carried out to investigate the function of MMPs during embryogenesis and postembryonic organogenesis. By using Xenopus development as a model system, we have previously shown that several MMP genes are expressed from neurulation to the completion of embryogenesis in distinct tissues/organs, suggesting that ECM remodeling during mid- to late embryogenesis occurs in an organ-specific manner. By using the recently developed transgenic technology for Xenopus laevis, we overexpressed Xenopus MMPs stromelysin-3 (ST3) and collagenase-4 (Col4) under the control of a ubiquitous promoter and observed that embryos with overexpressed ST3 or Col4, but not the control green fluorescent protein (GFP), died in a dose-dependent manner during late embryogenesis, The specificity of this embryonic lethal phenotype was confirmed by the failure of a catalytically inactive mutant of ST3 to affect development, Finally, overexpression of a mammalian membrane type-MMP also led to late embryonic lethality in Xenopus embryos, suggesting that membrane type-MMPs have functions in vivo for ECM remodeling, in addition to being activators of other pro-MMPs. These data together with the developmental expression of several MMPs during Xenopus development, suggest that MMPs play important roles during mid- to late embryogenesis and that proper regulation of MMP genes is critical for tissue morphogenesis and organogenesis. (C) 2001 Wiley-Liss, Inc. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. RP Shi, YB (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. RI Damjanovski, Sashko/N-8728-2015 NR 58 TC 27 Z9 27 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 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAY PY 2001 VL 221 IS 1 BP 37 EP 47 DI 10.1002/dvdy.1123 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 427EQ UT WOS:000168392200004 PM 11357192 ER PT J AU Dudek, SM AF Dudek, SM TI Multidimensional gene expression in cortical space - Commentary SO DEVELOPMENTAL SCIENCE LA English DT Editorial Material C1 NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Dudek, SM (reprint author), NICHHD, Dev Neurobiol Lab, NIH, Bldg 49,Room 5A38,MSC 4480,49 Convent Dr, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1363-755X J9 DEVELOPMENTAL SCI JI Dev. Sci. PD MAY PY 2001 VL 4 IS 2 BP 145 EP 146 PG 2 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA 461LW UT WOS:000170366600004 ER PT J AU Yakar, S Liu, JL Fernandez, AM Wu, YP Schally, AV Frystyk, J Chernausek, SD Mejia, W Le Roith, D AF Yakar, S Liu, JL Fernandez, AM Wu, YP Schally, AV Frystyk, J Chernausek, SD Mejia, W Le Roith, D TI Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity SO DIABETES LA English DT Article ID GROWTH-FACTOR-I; HORMONE-RELEASING HORMONE; FACTOR-BINDING PROTEIN-1; RECEPTOR SUBSTRATE-1; TRANSGENIC MICE; POTENT ANTAGONISTS; GLUCOSE-TOLERANCE; INTERFERON-GAMMA; RESISTANCE; SECRETION AB Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. To study the metabolic consequences of IGF-I deficiency, we used the liver IGF-I-deficient (LID) mouse model. The LID mice show a marked reduction (similar to 75%) in circulating IGF-I and elevated growth hormone (GH) levels. Interestingly, LTD mice show a fourfold increase in serum insulin levels (2.2 vs. 0.6 ng/ml in control mice) and abnormal glucose clearance after insulin injection. Fasting blood glucose levels and those after a glucose tolerance test were similar between the LID mice and their control littermates. Thus, the high levels of circulating insulin enable the LID mice to maintain normoglycemia in the presence of apparent insulin insensitivity. Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LLD mice. In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-l were normal in muscle of LID mice. Thus, the insulin insensitivity seen in the LID mice is muscle specific. Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. Treatment of the LID mice with GH-releasing hormone antagonist, which reduces GH levels, also increased insulin sensitivity. These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues. C1 NIDDK, Sect Cellular & Mol Physiol, Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, New Orleans, LA USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. Aarhus Univ Hosp, Inst Expt Clin Res, DK-8000 Aarhus, Denmark. Childrens Hosp, Dept Endocrinol, Cincinnati, OH USA. RP Le Roith, D (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Room 8D12,Bldg 10, Bethesda, MD 20892 USA. OI Schally, Andrew/0000-0003-1273-6747 NR 49 TC 226 Z9 243 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2001 VL 50 IS 5 BP 1110 EP 1118 DI 10.2337/diabetes.50.5.1110 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427EN UT WOS:000168392000025 PM 11334415 ER PT J AU Dubois-Laforgue, D Hendel, H Caillat-Zucman, S Zagury, JF Winkler, C Boitard, C Timsit, J AF Dubois-Laforgue, D Hendel, H Caillat-Zucman, S Zagury, JF Winkler, C Boitard, C Timsit, J TI A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes SO DIABETES LA English DT Article ID DENDRITIC CELLS; PROGRESSION; SUSCEPTIBILITY; MELLITUS; DISEASE; DESTRUCTION; FAMILIES; SDF-1 AB presence of the SDFI-3'A allele was associated with a 5-year reduction in the age at onset of diabetes (P = Type 1 diabetes results from the autoimmune destruction of pancreatic beta -cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. The recruitment of mononuclear cells within the islets of Langerhans is a critical step in the pathogenesis of the disease. Because chemokines are cytokines that promote migration of mononuclear cells, we hypothesized that polymorphisms in chemokine receptor or chemokine genes, CCR5 and SDF1, may be involved in susceptibility to or clinical expression of type 1 diabetes. The frequencies of the CCR5-Delta 32 and SDF1-3'A (801G -->A in the 3' untranslated region) variants were similar in 208 unrelated Caucasian patients with type 1 diabetes and in 120 Caucasian control subjects. They were ndt modified after stratification for the predisposing HLA-DR3 and -DR4 haplotypes, However, the SDF1-3'A variant was strongly associated with early onset (<15 years) of the disease (odds ratio 2.6, P = 0.0019), On average, the presence of the SDF1-3'A allele was associated with a 0.0067), Our results suggest that stromal cell-derived factor-1 may be implicated in the aggressiveness of the autoimmune process leading to type 1 diabetes, These preliminary data require replication in other populations. C1 Hop Necker Enfants Malad, Serv Immunol Clin, Unite Diabetol, F-75015 Paris, France. Hop Necker Enfants Malad, Immunol Lab, F-75015 Paris, France. Univ Paris 06, Unite Physiol Cellulaire, Paris, France. Hop Cochin, Inst Cochin Genet Mol, INSERM U342, F-75674 Paris, France. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Timsit, J (reprint author), Hop Necker Enfants Malad, Serv Immunol Clin, Unite Diabetol, 161 Rue Sevres, F-75015 Paris, France. FU NCI NIH HHS [N01-CO-56000] NR 20 TC 44 Z9 46 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2001 VL 50 IS 5 BP 1211 EP 1213 DI 10.2337/diabetes.50.5.1211 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427EN UT WOS:000168392000039 PM 11334429 ER PT J AU Williams, DE Knowler, WC Smith, CJ Hanson, RL Roumain, J Saremi, A Kriska, AM Bennett, PH Nelson, RG AF Williams, DE Knowler, WC Smith, CJ Hanson, RL Roumain, J Saremi, A Kriska, AM Bennett, PH Nelson, RG TI The effect of Indian or angle dietary preference on the incidence of diabetes in Pima Indians SO DIABETES CARE LA English DT Article ID PHYSICAL-ACTIVITY; FOOD FREQUENCY; INSULIN RESPONSES; GLYCEMIC INDEX; CARBOHYDRATE; GLUCOSE; FIBER; METABOLISM; MELLITUS; OBESITY AB OBJECTIVE - In short-term studies, adoption of a traditional diet is associated with reduction in metabolic abnormalities often found in populations experiencing rapid lifestyle changes. We examined rile long-term effects of a self-assessed traditional or nontraditional dietary pattern on the development of type 2 diabetes in 165 nondiabetic Pima Indians. RESEARCH DESIGN AND METHODS - Dietary intake was assessed in 1988 by a quantitative food frequency method. and subjects were asked to classify their diet as "Indian.'' "Anglo," or "mixed." The Indian diet reflects a preference for Sonoran-style and traditional desert foods. The Anglo diet reflects a preference for non-Sonoran-style foods typical of the remaining regions of the U.S. RESULTS - in women, the intake of complex carbohydrates, dietary fiber, insoluble fiber, vegetable proteins, and the proportion of total calories From complex carbohydrate and vegetable proteins were significantly higher (P < 0.05) in the Indian than in the Anglo diet. The mixed diet was intermediate in of ail these constituents. in men, the intake For these nutrients was also higher in the Indian than in the Angle group, but not significantly. Diabetes developed in 36 subjects (8 men and 28 women) during 6.2 years of follow-up (range 0.9-10.9). The crude incidence rates of diabetes were 23, 35, and 63 cases per 1,000 person-years in the Indian, mixed, and Anglo groups, respectively. After adjustment for age, sex, BMI, and total energy intake in a proportional hazards model, the risk of developing diabetes in the Angle-diet group was 2.5 times as high (95% CI 0.9-7.2) and the rate in the mixed-diet group was 1.3 times as high (0.6-3.3) as in the Indian-diet group. CONCLUSIONS - This study suggests that the adoption of an Anglo diet may increase the risk of developing diabetes in Pima Indians, but it does not provide unequivocal evidence For or against this hypothesis. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. Univ Calif Irvine, Irvine, CA USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. RP Williams, DE (reprint author), NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU NIDDK NIH HHS [N01-DK-62285] NR 29 TC 39 Z9 43 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2001 VL 24 IS 5 BP 811 EP 816 DI 10.2337/diacare.24.5.811 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 425VN UT WOS:000168312500004 PM 11347735 ER PT J AU Meneilly, GS McIntosh, CHS Pederson, RA Habener, JF Gingerich, R Egan, JM Elahi, D AF Meneilly, GS McIntosh, CHS Pederson, RA Habener, JF Gingerich, R Egan, JM Elahi, D TI Glucagon-like peptide-1(7-37) augments insulin release in elderly patients with diabetes SO DIABETES CARE LA English DT Letter ID GLUCOSE-TOLERANCE; YOUNG; RATS C1 Univ British Columbia, Dept Med, Vancouver, BC, Canada. Univ British Columbia, Dept Physiol, Vancouver, BC, Canada. NIA, Lab Clin Phsyiol, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Linco Res, St Charles, MO USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Mol Endocrinol Lab, Boston, MA 02115 USA. RP Meneilly, GS (reprint author), Vancouver Hosp & Hlth Sci Ctr, Rm S 169,UBC Site,2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 9 TC 9 Z9 9 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2001 VL 24 IS 5 BP 964 EP 965 DI 10.2337/diacare.24.5.964 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 425VN UT WOS:000168312500040 PM 11347771 ER PT J AU Simsir, A Palacios, D Linehan, WM Merino, MJ Abati, A AF Simsir, A Palacios, D Linehan, WM Merino, MJ Abati, A TI Detection of loss of heterozygosity at chromosome 3p25-26 in primary and metastatic ovarian clear-cell carcinoma: Utilization of microdissection and polymerase chain reaction in archival tissues SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 88th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 20-27, 1999 CL SAN FRANCISCO, CALIFORNIA SP US & Canadian Acad Pathol DE chromosome 3; loss of heterozygosity; clear-cell carcinoma; ovary ID FINE-NEEDLE ASPIRATION; TUMOR-SUPPRESSOR GENE; RENAL-CARCINOMA; SPECIMENS; DELETION; IDENTIFICATION; BORDERLINE; DIAGNOSIS AB Loss of heterozygosity (LOH) at the 3p region is Sound in lip to 50% of epithelial ovarian neoplasms. The von Hippel-Lindau (VHL) gene at the 3p25 locus is one of the the tumor-suppressor genes located at 3p. The role, if any, of the VHL gene locus is not clear in ovarian carcinogenesis. We analyzed primary and metastatic ovarian clear-cell carcinomas (OCCC) for LOH at 3p25 to determine its frequency and its diagnostic utility as an adjunctive tool in rite differential diagnosis of metastatic clear-cell carcinomas. Microdissection followed by single-step DNA extraction and polymerase chain reaction (PCR) amplification, using two polymorphic markers flanking the VHL gene locus, was done on archival histology and cytology samples from 9 patients with metastatic OCCC. Of the informative cases, 43% of the metastatic and 50% of the primary OCCC showed LOH. LOH at the VHL gene locus is not uncommon in clear-cell ovarian carcinoma. LOH at 3p25 in cytologic specimens may be a valuable adjunct in the diagnosis of OCCC metastasis in cytologically equivocal cases. OCCC should enter rite differential in clear-cell carcinomas of unknown primary that show LOH at 3p25. Published 2001 Wiley-Liss, Inc. C1 NIH, NCI, Pathol Lab, Cytopathol Sect, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NIH, NCI, Pathol Lab, Cytopathol Sect, 10 Ctr Dr,Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 20 TC 14 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 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD MAY PY 2001 VL 24 IS 5 BP 328 EP 332 DI 10.1002/dc.1070 PG 5 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 428VD UT WOS:000168481600005 PM 11335962 ER PT J AU Roy, PK Patel, SC Kataria, YP AF Roy, PK Patel, SC Kataria, YP TI Necrotizing fasciitis of abdominal wall in AIDS SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article ID PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; SOFT-TISSUE INFECTIONS C1 E Carolina Univ, Sch Med, Dept Med, Greenville, NC 27858 USA. RP Roy, PK (reprint author), NIH, Digest Dis Branch, Bldg 10,Rm 9C-103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 4 Z9 4 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD MAY PY 2001 VL 46 IS 5 BP 1139 EP 1142 DI 10.1023/A:1010790802197 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 428QQ UT WOS:000168472700032 PM 11341661 ER PT J AU Birger, Y Ito, Y West, KL Landsman, D Bustin, M AF Birger, Y Ito, Y West, KL Landsman, D Bustin, M TI HMGN4, a newly discovered nucleosome-binding protein encoded by an intronless gene SO DNA AND CELL BIOLOGY LA English DT Article ID GROUP CHROMOSOMAL-PROTEINS; MOBILITY GROUP PROTEIN-14; MURINE GENE; HMG-17; CHROMATIN; DNA; NUCLEUS; REGION; IDENTIFICATION; DISTINCT AB We describe a newly discovered nuclear protein, HMGN4, that is closely related to the canonical HMGN2 nucleosome-binding protein. The protein is encoded by an intronless gene, which, in humans, is located in the hereditary hemachromatosis region at position 6p21.3, A single similar to2-kb HMGN4 mRNA was found to be expressed, in variable amounts, in all human tissues tested; however, the HMGN4 transcript was significantly less abundant than that of HMGN2, The HMGN4 protein could be detected in HeLa cells by Western analysis with an antibody elicited against a unique region of the protein. Transfection of HeLa cells with a plasmid expressing HMGN4-GFP indicated that the protein localizes to the nucleus. Our results expand the multiplicity of the HMGN protein family and increase the known cellular repertoire of nucleosome-binding proteins. C1 NCI, Prot Sect, Lab Metab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Birger, Y (reprint author), NCI, Prot Sect, Lab Metab, Div Basic Sci,NIH, Bldg 37,Room 3D-12, Bethesda, MD 20892 USA. RI Landsman, David/C-5923-2009; Bustin, Michael/G-6155-2015; OI Landsman, David/0000-0002-9819-6675 NR 35 TC 21 Z9 21 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD MAY PY 2001 VL 20 IS 5 BP 257 EP 264 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 437FG UT WOS:000168979900002 PM 11410162 ER PT J AU Litt, MD Simpson, M Recillas-Targa, F Prioleau, MN Felsenfeld, G AF Litt, MD Simpson, M Recillas-Targa, F Prioleau, MN Felsenfeld, G TI Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci SO EMBO JOURNAL LA English DT Article DE acetylation; boundaries; chromatin domains; folate receptor; globin genes ID BETA-GLOBIN DOMAIN; CHROMATIN STRUCTURE; ACETYLTRANSFERASE ACTIVITY; GENE-EXPRESSION; IN-VIVO; DEACETYLATION; INSULATORS; ACTIVATION; DROSOPHILA; HYPERACETYLATION AB We have studied developmentally regulated patterns of histone acetylation at high resolution across similar to 54 kb of DNA containing three independently regulated but neighboring genetic loci. These include a folate receptor gene, a 16 kb condensed chromatin region, the chicken beta -globin domain and an adjacent olfactory receptor gene. Within these regions the relative levels of acetylation appear to fall into three classes. The condensed chromatin region maintains the lowest acetylation at every developmental stage. Genes that are inactive show similarly low levels, but activation results in a dramatic increase in acetylation. The highest levels of acetylation are seen at regulatory sites upstream of the genes. These patterns imply the action of more than one class of acetylation. Notably, there is a very strong constitutive focus of hyperacetylation at the 5' insulator element separating the globin locus from the folate receptor region, which suggests that this insulator element may harbor a high concentration of histone acetylases. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Prioleau, Marie-Noelle/G-9824-2014 NR 36 TC 292 Z9 302 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 1 PY 2001 VL 20 IS 9 BP 2224 EP 2235 DI 10.1093/emboj/20.9.2224 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 430WC UT WOS:000168597600012 PM 11331588 ER PT J AU Asano, K Shalev, A Phan, L Nielsen, K Clayton, J Valasek, L Donahue, TF Hinnebusch, AG AF Asano, K Shalev, A Phan, L Nielsen, K Clayton, J Valasek, L Donahue, TF Hinnebusch, AG TI Multiple roles for the C-terminal domain of eIF5 in translation initiation complex assembly and GTPase activation SO EMBO JOURNAL LA English DT Article DE eukaryotic translation initiation factor (eIF); GAP; Met-tRNA(i)(Met) binding; mRNA binding; scanning ID SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; PROTEIN-SYNTHESIS; BETA-SUBUNIT; BINDING-PROTEIN; START CODON; IN-VIVO; YEAST; EXCHANGE; GCN4 AB eIF5 stimulates the GTPase activity of eIF2 bound to Met-tRNA(i)(Met), and its C-terminal domain (eIF5-CTD) bridges interaction between eIF2 and eIF3/eIF1 in a multifactor complex containing Met-tRNA(i)(Met). The tif5-7A mutation in eIF5-CTD, which destabilizes the multifactor complex in vivo, reduced the binding of Met-tRNA(i)(Met) and mRNA to 40S subunits in vitro. Interestingly, eIF5-CTD bound simultaneously to the eIF4G subunit of the cap-binding complex and the NIP1 subunit of eIF3. These interactions may enhance association of eIF4G with eIF3 to promote mRNA binding to the ribosome, In vivo, tif5-7A eliminated eIF5 as a stable component of the pre-initiation complex and led to accumulation of 48S complexes containing eIF2; thus, conversion of 48S to 80S complexes is the rate-limiting defect in this mutant. We propose that eIF5-CTD stimulates binding of Met-tRNA(i)(Met) and mRNA to 40S subunits through interactions with eIF2, eIF3 and eIF4G; however, its most important function is to anchor eIF5 to other components of the 48S complex in a manner required to couple GTP hydrolysis to AUG recognition during the scanning phase of initiation. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RI Valasek, Leos/I-5743-2014 NR 28 TC 81 Z9 82 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 1 PY 2001 VL 20 IS 9 BP 2326 EP 2337 DI 10.1093/emboj/20.9.2326 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 430WC UT WOS:000168597600021 PM 11331597 ER PT J AU Musser, JM AF Musser, JM TI Single nucleotide polymorphisms in Mycobacterium tuberculosis structural genes SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID BIOLOGY C1 NIH, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), NIH, Hamilton, MT 59840 USA. NR 6 TC 6 Z9 6 U1 0 U2 0 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAY-JUN PY 2001 VL 7 IS 3 BP 486 EP 487 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 436TP UT WOS:000168952200034 PM 11384544 ER PT J AU Butler, AA LeRoith, D AF Butler, AA LeRoith, D TI Minireview: Tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology SO ENDOCRINOLOGY LA English DT Review ID FACTOR-I RECEPTOR; POSTNATAL-GROWTH; PERINATAL LETHALITY; TRANSGENIC MICE; RELAXATION; CANCER; SYSTEM; CELLS AB The insulin-like growth factors (IGF-I and IGF-II) and the IGF-I receptor are critically important for normal growth and development of the organism. Gene-deletion of these elements has demonstrated that IGF-I is important for both prenatal and postnatal development, whereas IGF-II is important during prenatal stages only. The IGF-I receptor gene-deleted mouse dies at birth apparently as a result of poor muscular development. Utilizing the conditional gene-deletion approach, we have demonstrated that mice lacking the liver IGF-I gene have an approximately 80% reduction in circulating total IGF-I levels. Despite this marked reduction, postnatal growth and development was normal, suggesting that liver IGF-I is not essential for this function. Local tissue IGF-I production was unaffected and may compensate for the lack of the liver IGF-I. Further studies are ongoing to establish the role of the endocrine us, the autocrine/paracrine IGF-I. C1 NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA. RP LeRoith, D (reprint author), NIDDK, NIH, Clin Endocrinol Branch, 3,NIH MSC 1758,Bldg 10,Room 8D12,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 139 Z9 142 U1 0 U2 5 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2001 VL 142 IS 5 BP 1685 EP 1688 DI 10.1210/en.142.5.1685 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427YN UT WOS:000168434500001 PM 11316729 ER PT J AU Falcon, J Galarneau, KM Weller, JL Ron, B Chen, G Coon, SL Klein, DC AF Falcon, J Galarneau, KM Weller, JL Ron, B Chen, G Coon, SL Klein, DC TI Regulation of arylalkylamine N-acetyltransferase-2 (AANAT2, EC 2.3.1.87) in the fish pineal organ: Evidence for a role of proteasomal proteolysis SO ENDOCRINOLOGY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; TROUT ONCORHYNCHUS-MYKISS; MELATONIN SYNTHESIS; IN-VITRO; PHOTORECEPTOR CELLS; CHICK PINEAL; SECRETION; LIGHT; PIKE; DARKNESS AB In fish, individual photoreceptor cells in the pineal organ and retina contain complete melatonin rhythm generating systems. In the pike and seabream, this includes a photodetector, circadian clock, and melatonin synthesis machinery; the trout lacks a functional clock. The melatonin rhythm is due in part to a nocturnal increase in the activity of the arylalkylamine N-acetyltransferase (AANAT) which is inhibited by light. Two AANATs have been identified in fish: AANAT1, more closely related to AANATs found in higher vertebrates, is specifically expressed in the retina; AANAT2 is specifically expressed in the pineal organ. We show that there is a physiological day/night rhythm in pineal AANAT2 protein in the pike, and that light exposure at midnight decreases the abundance of AANAT2 protein and activity. In culture, this decrease is blocked by inhibitors of the proteasomal degradation pathway. If glands are maintained under light at night, treatment with these inhibitors increases AANAT2 activity and protein. Organ culture studies with the trout and seabream also indicate that the light-induced decrease of AANAT2 activity is prevented when proteasomal proteolysis is blocked. A cAMP-dependent pathway protects AANAT2 protein from degradation. These results provide a clue to understanding how light regulates the daily rhythm in melatonin secretion in Gsh photoreceptor cells and provides evidence that proteasomal proteolysis is a conserved element in the regulation of AANAT in vertebrates. C1 NICHHD, Dev Neurobiol Lab, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. CNRS UMR 6558, Lab Neurobiol Cellulaire, Dept Neurosci, F-86022 Poitiers, France. Natl Ctr Mariculture, Oceanog & Limnol Res Inst, Fish Physiol Dept, IL-88112 Eilat, Israel. RP Klein, DC (reprint author), NIH 49-6A82, Bethesda, MD 20892 USA. RI FALCON, Jack/I-5302-2013; Deligiannidis, Kristina/C-3654-2014 OI FALCON, Jack/0000-0002-7572-6581; Deligiannidis, Kristina/0000-0001-7439-2236 NR 36 TC 58 Z9 65 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2001 VL 142 IS 5 BP 1804 EP 1813 DI 10.1210/en.142.5.1804 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427YN UT WOS:000168434500017 PM 11316744 ER PT J AU Wang, XL Zhou, J Doyle, ME Egan, JM AF Wang, XL Zhou, J Doyle, ME Egan, JM TI Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic B-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism SO ENDOCRINOLOGY LA English DT Article ID FACTOR-I IPF-1; TRANSCRIPTION FACTOR; BETA-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; MEDIATED PHOSPHORYLATION; GENE-TRANSCRIPTION; DIABETES-MELLITUS; INSULIN-SECRETION; BINDING-ACTIVITY; GLUCOSE AB Glucagon-like peptide-1 (GLP-1) enhances insulin secretion and synthesis. It also regulates the insulin, glucokinase, and GLUT2 genes. It mediates increases in glucose-stimulated insulin secretion by activating adenylyl cyclase and elevating free cytosolic calcium levels in the beta -cell. In addition, GLP-1 has been shown, both in vitro and in vivo, to be involved in regulation of the transcription factor, pancreatic duodenal homeobox-l protein (PDX-1), by increasing its total protein levels, its translocation to the nucleus and its binding and resultant increase in activity of the insulin gene promoter in beta -cells of the pancreas. Here we have investigated the role of protein kinase A (PKA) in these processes in RIN 1046-38 cells. Three separate inhibitors of PKA, and a cAMP antagonist, inhibited the effects of GLP-1 on PDX-1. Furthermore, forskolin, (which stimulates adenylyl cyclase and insulin secretion), and 8-Bromo-cAMP, (an analog of cAMP which also stimulates insulin secretion), mimicked the effects of GLP-1 on PDX-1. These effects were also prevented by PKA inhibitors. Glucose-mediated increases in nuclear translocation of PDX-1 were not prevented by PKA inhibitors. Our results suggest that regulation of PDX-1 by GLP-1 occurs through activation of adenylyl cyclase and the resultant increase in intracellular cAMP, in turn, activates PKA, which ultimately leads to increases in PDX-1 protein levels and translocation of the protein to the nuclei of beta -cells. C1 NIA, Diabet Sect, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, Diabet Sect, Gerontol Res Ctr, NIH, 23,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 32 TC 95 Z9 104 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2001 VL 142 IS 5 BP 1820 EP 1827 DI 10.1210/en.142.5.1820 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427YN UT WOS:000168434500019 PM 11316746 ER PT J AU Karas, M Koval, AP Zick, Y LeRoith, D AF Karas, M Koval, AP Zick, Y LeRoith, D TI The insulin-like growth factor I receptor-induced interaction of insulin receptor substrate-4 and Crk-II SO ENDOCRINOLOGY LA English DT Article ID TYROSINE PHOSPHORYLATION; GLUCOSE-HOMEOSTASIS; SIGNAL-TRANSDUCTION; PROTEINS; PROTOONCOGENE; PRODUCT; FAMILY; CELLS; IGF AB Stimulation of the insulin or insulin-like growth factor (IGF)-I receptor results in activation of several signaling pathways. Proteins of the insulin receptor substrate (IRS) family play important roles in mediating these signaling cascades. To date, four members of the IRS family of docking proteins have been characterized. Recently, we have reported that stimulation of the IGF-I receptor in 293 HEK cells regulates interaction of the newly discovered IRS-4 molecule with the Crk. family of proteins. In the present study, we characterize the molecular basis of these interactions. C- and N termini truncation analysis of IRS-4 demonstrated that the region between amino acids 678 and 800 of the IRS-4 molecule is involved in this interaction. This region contains a cluster of four tyrosines (Y-700, Y-717, Y-743, and Y-779). We hypothesize that one or more of these tyrosines are involved in the interaction between the SH2 domain of the Crk-II molecule when IRS-4 is phosphorylated upon IGF-I receptor activation. Additional mutational analyses confirmed this hypothesis. Interestingly, none of these four tyrosines was individually critical for the interaction between Crk-II and IRS-4, but when all four tyrosines were simultaneously mutated to phenylalanine, the IGF-I induced interaction between these molecules was abolished. Taken together, these results suggest a novel mechanism of Crk-II binding to tyrosine phosphorylated proteins. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Mol & Cell Biol, IL-76100 Rehovot, Israel. RP LeRoith, D (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10,Room 8D12,10 Ctr Dr,MSC 1758, Bethesda, MD 20892 USA. NR 21 TC 10 Z9 12 U1 0 U2 2 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2001 VL 142 IS 5 BP 1835 EP 1840 DI 10.1210/en.142.5.1835 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427YN UT WOS:000168434500021 PM 11316748 ER PT J AU Allaben, WT Bucher, JR Howard, PC AF Allaben, WT Bucher, JR Howard, PC TI International conference on the toxicology of fumonisin: Introduction SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Allaben, WT (reprint author), US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NR 2 TC 4 Z9 4 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2001 VL 109 SU 2 BP 237 EP 237 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 434PF UT WOS:000168824500008 ER PT J AU Gelderblom, WCA Abel, S Smuts, CM Marnewick, J Marasas, WFO Lemmer, ER Ramljak, D AF Gelderblom, WCA Abel, S Smuts, CM Marnewick, J Marasas, WFO Lemmer, ER Ramljak, D TI Fumonisin-induced hepatocarcinogenesis: Mechanisms related to cancer initiation and promotion SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article; Proceedings Paper CT ILSI North America International Conference on the Toxicology of Fumonisin CY JUN 28-30, 1999 CL ARLINGTON, VA DE fatty acids; fumonisins; Fusarium verticillioides; hepatocarcinogenesis; hypothesis; mechanisms; phospholipids ID HEPATOCYTE GROWTH-FACTOR; PRIMARY RAT HEPATOCYTES; CELL-CYCLE PROGRESSION; PROTEIN-KINASE-C; LIVER IN-VIVO; FUSARIUM-MONILIFORME; ARACHIDONIC-ACID; CLONAL ADAPTATION; B MYCOTOXINS; FACTOR-ALPHA AB We review the hepatocarcinogenic effects of fungal cultures of Fusarium verticillioides(= Fusarium moniliforme) strain MRC 826 in male ED IX rats. Subsequent chemical analyses of the fumonisin B (FB) mycotoxin content in the culture material used and long-term carcinogenesis studies with purified FB(1) provide information about dose-response effects, relevance of hepatotoxicity during FB(1)-induced carcinogenesis, and the existence of a no-effect threshold. Fumonisin intake levels of between 0.08 and 0.16 mg FB/100 g body weight (bw)/day over approximately 2 years produce liver cancer in male ED IX rats. Exposure levels < 0.08 mg FB/100 g bw/day fail to induce cancer, although mild toxic and preneoplastic lesions are induced. The nutritional status of the diets used in the long-term experiments was marginally deficient in lipotropes and vitamins and could have played an important modulating role in fumonisin-induced hepatocarcinogenesis. Short-term studies in a cancer initiation/promotion model in rat liver provided important information about the possible mechanisms involved during the initial stages of cancer development by this apparently nongenotoxic mycotoxin. These studies supported the findings of long-term investigations indicating that a cytotoxic/proliferative response is required for cancer induction and that a no-effect threshold exists for cancer induction. The mechanisms proposed far cancer induction are highlighted and include the possible role of oxidative damage during initiation and the disruption of lipid metabolism, integrity of cellular membranes, and altered growth-regulatory responses as important events during promotion. C1 S African MRC, PROMEC, ZA-7505 Tygerberg, South Africa. S African MRC, Natl Res Programme Nutr Intervent, ZA-7505 Tygerberg, South Africa. Univ Cape Town, MRC, Liver Res Ctr, Cape Town, South Africa. NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Gelderblom, WCA (reprint author), S African MRC, PROMEC, POB 19070, ZA-7505 Tygerberg, South Africa. EM wentzel.gelderblom@mrc.ac.za NR 79 TC 110 Z9 115 U1 0 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2001 VL 109 SU 2 BP 291 EP 300 DI 10.2307/3435021 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 434PF UT WOS:000168824500016 PM 11359698 ER PT J AU Melnick, RL AF Melnick, RL TI Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl)phthalate (DEHP)? SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE apoptosis; cell proliferation; di(2-ethylhexyl)phthalate; hypolipidemic drugs; peroxisome proliferation; peroxisome proliferator activated receptor ID ACTIVATED RECEPTOR-ALPHA; INDUCED HEPATOCYTE PROLIFERATION; HAMSTER EMBRYO CELLS; ACYL-COA OXIDASE; DNA-SYNTHESIS; PPAR-ALPHA; SPECIES-DIFFERENCES; IN-VITRO; LIVER CARCINOGENESIS; ELEMENT UPSTREAM AB Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, has been listed by the International Agency for Research on Cancer (IARC) and by the National Toxicology Program as a possible or reasonably anticipated human carcinogen because it induces dose-related increases in liver tumors in both sexes of rats and mice. Recently, the suggestion has been advanced that DEHP should be considered unlikely to be a human carcinogen because it is claimed that the carcinogenic effects of this agent in rodents are due to peroxisome proliferation and that humans are nonresponsive to this process. An IARC working group recently downgraded DEHP to "not classifiable as to its carcinogenicity to humans" because they concluded that DEHP produces liver tumors in rats and mice by a mechanism involving peroxisome proliferation, which they considered to be not relevant to humans. The literature review presented in this commentary reveals that, although our knowledge of the mechanism of peroxisome proliferation has advanced greatly over the past 10 years, our understanding of the mechanism(s) of carcinogenicty of peroxisome proliferators remains incomplete. Most important is that published studies have not established peroxisome proliferation per se as an obligatory pathway in the carcinogenicity of DEHP. No epidemiologic studies have been reported on the potential carcinogenicity of DEHP, and cancer epidemiologic studies of hypolipidemic fibrate drugs (peroxisome proliferators) are inconclusive. Most of the pleiotropic effects of peroxisome proliferators are mediated by the peroxisome proliferator activated receptor (PPAR), a ligand-activated transcription factor that is expressed at lower levels in humans than in rats and mice. In spite of this species difference in PPAR expression, hypolipidemic fibrates have been shown to induce hypolipidemia in humans and to modulate gene expression (e.g., genes regulating lipid homeostasis) in human hepatocytes by PPAR activation. Thus, humans are responsive to agents that induce peroxisome proliferation in rats and mice. Because peroxisome proliferators can affect multiple signaling pathways by transcriptional activation of PPAR-regulated genes, it is likely that alterations in specific regulated pathways (e.g., suppression of apoptosis, protooncogene expression) are involved in tumor induction by peroxisome proliferators. In addition, because DEHP also induces biological effects that occur independently of peroxisome proliferation (e.g., morphologic cell transformation and decreased levels of gap junction intercellular communication), it is possible that some of these responses also contribute to the carcinogenicity of this chemical. Last, species differences in tissue expression of PPARs indicate that it may not be appropriate to expect exact site correspondence for potential PPAR-mediated effects induced by peroxisome proliferators in animals and humans. Because peroxisome proliferation has nor been established as an obligatory step in the carcinogenicity of DEHP, the contention that DEHP poses no carcinogenic risk to humans because of species differences in peroxisome proliferation should be viewed as an unvalidated hypothesis. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Melnick, RL (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 55 TC 65 Z9 79 U1 1 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2001 VL 109 IS 5 BP 437 EP 442 DI 10.2307/3454700 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 438YA UT WOS:000169080800021 PM 11401753 ER PT J AU Garry, VF Tarone, RE Kirsch, IR Abdallah, JM Lombardi, DP Long, LK Burroughs, BL Barr, DB Kesner, JS AF Garry, VF Tarone, RE Kirsch, IR Abdallah, JM Lombardi, DP Long, LK Burroughs, BL Barr, DB Kesner, JS TI Biomarker correlations of urinary 2,4-d levels in foresters: Genomic instability and endocrine disruption SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE 2,4-D; foresters; reproductive hormones; V(D)J rearrangements ID 2,4-DICHLOROPHENOXYACETIC ACID; EXPOSURE; HERBICIDES; WORKERS; PESTICIDES; ADJUVANTS; LYMPHOMA; RISK; DNA AB Forest pesticide applicators constitute a unique pesticide use group. Aerial, mechanical-ground, and focal weed control by application of herbicides, in particular chlorophenoxy herbicides, yield diverse exposure scenarios. In the present work, we analyzed aberrations in G-banded chromosomes, reproductive hormone levels, and polymerase chain reaction-based V(D)J rearrangement frequencies in applicators whose exposures were mostly limited to chlorophenoxy herbicides. Data from appliers where chlorophenoxy use was less frequent were also examined. The biomarker outcome data were compared to urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) obtained at the time of maximum 2,4-D use. Further comparisons of outcome data were made to the total volume of herbicides applied during the entire pesticide-use season. Twenty-four applicators and 15 minimally exposed foresters (control) subjects were studied. Categorized by applicator method, men who used a hand-held, backpack sprayer in their applications showed the highest average level (453.6 ppb) of 2,4-D in urine. Serum luteinizing hormone (LH) values were correlated with urinary 2,4-D levels, but follicle-stimulating hormone and free and total testosterone were not. At the height of the application season; 6/7 backpack sprayers, 3/4 applicators who used multinozzle mechanical (boom) sprayers, 4/8 aerial applicators, and 2/5 skidder-radiarc (closed cab) appliers had two or more V(D)J region rearrangements per microgram of DNA. Only 5 of 15 minimally exposed (control) foresters had two or more rearrangements, and 3 of these 5 subjects demonstrated detectable levels of 2,4-D in the urine. Only 8/24 DNA samples obtained from the exposed group 10 months or more after their last chlorophenoxy use had two rearrangements per microgram of DNA, suggesting that the exposure-related effects observed were reversible and temporary. Although urinary 2,4-D levels were not correlated with chromosome aberration frequency, chromosome aberration frequencies were correlated with the total volume of herbicides applied, including products other than 2,4-D. In summary, herbicide applicators with high urinary levels of 2,4-D (backpack and boom spray applications) exhibited elevated LH levels. They also exhibited altered genomic stability as measured by V(D)J rearrangement frequency, which appears reversible months after peak exposure. Though highly detailed, the limited sample size warrants cautious interpretation of the data. C1 Univ Minnesota, Environm Med & Pathol Lab, Minneapolis, MN 55414 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Dept Genet, Med Branch, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NIOSH, Reprod Hlth Assessment Sect, Cincinnati, OH USA. RP Garry, VF (reprint author), Univ Minnesota, Environm Med & Pathol Lab, 421 29th Ave SE, Minneapolis, MN 55414 USA. EM garry001@maroon.tc.umn.edu RI Barr, Dana/E-2276-2013; Barr, Dana/E-6369-2011 NR 28 TC 11 Z9 13 U1 1 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2001 VL 109 IS 5 BP 495 EP 500 DI 10.2307/3454708 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 438YA UT WOS:000169080800029 ER PT J AU Weinberg, CR AF Weinberg, CR TI It's time to rehabilitate the P-value SO EPIDEMIOLOGY LA English DT Editorial Material C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NR 7 TC 28 Z9 30 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2001 VL 12 IS 3 BP 288 EP 290 DI 10.1097/00001648-200105000-00004 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 426UP UT WOS:000168367000004 PM 11337598 ER PT J AU Brinton, LA Lubin, JH Burich, MC Colton, T Hoover, RN AF Brinton, LA Lubin, JH Burich, MC Colton, T Hoover, RN TI Mortality among augmentation mammoplasty patients SO EPIDEMIOLOGY LA English DT Article DE breast implants; mortality; risk; respiratory diseases; brain neoplasms; respiratory tract neoplasms; suicide ID CONNECTIVE-TISSUE DISEASES; SILICONE BREAST-IMPLANTS; FEMALE HEALTH-PROFESSIONALS; RETROSPECTIVE COHORT; NEUROLOGIC DISEASE; CANCER DIAGNOSIS; WOMEN; RISK; POPULATION; DISORDERS AB Much attention has focused on disease risks among women receiving silicone breast implants, but there has been little evaluation of their mortality experience. We undertook a retrospective cohort study of 13,488 women receiving cosmetic implants and 3,936 patients with other types of plastic surgery at 18 plastic surgery practices. After an average of 13 years of follow-up, deficits in overall mortality were found as compared with the general population (U.S, rates) for both implant [255 deaths; standardized mortality ratio (SMR) = 0.69, 95% confidence interval (CI) = 0.6-0.8] and comparison subjects (125 deaths; SMR = 0.58, 95% CI = 0.5-0.7). These findings indicate that patients seeking plastic surgery are in general healthier than their peers. Implant patients, however, experienced excess risks of death compared with the general population for brain cancer (SMR = 2.45) and suicide (SMR = 1.54). Internal analyses showed a higher overall mortality among the implant than among the comparison patients (relative risk = 1.27, 95% CI = 1.0-1.6). This overall excess reflected increases for respiratory tract (SMR = 3.03) and brain (SMR = 2.25) cancers and for suicide (SMR = 4.24). C1 NCI, Environm Epidemiol Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Boston Univ, Dept Epidemiol & Biostat, Boston, MA 02215 USA. RP Brinton, LA (reprint author), NCI, Environm Epidemiol Branch, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 38 TC 58 Z9 58 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2001 VL 12 IS 3 BP 321 EP 326 DI 10.1097/00001648-200105000-00012 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 426UP UT WOS:000168367000012 PM 11337605 ER PT J AU Appella, E AF Appella, E TI Modulation of p53 function in cellular regulation SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Editorial Material C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 3 TC 20 Z9 20 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD MAY PY 2001 VL 268 IS 10 BP 2763 EP 2763 DI 10.1046/j.1432-1327.2001.02224.x PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437AP UT WOS:000168968300001 PM 11358489 ER PT J AU Appella, E Anderson, CW AF Appella, E Anderson, CW TI Post-translational modifications and activation of p53 by genotoxic stresses SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Review DE DNA damage; phosphorylation; acetylation; stability; transcriptional activation; CBP; p300; MDM2; PML; ATM ID DEPENDENT PROTEIN-KINASE; TUMOR-SUPPRESSOR PROTEIN; DAMAGE-INDUCED PHOSPHORYLATION; GLOBAL GENOMIC REPAIR; DNA-DAMAGE; IN-VIVO; P53-DEPENDENT APOPTOSIS; ENHANCED PHOSPHORYLATION; PREMATURE SENESCENCE; CATALYTIC SUBUNIT AB In unstressed cells, the tumor suppressor protein p53 is present in a latent state and is maintained at low levels through targeted degradation. A variety of genotoxic stresses initiate signaling pathways that transiently stabilize the p53 protein, cause it to accumulate in the nucleus, and activate it as a transcription factor. Activation leads either to growth arrest at the G(1)/S or G(2)/M transitions of the cell cycle or to apoptosis. Recent studies point to roles for multiple post-translational modifications in mediating these events in response to genotoxic stresses through several potentially interacting but distinct pathways. The approximate to 100 amino-acid N-terminal and approximate to 90 amino-acid C-terminal domains are highly modified by post-translational modifications. The N-terminus is heavily phosphorylated while the C-terminus contains phosphorylated, acetylated and sumoylated residues. Antibodies that recognize p53 only when it has been modified at specific sites have been developed, and studies with these reagents show that most known post-translational modifications are induced when cells are exposed to genotoxic stresses. These recent results, coupled with biochemical and genetic studies, suggest that N-terminal phosphorylations are important for stabilizing p53 and are crucial for acetylation of C-terminal sites, which in combination lead to the full p53-mediated response to genotoxic stresses. Modifications to the C-terminus inhibit the ability of this domain to negatively regulate sequence-specific DNA binding; additionally, they modulate the stability, the oligomerization state, the nuclear import/export process and the degree of ubiquitination of p53. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. RP Appella, E (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 80 TC 754 Z9 773 U1 11 U2 57 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD MAY PY 2001 VL 268 IS 10 BP 2764 EP 2772 DI 10.1046/j.1432-1327.2001.02225.x PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437AP UT WOS:000168968300002 PM 11358490 ER PT J AU Correale, P Campoccia, G Tsang, KY Micheli, L Cusi, MG Sabatino, M Bruni, G Sestini, S Petrioli, R Pozzessere, D Marsili, S Fanetti, G Giorgi, G Francini, G AF Correale, P Campoccia, G Tsang, KY Micheli, L Cusi, MG Sabatino, M Bruni, G Sestini, S Petrioli, R Pozzessere, D Marsili, S Fanetti, G Giorgi, G Francini, G TI Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2: results from a phase Ib clinical trial SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE phase Ib clinical trial; immunotherapy; hr-GM-CSF; hr-IL-2; dentritic cells; antigen-specific immunoreactivity ID COLONY-STIMULATING FACTOR; T-LYMPHOCYTES; HUMAN BLOOD; II TRIAL; IN-VIVO; INTERLEUKIN-2; CARCINOMA; IMMUNOTHERAPY; GENERATION; RESPONSES AB Experimental findings suggest that granulocyte-monocyte-colony stimulating factor (GM-CSF) synergistically interacts with interleukin-2 (IL-2) in generating an efficient antigen-specific immune response. We evaluated the toxicity antitumour activity and immunobiological effects of human recombinant (hr)-GM-CSF and hr-IL-2 in 25 cancer patients who subcutaneously (s.c.) received hr-GM-CSF 150 mug/day for 5 days, followed by hrIL-2 s.c. for 10 days and 15 days rest. Two of the most common side-effects were bone pain and fever. Of the 24 patients evaluable for response, 3 achieved partial remission, 13 experienced stable disease, and 8 progressed. Cytokine treatment increased the number of monocytes, dendritic cells (DC), and lymphocytes (memory T cells) in the peripheral blood and enhanced the antigen-specific immunoreactivity of these patients. Our results show that the hr-GM-CSF and hr-IL-2 combination is active and well tolerated. Its biological activity may support tumour associated antigen (TAA)-specific anticancer immunotherapy by increasing antigen presenting cell (APC) activity and T cell immune competence in vivo. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 Univ Siena, Div Med Oncol, I-53100 Siena, Italy. Univ Siena, Blood Bank, I-53100 Siena, Italy. NCI, Expt Oncol Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD USA. Univ Siena, Dept Pharmacol Giorgio Segre, I-53100 Siena, Italy. Univ Siena, Dept Mol Biol, I-53100 Siena, Italy. RP Francini, G (reprint author), Univ Siena, Div Med Oncol, Viale Bracci 11, I-53100 Siena, Italy. RI Correale, Pierpaolo/K-1640-2016 OI Correale, Pierpaolo/0000-0003-2154-6734 NR 32 TC 33 Z9 33 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAY PY 2001 VL 37 IS 7 BP 892 EP 902 DI 10.1016/S0959-8049(01)00063-6 PG 11 WC Oncology SC Oncology GA 432UV UT WOS:000168714800018 PM 11313178 ER PT J AU Greenwald, P Clifford, CK Milner, JA AF Greenwald, P Clifford, CK Milner, JA TI Diet and cancer prevention SO EUROPEAN JOURNAL OF CANCER LA English DT Review DE cancer prevention; diet and cancer; folate; gene-nutrient interactions; genetic; polymorphisms ID POLYUNSATURATED FATTY-ACIDS; METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM; NUTRITION INTERVENTION TRIALS; RANDOMIZED CONTROLLED TRIAL; DISEASE-SPECIFIC MORTALITY; TIME PHYSICAL-ACTIVITY; CELL-CYCLE ARREST; BREAST-CANCER; PROSTATE-CANCER; COLON-CANCER AB Research from several sources provides strong evidence that vegetables, fruits, and whole grains, dietary fibre, certain micronutrients. some fatty acids and physical activity protect against some cancers. In contrast, other factors, such as obesity, alcohol, some fatty acids and food preparation methods may increase risks. Unravelling the multitude of plausible mechanisms for the effects of dietary factors on cancer risk will likely necessitate that nutrition research moves beyond traditional epidemiological and metabolic studies. Nutritional sciences must build on recent advances in molecular biology and genetics to move the discipline from being largely 'observational' to focusing on 'cause and effect'. Such basic research is fundamental to cancer prevention strategies that incorporate effective dietary interventions for target populations. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. hll rights reserved. C1 NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Rockville, MD 20852 USA. RP Greenwald, P (reprint author), NCI, Div Canc Prevent, NIH, Bldg 31,Room 10A52,31 Ctr Dr,MSC 2580, Bethesda, MD 20892 USA. NR 202 TC 185 Z9 192 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAY PY 2001 VL 37 IS 8 BP 948 EP 965 DI 10.1016/S0959-8049(01)00070-3 PG 18 WC Oncology SC Oncology GA 434DB UT WOS:000168798900011 PM 11334719 ER PT J AU Lu, KM Lee, MH Carpten, JD Sekhon, M Patel, SB AF Lu, KM Lee, MH Carpten, JD Sekhon, M Patel, SB TI High-resolution physical and transcript map of human chromosome 2p21 containing the sitosterolaemia locus SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE BAC contig; mapping; positional cloning; atherosclerosis genes ID RADIATION HYBRID MAP; HUMAN GENOME; CHOLESTEROL-BIOSYNTHESIS; POSITIONAL CLONING; HUMAN GENES; XANTHOMATOSIS; DISEASE; EXPRESSION; ABSORPTION; REGION AB Sitosterolaemia (phytosterolaemia) is an autosomal recessive disorder characterised by the presence of tendon xanthomas in the face of normal or mildly elevated plasma cholesterol levels, premature atherosclerotic disease and has diagnostically elevated plasma and tissue plant sterol concentrations. Affected individuals show an increased absorption of both cholesterol and sitosterol from the diet, decreased bile clearance of these sterols and their metabolites resulting in markedly expanded whole body cholesterol and sitosterol pools. The defective gene is therefore hypothesised to play a crucial role in regulating dietary cholesterol absorption, and its elucidation may shed light on these molecular processes. We have previously localised the defective gene to human chromosome 2p21, between microsatellite markers D251788 and D2S1352, a distance of approximately 15 cM. Recently, the disease locus interval has been narrowed to lie between D2S2294 and D2S2291/D2S2174. We have constructed a high-resolution YAC and BAC contigs by using known STSs and generating novel STSs from the minimal interval. Eight previously identified genes and 60 ESTs were mapped to these contigs. The BAC contig contains 60 BAC clones and 108 STSs and encompasses a physical distance of approximately 2.0 cM between microsatellite markers D2S2294 and D2S2291. These results will not only facilitate cloning of the sitosterolaemia gene, but also other disease genes located in this region, and accelerate sequencing of the corresponding genomic clones. C1 Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. NHGRI, Prostate Canc Invest Grp, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA. RP Patel, SB (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, STR 541,114 Doughty St, Charleston, SC 29403 USA. OI Patel, Shailendra/0000-0003-0046-5513 FU NCRR NIH HHS [M01 RR001070, MO1 RR01070-25, M01 RR000633]; NHLBI NIH HHS [HL60616, R01 HL060613] NR 43 TC 11 Z9 11 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAY PY 2001 VL 9 IS 5 BP 364 EP 374 DI 10.1038/sj.ejhg.5200627 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 434DC UT WOS:000168799000007 PM 11378825 ER PT J AU Lee, MH Gordon, D Ott, J Lu, KM Ose, L Miettinen, T Gylling, H Stalenhoef, AF Pandya, A Hidaka, H Brewer, B Kojima, H Sakuma, N Pegoraro, R Salen, G Patel, SB AF Lee, MH Gordon, D Ott, J Lu, KM Ose, L Miettinen, T Gylling, H Stalenhoef, AF Pandya, A Hidaka, H Brewer, B Kojima, H Sakuma, N Pegoraro, R Salen, G Patel, SB TI Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE genetics; homozygosity mapping; linkage; cholesterol; atherosclerosis; diet ID INCREASED SITOSTEROL ABSORPTION; LINKAGE DISEQUILIBRIUM; BETA-SITOSTEROLEMIA; XANTHOMATOSIS; DISEASE; PLASMA; HETEROZYGOTES; POPULATIONS; ELIMINATION; PEDIGREE AB Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM. C1 Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. Rikshosp, Lipid Res Clin, N-0027 Oslo, Norway. Univ Helsinki, Cent Hosp, Dept Internal Med, FIN-00290 Helsinki, Finland. Univ Nijmegen, Ctr Med, NL-6500 HB Nijmegen, Netherlands. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA 23298 USA. Sanyo Elect Grp Hlth Insurance Assoc, Osaka 5700079, Japan. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Shiga Univ Med Sci, Dept Med 3, Shiga 52021, Japan. Nagoya City Univ, Dept Med 3, Nagoya, Aichi 467861, Japan. Univ Natal, Fac Med, ZA-4013 Congella, South Africa. Univ Med & Dent New Jersey, Div Gastroenterol, Newark, NJ 07103 USA. RP Patel, SB (reprint author), Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, STR 541,MUSC,114 Doughty St, Charleston, SC 29403 USA. RI Stalenhoef, A.F.H./H-8094-2014; OI Patel, Shailendra/0000-0003-0046-5513 FU NCRR NIH HHS [M01 RR000633, M01 RR001070, MO1 RR01070-25]; NHGRI NIH HHS [HG00008, R01 HG000008]; NHLBI NIH HHS [HL60616, R01 HL060613] NR 32 TC 28 Z9 30 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAY PY 2001 VL 9 IS 5 BP 375 EP 384 DI 10.1038/sj.ejhg.5200628 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 434DC UT WOS:000168799000008 PM 11378826 ER PT J AU Kissel, K Santoso, S Hofmann, C Stroncek, D Bux, J AF Kissel, K Santoso, S Hofmann, C Stroncek, D Bux, J TI Molecular basis of the neutrophil glycoprotein NB1 (CD177) involved in the pathogenesis of immune neutropenias and transfusion reactions SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE neutrophil; granulocyte; NB1; antigen; primary structure ID UROKINASE PLASMINOGEN-ACTIVATOR; NATURAL-KILLER CELLS; FC-GAMMA-RECEPTOR; ANTIGEN NB1; MEMBRANE-PROTEIN; LUNG INJURY; ANTIBODIES; EXPRESSION; PREDICTION; MEMBER AB The human granulocyte alloantigen NB1, recently clustered as CD177, is heterogenously expressed on neutrophils of 88-97% of healthy individuals. Since its molecular nature has remained unknown, we isolated NB1 glycoprotein from granulocyte lysate by immunoaffinity chromatography. MALDI-TOF mass spectrometry identified a 50,556 Da glycoprotein which was reduced to 43,069 Da after removal of N-linked carbohydrates. Following N-terminal amino acid sequencing and NB1-specific primer construction, rapid amplification of cDNA ends PCR yielded a 1,614-bp cDNA for NB1. COS-7 cells transfected with the cDNA expressed immunoreactive NB1 glycoprotein. A 1,311-bp sequence was identified to be the entire coding region. The 5' and 3' untranslated regions consist of 27 bp and 276 bp, respectively. The open reading frame codes for 437 amino acids of which the first 21 form the signal peptide. The remaining 416 residues form a N-terminal extracellular protein with two cysteine-rich domains, three N-linked glycosylation sites and short transmembrane and cytoplasmic segments including a glycosyl-phosphatidylinositol attachment (w) site. Database searches revealed homology to Ly-6 (uPAR) domain, suggesting that NBI belongs to urokinase plasminogen activator receptor/CD59/Ly-6 snake toxin superfamily. C1 Univ Giessen, Inst Clin Immunol & Transfus Med, D-35385 Giessen, Germany. NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD USA. RP Bux, J (reprint author), Univ Giessen, Inst Clin Immunol & Transfus Med, Langhansstr 7, D-35385 Giessen, Germany. NR 47 TC 49 Z9 50 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAY PY 2001 VL 31 IS 5 BP 1301 EP 1309 DI 10.1002/1521-4141(200105)31:5<1301::AID-IMMU1301>3.0.CO;2-J PG 9 WC Immunology SC Immunology GA 434KY UT WOS:000168814900002 PM 11465086 ER PT J AU Kovacs, JA Vogel, S Metcalf, JA Baseler, M Stevens, R Adelsberger, J Lempicki, R Hengel, RL Sereti, I Lambert, L Dewar, RL Davey, RT Walker, RE Falloon, J Polis, MA Masur, H Lane, HC AF Kovacs, JA Vogel, S Metcalf, JA Baseler, M Stevens, R Adelsberger, J Lempicki, R Hengel, RL Sereti, I Lambert, L Dewar, RL Davey, RT Walker, RE Falloon, J Polis, MA Masur, H Lane, HC TI Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE AIDS/HIV; immunomodulator; cytokine; T lymphocyte ID T-CELLS; IN-VIVO; THERAPY; LYMPHOCYTES; PHENOTYPE; NAIVE AB To characterize the immunological effects of intermittent IL-2 therapy, which leads to selective increases in CD4(+) T lymphocytes in HIV-infected patients, 11 patients underwent extensive immunological evaluation. While IL-2 induced changes in both CD4(+) and CD8(+) cell number acutely, only CD4(+) cells showed sustained increases following discontinuation of IL-2. Transient increases in expression of the activation markers CD38 and HLA-DR were seen on both CD4(+) acid CD8(+) cells, but CD25 (a chain of the IL-2 receptor) increased exclusively on CD4(+) cells. This increase in CD25 expression was sustained for months following discontinuation of IL-2, and was seen in naive as well as memory cells. IL-2 induced cell proliferation. but tachyphylaxis to these proliferative effects developed after 1 week despite continued IL-2 administration. It thus appears that sustained CD25 expression selectively on CD4(+) cells is a critical component of the immunological response to IL-2, and that intermittent administration of IL-2 is necessary to overcome the tachyphylaxis to IL-2-induced proliferation. C1 NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. SAIC Frederick, Frederick, MD USA. Georgetown Univ, Washington, DC 20057 USA. RP Kovacs, JA (reprint author), Bldg 10,Room 7D43,MSC 1662, Bethesda, MD 20892 USA. RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268 FU NCI NIH HHS [N01-CO-56000] NR 22 TC 49 Z9 49 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAY PY 2001 VL 31 IS 5 BP 1351 EP 1360 DI 10.1002/1521-4141(200105)31:5<1351::AID-IMMU1351>3.0.CO;2-9 PG 10 WC Immunology SC Immunology GA 434KY UT WOS:000168814900008 PM 11465092 ER PT J AU Dongre, AR Kovats, S deRoos, P McCormack, AL Nakagawa, T Paharkova-Vatchkova, V Eng, J Caldwell, H Yates, JR Rudensky, AY AF Dongre, AR Kovats, S deRoos, P McCormack, AL Nakagawa, T Paharkova-Vatchkova, V Eng, J Caldwell, H Yates, JR Rudensky, AY TI In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE MHC class II presentation; cytosolic peptide; tandem mass-spectrometry ID COMPLEX CLASS-II; AMINO-ACID-SEQUENCES; BOUND SELF-PEPTIDES; INVARIANT CHAIN; T-CELLS; ANTIGEN PRESENTATION; PROCESSING PATHWAYS; EXOGENOUS ANTIGEN; IN-VIVO; MOLECULES AB We report a strategy for high through-put sequence analyses of large MHC class Ii-bound peptide repertoires which combines automated electrospray ionization tandem mass-spectrometry with computer-assisted interpretation of the tandem mass spectra using the algorithm SEQUEST. This powerful approach discerned 128 peptide sequences displayed by the murine MHC class II molecule I-A(b) in activated B cells and macrophages, including a surprisingly large number of peptides derived from self cytosolic proteins. Mice lacking the chaperone molecule H-2M were used to generate T cells specific for selected self peptides. Functional T cell analyses of ex vivo antigen-presenting cells indicated that peptides originating from cytosolic proteins are efficiently presented by splenic and thymic dendritic cells, but less so by resting B cells or thymic cortical epithelial cells. These results suggest that central tolerance to at least some MHC class Ii-bound self peptides derived from cytosolic proteins exists in vivo. C1 Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Mol Biotechnol, Seattle, WA 98195 USA. NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Hamilton, MT USA. Beckman Res Inst, Div Immunol, Duarte, CA USA. RP Rudensky, AY (reprint author), Univ Washington, Sch Med, Howard Hughes Med Inst, Box 357370, Seattle, WA 98195 USA. RI Eng, Jimmy/I-4202-2012; Eng, Jimmy/C-6556-2017; OI Eng, Jimmy/0000-0001-6352-6737; Eng, Jimmy/0000-0001-6352-6737; Kovats, Susan/0000-0001-5479-9952 NR 30 TC 98 Z9 101 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAY PY 2001 VL 31 IS 5 BP 1485 EP 1494 DI 10.1002/1521-4141(200105)31:5<1485::AID-IMMU1485>3.0.CO;2-A PG 10 WC Immunology SC Immunology GA 434KY UT WOS:000168814900022 PM 11465105 ER PT J AU Karakurt, A Dalkara, S Ozalp, M Ozbey, S Kendi, E Stables, JP AF Karakurt, A Dalkara, S Ozalp, M Ozbey, S Kendi, E Stables, JP TI Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE oxime and oxime ethers; (arylalkyl)imidazoles; anticonvulsant activity; antimicrobial activity; E/Z isomers; X-ray crystallography ID DENZIMOL; AGENTS; DRUG AB In this study, oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2-naphthyl)-2-(imidozole-1-yl)ethanone] were prepared as potential anticonvulsant compounds. Nafimidone oxime was synthesized by the reaction of nafimidone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) tests in mice and rats according to procedures of the Antiepileptic Drug Development (ADD) program of the National Institutes of Health (NIH). In addition to anticonvulsant evaluation, compounds were also screened for possible antibacterial and antifungal activities because of the structural resemblance to the azole antifungals, especially to oxiconazole. All compounds were evaluated against three human pathogenic fungi and four bacteria using the microdilution method. Most of the compounds exhibited both anticonvulsant and antimicrobial activities; the 0-alkyl substituted compounds (2, 3, 4 and 5) were found to be more active than the O-arylalkyl substituted compounds in both screening paradigms. (C) 2001 Editions scientifiques et medicales Elsevier SAS. C1 Hacettepe Univ, Fac Pharm, Dept Pharmaceut Chem, TR-06100 Ankara, Turkey. Hacettepe Univ, Fac Pharm, Pharmaceut Microbiol Dept, TR-06100 Ankara, Turkey. Hacettepe Univ, Fac Engn, Dept Engn Phys, TR-06532 Ankara, Turkey. NINDS, Epilepsy Branch, NIH, Bethesda, MD 20892 USA. RP Dalkara, S (reprint author), Hacettepe Univ, Fac Pharm, Dept Pharmaceut Chem, TR-06100 Ankara, Turkey. EM dalkara@tr.net NR 22 TC 89 Z9 94 U1 2 U2 16 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD MAY PY 2001 VL 36 IS 5 BP 421 EP 433 DI 10.1016/S0223-5234(01)01223-5 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 462FC UT WOS:000170409200003 PM 11451531 ER PT J AU Petralia, RS Wang, YX Sans, N Worley, PF Hammer, JA Wenthold, RJ AF Petralia, RS Wang, YX Sans, N Worley, PF Hammer, JA Wenthold, RJ TI Glutamate receptor targeting in the postsynaptic spine involves mechanisms that are independent of myosin Va SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebellum; delta; AMPA; dilute mouse; rat ID LONG-TERM POTENTIATION; DENDRITIC SPINES; AMPA RECEPTORS; PURKINJE-CELLS; ENDOPLASMIC-RETICULUM; UNCONVENTIONAL MYOSIN; FIBER SYNAPSES; NMDA RECEPTOR; ACTIN; RAT AB Targeting of glutamate receptors (GluRs) to synapses involves rapid movement of intracellular receptors. This occurs in forms of synaptic upregulation of receptors, such as long-term potentiation. Thus, many GluRs are retained in a cytoplasmic pool in dendrites, and are transported to synapses for upregulation, presumably via motor proteins such as myosins travelling along cytoskeletal elements that extend up into the spine. In this ultrastructural immunogold study of the cerebellar cortex, we compared synapses between normal rats/mice and dilute lethal mutant mice. These mutant mice lack myosin Va, which has been implicated in protein trafficking at synapses. The postsynaptic spine in the cerebellum lacks the inositol trisphosphate receptor (IP3R) -laden reticular tubules that are found in normal mice and rats (Takagishi et al., Neurosci. Lett., 1996, 215, 169). Thus, we tested the hypothesis that myosin Va is necessary for transport of GluRs and associated proteins to spine synapses. We found that these spines retain a normal distribution of (i) GluRs (delta 1/2, GluR2/3 and mGluR1 alpha), (ii) at least one associated MAGUK (membrane-associated guanylate kinase) protein, (iii) Homer (which interacts with mGluR1 alpha and IP3Rs), (iv) the actin cytoskeleton, (v) the reticulum-associated protein BiP, and (vi) the motor-associated protein, dynein light chain. Thus, while myosin Va may maintain the IP3R-laden reticulum in the spine for proper calcium regulation, other mechanisms must be involved in the delivery of GluRs and associated proteins to synapses. Other possible mechanisms include diffusion along the extrasynaptic membrane and delivery via other motors running along the spine's actin cytoskeleton. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Petralia, RS (reprint author), NIDCD, Neurochem Lab, NIH, 36-5D08,36 Convent Dr MSC 4162, Bethesda, MD 20892 USA. NR 54 TC 48 Z9 51 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAY PY 2001 VL 13 IS 9 BP 1722 EP 1732 DI 10.1046/j.0953-816x.2001.01553.x PG 11 WC Neurosciences SC Neurosciences & Neurology GA 437AJ UT WOS:000168967800008 PM 11359524 ER PT J AU Cavallaro, S Schreurs, BG Zhao, WQ D'Agata, V Alkon, DL AF Cavallaro, S Schreurs, BG Zhao, WQ D'Agata, V Alkon, DL TI Gene expression profiles during long-term memory consolidation SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE associative learning; classical conditioning; eyelid conditioning; gene expression; long-term memory; microarray; nictitating membrane response; rabbit ID NICTITATING-MEMBRANE RESPONSE; GROWTH-FACTOR-I; POSITRON-EMISSION TOMOGRAPHY; PROTEIN-TYROSINE-PHOSPHATASE; PURKINJE-CELL DENDRITES; TRANSCRIPTION FACTOR; CEREBELLAR CORTEX; SUPPRESSOR GENES; BINDING-PROTEIN; LOBULE HVI AB Changes in gene expression have been postulated to occur during long-term memory (LTM). We used high-density cDNA microarrays to assess changes in gene expression 24 h after rabbit eye blink conditioning. Paired animals were presented with a 400 ms, 1000 Hz, 82 dB tone conditioned stimulus that coterminated with a 100 ms, 60 Hz, 2 mA electrical pulse unconditioned stimulus. Unpaired animals received the same conditioned and unconditioned stimuli but presented in an explicitly unpaired manner. Differences in expression levels between paired and unpaired animals in the hippocampus and cerebellar lobule HVI, two regions activated during eye blink conditioning, indicated the involvement of novel genes as well as the participation of previously implicated genes. Patterns of gene expression were validated by in situ hybridization. Surprisingly, the data suggest that an underlying mechanism of LTM involves widespread decreased, rather than increased, gene expression. These results demonstrate the feasibility and utility of a cDNA microarray system as a tool for dissecting the molecular mechanisms of associative memory. C1 Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. CNR, Inst Bioimaging & Pathophysiol Cent Nervous Syst, I-95123 Catania, Italy. NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20892 USA. W Virginia Univ, Dept Neurol, Morgantown, WV 26056 USA. RP Cavallaro, S (reprint author), Blanchette Rockefeller Neurosci Inst, Acad & Res Bldg,Room 315,9601 Med Ctr Dr, Rockville, MD 20850 USA. RI D'Agata, Velia/F-3622-2010; Cavallaro, Sebastiano/F-3104-2010; OI D'Agata, Velia/0000-0003-1114-8265; Cavallaro, Sebastiano/0000-0001-7590-1792; Schreurs, Bernard/0000-0002-5776-0807 NR 45 TC 43 Z9 47 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAY PY 2001 VL 13 IS 9 BP 1809 EP 1815 DI 10.1046/j.0953-816x.2001.01543.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 437AJ UT WOS:000168967800016 PM 11359532 ER PT J AU Olivero, OA Reddy, MK Pietras, SM Poirier, MC AF Olivero, OA Reddy, MK Pietras, SM Poirier, MC TI Plasma drug levels compared with DNA incorporation of 3'-azido-3'-deoxythymidine (AZT) in adult cynomolgus (Macaca fascicularis) monkeys SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE nucleoside analogs; zidovudine; cynomolgus; genotoxicity ID VIRUS REVERSE-TRANSCRIPTASE; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; CELLULAR PHARMACOLOGY; ZIDOVUDINE; 3'-AZIDO-3'-DEOXYTHYMIDINE; CELLS; PHOSPHORYLATION; AZIDOTHYMIDINE; DAMAGE; MICE AB Zidovudine (3 ' -azido-3 ' -deoxythymidine, AZT), widely used for the therapy of the Human Immunodeficiency Virus-1 (HIV-1), is a nucleoside analog of thymidine that becomes phosphorylated and incorporated into nuclear and mitochondrial DNA. Levels of AZT incorporation into DNA of humans, monkeys, and mice are highly variable and suggest interindividual variability in phosphorylation pathways. In addition, studies in rhesus monkeys (1) have shown a lack of correlation between levels of unbound AZT in plasma and tissue AZT-DNA. However, the correlation between plasma AZT and tissue AZT-DNA has not been previously examined in the same primate. Here we examine the relationship between AZT-DNA incorporation in leukocytes and multiple organs, and levels of the drug circulating in plasma of adult female cynomolgus (Macaca fascicularis) monkeys. Three monkeys were dosed with 40.0 mg of AZT/day for 30 days by naso-gastric intubation. The average daily dose of 9.9 mg of AZT/kg/body wt was similar to the similar to8.6 mg of AZT/kg/body wt (600 mg/day) given to adult HIV-I-infected patients. In all three monkeys, at the time of sampling, values for AZT concentrations in plasma were similar and values for AZT incorporation into leukocyte DNA (86.1, 100.0, and 114.1 molecules of AZT/10(6) nucleotides) were also similar. AZT-DNA incorporation was defected in liver, uterus, spleen, and kidney from the three AZT-exposed animals, with values for positive samples ranging from 5.8 to 97.4 molecules of AZT/10(6) nucleotides, In brain cortex and lung DNA from AZT-exposed animals, AZT incorporation was undetectable. The data suggest that organ-specific differences in AZT uptake and/or metabolism may contribute to AZT phosphorylation and subsequent drug incorporation into DNA. In addition, AZT-DNA levels in monkey organs were similar to or lower than values observed in peripheral leukocytes of adult AIDS patients. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP Olivero, OA (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, 37 Convent Dr,Bldg 37,Room 2A01, Bethesda, MD 20892 USA. NR 27 TC 8 Z9 9 U1 0 U2 0 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 0037-9727 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAY PY 2001 VL 226 IS 5 BP 446 EP 449 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 429XD UT WOS:000168542500009 PM 11393173 ER PT J AU Sosne, G Chan, CC Thai, K Kennedy, M Szliter, EA Hazlett, LD Kleinman, HK AF Sosne, G Chan, CC Thai, K Kennedy, M Szliter, EA Hazlett, LD Kleinman, HK TI Thymosin beta 4 promotes corneal wound healing and modulates inflammatory mediators in vivo SO EXPERIMENTAL EYE RESEARCH LA English DT Letter ID ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; MESSENGER-RNA; GROWTH-FACTOR; INTERLEUKIN-6; FIBRONECTIN; EXPRESSION; MIGRATION C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Henry Ford Hosp, Eye Care Serv, Detroit, MI 48202 USA. NEI, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Bethesda, MD 20814 USA. Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI USA. RP Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. FU NEI NIH HHS [P30EY04068, R01EY02986] NR 27 TC 88 Z9 103 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD MAY PY 2001 VL 72 IS 5 BP 605 EP 608 DI 10.1006/exer.2000.0985 PG 4 WC Ophthalmology SC Ophthalmology GA 429HC UT WOS:000168509500012 PM 11311052 ER PT J AU Smith, WB White, JD AF Smith, WB White, JD TI Complementary and alternative medicine in cancer: a National Cancer Institute perspective SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Editorial Material ID SHARK CARTILAGE; PREVALENCE; ANGIOGENESIS; TUMOR C1 NCI, Res Dev & Support Program, Off Canc Complementary & Alternat Med, NIH,EPN, Rockville, MD 20852 USA. RP Smith, WB (reprint author), NCI, Res Dev & Support Program, Off Canc Complementary & Alternat Med, NIH,EPN, 6130 Execut Blvd,Suite 102, Rockville, MD 20852 USA. NR 15 TC 1 Z9 1 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2001 VL 1 IS 3 BP 339 EP 341 DI 10.1517/14712598.1.3.339 PG 3 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 510QM UT WOS:000173218800001 PM 11727509 ER PT J AU Ross, RW Wright, ME Tavel, JA AF Ross, RW Wright, ME Tavel, JA TI Ongoing trials of immune-based therapies for HIV infection in adults SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE AIDS; HIV; immune-based therapies ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED TRIAL; CD4 CELL COUNTS; COMBINATION ANTIRETROVIRAL THERAPY; COLONY-STIMULATING FACTOR; PHASE-II TRIAL; SUBCUTANEOUS INTERLEUKIN-2; INTRAVENOUS INTERLEUKIN-2; INTERFERON-ALPHA AB Highly active antiretroviral therapy (HAART) can significantly alter the clinical course of patients infected With HIV. Unfortunately, effective lifelong HAART may not be a practical or achievable goal because of toxicities, cost, development of viral resistance and patient compliance issues. Immune-based therapies (IBTs) that target the host immune system may serve as rational additions to our current antiretroviral strategies. Investigations into IL-2 have culminated in two large Phase III clinical trials. Multiple therapeutic vaccine candidates are in various phases of investigation. In addition, gene therapy has been proposed as a potential treatment for HIV and Phase I trials are ongoing. Although IBTs are being investigated on many fronts, they remain difficult to study due to a lack of validated surrogate end points. C1 NIAID, NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Tavel, JA (reprint author), NIAID, NIH, Dept Crit Care Med, 9000 Rockville Pike,Bldg 10,Room 11C103, Bethesda, MD 20892 USA. NR 53 TC 10 Z9 11 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2001 VL 1 IS 3 BP 413 EP 424 DI 10.1517/14712598.1.3.413 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 510QM UT WOS:000173218800007 PM 11727515 ER PT J AU Phan, GQ Wang, E Marincola, FM AF Phan, GQ Wang, E Marincola, FM TI T-cell-directed cancer vaccines: mechanisms of immune escape and immune tolerance SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE immune escape; immune tolerance; immunotherapy; melanoma; T-lymphocyte; vaccines ID TUMOR-INFILTRATING LYMPHOCYTES; MHC CLASS-I; GROWTH-FACTOR-BETA; NECROSIS-FACTOR-ALPHA; MELANOMA-ASSOCIATED ANTIGENS; HLA-CLASS-II; METASTATIC MELANOMA; KILLER-CELL; INTERFERON-GAMMA; BREAST-CANCER AB Recent clinical trials using vaccines directed toward tumour-associated antigens (TA) have shown the increasing capacity of vaccines to cause immunologic responses. In fact, strongly reactive TA-specific cytolytic T-lymphocytes and tumour-infiltrating lymphocytes (TIL) can be identified and expanded ex vivo from patients with metastatic melanoma vaccinated with melanoma-associated antigens. Paradoxically, this strong immunological response does not correlate with clinical tumour regression. Proposed mechanisms responsible for this glaring inconsistency are numerous and varied; systemic immunosuppressive as well as local mechanistic factors are implicated. In this review we will critically evaluate the possible mechanisms that allow tumours to escape immune destruction and be tolerated by the immune system. In addition, strategies that may allow further insight into the biology of tumour rejection are discussed, in the hope of deepening the understanding of this phenomenon and enhancing its therapeutic potential. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 171 TC 20 Z9 20 U1 0 U2 2 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2001 VL 1 IS 3 BP 511 EP 523 DI 10.1517/14712598.1.3.511 PG 13 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 510QM UT WOS:000173218800014 PM 11727522 ER PT J AU Rodgers, GP Saunthararajah, Y AF Rodgers, GP Saunthararajah, Y TI Advances in experimental treatment of beta-thalassaemia SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Review DE histone deacetylase inhibitors; methyl-transferase inhibitors; sickle cell disease; thalassaemia; treatment ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; GLOBIN GENE-EXPRESSION; SICKLE-CELL-ANEMIA; FETAL HEMOGLOBIN INDUCTION; ORAL SODIUM PHENYLBUTYRATE; THALASSEMIA MAJOR; GAMMA-GLOBIN; MARROW TRANSPLANTATION; HISTONE DEACETYLASE; HYDROXYUREA THERAPY AB beta -Thalassaemia is highly prevalent and world wide in its distribution. The gene to modify the clinical course of patients with transfusion-dependent thalassaemia (thalassaemia major), the gamma -globin gene, is already present in these patients but silenced in the course of development. During erythropoiesis, progenitors are believed to go through a phase where the milieu favours gamma -globin production. One pharmacological strategy to increase gamma -globin production is directed at recruiting such early progenitors through the use of cytotoxic agents (+/- erythropoietin) that presumably deplete more mature progenitors. Another promising strategy is to use chromatin-modifying agents that prevent the silencing of the gamma -globin gene that occurs during development. These agents, the methyl-transferase inhibitors and histone deacetylase inhibitors, either alone or in combination, may be able to produce the robust increase in gamma -globin and hence fetal haemoglobin and total haemoglobin, needed to successfully treat thalassaemia major. Studies of these agents, which are already available for clinical trials, should be encouraged. C1 NIDDKD, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. RP Saunthararajah, Y (reprint author), Univ Illinois, Sect Hematol Oncol MC734, MBRB Rm 3150,900 S Ashland Ave, Chicago, IL 60607 USA. NR 53 TC 24 Z9 24 U1 0 U2 2 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1354-3784 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD MAY PY 2001 VL 10 IS 5 BP 925 EP 934 DI 10.1517/13543784.10.5.925 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 428PJ UT WOS:000168469800010 PM 11322866 ER PT J AU Fletcher, CF Tottene, A Lennon, VA Wilson, SM Dubel, SJ Paylor, R Hosford, DA Tessarollo, L Tessarollo, L McEnery, MW Pietrobon, D Copeland, NG Jenkins, NA AF Fletcher, CF Tottene, A Lennon, VA Wilson, SM Dubel, SJ Paylor, R Hosford, DA Tessarollo, L Tessarollo, L McEnery, MW Pietrobon, D Copeland, NG Jenkins, NA TI Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity SO FASEB JOURNAL LA English DT Article C1 NCI, Mouse Canc Genet Program, FCRDC, Frederick, MD 21702 USA. Univ Padua, Ctr Biomembranes, Dept Biomed Sci, I-35121 Padua, Italy. Univ Padua, Ctr Biomembranes, CNR, I-35121 Padua, Italy. Mayo Clin, Mayo Grad Sch, Dept Immunol, Rochester, MN 55905 USA. Mayo Clin, Mayo Grad Sch, Dept Neurol, Rochester, MN 55905 USA. Mayo Clin, Mayo Med Sch, Dept Immunol, Rochester, MN 55905 USA. Mayo Clin, Mayo Med Sch, Dept Neurol, Rochester, MN 55905 USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Glaxo Wellcome Res & Dev Ltd, Clin Genet Dis Sci, Stevenage SG1 2NY, Herts, England. RP Fletcher, CF (reprint author), GNF, 3118 Merryfield Row, San Diego, CA 92121 USA. FU Telethon [E.1297] NR 0 TC 123 Z9 129 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2001 VL 15 IS 7 BP 1288 EP 1290 PG 3 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 431WR UT WOS:000168655200038 PM 11344116 ER PT J AU Kazerouni, N Sinha, R Hsu, CH Greenberg, A Rothman, N AF Kazerouni, N Sinha, R Hsu, CH Greenberg, A Rothman, N TI Analysis of 200 food items for benzo[a]pyrene and estimation of its intake in an epidemiologic study SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE polycyclic aromatic hydrocarbons; benzo[a]pyrene; meat; pork; chicken; seafood; vegetables; fruit; grains; fat; sweets; pan-fry; oven-broil; grill; barbecue; carcinogenic; food frequency questionnaire; cancer ID POLYCYCLIC AROMATIC-HYDROCARBONS; HETEROCYCLIC AMINE CONTENT; COLORECTAL-CANCER; GASTROINTESTINAL-TRACT; VARYING DEGREES; COOKING METHOD; MEAT-PRODUCTS; DIETARY FIBER; FRIED FOODS; WELL-DONE AB Animal studies have shown that dietary intake of benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), causes increased levels of tumors at several sites, particularly in the upper gastrointestinal tract. However, the role of dietary intake of BaP and cancer in humans is not clear. We created a BaP database of selected food products that could be linked to Food Frequency Questionnaires (FFQs) to estimate BaP intake. BaP levels were measured for each food line-item (composite samples) which consisted of a variety of foods in a FFQ. Composite sample parts were derived from the Second National Health and Nutrition Examination Survey (NHANES II) which represents the most common food items consumed by the general population. Meat samples were cooked by different techniques in controlled conditions, and by various restaurants and fast-food chains. Non-meat products were purchased from the major national supermarket chains. The quantities of BaP were measured using a thin-layer chromatography (TLC)/spectrofluorometer technique and were highly correlated with both BaP (radius = 0.99) and sum of carcinogenic PAH (r = 0.98) measured by HPLC technique. We linked our database to the results from a FFQ and estimated the daily BaP intake of various food items in 228 subjects in the Washington, DC metropolitan area. The highest levels of BaP (up to about 4 ng BaP/g of cooked meat) were found in grilled/barbecued very well done steaks and hamburgers and in grilled/barbecued well done chicken with skin. BaP concentrations were lower in meats that were grilled/barbecued to medium done and in all broiled or pan-fried meat samples regardless of doneness level. The BaP levels in non-meat items were generally low. However, certain cereals and greens (e.g. kale, collard greens) had levels up to 0.5 ng/g. In our population, the bread/cereal/grain, and grilled/barbecued meat, respectively, contributed 29 and 21 percent to the mean daily intake of BaP: This database may be helpful in initial attempts to assess dietary BaP exposures in studies of cancer etiology, Published by Elsevier Science Ltd. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Rutgers State Univ, Cook Coll, Dept Environm Sci, New Brunswick, NJ 08903 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Kazerouni, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Rm 7033,6120 Execut Blvd, Bethesda, MD 20892 USA. RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 57 TC 271 Z9 285 U1 4 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD MAY PY 2001 VL 39 IS 5 BP 423 EP 436 DI 10.1016/S0278-6915(00)00158-7 PG 14 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 431NZ UT WOS:000168638600002 PM 11313108 ER PT J AU Normanno, N Bianco, C De Luca, A Salomon, DS AF Normanno, N Bianco, C De Luca, A Salomon, DS TI The role of EGF-related peptides in tumor growth SO FRONTIERS IN BIOSCIENCE LA English DT Review DE EGF; growth factors; carcinoma; oncogenes; review ID MAMMARY EPITHELIAL-CELLS; HUMAN-BREAST-CANCER; ALPHA TRANSGENIC MICE; DIFFERENTIAL IMMUNOHISTOCHEMICAL DETECTION; HER2/NEU-OVEREXPRESSING METASTATIC BREAST; RECEPTOR MONOCLONAL-ANTIBODIES; HUMAN PANCREATIC-CARCINOMA; DIPHTHERIA-TOXIN RECEPTOR; EARLY MOUSE DEVELOPMENT; ERBB SIGNALING NETWORK AB The epidermal growth factor (EGF) family of peptides encodes several proteins that can function as growth factors. The EGF-like peptides, with the exception of proteins of the EGF-CFC subfamily, bind and activate tyrosine kinase receptors that belong to the erbB family. The EGF-like peptides are overexpressed in a majority of human carcinomas as compared with their nontransformed counterpart. By using different approaches, it has been shown that several different EGF-like peptides function as autocrine growth factors in carcinoma cell lines of different histological origin. Direct evidence that the EGF-like growth factors might function as transforming genes has been provided by in vitro and in vivo studies. In particular, the development of different transgenic mouse lines in which EGF-like growth factors have been overexpressed by means of tissue-specific or nonspecific promoters has provided invaluable information relating to their ability to function as dominantly transforming oncogenes. Cooperation of the EGF-like peptides with cellular protooncogenes in determining cell transformation has been demonstrated by using both in vitro and transgenic mice systems. Taken together, these data strongly suggest that the EGF-like peptides are involved in the pathogenesis of human carcinomas, and that they might represent suitable targets for novel therapeutic approaches. C1 ITN Fdn Pascale, Oncol Sperimentale D, I-80131 Naples, Italy. NCI, Tumor Growth Factor Sect, LTIB, NIH, Bethesda, MD 20892 USA. RP Normanno, N (reprint author), ITN Fdn Pascale, Oncol Sperimentale D, Via M Semola, I-80131 Naples, Italy. RI De Luca, Antonella/J-8737-2016 OI De Luca, Antonella/0000-0001-5762-447X NR 196 TC 101 Z9 107 U1 2 U2 11 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2001 VL 6 BP D685 EP D707 DI 10.2741/Normano PG 23 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 427NE UT WOS:000168411500002 PM 11333208 ER PT J AU Berger, F Soligo, D Schwarz, K Bossolasco, P Schrezenmeier, H Kubanek, B Deliliers, GL Licht, T AF Berger, F Soligo, D Schwarz, K Bossolasco, P Schrezenmeier, H Kubanek, B Deliliers, GL Licht, T TI Efficient retrovirus-mediated transduction of primitive human peripheral blood progenitor cells in stroma-free suspension culture SO GENE THERAPY LA English DT Article DE hematopoietic stem cells; gene therapy; growth factors; rhodamine; multidrug resistance; P-glycoprotein ID HEMATOPOIETIC STEM-CELLS; BONE-MARROW CELLS; COMBINED IMMUNODEFICIENT MICE; MULTIDRUG-RESISTANCE GENE; HUMAN MDR1 GENE; P-GLYCOPROTEIN EXPRESSION; GREEN FLUORESCENT PROTEIN; COLONY-STIMULATING FACTOR; LONG-TERM HEMATOPOIESIS; EX-VIVO EXPANSION AB Retroviral transduction of hematopoietic cells has resulted in unsatisfactory gene marking in clinical studies. Since cytokine-stimulated stem cells have engrafted poorly in animal models, we investigated phenotypic changes during culture of peripheral blood progenitor cells (PBPC). Human CD34(+) HLA-DRlow cells, immunomagnetically separated from PBPC collections, were found to extrude rhodamine-123, which is characteristic for primitive hematopoietic cells. Cells were grown in suspension cultures supplemented with cytokines. While interleukin-3-containing factor combinations promoted cell proliferation they caused loss of rhodamine-123 extrusion and reduced the frequencies of cobblestone area-forming cells (CAFC), Several other cytokines failed to stimulate cell divisions, which are required for retroviral transduction. A combination including Flt-3 ligand (FL), interleukin-6 and stem cell factor (SCF) preserved an immature phenotype for 5 to 6 days and stimulated cell divisions, which was improved upon addition of leukemia inhibitory factor and interleukin-ll. Furthermore, the CAFC frequency among cells treated with these cytokines was increased as compared with widely used cocktails containing interleukin-3, interleukin-6 and SCF. Rhodamine-123 appeared to be a particularly sensitive indicator for differentiation of PBPC, For analysis of gene transfer, amphotropic retroviruses conferring an MDR1 cDNA were added repeatedly for 6 days to cytokine-treated PBPC stroma-free cultures. Proviral cDNA was detected by polymerase chain reaction in 68% of cobblestone areas derived from CD34(+) HLA-DRlow cells that had been exposed to Flt-3 ligand, interleukin-6 and SCF. In summary conditions were identified that facilitate efficient transduction of early PBPC with amphotropic retroviruses while preserving a primitive phenotype for extended periods. C1 Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, D-81675 Munich, Germany. Osped Fatebenefratelli & Oftalm, Fdn Matarelli, Milan, Italy. Osped Maggiore, IRCCS, Bone Marrow Transplantat Unit, Milan, Italy. Free Univ Berlin, Klinikum Benjamin Franklin, D-12200 Berlin, Germany. Univ Ulm Klinikum, Ulm, Germany. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Licht, T (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, Ismaninger Str 22, D-81675 Munich, Germany. NR 64 TC 3 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAY PY 2001 VL 8 IS 9 BP 687 EP 696 DI 10.1038/sj.gt.3301455 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 431PA UT WOS:000168638700004 PM 11406763 ER PT J AU Phillips, JL Ghadimi, BM Wangsa, D Padilla-Nash, H Worrell, R Hewitt, S Walther, M Linehan, WM Klausner, RD Ried, T AF Phillips, JL Ghadimi, BM Wangsa, D Padilla-Nash, H Worrell, R Hewitt, S Walther, M Linehan, WM Klausner, RD Ried, T TI Molecular cytogenetic characterization of early and late renal cell carcinomas in Von Hippel-Lindau disease SO GENES CHROMOSOMES & CANCER LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; IN-SITU HYBRIDIZATION; VHL GENE; CHROMOSOME-ABNORMALITIES; TUMOR-SUPPRESSOR; SHORT ARM; DELETIONS; INACTIVATION; ABERRATIONS; TRISOMY-7 AB Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1-2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21-22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs. Published 2001 Wiley-Liss. Inc.(dagger) C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Phillips, JL (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 30 TC 23 Z9 23 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 2001 VL 31 IS 1 BP 1 EP 9 DI 10.1002/gcc.1111 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 420NT UT WOS:000168011600001 PM 11284029 ER PT J AU Perotti, D Testi, MA Mondini, P Pilotti, S Green, ED Pession, A Sozzi, G Pierotti, MA Fossati-Bellani, F Radice, P AF Perotti, D Testi, MA Mondini, P Pilotti, S Green, ED Pession, A Sozzi, G Pierotti, MA Fossati-Bellani, F Radice, P TI Refinement within single yeast artificial chromosome clones of a minimal region commonly deleted on the short arm of chromosome 7 in Wilms tumours SO GENES CHROMOSOMES & CANCER LA English DT Article ID ALLELE LOSS; HETEROZYGOSITY; TUMORS; LOCUS; GENE; ABNORMALITIES; 11P15.5; MAP AB Cytogenetic and molecular data indicate an involvement of genes mapped to the proximal portion of the short arm of chromosome 7 (7p) in Wilms tumours (WTs). We have analysed 38 WTs using a panel of eight microsatellite markers mapped to proximal 7p. Loss of heterozygosity (LOH) in tumour, compared with matched constitutional DNA, was identified in eight cases. To define better the minimal region commonly deleted in these tumours, they were analysed with nine additional markers, mapped within the region of interest. One tumour (case 30) showed LOH for only one marker (D7S510), while maintaining heterozygosity for the two immediately flanking loci (07S555 and D7S668). This result was confirmed by fluorescence in situ hybridisation analysis, which showed that in the majority (65%) of nuclei from tumour 30 hybridising with a bacterial artificial chromosome clone containing the D7S510 locus, only one signal was visible. Noticeably, both markers defining the limits of the observed deleted region are simultaneously present within two distinct overlapping yeast artificial chromosome (YAC) clones mapped to chromosome bands 7p13-p14. This suggests that the maximum length of the missing DNA fragment was approximately 1.3 Mb, corresponding to the length of the smaller of the two YAC clones. In all other cases that showed LOH, the deletion encompassed the 7p13-p14 region. For this reason, we speculate that the identified interval contains a gene whose inactivation is important for the development of at least a fraction of WTs. (C) 2001 Wiley-Liss, Inc. C1 Ist Nazl Tumori, Dept Expt Oncol, I-20133 Milan, Italy. Ist Nazl Tumori, Dept Pathol, I-20133 Milan, Italy. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Bologna, Dept Pediat Med & Surg Sci, Bologna, Italy. Ist Nazl Tumori, Dept Med Oncol, I-20133 Milan, Italy. RP Radice, P (reprint author), Ist Nazl Tumori, Dept Expt Oncol, Via Venezian 1, I-20133 Milan, Italy. RI Pession, Annalisa/B-9014-2012; Radice, Paolo/O-3119-2013; Perotti, Daniela/C-2013-2017; sozzi, gabriella/G-8259-2011; Testi, Maria Adele/D-6994-2017; OI Perotti, Daniela/0000-0002-6703-2889; sozzi, gabriella/0000-0001-9360-6914; Testi, Maria Adele/0000-0002-9462-0336; Pession, Annalisa/0000-0001-9035-9698; Pierotti, Marco Alessandro/0000-0002-7431-8332 NR 33 TC 13 Z9 15 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 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAY PY 2001 VL 31 IS 1 BP 42 EP 47 DI 10.1002/gcc.1116 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 420NT UT WOS:000168011600006 PM 11284034 ER PT J AU Sen, R Nagai, H Shimamoto, N AF Sen, R Nagai, H Shimamoto, N TI Conformational switching of Escherichia coli RNA polymerase-promoter binary complex is facilitated elongation factor GreA and GreB SO GENES TO CELLS LA English DT Article ID TRANSCRIPT CLEAVAGE FACTORS; P-R PROMOTER; TERNARY COMPLEXES; NASCENT TRANSCRIPT; FACTOR-SII; IN-VIVO; INITIATION; GENE; DNA; MECHANISM AB Background: The initiation arrest at a modified lambdaP(R) promoter is caused by irreversible divergence of the reaction pathway into productive and arrested branches. Escherichia coli GreA and GreB induce cleavage of the nascent transcript and relieve arrest in elongation. They also reduce abortive synthesis at several promoters and relieve initiation arrest. Their mechanism of action during initiation, and its relationship to the branched initiation pathway are unknown. Results: The Gre factors mitigated initiation arrest only when they were added to the binary complex of the holoenzyme bound to the lambdaP(R) promoter, prior to RNA synthesis. They exerted little effect when they were added to ternary initiation complexes. They accelerated the exchange of the binary complex with its free components by 6-9-fold. When they are present, a high concentration of the initiating nucleotide increased yield of the full-length transcript, whereas a low concentration did not. Conclusions: All the results presented above can be explained by a model where the productive and arrested pathways diverge at the binary complex stage. The Gre factors relieve the initiation arrest by introducing reversibility between subspecies of the binary complex that are precursors of the two pathways. RNA cleavage is unlikely to cause relief of initiation arrest. C1 Natl Inst Genet, Struct Biol Ctr, Shizuoka 411, Japan. RP Shimamoto, N (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 308, Bethesda, MD 20892 USA. RI Nagai, Hiroki/G-4113-2015 NR 34 TC 13 Z9 14 U1 1 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1356-9597 J9 GENES CELLS JI Genes Cells PD MAY PY 2001 VL 6 IS 5 BP 389 EP 401 DI 10.1046/j.1365-2443.2001.00436.x PG 13 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 439AC UT WOS:000169085700001 PM 11380617 ER PT J AU Xu, XL Li, CL Garrett-Beal, L Larson, D Wynshaw-Boris, A Deng, CX AF Xu, XL Li, CL Garrett-Beal, L Larson, D Wynshaw-Boris, A Deng, CX TI Direct removal in the mouse of a flexed neo gene from a three-loxP conditional knockout allele by two novel approaches SO GENESIS LA English DT Article DE conditional knockout; neo deletion; Brca1; Ella-Cre; pronuclear injection ID CRE RECOMBINASE; MUTATION; PROLIFERATION; EMBRYOS; GENOME; SERIES; BRCA1 AB The presence in an intron of the ploxP-neo-loxP cassette often results in severe interference with gene expression. Consequently, many investigators selectively remove the ploxP-neo-loxP cassette by transient expression of Cre in ES cells, Although effective, the added manipulation of the ES cells may reduce the likelihood that a clone will be able to transmit via the germline, Therefore, we developed two novel approaches that remove the ploxP-neo-loxP by Cre-mediated recombination in mouse. First, the ploxP-neo-loxP-containing mice were crossed with Ella-Cre transgenic mice. Second, a Cre-expression plasmid was injected into pronuclei of fertilized eggs bearing the ploxP-neo-loxP allele, Both approaches produced mosaic mice with partial and complete excision. These mosaic mice were then mated, and the neo-less conditional knockout allele was found in the offspring after screening only a few litters. These procedures provide options for removing neo directly in the mouse in addition to the commonly used approach that deletes neo in ES cells. genesis 30: 1-6, 2001, Published 2001 Wiley-Liss, Inc.(dagger) C1 NIDDK, Genet Dev & Dis Branch, Bethesda, MD USA. NIH, Natl Ctr Human Genome Res, Genet Dis Res Branch, Bethesda, MD 20892 USA. Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. RP Deng, CX (reprint author), NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 20 TC 70 Z9 75 U1 0 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1526-954X J9 GENESIS JI Genesis PD MAY PY 2001 VL 30 IS 1 BP 1 EP 6 DI 10.1002/gene.1025 PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 440AU UT WOS:000169151600001 PM 11353511 ER PT J AU Kaplan, N Morris, R AF Kaplan, N Morris, R TI Issues concerning association studies for fine mapping a susceptibility gene for a complex disease SO GENETIC EPIDEMIOLOGY LA English DT Article DE fine mapping; linkage disequilibrium; association test; TDT; coalescent process ID LINKAGE DISEQUILIBRIUM; TRANSMISSION/DISEQUILIBRIUM TEST; SAMPLE-SIZE; RECOMBINATION; TRANSMISSION; ALLELE; POWER; LOCUS; MAP AB The usefulness of association studies for fine mapping loci with common susceptibility alleles for complex genetic diseases in outbred populations is unclear. We investigate this issue for a battery of tightly linked anonymous genetic markers spanning a candidate region centered around a disease locus, and study the joint behavior of chi-square statistics used to discover and to localize the disease locus. We used simulation methods based on a coalescent process with mutation, recombination, and genetic drift to examine the spatial distribution of markers with large noncentrality parameters in a case-control study design. Simulations with a disease allele at intermediate frequency, presumably representing an old mutation, tend to exhibit the largest noncentrality parameter values st markers near the disease lotus. In contrast, simulations with a disease allele at low frequency, presumably representing a young mutation, often exhibit the largest noncentrality parameter values at markers scattered over the candidate region. In the former cases, sample sizes or marker densities sufficient to detect association are likely to lead to useful localization, whereas, in the latter case, localization of the disease locus within the. candidate region is much less likely. regardless of the sample size or density of the map. The effects of increasing sample size or marker density are also investigated. Based upon a single marker analysis, we find that a simple strategy of choosing the marker with the smallest associated P value to begin a laboratory search for the disease locus performs adequately for a common disease allele. We also investigated a strategy of pooling nearby sites to form multiple allele markers. Using multiple degree of freedom chi-square tests for two or three nearby sites, we found no clear advantage of this form of pooling over a single marker analysis. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Analyt Sci Inc, Durham, NC USA. N Carolina State Univ, Dept Stat, Biomath Program, Raleigh, NC 27695 USA. RP Kaplan, N (reprint author), NIEHS, Biostat Branch, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. NR 36 TC 37 Z9 40 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2001 VL 20 IS 4 BP 432 EP 457 DI 10.1002/gepi.1012 PG 26 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 425XE UT WOS:000168316300004 PM 11319784 ER PT J AU Strunnikov, AV Aravind, L Koonin, EV AF Strunnikov, AV Aravind, L Koonin, EV TI Saccharomyces cerevisiae SMT4 encodes an evolutionarily conserved protease with a role in chromosome condensation regulation SO GENETICS LA English DT Article ID SISTER-CHROMATID COHESION; ANAPHASE-PROMOTING COMPLEX; DNA-REPLICATION; 13S CONDENSIN; TRANSCRIPTION FACTOR; NUCLEOTIDE-SEQUENCE; CENTROMERE PROTEIN; BUDDING YEAST; CELL-CYCLE; S-PHASE AB In a search for regulatory genes affecting the targeting of the condensin complex to chromatin in Saccharomyces cerevisiae, we identified a member of the adenovirus protease family, SMT4. SMT4 overexpression suppresses the temperature-sensitive conditional lethal phenotype of smc2-6 but not smc2-8 or smc4-1. A disruption allele of SMT4 has a prominent chromosome phenotype: impaired targeting of Smc4p-GFP to rDNA chromatin. Site-specific mutagenesis of the predicted protease active site cysteine and histidine residues of Smt lp abolishes the SMT4 function in vivo. The previously uncharacterized SIZ1 ((SAP and Miz) gene, which encodes a protein containing a predicted DNA-binding SAP module and a Mit finger, is identified as a bypass suppressor of the growth defect associated with the SMT4 disruption. The SIZ1 gene disruption is synthetically lethal with the SIZ2 deletion. We propose that SMT4, SIZ1, and SIZ2 are involved in a novel pathway of chromosome maintenance. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Strunnikov, AV (reprint author), NICHHD, LGRD, NIH, 18T Lib Dr,Rm 106, Bethesda, MD 20892 USA. OI Strunnikov, Alexander/0000-0002-9058-2256 NR 55 TC 93 Z9 96 U1 0 U2 0 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2001 VL 158 IS 1 BP 95 EP 107 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 431NG UT WOS:000168637000009 PM 11333221 ER PT J AU Rattray, AJ McGill, CB Shafer, BK Strathern, JN AF Rattray, AJ McGill, CB Shafer, BK Strathern, JN TI Fidelity of mitotic double-strand-break repair in Saccharomyces cerevisiae: A role for SAE2/COM1 SO GENETICS LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; INDUCED DNA-REPLICATION; GENE AMPLIFICATION; ESCHERICHIA-COLI; NONHOMOLOGOUS RECOMBINATION; INVERTED REPEATS; MISMATCH REPAIR; MAT LOCUS; YEAST; TRANSFORMATION AB Errors associated with the repair of DNA double-strand breaks (DSBs) include point mutations caused by misincorporation during repair DNA synthesis or novel junctions made by nonhomologous end joining (NMEJ). We previously demonstrated that DNA synthesis is similar to 100-fold more error prone when associated with DSB repair. Here we describe a genetic screen for mutants that affect the fidelity of DSB repair. The substrate consists of inverted repeats of the trp1 and CAN1 genes. Recombinational repair of a site-specific DSB within the repeat yields TRP1 recombinants. Errors in the repair process can be detected by the production of canavanine-resistant (can1) mutants among the TRP1 recombinants. In wild-type cells the recombinational repair process is efficient and fairly accurate. Errors resulting in can1 mutations occur in <1% of the TRP1 recombinants and most appear to be point mutations. We isolated several mutant strains with altered fidelity of recombination. Here we characterize one of these mutants that revealed an similar to 10-fold elevation in the frequency of can1 mutants among TRP1 recombinants. The gene was cloned by complementation of a coincident sporulation defect and proved to be an allele of SAE2/COM1. Physical analysis of the can1 mutants from sae2/com1 strains revealed that many were a novel class of chromosome rearrangement that could reflect break-induced replication (BIR) and NHEJ. Strains with either the mre11s-H125N or rad50s-K81I alleles had phenotypes in this assay that are similar to that of the sae2/com1 Delta strain. Our data suggest that Sae2p/Com1p plays a role in ensuring that both ends of a DSB participate in a recombination event, thus avoiding BIR, possibly by regulating the nuclease activity of the Mre11p/Rad50p/Xrs2p complex. C1 NCI, FCRDC, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Strathern, JN (reprint author), NCI, FCRDC, Gene Regulat & Chromosome Biol Lab, Bldg 539,Room 151,POB B, Frederick, MD 21702 USA. RI Rattray, Alison/A-4847-2008 NR 64 TC 112 Z9 113 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2001 VL 158 IS 1 BP 109 EP 122 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 431NG UT WOS:000168637000010 PM 11333222 ER PT J AU Collins, FS AF Collins, FS TI Contemplating the end of the beginning SO GENOME RESEARCH LA English DT Editorial Material ID SEQUENCE C1 NHGRI, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, Bethesda, MD 20892 USA. EM fc23a@nih.gov NR 3 TC 28 Z9 29 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2001 VL 11 IS 5 BP 641 EP 643 DI 10.1101/gr.189801 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 429DW UT WOS:000168501600002 PM 11337461 ER PT J AU Green, ED Chakravarti, A AF Green, ED Chakravarti, A TI The human genome sequence expedition: Views from the "Base Camp" SO GENOME RESEARCH LA English DT Editorial Material ID SINGLE NUCLEOTIDE POLYMORPHISMS; PROJECT; COLLECTION; GENES C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov NR 27 TC 14 Z9 14 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAY PY 2001 VL 11 IS 5 BP 645 EP 651 DI 10.1101/gr.188701 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 429DW UT WOS:000168501600003 PM 11337462 ER PT J AU Makalowski, W AF Makalowski, W TI Are we polyploids? A brief history of one hypothesis SO GENOME RESEARCH LA English DT Editorial Material ID VERTEBRATE GENOME; GENE NUMBER; EVOLUTION; SEQUENCE; DUPLICATIONS C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM makalowski@ncbi.nlm.nih.gov RI Makalowski, Wojciech/I-2843-2016 NR 27 TC 39 Z9 39 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD MAY PY 2001 VL 11 IS 5 BP 667 EP 670 DI 10.1101/gr.188801 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 429DW UT WOS:000168501600006 PM 11337465 ER PT J AU Bryda, EC Kim, HJ Legare, ME Frankel, WN Noben-Trauth, K AF Bryda, EC Kim, HJ Legare, ME Frankel, WN Noben-Trauth, K TI High-resolution genetic and physical mapping of modifier-of-deafwaddler (mdfw) and waltzer (Cdh23(v)) SO GENOMICS LA English DT Article ID DEAFNESS; MICE; MAP AB Modifier-of-deafwaddler (mdfw) and waltzer (Cdh23(v)) are loci on mouse chromosome 10 encoding factors that are essential for the function of auditory hair cells. The BALB/cByJ-specific mdfw allele encodes a necessary and sufficient modifier that induces progressive early onset hearing loss in CBy-dfw(2J) heterozygotes. Recessive mutations in the waltzer locus result in:circling behavior and congenital deafness. In this report we present a high-resolution integrated genetic and physical map of mdfw and Cdh23(v). Our genetic analyses localize mdfw, between markers D10Mit60 and 148M13T7 within a 1.01-cM region. The Cdh23(v) critical interval is fully contained within the mdfw, region and localizes between markers 146O23T7 and 148M13T7 within a 0.35-cM interval that is represented in an approximate to 500-kb BAC contig, Our data suggest that mdfw and Cdh23(v) are allelic, (C) 2001 Academic Press. C1 Natl Inst Deafness & Other Commun Disorders, Unit Neurogenet, NIH, Rockville, MD 20850 USA. Marshall Univ, Sch Med, Dept Microbiol Mol Genet & Immunol, Huntington, WV 25704 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Noben-Trauth, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Unit Neurogenet, NIH, 5 Res Court, Rockville, MD 20850 USA. FU NIDCD NIH HHS [Z01 DC00036-02, DC03611, DC03771]; NINDS NIH HHS [NS31348] NR 8 TC 25 Z9 26 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD MAY 1 PY 2001 VL 73 IS 3 BP 338 EP 342 DI 10.1006/geno.2001.6538 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 433RW UT WOS:000168774400011 PM 11350126 ER PT J AU Nycum, LR Smith, LM Farley, JH Kost, ER Method, MW Birrer, MJ AF Nycum, LR Smith, LM Farley, JH Kost, ER Method, MW Birrer, MJ TI The role of p27 in endometrial carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Article DE cyclin-dependent kinase inhibitor; endometrial cancer; Kip 1; immunohistochemistry ID KINASE INHIBITOR P27; BREAST-CANCER CELLS; GROWTH ARREST; CYCLIN E-CDK2; P27(KIP1); EXPRESSION; PROTEIN AB Objective. The cyclin-dependent kinase inhibitor p27 has been shown to mediate cell growth arrest in response to various environmental stimuli. p27 protein levels have shown prognostic value in several different types of cancer. We examined the prognostic value of p27 protein expression in endometrial cancer, the most common gynecologic malignancy. Methods. A total of 95 paraffin-embedded tumor blocks were obtained and stained via immunohistochemical techniques with a monoclonal antibody against p27. Ten high-power fields were evaluated per slide with at least 1000 cells per slide and two slides per specimen evaluated by two reviewers for nuclear and cytoplasmic staining. The specimens were evaluated for associations with age, stage, grade, and histology. Statistical analysis was performed using the Student t test, chi (2) Kaplan-Meier, and likelihood ratios to assess the data and to generate P values. Results. A total of 91 patients met inclusion criteria for statistical analysis. Fifty-three patients were stage I, 13 stage II, 14 stage III and 11 stage IV with a positive stain (> 50% of cells) for p27 obtained in 32.1, 23.1, 35.7, and 36.4%, respectively (Student t test P = 0.77). Survival data were available on 24 advanced stage patients. 027 protein immunostaining showed no association with patient survival. We also found no association of p27 staining with age or histology. Notably, we found a trend in increasing staining: with increase in grade, particularly with stage I patients. Also, there was an association of the nuclear and cytoplasmic staining and stage (P = 0.05), but it had no correlation with patient survival. Conclusion. Our study showed decreased p27 protein staining in endometrial cancers compared to normal endometrial cells. We found that p27 protein staining shows no association with stage, age, or histology and is not prognostic for survival in advanced endometrial cancers. However, there may be a trend associated with increased p27 protein staining with advanced grades of tumors. (C) 2001 Academic Press. C1 NCI, Gaithersburg, MD 20877 USA. Keesler AF, Med Ctr, Biloxi, MS USA. Brooke Army Med Ctr, Ft Sam Houston, TX USA. Tripler Army Med Ctr, TAMC, HI USA. Colorado State Univ, Washington, DC USA. David Grant Med Ctr, Travis AFB, CA USA. Walter Reed Army Med Ctr, Rockville, MD USA. RP Nycum, LR (reprint author), NCI, Gaithersburg, MD 20877 USA. NR 30 TC 20 Z9 27 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2001 VL 81 IS 2 BP 242 EP 246 DI 10.1006/gyno.2001.6144 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 431QV UT WOS:000168642800021 PM 11330957 ER PT J AU Bachrich, T Thalhammer, T Jager, W Haslmayer, P Alihodzic, B Bakos, S Hitchman, E Senderowicz, AM Penner, E AF Bachrich, T Thalhammer, T Jager, W Haslmayer, P Alihodzic, B Bakos, S Hitchman, E Senderowicz, AM Penner, E TI Characterization of autoantibodies against uridine-diphosphate glucuronosyltransferase in patients with inflammatory liver diseases SO HEPATOLOGY LA English DT Article ID AUTOIMMUNE HEPATITIS; CYTOCHROMES P450; RAT; FLAVOPIRIDOL; GLUCURONIDATION; METABOLISM; INHIBITOR AB Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver-kidney microsomal autoantibodies and was termed LKM-3. To evaluate the nature of LKM-3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and I of 27 of the I-ICV patients. The anti-UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT-isoform involved in the bilirubin glucuronidation, Additionally, these sera were able to block UGT-mediated substrate glucuronidation in vitro, The prevalence for UGT1A1 was shown by 2 independent techniques: (I) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT-isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation, In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT-mediated glucuronidation in vitro, but it is unlikely that anti-UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range. C1 Univ Vienna, Dept Pathophysiol, A-1090 Vienna, Austria. Univ Vienna, Clin Internal Med 4, Dept Gastroenterol & Hepatol, A-1090 Vienna, Austria. Univ Vienna, Inst Pharmaceut Chem, A-1090 Vienna, Austria. Natl Inst Dent & Craniofacial Res, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. RP Thalhammer, T (reprint author), Univ Vienna, Dept Pathophysiol, AKH Erweiterungsbau Ost, A-1090 Vienna, Austria. RI Jager, Walter/I-6242-2013 OI Jager, Walter/0000-0002-4970-8179 NR 25 TC 12 Z9 12 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2001 VL 33 IS 5 BP 1053 EP 1059 DI 10.1053/jhep.2001.24101 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 426RW UT WOS:000168363000006 PM 11343231 ER PT J AU Sugatani, J Kojima, H Ueda, A Kakizaki, S Yoshinari, K Gong, QH Owens, IS Negishi, M Sueyoshi, T AF Sugatani, J Kojima, H Ueda, A Kakizaki, S Yoshinari, K Gong, QH Owens, IS Negishi, M Sueyoshi, T TI The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR SO HEPATOLOGY LA English DT Article ID NAJJAR TYPE-I; GILBERTS-SYNDROME; CYP2B GENE; EXPRESSION; PROMOTER; DISEASE; UDP-GLUCURONOSYLTRANSFERASE-1; METABOLISM AB The UDP-glucuronosyltransferase, UGTIA1, is the critical enzyme responsible for detoxification of the potentially neurotoxic bilirubin by conjugating it with glucuronic acid. For decades, phenobarbital (PB) treatment for hyperbilirubinemia has been known to increase expression of the UGTIA1 gene in liver. We have now delineated the PB response activity to a 290-bp distal enhancer sequence (-3483/-3194) of the UGTIA1 gene. The enhancer contains 3 putative nuclear receptor motifs, and it was activated by the nuclear orphan receptor, human constitutive active receptor (hCAR), in cotransfected HepG2 cells. Bacterially expressed hCAR, acting as a heterodimer with in vitro-translated retinoid X receptor (RXR alpha), only bound to 1 of the 3 NR motifs, named gtNR1 in a gel-shift assay. Consistently, mutations of the gtNR1 site significantly decreased the activation by hCAR of the 290-bp DNA in transfection assays. Moreover, the 290-bp DNA was effectively activated in mouse primary hepatocytes in response to PB, offering an excellent clinical test for the examination of the responsiveness of the UGTIA1 to PB in the human population, particularly individuals with hyperbilirubinemia. C1 NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. NICHHD, Bethesda, MD 20892 USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 268 Z9 275 U1 0 U2 9 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2001 VL 33 IS 5 BP 1232 EP 1238 DI 10.1053/jhep.2001.24172 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 426RW UT WOS:000168363000028 PM 11343253 ER PT J AU Umemura, T Yeo, AET Sottini, A Moratto, D Tanaka, Y Wang, RYH Shih, JWK Donahue, P Primi, D Alter, HJ AF Umemura, T Yeo, AET Sottini, A Moratto, D Tanaka, Y Wang, RYH Shih, JWK Donahue, P Primi, D Alter, HJ TI SEN virus infection and its relationship to transfusion-associated hepatitis SO HEPATOLOGY LA English DT Article ID NON-B-HEPATITIS; NON-A; LIVER-DISEASE; C VIRUS; UNITED-STATES; DNA; TTV; SEQUENCES; NUCLEOTIDE; ANTIBODY AB SEN virus (SEN-V) is a recently identified single-stranded, circular DNA virus. Two SEN-V variants (SENV-D and SENV-H) were assayed by polymerase chain reaction (PCR) to investigate their role in the causation of transfusion-associated non-A to E hepatitis, The incidence of SEN-V infection after transfusion was 30% (86 of 286) compared with 3% (3 of 97) among nontransfused controls (P < .001). Transfusion risk increased with the number of units transfused (P < .0001) and donor-recipient linkage for SEN-V was shown by sequence homology. The prevalence of SEN-V in 436 volunteer donors was 1.8%, Among patients with transfusion-associated non-A to E hepatitis, 11 of 12 (92%) were infected with SEN-V at the time of transfusion compared with 55 of 225 (24%) identically followed recipients who did not develop hepatitis (P < .001). No effect of SEN-V on the severity or persistence of coexistent hepatitis C virus (HCV) infection was observed. In 31 infected recipients, SEN-V persisted for greater than 1 year in 45% and for up to 12 years in 13%, SEN-V-specific RNA (a possible replicative intermediate) was recovered from liver tissue. In summary, SENV-D and -H were present in nearly 2% of US donors, and were unequivocally transmitted by transfusion and frequently persisted. The strong association of SEN-V with transfusion-associated non-A to E hepatitis compared with controls raises the possibility, but does not establish that SEN-V might be a causative agent of posttransfusion hepatitis. The vast majority of SEN-V-infected recipients did not develop hepatitis. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. DiaSorin Inc, Brescia, Italy. DiaSorin Inc, Stillwater, OK USA. RP Alter, HJ (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room IC711, Bethesda, MD 20892 USA. NR 32 TC 111 Z9 132 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2001 VL 33 IS 5 BP 1303 EP 1311 DI 10.1053/jhep.2001.24268 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 426RW UT WOS:000168363000035 PM 11343260 ER PT J AU Zheng, SL Xu, JF Isaacs, SD Wiley, K Chang, BL Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB AF Zheng, SL Xu, JF Isaacs, SD Wiley, K Chang, BL Bleecker, ER Walsh, PC Trent, JM Meyers, DA Isaacs, WB TI Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families SO HUMAN GENETICS LA English DT Article ID SUSCEPTIBILITY LOCUS; INHERITANCE; TESTS; MAPS; SCAN AB Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning similar to 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric Linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (greater than or equal to 65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned similar to 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. RP Isaacs, WB (reprint author), Johns Hopkins Hosp, Marburg 115,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCI NIH HHS [CA58236] NR 25 TC 30 Z9 32 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2001 VL 108 IS 5 BP 430 EP 435 DI 10.1007/s004390100513 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 438HY UT WOS:000169048600011 PM 11409871 ER PT J AU Hubbard, WJ Moore, JK Contreras, JL Smyth, CA Chen, ZW Lobashevsky, AL Nagata, K Neville, DM Thomas, JM AF Hubbard, WJ Moore, JK Contreras, JL Smyth, CA Chen, ZW Lobashevsky, AL Nagata, K Neville, DM Thomas, JM TI Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques SO HUMAN IMMUNOLOGY LA English DT Article ID PERIPHERAL-BLOOD; SURFACE-MOLECULE; IN-VIVO; MEMORY; MONKEYS; ANTI-CD3-IMMUNOTOXIN; PERITRANSPLANT; LYMPHOCYTES; CD45RO; DEOXYSPERGUALIN AB T-cell reduction utilizing specific antibody has been widely used in human transplantation, and is a cornerstone of several tolerance induction strategies in nonhuman primates. We have established a population of long-term tolerant rhesus macaques induced with an anti-CD3 epsilon immunotoxin (IT). This treatment effects transient, specific and profound ablation of T cells in blood and lymphoid tissues. Tn most instances the IT was used in combination with the NF-kappaB inhibitor, 15-Deoxyspergualin. This 2-week long protocol produces a "window of opportunity" for tolerization in which the animal exhibits an enduring quiescent state of unresponsiveness to the allograft, all accomplished without maintenance immunosuppressive drugs. During this induction period, the treated immune system bears some resemblance to that of the neonate, in that T cell numbers are abnormally low and antigen presentation by dendritic cells is precluded by an arrest in their NF-kappaB dependant maturation. In addition, IL-4 production is prominent during and after the tolerance induction interval. For this study we focused on measuring the monkey's ability to repopulate T cells with particular emphasis on the memory T-cell phenotype. Three "memory" phenotypes were utilized; CD3(+)CD45RO(+), CD3(+)CRTH2(+), and CD3(+)CD4(+)CD8(+). All three phenotypes exhibited different patterns of recovery, all of which included transient bursts in their numbers during repopulation. We also estimated thymic activity after T-cell ablation with the use of a newly-described RTE or recent thymic emigre phenotype (a naive CD8(+)CD103(+) T cell). This marker revealed production of RTE cells including supranormal levels at approximately 6 months post-transplant, implicating thymic function in the repopulation of T-cells. Finally, we measured antibody responses to a panel of antigens (vaccines, environmental antigen, and foreign proteins) that indicated there was no apparent loss of immunologic function during or after the tolerance induction period. Results of studies of T-cell receptor repertoire expression suggest preservation of the pretreatment repertoire, which is consistent with rapid recovery of immune competence to the test antigens. Taken together, these results suggest that while aggressive, this tolerance induction prorocol does not appear to incur a prolonged immunologically-compromised state, if at all. (C) American Society for Histocompatibility and Immunogenetics, 2001. Published by Elsevier Science Inc. C1 Univ Alabama, Dept Surg, Div Transplant Immunol, Birmingham, AL 35294 USA. Harvard Univ, Sch Med, Beth Israel Hosp, Boston, MA USA. NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Thomas, JM (reprint author), Univ Alabama, Dept Surg, Div Transplant Immunol, Birmingham, AL 35294 USA. NR 31 TC 20 Z9 20 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD MAY PY 2001 VL 62 IS 5 BP 479 EP 487 DI 10.1016/S0198-8859(01)00235-X PG 9 WC Immunology SC Immunology GA 430AD UT WOS:000168550200003 PM 11334671 ER PT J AU Wan, MM Zhao, KJ Lee, SSJ Francke, U AF Wan, MM Zhao, KJ Lee, SSJ Francke, U TI MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID X-CHROMOSOME INACTIVATION; CPG-BINDING PROTEIN-2; GENE-EXPRESSION; TRANSCRIPTIONAL REPRESSION; METHYLATED DNA; LINKED INHERITANCE; EXCLUSION MAP; ACETYLATION; CHROMATIN; DEACETYLASE AB Rett syndrome (RTT) is a mostly sporadic disorder of developmental regression, with loss of speech and purposeful hand use, microcephaly and seizures. It affects 1 in 10 000-15 000 females. RTT is caused by mutations in the MECP2 gene, which is located in Xq28 and subject to X inactivation. MECP2 encodes a methyl-CpG-binding protein that binds to 5-methyl-cytosine in DNA through its methyl-binding domain. Recruitment of a transcriptional silencing complex through MeCP2's transcriptional repression domain results in histone deacetylation and chromatin condensation. To study the effects of two common truncating RTT mutations (R168X and 803delG), we examined mutant MeCP2 expression and global histone acetylation levels in clonal cell cultures from a female RTT patient with the mutant R168X allele on the active X chromosome, as well as in cells from a male hemizygous for the frameshift mutation 803delG (V288X), Both mutant alleles generated stable RNA transcripts, but no intact MeCP2 protein was detected with an antibody against the C-terminal region of MeCP2, Western blots with antibodies against acetylated histones H3 and H4 revealed that H4, but not H3, was hyperacetylated. By using antibodies against individual acetylated lysine residues, the observed H4 hyperacetylation was attributed to increased acetylation of lysine 16. Therefore, expression of endogenous truncating MECP2 alleles, in the absence of wild-type MeCP2 protein, is specifically associated with an increase in the mono-acetylated histone isoform H4K16, This observed effect may result in over-expression of MeCP2 target genes and, thus, play a role in the pathogenesis of RTT. C1 Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD USA. RP Francke, U (reprint author), Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. NR 46 TC 54 Z9 55 U1 0 U2 1 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 MAY 1 PY 2001 VL 10 IS 10 BP 1085 EP 1092 DI 10.1093/hmg/10.10.1085 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 433RN UT WOS:000168773700009 PM 11331619 ER PT J AU Thayer, KA Ruhlen, RL Howdeshell, KL Buchanan, DL Cooke, PS Preziosi, D Welshons, WV Haseman, J vom Saal, FS AF Thayer, KA Ruhlen, RL Howdeshell, KL Buchanan, DL Cooke, PS Preziosi, D Welshons, WV Haseman, J vom Saal, FS TI Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17 alpha-ethinyl oestradiol SO HUMAN REPRODUCTION LA English DT Article; Proceedings Paper CT International Workshop on Hormones and Endocrine Disrupters in Food and Water CY MAY 27-30, 2000 CL COPENHAGEN UNIV HOSP, COPENHAGEN, DENMARK SP European Commiss, Danish Minist Hlth, Danish Minist Food, Agr & Fisheries HO COPENHAGEN UNIV HOSP DE endocrine disruption; fetus; oral contraceptive; prostate; testes ID ETHINYL ESTRADIOL; DIETHYLSTILBESTROL DES; SEX-HORMONES; ORAL-CONTRACEPTIVES; REPRODUCTIVE-ORGANS; CELL HYPERPLASIA; SERTOLI CELLS; TESTIS SIZE; HUMAN-SERUM; ADULT-RATS AB Approximately 2 million women in the USA and Europe continue taking oral contraceptives each year during undetected pregnancy due primarily to non-compliance and also to individual variation in sensitivity to hormones in the contraceptives, Prenatal exposure to oral contraceptives containing 17 alpha -ethinyl oestradiol (EE) has generally not been associated with an increased incidence of externally observable malformations at birth. The purpose of this study was to assess effects on reproductive organs in adult male mice that had been exposed during gestation day 0 through 17 (equivalent to gestation week 16 in humans) to clinically relevant (similar to0.5 mug/kg/day) and lower doses of EE. Doses used in this study ranged from 0.002 to 2 mug/kg/day, By 5 months of age, prostate weight was significantly (P < 0.05) higher than controls in most treatment groups of EE (0.02-2 mug/kg). Prostatic androgen receptor populations were significantly elevated only in the 0.02 mug/kg group, suggesting different mechanisms for the increase in prostate weight at different doses. Daily sperm production (DSP) and DSP per gramme of testis were reduced in all treatment groups during adolescence, hut not later in adulthood. These findings are consistent with prior studies showing that prenatal exposure of mice to very low doses of a number of oestrogenic chemicals can alter the adult male reproductive system without causing gross external malformations. C1 Univ Missouri, Dept Biol Sci, Columbia, MO USA. Univ Missouri, Dept Vet Biomed Sci, Columbia, MO 65211 USA. Univ Illinois, Dept Vet Biosci, Urbana, IL 61801 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Thayer, KA (reprint author), Wildlife & Contaminant World Wildlife Fund, 1250 24th St,NW, Washington, DC 20037 USA. EM kristina.thayer@wwfus.org FU NCI NIH HHS [CA50354]; NIEHS NIH HHS [ES08293] NR 62 TC 91 Z9 94 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD MAY PY 2001 VL 16 IS 5 BP 988 EP 996 DI 10.1093/humrep/16.5.988 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 431TK UT WOS:000168646500029 PM 11331650 ER PT J AU Nelson, CR Knapp, DA AF Nelson, CR Knapp, DA TI Trends in anti-hypertensive drug therapy by US office-based physicians - Response SO HYPERTENSION LA English DT Letter C1 Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, College Pk, MD 20742 USA. RP Nelson, CR (reprint author), NHLBI, Div Epidemiol & Clin Applicat, NIH, 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 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2001 VL 37 IS 5 BP E12 EP E12 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 436KF UT WOS:000168934500029 ER PT J AU Kumar, S Wolfson, HJ Nussinov, R AF Kumar, S Wolfson, HJ Nussinov, R TI Protein flexibility and electrostatic interactions SO IBM JOURNAL OF RESEARCH AND DEVELOPMENT LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; HIV-INACTIVATING PROTEIN; SALT BRIDGE; THERMAL-STABILITY; FOLDING FUNNELS; NMR STRUCTURE; CYANOVIRIN-N; BINDING; MOTIONS; COMPLEX AB In this paper we address the interrelationship between electrostatic interactions and protein flexibility. Protein flexibility may imply small conformational changes due to the movement of backbone and of side-chain atoms, and/or large-scale molecular motions, in which parts of the protein move as rigid bodies with respect to one another. In particular, we focus on oppositely charged side chains interacting to form salt bridges. The paper has two parts: In the first, we illustrate that the majority of the salt bridges are formed within the independently folding, compact hydrophobic units (HFUs) of the proteins. On the other hand, salt bridges forming across the HFUs, where one amino acid resides in one HFU and its pairing "spouse" in a second, appear to be avoided. In the second part of the paper, we address electrostatic interactions in conformational isomers around the native state. We pick the protein Cyanovirin-N as an example. We show that salt bridges and ion pairs, with less optimal geometry, often interconvert between being stabilizing and destabilizing. We conclude that the stabilizing, or destabilizing, contribution of a salt bridge to protein structure is conformer-dependent. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Frederick, MD 21702 USA. Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. RP Kumar, S (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; OI Kumar, Sandeep/0000-0003-2840-6398 NR 55 TC 20 Z9 20 U1 0 U2 4 PU IBM CORP PI ARMONK PA OLD ORCHARD RD, ARMONK, NY 10504 USA SN 0018-8646 J9 IBM J RES DEV JI IBM J. Res. Dev. PD MAY-JUL PY 2001 VL 45 IS 3-4 BP 499 EP 512 PG 14 WC Computer Science, Hardware & Architecture; Multidisciplinary Sciences SC Computer Science; Science & Technology - Other Topics GA 457UE UT WOS:000170154600011 ER PT J AU Tsai, CJ Ma, B Sham, YY Kumar, S Wolfson, HJ Nussinov, R AF Tsai, CJ Ma, B Sham, YY Kumar, S Wolfson, HJ Nussinov, R TI A hierarchial, building-block-based computational scheme for protein structure prediction SO IBM JOURNAL OF RESEARCH AND DEVELOPMENT LA English DT Article ID HYDROPHOBIC FOLDING UNITS; INORGANIC PYROPHOSPHATASE; GLOBULAR-PROTEINS; CRYSTAL-STRUCTURE; ADENYLATE KINASE; LOCAL-STRUCTURE; BINDING; ENERGY; MOTIFS AB Protein folding is a hierarchical event in which transiently formed local structural elements assemble to yield the native conformation. We outline the hierarchical building block protein folding model, which is based on two premises. First, while the local building block elements may be unstable, they nevertheless have higher population times than all alternate conformations; second, protein folding progresses through a combinatorial assembly of these elements. In accordance with this model, we describe a building block cutting algorithm, implementing its rationale. Through its automated iterative application to the native structure we obtain an anatomy tree, in terms of protein folding. The anatomy tree automatically yields the most likely folding pathway. In particular, we describe how, by using this algorithm and the building blocks which are obtained, we expect to reduce substantially the computational time involved in simulations of protein folding. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Frederick, MD 21702 USA. IBM Corp, Div Res, Thomas J Watson Res Ctr, Yorktown Heights, NY 10598 USA. Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. RP Tsai, CJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Bldg 469,Room 151, Frederick, MD 21702 USA. RI Wolfson, Haim/A-1837-2011; Sham, Yuk/A-6472-2011; Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X NR 27 TC 10 Z9 10 U1 1 U2 3 PU IBM CORP PI ARMONK PA OLD ORCHARD RD, ARMONK, NY 10504 USA SN 0018-8646 J9 IBM J RES DEV JI IBM J. Res. Dev. PD MAY-JUL PY 2001 VL 45 IS 3-4 BP 513 EP 523 PG 11 WC Computer Science, Hardware & Architecture; Multidisciplinary Sciences SC Computer Science; Science & Technology - Other Topics GA 457UE UT WOS:000170154600012 ER PT J AU Davie, B Florence, V Friede, A Sheehan, J Sisk, JE AF Davie, B Florence, V Friede, A Sheehan, J Sisk, JE TI Bringing health-care applications to the Internet SO IEEE INTERNET COMPUTING LA English DT Article C1 Cisco Syst, Chelmsford, MA USA. Natl Lib Med, Bethesda, MD 20894 USA. Mt Sinai Sch Med, New York, NY USA. RP Davie, B (reprint author), Cisco Syst, Chelmsford, MA USA. OI Florance, Valerie/0000-0001-9135-3562 NR 6 TC 2 Z9 2 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1089-7801 J9 IEEE INTERNET COMPUT JI IEEE Internet Comput. PD MAY-JUN PY 2001 VL 5 IS 3 BP 42 EP 48 DI 10.1109/4236.935176 PG 7 WC Computer Science, Software Engineering SC Computer Science GA 436BH UT WOS:000168916300007 ER PT J AU Cohen, SG King, JR AF Cohen, SG King, JR TI Skin tests - A historic trail SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Review AB Based on review of the flow of archival to current day medical literature and communications, the historical highlights of skin testing are traced, summarizing the uncovering of knowledge on the special property of cutaneous tissue to mirror and mediate expressions of local and systemic immune phenomena. Derivation of leads for design of investigations and applications of that endowed skin capacity are exemplified in 19th century accounts of early, inadvertently affected, tissue reactions to microbial reinfection and attempted immunizations against hay fever with causative pollens introduced through mucous membrane and skin routes. Translation of experimental findings to the development of clinically useful diagnostic materials and methods by the second decade of the 20th century are described-particularly preparation of specific antigenic and allergenic extracts and introduction of inventive ophthalmic, scarification, intracutaneous, percutaneous, puncture, passive transfer (P-K), and patch techniques-for study of hypersensitivity atopic and infectious processes, their immune system inter-relationships, pathogenetic mechanisms and interpretations of symptom manifestations. Through reflection on and recount of seminal and pivotal findings along the pathway that established skin testing as a key resource for physicians dealing with allergic, asthmatic, immunologic, infectious and dermatologic diseases, the reader is appraised of the important role the modality also played as a research tool. References are made to the rewarding use of skin test protocols in generating information that contributed to the definition of mechanisms and agents of immediate hypersensitivity and atopic diseases, immune complex and cell mediated delayed reactions and disorders, immunotherapeutic hyposensitization and blocking antibody, bacterial allergy, histamine release, and epidemiologic features of allergen affected populations. C1 NIAID, NIH, Bethesda, MD 20892 USA. Natl Lib Med, NIH, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, NIH, Rockledge B,Room 3125,MHC 7600, Bethesda, MD 20892 USA. NR 218 TC 3 Z9 3 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8561 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD MAY PY 2001 VL 21 IS 2 BP 191 EP + DI 10.1016/S0889-8561(05)70202-2 PG 60 WC Allergy; Immunology SC Allergy; Immunology GA 443DW UT WOS:000169326100002 ER PT J AU Hall, ER Wierzba, TF Ahren, C Rao, MR Bassily, S Francis, W Girgis, FY Safwat, M Lee, YJ Svennerholm, AM Clemens, JD Savarino, SJ AF Hall, ER Wierzba, TF Ahren, C Rao, MR Bassily, S Francis, W Girgis, FY Safwat, M Lee, YJ Svennerholm, AM Clemens, JD Savarino, SJ TI Induction of systemic antifimbria and antitoxin antibody responses in Egyptian children and adults by an oral, killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine SO INFECTION AND IMMUNITY LA English DT Article ID INTESTINAL IMMUNE-RESPONSES; WHOLE-CELL; COLONIZATION FACTORS; IMMUNOGENICITY; DIARRHEA; SAFETY; IMMUNIZATION; DISEASE AB We assessed serologic responses to an oral, killed whole-cell enterotoxigenic Escherichia coli plus cholera toxin B-subunit (ETEC-rCTB) vaccine in 73 Egyptian adults, 105 schoolchildren, and 93 preschool children. Each subject received two doses of vaccine or placebo 2 weeks apart, giving blood before immunization and 7 days after each dose. Plasma antibodies to rCTB and four vaccine-shared colonization factors (CFs) were measured by enzyme-linked immunosorbent assay. Immunoglobulin A (IgA) antibodies to rCTB and CFA/I were measured in all subjects, and those against CS1, CS2, and CS4 were measured in all children plus a subset of 33 adults. IgG antibodies to these five antigens were measured in a subset of 30 to 33 subjects in each cohort. Seroconversion was defined as a >2-fold increase in titer after vaccination. IgA and IgG seroconversion to rCTB was observed in 94 to 95% of adult vaccinees, with titer increases as robust as those previously reported for these two pediatric cohorts. The proportion showing IgA seroconversion to each CF antigen among vaccinated children (range, 70 to 96%) and adults (31 to 69%), as well as IgG seroconversion in children (44 to 75%) and adults (25 to 81%), was significantly higher than the corresponding proportion in placebo recipients, except for IgA responses to CS2 in adults. IgA anti-CF titers peaked after one dose in children, whereas in all age groups IgG antibodies rose incrementally after each dose. Independently, both preimmunization IgA titer and age were inversely related to the magnitude of IgA responses. In conclusion, serologic responses to the ETEC rCTB vaccine mag serve as practical immune outcome measures in future pediatric trials in areas where ETEC is endemic. C1 USN, Med Res Unit 3, Cairo, Egypt. Egyptian Minist Hlth & Populat, Benha, Qalyubia Govern, Egypt. Univ Gothenburg, Dept Med Microbiol & Immunol, Gothenburg, Sweden. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Savarino, SJ (reprint author), USN, Med Res Ctr, Enter Dis Dept, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. FU NICHD NIH HHS [Y1-HD-0026-01] NR 21 TC 39 Z9 40 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2001 VL 69 IS 5 BP 2853 EP 2857 DI 10.1128/IAI.69.5.2853-2857.2001 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 423CT UT WOS:000168158400011 PM 11292698 ER PT J AU Wolf, K Fischer, E Mead, D Zhong, GM Peeling, R Whitmire, B Caldwell, HD AF Wolf, K Fischer, E Mead, D Zhong, GM Peeling, R Whitmire, B Caldwell, HD TI Chlamydia pneumoniae major outer membrane protein is a surface-exposed antigen that elicits antibodies primarily directed against conformation-dependent determinants SO INFECTION AND IMMUNITY LA English DT Article ID PROTECTIVE MONOCLONAL-ANTIBODIES; SP STRAIN TWAR; TRACHOMATIS INFECTIVITY; PHAGE DISPLAY; NEUTRALIZATION; EPITOPES; CELLS; GENES; IDENTIFICATION; PURIFICATION AB The major outer membrane protein MOMP of Chlamydia trachomatis serovariants is known to be an immunodominant surface antigen. Moreover, it is known that the C:. trachomatis MOMP elicits antibodies that recognize both linear and conformational antigenic determinants. In contrast, it has been reported that the MOMP of Chlamydia pneumoniae is not surface exposed and is immunorecessive. We hypothesized that the discrepancies between C, trachomatis and C, pneumoniae MOMP exposure on intact chlamydiae and immunogenic properties might be because the focus of the host's immune response is directed to conformational epitopes of the C, pneumoniae MOMP. We therefore conducted studies aimed at defining the surface exposure of MOMP and the conformational dominance of MOMP antibodies. We present here a description of C, pneumoniae species-specific monoclonal antibody (MAb), GZD1E8, which recognizes a conformational epitope on the surface of C, pneumoniae. This MAb is potent in the neutralization of C. pneumoniae infectivity in vitro. Another previously described C, pneumoniae species-specific monoclonal antibody, RR-402, displayed vent similar characteristics. However, the antigenic determinant recognized by RR-402 has yet to be identified. We show by immunoprecipitation of C, pneumoniae with GZD1E8 and RR-402 MAbs and by mass spectrometry anal sis of immunoprecipitated proteins that both antibodies GZD1E8 and RR-402 recognize the MOMP of C. pneumoniae and that this protein is localized on the surface of the organism. We also show that human sera from C pneumoniae-positive donors consistently recognize the MOMP by immunoprecipitation, indicating that the MOMP of C. pneumoniae is an immunogenic protein. These findings have potential implications for both C. pneumoniae vaccine and diagnostic assay development. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Microscopy Branch, NIH, Hamilton, MT 59840 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. Lab Ctr Dis Control, Winnipeg, MB R3E 3R2, Canada. RP Wolf, K (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, 900 S 4th St, Hamilton, MT 59840 USA. NR 42 TC 46 Z9 48 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2001 VL 69 IS 5 BP 3082 EP 3091 DI 10.1128/IAI.69.5.3082-3091.2001 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 423CT UT WOS:000168158400040 PM 11292727 ER PT J AU Thomas, V Anguita, J Samanta, S Rosa, PA Stewart, P Barthold, SW Fikrig, E AF Thomas, V Anguita, J Samanta, S Rosa, PA Stewart, P Barthold, SW Fikrig, E TI Dissociation of infectivity and pathogenicity in Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; IN-VIVO; GENE-EXPRESSION; PLASMID; PROTEIN; VITRO; MICE; OSPD; PROTECTION; INDUCTION AB Clonal Borrelia burgdorferi N40 (cN40) passaged 75 times in vitro (N40-75) infects mice but does not cause disease. N40-75 passaged 45 times further in vitro (N40-120),vas no longer infectious and lacked genes encoded on linear plasmids 38 and 28-1, among other differences. These data suggest that B. burgdorferi cN40, N40-75. and N40-120 have distinct phenotypes that can be used to dissect the genetic elements responsible for pathogenicity and infectivity. C1 Yale Univ, Sch Med, Rheumatol Sect, Dept Internal Med,Lab Clin Invest 608, New Haven, CT 06520 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Calif Davis, Sch Med, Ctr Comparat Med, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med, Ctr Comparat Med, Davis, CA 95616 USA. RP Fikrig, E (reprint author), Yale Univ, Sch Med, Rheumatol Sect, Dept Internal Med,Lab Clin Invest 608, POB 208031, New Haven, CT 06520 USA. RI Anguita, Juan/D-5432-2011 OI Anguita, Juan/0000-0003-2061-7182 FU NIAMS NIH HHS [R03 AR045740, R03 AR045740-03] NR 34 TC 16 Z9 16 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2001 VL 69 IS 5 BP 3507 EP 3509 DI 10.1128/IAI.69.5.3507-3509.2001 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 423CT UT WOS:000168158400098 PM 11292785 ER PT J AU Da Silva, DM Velders, MP Nieland, JD Schiller, JT Nickoloff, BJ Kast, WM AF Da Silva, DM Velders, MP Nieland, JD Schiller, JT Nickoloff, BJ Kast, WM TI Physical interaction of human papillomavirus virus-like particles with immune cells SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE antigen presentation; CD16; Fc receptor; papillomavirus; vaccine; virus-like particles ID FC-GAMMA-RIII; HUMAN-IMMUNODEFICIENCY-VIRUS; SURFACE HEPARAN-SULFATE; MAJOR CAPSID PROTEIN; HERPES-SIMPLEX VIRUS; ANTIGEN PRESENTATION; SIGNAL-TRANSDUCTION; LANGERHANS CELLS; ALPHA-6 INTEGRIN; IGG FC AB Human papillomavirus virus-like particles (HPV VLP) and chimeric VLP are immunogens that are able to elicit potent anti-viral/tumor a and T cell responses. To investigate the immunogenicity of VLP, we determined which cells of the immune system are able to bind HPV-16 VLP, VLP were found to bind very well to human and mouse immune cells that expressed markers of antigen-presenting cells (APC) such as MHC class II, CD80 and CD86, including dendritic cells, macrophages and B cells, mAb blocking studies identified Fc gamma RIII (CD16) as one of the molecules to which the VLP can bind both on immune cells and foreskin epithelium. However, transfection of a CD16(-) hell line with CD16 did not confer binding of VLP. Splenocytes from Fc gamma RIII knockout mice Showed a 33% decrease in VLP binding overall and specifically to subsets of APC, These combined data support a role for CD16 as an accessory molecule in an HPV VLP-receptor complex, possibly contributing to the immunogenicity of HPV VLP. C1 Loyola Univ, Cardinal Bernardin Canc Ctr, Canc Immunol Program, Maywood, IL 60153 USA. Loyola Univ, Dept Microbiol & Immunol, Maywood, IL 60153 USA. NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Kast, WM (reprint author), Loyola Univ, Cardinal Bernardin Canc Ctr, Canc Immunol Program, 2160 S 1st Ave, Maywood, IL 60153 USA. FU NCI NIH HHS [R01 CA74397, R01 CA74399, P01 CA74182] NR 48 TC 37 Z9 41 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD MAY PY 2001 VL 13 IS 5 BP 633 EP 641 DI 10.1093/intimm/13.5.633 PG 9 WC Immunology SC Immunology GA 431FA UT WOS:000168620100004 PM 11312251 ER PT J AU Hemmi, H Yoshino, M Yamazaki, H Naito, M Iyoda, T Omatsu, Y Shimoyama, S Letterio, JJ Nakabayashi, T Tagaya, H Yamane, T Ogawa, M Nishikawa, S Ryoke, K Inaba, K Hayashi, S Kunisada, T AF Hemmi, H Yoshino, M Yamazaki, H Naito, M Iyoda, T Omatsu, Y Shimoyama, S Letterio, JJ Nakabayashi, T Tagaya, H Yamane, T Ogawa, M Nishikawa, S Ryoke, K Inaba, K Hayashi, S Kunisada, T TI Skin antigens in the steady state are trafficked to regional lymph nodes by transforming growth factor-beta 1-dependent cells SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE autoantigen; dendritic cell; hepatocyte growth factor (Hgf); Langerhans cell; melanin granule; steel factor (Mgf) ID COLONY-STIMULATING FACTOR; EPIDERMAL LANGERHANS CELLS; DENDRITIC CELLS; BONE-MARROW; IMMUNE-RESPONSES; DRAINING LYMPH; IN-VIVO; CONTACT HYPERSENSITIVITY; KERATINOCYTE EXPRESSION; PROGENITOR CELLS AB Antigen capturing in the skin and antigen trafficking into regional lymph nodes (LN) initiate immune responses, In this study, employing melanin granule (MG) as an easily traceable antigen in two mouse strains that carried steel factor or hepatocyte growth factor transgenes and had melanocytosis in the epidermis or in the dermis respectively, we investigated the mechanism of antigen trafficking from the skin, MG captured in the epidermis or dermis accumulated in the regional LN, but not other tissues, Only in alymphoplastic mice did MG-laden cells pass through the lymphatics and reached many tissues. Since inflammatory regions were not observed in the skin of either type of transgenic mouse, our developmental system enables us to investigate constitutive capturing and trafficking of insoluble antigens in the steady state, Both dendritic cells and macrophages were laden with MG in the regional LN. To determine which cells traffic antigens to the LN, we prepared double mutants that carried the transgenes and lacked transforming growth factor (TGF)-beta1, since mice lacking TGF-beta1 are reported to be deficient of Langerhans cells, Few MG were observed in the regional LN of these double-mutant mice, We also showed that signaling via macrophage colony stimulating factor receptor or Flt3/Flk2 is not essential for development of the cells for this antigen trafficking, These results indicate that antigens in the epidermis and dermis in the steady state are trafficked into regional LN only by TGF-beta1-dependent cells, which may be a dendritic cell lineage. C1 Tottori Univ, Sch Life Sci, Dept Immunol, Yonago, Tottori 6838503, Japan. Tottori Univ, Fac Med, Dept Oral & Maxillofacial Surg, Yonago, Tottori 6838503, Japan. Gifu Univ, Dept Hyg, Gifu 5008705, Japan. Hlth Sci Univ Hokkaido, Dept Internal Med, Ishikari, Hokkaido 0610293, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Dept Mol Genet, Kyoto 6068502, Japan. Kyoto Univ, Grad Sch Biostudies, Kyoto 6068502, Japan. Kyoto Univ, Grad Sch Sci, Immunobiol Lab, Kyoto 6068502, Japan. Niigata Univ, Sch Med, Dept Pathol 2, Niigata 9518510, Japan. RP Hayashi, S (reprint author), Tottori Univ, Sch Life Sci, Dept Immunol, Yonago, Tottori 6838503, Japan. NR 61 TC 115 Z9 116 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD MAY PY 2001 VL 13 IS 5 BP 695 EP 704 DI 10.1093/intimm/13.5.695 PG 10 WC Immunology SC Immunology GA 431FA UT WOS:000168620100010 PM 11312257 ER PT J AU Wellmann, A Flemming, P Behrens, P Wuppermann, K Lang, H Oldhafer, K Pastan, I Brinkmann, U AF Wellmann, A Flemming, P Behrens, P Wuppermann, K Lang, H Oldhafer, K Pastan, I Brinkmann, U TI High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: Correlation with tumor progression SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE spindle checkpoint; cell-cycle; stem cell ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN HEPATOCELLULAR CARCINOMAS; IN-SITU HYBRIDIZATION; CHROMOSOME-SEGREGATION; MITOTIC SPINDLE; BREAST-CANCER; HUMAN HOMOLOG; CAS PROTEIN; CELLS; CSE1 AB The CSE1L/CAS protein (CAS) is a Ran-binding protein with a function as nuclear transport (export) factor. Like recently observed for ran and other lan-binding proteins, CSE1L/CAS simultaneously plays a role in the mitotic spindle checkpoint, which assures genomic stability during cell division. This checkpoint is frequently disturbed in neoplasias of various origin, including hepatic tumors. We have evaluated by immunohistology the expression of CAS in adult and embryonic liver, hepatitis, and in liver hyperplasias. Normal hepatocytes revealed no CAS expression while embryonic liver showed strong expression in all parenchymal cells. Bile ducts stained positive with anti-CAS antibodies, and strong CAS expression was also detected at the intel face between bile ducts and hepatocytes under conditions associated with regenerative proliferation. The localization of these CAS expressing cells correlated with the distribution of 'oval' putative liver stem-cells. In active viral (but not in inactive) hepatitis, strong hepatocytal CAS expression correlates in site and intensity with degree of inflammation. Neoplastic liver demonstrated different degrees of CAS expression: no remarkable expression in adenomas, moderate expression in a narrow rim of hepatocytes and in periseptal cholangiolar proliferations in focal nodular hyperplasia, and strong CAS expression in hepatocellular carcinoma. Less differentiated tumors stain stronger than well differentiated. Cholangio-cellular carcinomas show even stronger CAS expression than hepatocellular carcinomas. Our observation of strong expression of CAS in liver cells that are committed for proliferation among them possibly liver stem cells, and in liver neoplasms, is consistant with the fact that CAS functions not solely as a nuclear transport factor but that it is also essential for cell proliferation, particularly for the mitotic spindle checkpoint. Interestingly, genomic instability is frequently observed in hepatic tumors which we have shown here to express large amounts of GAS. Since the degree of GAS-expression correlates with the grade of tumor dedifferentiation, we suggest that CAS should also be further investigated as prognostic marker for hepatic neoplasms. C1 Epidauros Biotechnol, D-82347 Bernried, Germany. Univ Bonn, Inst Pathol, Hannover, Germany. Med Univ Hannover, Inst Pathol, Hannover, Germany. Med Univ, Dept Visceral Surg, Essen, Germany. NIH, Natl Canc Inst, Div Basic Sci, Bethesda, MD 20892 USA. RP Brinkmann, U (reprint author), Epidauros Biotechnol, Neuland 1, D-82347 Bernried, Germany. NR 31 TC 34 Z9 39 U1 0 U2 1 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD MAY PY 2001 VL 7 IS 5 BP 489 EP 494 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 422AD UT WOS:000168095000004 PM 11295109 ER PT J AU Weyer, C Vozarova, B Ravussin, E Tataranni, PA AF Weyer, C Vozarova, B Ravussin, E Tataranni, PA TI Changes in energy metabolism in response to 48 h of overfeeding and fasting in Caucasians and Pima Indians SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE energy metabolism; diet-induced thermogenesis; respiratory chamber; metabolic adaptation; ethnicity ID BODY-WEIGHT; RESPIRATORY CHAMBER; YOUNG MEN; EXPENDITURE; THERMOGENESIS; FAT; BALANCE; HUMANS; TERM; DIET AB dOBJECTIVE: Differences in the metabolic response to overfeeding and starvation may confer susceptibility or resistance to obesity in humans. To further examine this hypothesis, we assessed the changes in 24 h energy metabolism in response to shortterm overfeeding and fasting in Caucasians (C) and Pima Indians (I), a population with a very high propensity for obesity. METHODS: We measured the changes in 24 h energy expenditure (24-EE) and 24 h respiratory quotient (24-RQ) in response to 48 h of mixed diet overfeeding (100% above energy requirements) and fasting in a whole body respiratory chamber in 14 male subjects (7 C/71, age 30 +/- 6y, mean +/- s.d.). Results were compared to a 24 h measurement under eucaloric conditions. RESULTS: Mean 24-EE increased in response to overfeeding and decreased in response to fasting (all changes P < 0.01), with no differences between C (+ 9.1% and -9.1%) and 1 (+8.6% and -9.6%). Similarly mean 24-RQ increased/decreased in response to overfeeding/fasting, respectively (all changes P < 0.01), again with no differences between C (+ 0.06 and -0.05) and I (+ 0.05 and -0.05). The changes in 24-EE in response to overfeeding and fasting were positively correlated (r= 0.70, P < 0.01), whereas those in 24-RQ were not (r= 0.40, NS). CONCLUSIONS: Pima Indians do not appear to have an impaired metabolic response to short-term overfeeding and fasting that could explain their propensity for obesity. Individuals with a large increase in energy expenditure in response to overfeeding appear to have a small decrease in energy expenditure in response to starvation (spendthrift phenotype) and vice versa (thrifty phenotype). C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Weyer, C (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Rm 5-41, Phoenix, AZ 85016 USA. OI de Courten, Barbora/0000-0001-8760-2511 NR 39 TC 30 Z9 30 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2001 VL 25 IS 5 BP 593 EP 600 DI 10.1038/sj.ijo.0801610 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 425MQ UT WOS:000168294900001 PM 11360139 ER PT J AU Yoshida, Y Hosokawa, K Dantes, A Kotsuji, F Kleinman, HK Amsterdam, A AF Yoshida, Y Hosokawa, K Dantes, A Kotsuji, F Kleinman, HK Amsterdam, A TI Role of laminin in ovarian cancer turner growth and metastasis via regulation of Mdm2 and Bcl-2 expression SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE laminin; laminin peptides; ovarian cancer; Mdm2; Bcl-2 ID CELL-BINDING SEQUENCES; BASEMENT-MEMBRANE; ALPHA-1 CHAIN; TUMOR-GROWTH; A-CHAIN; SYNTHETIC PEPTIDE; GRANULOSA-CELLS; IKVAV SEQUENCE; GAMMA-1 CHAIN; IDENTIFICATION AB Ovarian cancer is among the most lethal cancers in women because of its high metastatic potential and lack of response to therapy. An experimental model to study this disease was developed using a transformed granulosa cell line expressing a mutant p53 and Ha-ras. When injected into the ovary of nude mice in the presence of laminin-l, tumors develop in the ovary and peritoneum and metastasize to various organs, leading to death within 21 days. In contrast, when cells were injected in the presence of gelatin, development of tumors was slower and no metastases were observed by day 21. Here we investigated the possible mechanism by which laminin-l exerts its promotion of tumorigenesis and metastasis. Cells were co-injected with laminin-l and active laminin peptides from the al; (A13: RQVFQVAYIIIKA, A12: WVTVTLDL RQVFQ, AG73: LQVQLSIR, IKVAV) and beta1 (YIGSR) chains. Ovarian tumor growth and metastasis were increased in the presence of laminin-l plus either AG73 peptide, IKVAV, or A13, and were significantly reduced in the presence of A12 or YIGSR. Expression of Bcl-2 and Mdm2 was higher by 3.5- and about 100-fold, respectively, in ovarian tumors grown in the presence of laminin compared to tumors grown in the presence of gelatin. Moreover, peptides A13 and AG73 further elevated Bcl-2 expression by 6- and 7-fold respectively, while IKVAV yielded expression similar to laminin-l. YIGSR and A12 reduced the expression of Bcl-2 by 7- and 3-fold, respectively, compared to treatment with laminin-l. A13 and AG73 increased Mdm2 expression by 1.8- and 1.3-fold, respectively, while IKVAV, A12, and YIGSR were without effect. Thus, laminin-l exerts its proliferative effect on the development of ovarian tumors via upregulation of survival genes such as Bcl-2 and Mdm2. Peptides A13 and AG73 (which increased tumor growth and spread) enhance the expression of these genes and A12 and YIGSR (which decrease tumor growth and spread) attenuate their expression. IKVAV probably enhances tumor growth and metastasis by another mechanism. C1 Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. Fukui Med Univ, Dept Obstet & Gynecol, Fukui 9101193, Japan. NIDCR, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Amsterdam, A (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. NR 57 TC 18 Z9 18 U1 0 U2 2 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD MAY PY 2001 VL 18 IS 5 BP 913 EP 921 PG 9 WC Oncology SC Oncology GA 422WE UT WOS:000168141600002 PM 11295035 ER PT J AU Neimark, H Johansson, KE Rikihisa, Y Tully, JG AF Neimark, H Johansson, KE Rikihisa, Y Tully, JG TI Proposal to transfer some members of the genera Haemobartonella and Eperythrozoon to the genus Mycoplasma with descriptions of 'Candidatus Mycoplasma haemofelis', 'Candidatus Mycoplasma haemomuris', 'Candidatus Mycoplasma haemosuis' and 'Candidatus Mycoplasma wenyonii' SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article DE 16S rRNA; Rickettsiales; Anaplasmataceae; Mollicutes; phylogeny ID ELECTRON-MICROSCOPIC FEATURES; CHAIN-REACTION ASSAY; RIBOSOMAL-RNA GENE; SUIS INFECTION; DNA-PROBE; H-FELIS; SWINE; BLOOD; LIGHT; CATS AB Cell-wall-less uncultivated parasitic bacteria that attach to the surface erythrocytes currently are classified in the order Rickettsiales, family Cell-wall-less uncultivated parasitic bacteria that attach to the surface of host Anaplasmataceae, in the genera Haemobartonella and Eperythrozoon, Recently 16S rRNA gene sequences have been determined for four of these species: Haemobartonella felis and Haemobartonella muris and Eperythrozoon suis and Eperythrozoon wenyonii. Phylogenetic analysis of these sequence data shows that these haemotrophic bacteria are closely related to species in the genus Mycoplasma (class Mollicutes). These haemotrophic bacteria form a new phylogenetic cluster within the so-called pneumoniae group of Mycoplasma and share properties with one another as well as with other members of the pneumoniae group. These studies clearly indicate that the classification of these taxa should be changed to reflect their phylogenetic affiliation and the following is proposed: (i) that Haemobartonella felis and Haemobartonella muris should be transferred to the genus Mycoplasma as 'Candidatus Mycoplasma haemofelis' and 'Candidatus Mycoplasma haemomuris' and (ii) that Eperythrozoon suis and Eperythrozoon wenyonii should be transferred to the genus Mycoplasma as 'Candidatus Mycoplasma haemosuis' and 'Candidatus Mycoplasma wenyonii', The former Haemobartonella and Eperythrozoon species described here represent a new group of parasitic mycoplasmas that possess a pathogenic capacity previously unrecognized among the mollicutes. These haemotrophic mycoplasmas have been given the trivial name haemoplasmas. These results call into question the affiliation of the remaining officially named species of Haemobartonella and Eperythrozoon which should be considered species of uncertain affiliation pending the resolution of their phylogenetic status. C1 SUNY Brooklyn, Coll Med, Dept Microbiol & Immunol, Brooklyn, NY 11203 USA. Natl Vet Inst, Dept Bacteriol, S-75189 Uppsala, Sweden. Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. NIAID, Frederick Canc Res & Dev Ctr, Mycoplasma Sect, Frederick, MD 21707 USA. RP Neimark, H (reprint author), SUNY Brooklyn, Coll Med, Dept Microbiol & Immunol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. NR 64 TC 222 Z9 249 U1 0 U2 6 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1466-5026 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD MAY PY 2001 VL 51 BP 891 EP 899 PN 3 PG 9 WC Microbiology SC Microbiology GA 435UP UT WOS:000168900000019 PM 11411711 ER PT J AU Ulyanova, T Szel, A Kutty, RK Wiggert, B Caffe, AR Chader, GJ van Veen, T AF Ulyanova, T Szel, A Kutty, RK Wiggert, B Caffe, AR Chader, GJ van Veen, T TI Oxidative stress induces heme oxygenase-1 immunoreactivity in Muller cells of mouse retina in organ culture SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; HUMAN SKIN FIBROBLASTS; CARBON-MONOXIDE; MESSENGER-RNA; NITRIC-OXIDE; RAT RETINA; LIPID-PEROXIDATION; GENE-TRANSFER; EXPRESSION; INDUCTION AB PURPOSE. Heme oxygenase (HO)-1 immunoreactivity (IR) was examined in normal untreated retina and in retinal explants after in vitro treatment with stress agents. METHODS. Enucleated eyes from young adult C3H mice were immediately fixed and cryosectioned and the retina sections processed for immunocytochemistry with antibodies against HO-1 and glial fibrillary acidic protein (GFAP). From other eyes retinas were isolated and maintained in organ culture, either untreated for 4 days maximum or for 21 hours during which the explants were treated the first 3 hours with selected doses of sodium arsenate or hydrogen peroxide. Thereafter, the explants were processed identically with the normal tissue. RESULTS. In the normal retina, HO-1 and GFAP IR was very low. The culturing itself resulted in an increase in both HO-I and GFAP immunolabeling in Muller cells of explanted retinas. Both sodium arsenate and hydrogen peroxide further induced strong HO-1 IR in Muller cells but not in other retinal cells. In contrast to HO-1, GFAP staining in Muller cells was not altered as a result of treatment, either by sodium arsenate or hydrogen peroxide at any concentration used. CONCLUSION. The results show for the first time that HO-1 can be induced in the retina in vitro by conditions of oxidative stress and that enzyme expression is confined exclusively to Muller cells. C1 Washington Univ, Dept Internal Med, St Louis, MO USA. Semmelweis Univ, Dept Anat 2, H-1085 Budapest, Hungary. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Lund Univ, Wallenberg Retina Ctr, Dept Ophthalmol, S-22100 Lund, Sweden. Fdn Fighting Blindness, Baltimore, MD USA. RP van Veen, T (reprint author), Univ Lund Hosp, Wallenberg Retina Ctr, BMC, Dept Ophthalmol, B13,Klinikgatan 26, S-22184 Lund, Sweden. EM theo.van_veen@oft.lu.se NR 52 TC 23 Z9 23 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2001 VL 42 IS 6 BP 1370 EP 1374 PG 5 WC Ophthalmology SC Ophthalmology GA 433DB UT WOS:000168739100037 PM 11328753 ER PT J AU Carvalho, EM Bacellar, O Porto, AF Braga, S Galvao-Castro, B Neva, F AF Carvalho, EM Bacellar, O Porto, AF Braga, S Galvao-Castro, B Neva, F TI Cytokine profile and immunomodulation in asymptomatic human T-lymphotropic virus type 1-infected blood donors SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE cellular immunity in HTLV-1; cytokines in HTLV-1; HTLV-1; immune response in HTLV-1; immunomodulation in HTLV-1 ID TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; HTLV-I; INTERFERON-GAMMA; CELL CLONES; INTERLEUKIN-2; INFECTION; DISEASE; SECRETE; TH1 AB The modulation of the immune response has been used as therapy for clinical disorders associated with human T-lymphotropic virus type 1 (HTLV-1) infection. In this study, the cytokine profile was evaluated in 26 asymptomatic HTLV-1 blood donors. Additionally, both the cell responsible for producing interferon-gamma (IFN-gamma) and the role of exogenous interleukin (IL)-10 in downregulating IFN-gamma production were studied. Cytokine levels were determined in supernatants of unstimulated lymphocyte cultures by enzyme-linked immunosorbent assay. The levels of IFN-gamma, tumor necrosis factor-alpha, IL-5, and IL-10 were higher in supernatants of the lymphocyte cultures taken from HTLV-1-infected donors than in those taken from healthy subjects. Although depletion of CD8(+) T cells and natural killer cells did not affect IFN-gamma production, depletion of CD4(+) T cells significantly decreased IFN-gamma production. Furthermore, at a concentration of 2 ng/ml, IL-10 had only a minimum effect on IFN-gamma production, although at high concentrations (100 ng/ml), IL-10 decreased IFN-gamma production by 50% in HTLV-1-infected individuals. These data indicate that both T helper 1 and T helper 2 cytokines are elevated in HTLV-1 infection and that IL-10 in high concentrations modulates IFN-gamma production in these patients. C1 Univ Fed Bahia, Serv Imunol, Hosp Univ Prof Edgard Santos, Salvador, BA, Brazil. Fdn Oswaldo Cruz, Lab Avancado Saude Publ, Salvador, BA, Brazil. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Carvalho, EM (reprint author), Univ Fed Bahia, Serv Imunol, Hosp Univ Prof Edgard Santos, Salvador, BA, Brazil. FU NIAID NIH HHS [AI-30639] NR 19 TC 60 Z9 65 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. PD MAY 1 PY 2001 VL 27 IS 1 BP 1 EP 6 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 442YJ UT WOS:000169312300001 PM 11404513 ER PT J AU Liu, JH Burdette, JE Xu, HY Gu, CG van Breemen, RB Bhat, KPL Booth, N Constantinou, AI Pezzuto, JM Fong, HHS Farnsworth, NR Bolton, JL AF Liu, JH Burdette, JE Xu, HY Gu, CG van Breemen, RB Bhat, KPL Booth, N Constantinou, AI Pezzuto, JM Fong, HHS Farnsworth, NR Bolton, JL TI Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE estrogen receptor; alkaline phosphatase; progesterone receptor; pS2; dietary supplement; phytoestrogens; isoflavones ID ULTRAFILTRATION-MASS-SPECTROMETRY; BREAST-CANCER CELLS; RECEPTOR-BETA; DIETARY PHYTOESTROGENS; LIQUID-CHROMATOGRAPHY; CIMICIFUGA-RACEMOSA; AMERICAN GINSENG; GENE-EXPRESSION; PS2 EXPRESSION; BLACK COHOSH AB Eight botanical preparations that are commonly used for the treatment of menopausal symptoms were tested for estrogenic activity. Methanol extracts of red clover (Trifolium pratense L.), chasteberry (Vitex agnus-castus L.), and hops (Humulus lupulus L.) showed significant competitive binding to estrogen receptors alpha (ER alpha) and beta (ER beta). With cultured Ishikawa (endometrial) cells, red clover and hops exhibited estrogenic activity as indicated by induction of alkaline phosphatase (AP) activity and up-regulation of progesterone receptor (PR) mRNA. Chasteberry also stimulated PR expression, but no induction of AP activity was observed. In S30 breast cancer cells, pS2 (presenelin-2), another estrogen-inducible gene, was up-regulated in the presence of red clover, hops, and chasteberry. Interestingly, extracts of Asian ginseng (Panax ginseng C.A. Meyer) and North American ginseng (Panax quinquefolius L.) induced pS2 mRNA expression in S30 cells, but no significant ER binding affinity, AP induction, or PR expression was noted in Ishikawa eels. Dong quai [Angelica sinensis (Oliv.) Diels] and licorice (Glycyrrhiza glabra L.) showed only weak ER binding and PR and pS2 mRNA induction. Black cohosh [Cimicifuga racemosa (L.) Nutt.] showed no activity in any of the above in vitro assays. Bioassay-guided isolation utilizing ER competitive binding as a monitor and screening using ultrafiltration LC-MS revealed that genistein was the most active component of red clover. Consistent with this observation, genistein was found to be the most effective of four red clover isoflavones tested in the above in vitro assays. Therefore, estrogenic components of plant extracts can be identified using assays for estrogenic activity along with screening and identification of the active components using ultrafiltration LC-RIS. These data suggest a potential use for some dietary supplements, ingested by human beings, in the treatment of menopausal symptoms. C1 Univ Illinois, Program Collaborat Res Pharmaceut Sci, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res,Coll Pharm, Chicago, IL 60612 USA. Univ Illinois, Dept Surg Oncol, Chicago, IL 60612 USA. RP Bolton, JL (reprint author), Univ Illinois, Program Collaborat Res Pharmaceut Sci, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res,Coll Pharm, M-C 781,833 S Wood St, Chicago, IL 60612 USA. OI Constantinou, Andreas/0000-0003-0365-1821 FU NCCIH NIH HHS [P50 AT00155] NR 53 TC 257 Z9 283 U1 5 U2 45 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD MAY PY 2001 VL 49 IS 5 BP 2472 EP 2479 DI 10.1021/jf0014157 PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 436AW UT WOS:000168915200060 PM 11368622 ER PT J AU Martin, R Gran, B Zhao, YD Markovic-Plese, S Bielekova, B Marques, A Sung, MH Hemmer, B Simon, R McFarland, HF Pinilla, C AF Martin, R Gran, B Zhao, YD Markovic-Plese, S Bielekova, B Marques, A Sung, MH Hemmer, B Simon, R McFarland, HF Pinilla, C TI Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS lyme disease SO JOURNAL OF AUTOIMMUNITY LA English DT Article; Proceedings Paper CT International Symposium on Autoimmunity Induced by Infection or Immunization CY NOV 28-DEC 01, 2000 CL LES PENSIERES, FRANCE SP Merieux Fdn DE T cell recognition; autoimmunity; multiple sclerosis; molecular mimicry ID MYELIN BASIC-PROTEIN; ALTERED PEPTIDE LIGANDS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; COMBINATORIAL LIBRARIES; DEMYELINATING DISEASES; RECEPTOR; RECOGNITION; IDENTIFICATION; TCR; HETEROGENEITY AB The concept of molecular mimicry provides and elegant framework as to how cross-reactivity between antigens from a foreign agent with self proteins may trigger autoimmune diseases. While it was previously thought that sequence and structural homology between foreign and self proteins or the sharing of T cell receptor (TCR) and MHC-binding motifs are required for molecular mimicry to occur, we have shown that even completely unrelated peptide sequences may lead to cross-recognition by T cells. The use of synthetic combinatorial peptide libraries in the positional scanning format (PS-SCL) together with novel biometric prediction approaches has allowed us to describe the recognition profiles of individual autoreactive T cell clones (TCC) with unprecedented accuracy. Through studies of myelin-specific TCC as well as clones from the nervous system of patients suffering from chronic central nervous (CNS) Lyme disease it has become clear that at least some T cells are more degenerate than previously anticipated. These data will not only help us to redefine what constitutes specific T cell recognition, but also allow us to study in more detail the biological role of molecular mimicry. A recent clinical trial with an altered peptide ligand (APL) of one of the candidate myelin basic protein (MBP) epitopes in MS (amino acids 83-99) has shown that such a modified MBP peptide may not only have therapeutic efficacy, but also bears the potential to exacerbate disease. Thus, we provide firm evidence that the basic principles of cross-recognition and their pathogenetic significance are relevant in MS. (C) 2001 Academic Press. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Rockville, MD 20854 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. Univ Marburg, Dept Neurol, D-35039 Marburg, Germany. RP Martin, R (reprint author), NINDS, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. RI Gran, Bruno/A-2288-2013 OI Gran, Bruno/0000-0001-6384-2342 NR 48 TC 51 Z9 52 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD MAY PY 2001 VL 16 IS 3 SI SI BP 187 EP 192 DI 10.1006/jaut.2000.0501 PG 6 WC Immunology SC Immunology GA 431XG UT WOS:000168656600003 PM 11334482 ER PT J AU McCarty, D Weisner, C Huebner, RB AF McCarty, D Weisner, C Huebner, RB TI Special section - Applications of health services research in the treatment and prevention of alcohol abuse - Introduction SO JOURNAL OF BEHAVIORAL HEALTH SERVICES & RESEARCH LA English DT Editorial Material C1 Oregon Hlth Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. NIAAA, Div Clin & Prevent Res, Rockville, MD 20852 USA. RP McCarty, D (reprint author), Oregon Hlth Sci Univ, Dept Publ Hlth & Prevent Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. FU NIAAA NIH HHS [P50 AA 05595, R37 AA 10359, R01-AA-11363]; NIDA NIH HHS [P50-DA-10233] NR 6 TC 0 Z9 0 U1 1 U2 1 PU ASPEN PUBL INC PI GAITHERSBURG PA 200 ORCHARD RIDGE DR, STE 200, GAITHERSBURG, MD 20878 USA SN 1094-3412 J9 J BEHAV HEALTH SER R JI J. Behav. Health Serv. Res. PD MAY PY 2001 VL 28 IS 2 BP 115 EP 117 DI 10.1007/BF02287454 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 424LL UT WOS:000168233700001 PM 11338323 ER PT J AU Kontaxis, G Bax, A AF Kontaxis, G Bax, A TI Multiplet component separation for measurement of methyl C-13-H-1 dipolar couplings in weakly aligned proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE dipolar coupling; IPAP-editing; liquid crystal; methyl group; multiplet editing ID LIQUID-CRYSTALLINE MEDIUM; 2-DIMENSIONAL NMR-SPECTRA; ORIENTED MACROMOLECULES; ALIGNMENT; CONSTANTS; PHASE; EXCITATION; GELS AB A simple spectral editing procedure is described that generates separate subspectra for the methyl C-13-H-1(3) multiplet components of H-1-C-13 HSQC spectra. The editing procedure relies on co-addition of in-phase and antiphase spectra and yields H-1-coupled constant-time HSQC subspectra for the methyl region that have the simplicity of the regular decoupled CT-HSQC spectrum. Resulting spectra permit rapid and reliable measurement of H-1-C-13 J and dipolar couplings. The editing procedure is illustrated for a Ca2+-calmodulin sample in isotropic and liquid crystalline phases. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Kontaxis, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 38 TC 34 Z9 34 U1 0 U2 6 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAY PY 2001 VL 20 IS 1 BP 77 EP 82 DI 10.1023/A:1011280529850 PG 6 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 432CJ UT WOS:000168669300010 PM 11430758 ER PT J AU Collins, MT Chebli, C Jones, J Kushner, H Consugar, M Rinaldo, P Wientroub, S Bianco, P Robey, PG AF Collins, MT Chebli, C Jones, J Kushner, H Consugar, M Rinaldo, P Wientroub, S Bianco, P Robey, PG TI Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE fibrous dysplasia; phosphaturia; tumor-induced osteomalacia; phosphotonin; McCune-Albright syndrome ID MCCUNE-ALBRIGHT SYNDROME; STIMULATORY G-PROTEIN; HYPOPHOSPHATEMIC OSTEOMALACIA; GENE; MUTATIONS; RICKETS; CYCLASE AB Fibrous dysplasia (FD) of bone is characterized by focal replacement of normal bone and marrow with abnormal bone and fibrous tissue. It arises from postzygotic activating mutations of the GNAS1 gene. Hypophosphatemia due to renal phosphate wasting has been reported in association with FD as a part of the McCune-Albright Syndrome (MAS), which is characterized by FD, skin hyperpigmentation, and precocious puberty. To date, the prevalence and mechanism of phosphate wasting has not been well studied. We evaluated 42 patients with FD/MAS. Serum and urine samples were tested for indices of mineral metabolism, amino acid handling, and markers of bone metabolism. Twenty (48%) patients had some degree of renal phosphate wasting. Nephrogenous cyclic adenosine monophosphate (cAMP) was normal in FD patients, suggesting that the underlying cause of phosphate wasting is not the presence of activating GNAS1 mutations in the kidney. In addition, there was evidence of a more generalized renal tubulopathy as represented by the presence of abnormal vitamin D metabolism, proteinuria in 36 (86%) patients, and aminoaciduria in 39 (94%) patients. Renal phosphate wasting significantly correlated with the degree of bone involvement, as assessed by serum and urine markers of bone metabolism, suggesting that a circulating factor produced by FD bone and impacting on the kidney may be the mechanism, These data show that phosphaturia as part of a generalized renal tubulopathy represents the most common extraskeletal manifestation of FD and that the observed tubulopathy is similar to that seen in tumor-induced osteomalacia (TIO). C1 NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Westchester Cty Med Ctr, Dept Orthoped Surg, Valhalla, NY 10595 USA. NIAMSD, Arthrit Res Branch, NIH, Bethesda, MD 20892 USA. Biomed Comp Res Inst, Philadelphia, PA USA. Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Biochim Genet Lab, Rochester, MN 55905 USA. Tel Aviv Med Ctr, Dana Childrens Hosp, Dept Pediat Orthoped Surg, IL-64239 Tel Aviv, Israel. Univ Rome La Sapienza, Dept Expt Med, Div Pathol, I-00185 Rome, Italy. RP Collins, MT (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [E.1029] NR 37 TC 93 Z9 97 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD MAY PY 2001 VL 16 IS 5 BP 806 EP 813 DI 10.1359/jbmr.2001.16.5.806 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 423WV UT WOS:000168201500002 PM 11341325 ER PT J AU Morrison, DK AF Morrison, DK TI KSR: a MAPK scaffold of the Ras pathway? SO JOURNAL OF CELL SCIENCE LA English DT Article DE signal transduction; KSR MAPK cascade; scaffolding protein ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION; GENE ENCODES; C-ELEGANS; SUPPRESSOR; PHOSPHORYLATION; IDENTIFICATION; BINDING; CASCADE; SITES AB Kinase Suppressor of Ras (KSR) is an intriguing component of the Ras pathway that was first identified by genetic studies performed in Drosophila melanogaster and Caenorhabditis elegans. In both organisms, inactivating mutations in KSR suppress the phenotypic effects induced by activated Ras, These findings together with the fact that KSR contains many structural features characteristic of a protein kinase led to early speculation that KSR is a kinase functioning upstream of the Ras pathway component Raf-1 or in a parallel Ras-dependent pathway. However, in the six years since its discovery, KSR has been found to lack several key properties of known protein kinases, which has cast doubt on whether KSR is indeed a functional enzyme, A major breakthrough in our understanding of the role of KSR in signal transduction has come from recent findings that KSR interacts with several components of the MAP kinase cascade, including Raf-1, MEK1/2 and ERK1/2, The model now emerging is that KSR acts as a scaffolding protein that coordinates the assembly of a membrane-localized, multiprotein MAP kinase complex, a vital step in Ras-mediated signal transduction. Thus, while Kinase Suppressor of Ras may be its name, phosphorylation may not be its game. C1 NCI, Regulat Cell Growth Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Regulat Cell Growth Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 23 TC 166 Z9 174 U1 0 U2 5 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 MAY PY 2001 VL 114 IS 9 BP 1609 EP 1612 PG 4 WC Cell Biology SC Cell Biology GA 433KE UT WOS:000168757900003 PM 11309192 ER PT J AU Neumann, M Afonina, E Ceccherini-Silberstein, F Schlicht, S Erfle, V Pavlakis, GN Brack-Werner, R AF Neumann, M Afonina, E Ceccherini-Silberstein, F Schlicht, S Erfle, V Pavlakis, GN Brack-Werner, R TI Nucleocytoplasmic transport in human astrocytes: decreased nuclear uptake of the HIV Rev shuttle protein SO JOURNAL OF CELL SCIENCE LA English DT Article DE astrocytes; shuttling; HIV; Rev; PKI; importin beta; exportin 1; B23; Ran/TC4 ID IMMUNODEFICIENCY-VIRUS TYPE-1; NF-KAPPA-B; CYTOPLASMIC-RETENTION; SUBCELLULAR-LOCALIZATION; CELL-LINE; IN-VITRO; INTRACELLULAR TRAFFICKING; INTRAMOLECULAR MASKING; MONOCLONAL-ANTIBODIES; MUTATIONAL ANALYSIS AB Astrocytes are cellular targets for the human immunodeficiency virus (HIV) that limit virus production, owing, at least in part, to the diminished functionality of the viral post-transcriptional stimulatory factor Rev. To understand the trafficking process in astrocytes, we compared nucleocytoplasmic transport of Rev and various proteins with well-characterized nucleocytoplasmic transport features in human astrocytes and control cells (HeLa), Localization and trafficking characteristics of several cellular and viral proteins, as well as nuclear trafficking of classical peptide signals upon microinjection were similar in both cell types, indicating maintenance of general features of nucleocytoplasmic transport in astrocytes, Quantification of fluorescence in living cells expressing Rev fused to green fluorescent protein (GFP) indicated a strong shift in intracellular distribution of Rev in astrocytes, with 50-70% of Rev in the cytoplasm, whereas the cytoplasmic proportion of Rev in HeLa cells is around 10%, The dynamics of nucleocytoplasmic trafficking of Rev were compared in astrocytes and Rev-permissive cells by monitoring migration of Rev-GFP in cell fusions using highly sensitive time-lapse imaging. Nuclear uptake of Rev was dramatically retarded in homo-polykaryons of astrocytes compared with control cells. Diminished nuclear uptake of Rev was also observed in hetero-polykaryons of Rev-permissive cells and astrocytes, These results indicate that astrocytes contain a cytoplasmic activity that interferes with nuclear uptake of Rev. Our studies suggest a model in which Rev is prevented from functioning efficiently in astrocytes by specific alterations of its nucleocytoplasmic trafficking properties. C1 GSF, Natl Res Ctr Environm & Hlth, Inst Mol Virol, D-85764 Neuherberg, Germany. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Brack-Werner, R (reprint author), GSF, Natl Res Ctr Environm & Hlth, Inst Mol Virol, D-85764 Neuherberg, Germany. RI Brack-Werner, Ruth/M-4615-2014 OI Brack-Werner, Ruth/0000-0002-8651-9318 NR 93 TC 35 Z9 36 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY PY 2001 VL 114 IS 9 BP 1717 EP 1729 PG 13 WC Cell Biology SC Cell Biology GA 433KE UT WOS:000168757900014 PM 11309202 ER PT J AU Hildesheim, J Kuhn, U Yee, CL Foster, RA Yancey, KB Vogel, JC AF Hildesheim, J Kuhn, U Yee, CL Foster, RA Yancey, KB Vogel, JC TI The hSkn-1a POU transcription factor enhances epidermal stratification by promoting keratinocyte proliferation SO JOURNAL OF CELL SCIENCE LA English DT Article DE HaCaT cells; human keratinocyte; proliferation; differentiation; raft cultures ID PITUITARY-HORMONE DEFICIENCY; TISSUE-SPECIFIC EXPRESSION; DNA-BINDING DOMAIN; JUN FAMILY MEMBERS; C-FOS; TERMINAL DIFFERENTIATION; CELL PHENOTYPES; GENE-EXPRESSION; CROSS-LINKING; LYMPHOCYTES-T AB Skn-1a is a POU transcription factor that is primarily expressed in the epidermis and is known to modulate the expression of several genes associated with keratinocyte differentiation. However, the formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation, and a role for Skn-1a in this process has not been previously demonstrated. Here, our results show, surprisingly, that human Skn-1a contributes to epidermal stratification by primarily promoting keratinocyte proliferation and secondarily by enhancing the subsequent keratinocyte differentiation. In organotypic raft cultures of both primary human keratinocytes and immortalized HaCaT keratinocytes, human Skn-1a expression is associated with increased keratinocyte proliferation and re-epithelialization of the dermal substrates, resulting in increased numbers of keratinocytes available for the differentiation process. in these same raft cultures, human Skn-1a expression enhances the phenotypic changes or keratinocyte differentiation and the upregulated expression of keratinocyte differentiation genes. Conversely, expression of a dominant negative human Skn-1a transcription factor lacking the C-terminal transactivation domain blocks keratinocytes from proliferating and stratifying, Keratinocyte stratification is dependent on a precise balance between keratinocyte proliferation and differentiation, and our results suggest that human Skn-1a has an important role in maintaining epidermal homeostasis by promoting keratinocyte proliferation. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238,10 Ctr Dr MSC 1908, Bethesda, MD 20892 USA. NR 68 TC 18 Z9 21 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY PY 2001 VL 114 IS 10 BP 1913 EP 1923 PG 11 WC Cell Biology SC Cell Biology GA 438GU UT WOS:000169045900014 PM 11329378 ER PT J AU Viswanadhan, VN Mueller, GA Basak, SC Weinstein, JN AF Viswanadhan, VN Mueller, GA Basak, SC Weinstein, JN TI Comparison of a neural net-based QSAR algorithm (PCANN) with hologram- and multiple linear regression-based QSAR approaches: Application to 1,4-dihydropyridine-based calcium channel antagonists SO JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES LA English DT Article; Proceedings Paper CT 2nd Indo-US Workshop on Mathermatical Chemistry with Applications to Drug Discovery, Cheminformatics, and Bioinformatics CY MAY 30-JUN 03, 2000 CL UNIV MINNESOTA DULUTH, DULUTH, MINNESOTA SP Univ Minnesota Duluth, Nat Resources Res Inst, Visva Bharati Univ, Santinietan, W Bengal HO UNIV MINNESOTA DULUTH ID PARTIAL LEAST-SQUARES; DIHYDROFOLATE-REDUCTASE; TOPOLOGICAL INDEXES; NETWORKS; BLOCKERS; BINDING; DISCRIMINATION; PHARMACOLOGY; SIMILARITY; PARAMETERS AB A QSAR algorithm (PCANN) has been developed and applied to a set of calcium channel blockers which are of special interest because of their role in cardiac disease and also because many of them interact with P-glycoprotein, a membrane protein associated with multidrug resistance to anticancer agents. A database of 46 1,4-dihydropyridines with known Ca2+ channel binding affinities was employed for the present analysis. The QSAR algorithm can be summarized as follows: (1) a set of 90 graph theoretic and information theoretic descriptors representing various structural and topological characteristics was calculated for each of the 1,4-dihydropyridines and (2) principal component analysis (PCA) was used to compress these 90 into the eight best orthogonal composite descriptors for the database. These eight sufficed to explain 96% of the variance in the original descriptor set. (3) Two important empirical descriptors, the Leo-Hansch lipophilic constant and the Hammet electronic parameter. were added to the list of eight. (4) The 10 resulting descriptors were used as inputs to a back-propagation neural network whose output was the predicted binding affinity. (5) The predictive ability of the network was assessed by cross-validation, A comparison of the present approach with two other QSAR approaches (multiple linear regression using the same variables and a Hologram QSAR model) is made and shows that the PCANN approach can yield better predictions, once the right network configuration is identified. The present approach (PCANN) may prove useful for rapid assessment of the potential for biological activity when dealing with large chemical libraries. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Nat Resources Res Inst, Ctr Water & Environm, Duluth, MN 55811 USA. RP Viswanadhan, VN (reprint author), Amgen Inc, 1 Amgen Ctr Dr,M-S 14-2-B, Thousand Oaks, CA 91320 USA. NR 57 TC 36 Z9 37 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0095-2338 J9 J CHEM INF COMP SCI JI J. Chem. Inf. Comput. Sci. PD MAY-JUN PY 2001 VL 41 IS 3 BP 505 EP + DI 10.1021/ci000072+ PG 8 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 438UV UT WOS:000169073400005 PM 11410024 ER PT J AU Voigt, JH Bienfait, B Wang, SM Nicklaus, MC AF Voigt, JH Bienfait, B Wang, SM Nicklaus, MC TI Comparison of the NCI open database with seven large chemical structural databases SO JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES LA English DT Article; Proceedings Paper CT 2nd Indo-US Workshop on Mathermatical Chemistry with Applications to Drug Discovery, Cheminformatics, and Bioinformatics CY MAY 30-JUN 03, 2000 CL UNIV MINNESOTA DULUTH, DULUTH, MINNESOTA SP Univ Minnesota Duluth, Nat Resources Res Inst, Visva Bharati Univ, Santinietan, W Bengal HO UNIV MINNESOTA DULUTH ID DRUG INFORMATION-SYSTEM; MOLECULAR DIVERSITY; DESCRIPTORS; SELECTION; NONDRUGS; MODULE AB Eight large chemical databases have been analyzed and compared to each other. Central to this comparison is the open National Cancer Institute (NCI) database, consisting of approximately 250 000 structures. The other databases analyzed are the Available Chemicals Directory ("ACD," from MDL, release 1.99, 3D-version); the ChemACX ("ACX," from CamSoft, Version 4.5); the Maybridge Catalog and the Asinex database (both as distributed by CamSoft as part of ChemInfo 4.5); the Sigma-Aldrich Catalog (CD-ROM, 1999 Version); the World Drug Index ("WDI," Derwent, version 1999.03): and the organic part of the Cambridge Crystallographic Database ("CSD," from Cambridge Crystallographic Data Center, 1999 Version 5.18). The database properties analyzed are internal duplication rates; compounds unique to each database; cumulative occurrence of compounds in an increasing number of databases, overlap of identical compounds between two databases: similarity overlap: diversity; and others. The crystallographic database CSD and the WDI show somewhat less overlap with the other databases than those with each other. In particular the collections of commercial compounds and compilations of vendor catalogs have a substantial degree of overlap among each other. Still, no database is completely a subset of any other, and each appears to have its own niche and thus "raison d'etre". The NCI database has by far the highest number of compounds that are unique to it. Approximately 200 000 of the NCI structures were not found in any of the other analyzed databases. C1 NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. Georgetown Univ, Med Ctr, Struct Biol & Canc Drug Discovery Program, Lombardi Canc Ctr, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. RP Nicklaus, MC (reprint author), NCI, Med Chem Lab, Canc Res Ctr, NIH, 376 Boyles St, Frederick, MD 21702 USA. RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 NR 29 TC 134 Z9 137 U1 5 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0095-2338 J9 J CHEM INF COMP SCI JI J. Chem. Inf. Comput. Sci. PD MAY-JUN PY 2001 VL 41 IS 3 BP 702 EP 712 DI 10.1021/ci000150t PG 11 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 438UV UT WOS:000169073400030 PM 11410049 ER PT J AU Hummer, G AF Hummer, G TI Fast-growth thermodynamic integration: Error and efficiency analysis SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID FREE-ENERGY DIFFERENCES; MOLECULAR-DYNAMICS SIMULATIONS; MONTE-CARLO DATA; MEAN-FORCE; NONEQUILIBRIUM MEASUREMENTS; PERTURBATION CALCULATIONS; COMPUTER-SIMULATIONS; CUMULANT EXPANSION; PAIR POTENTIALS; IONIC HYDRATION AB Equilibrium free energy differences can be calculated accurately from repeated fast-growth thermodynamic integration (TI) based on Jarzynski's identity [Phys. Rev. Lett. 78, 2690 (1997)]. We derive expressions for the free energy differences. Error estimates allow us to quantify the relative efficiency of performing many fast-growth vs few slow-growth TIs for a given total computational cost. Fast-growth TI is illustrated through the calculation of the potential of mean force between two methane molecules and compared to umbrella sampling analyzed by using the weighted histogram analysis method. Fast-growth TI is well suited for parallel computer architectures, requiring only the simplest parallelism with repeated runs for different starting conditions. (C) 2001 American Institute of Physics. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 51 TC 146 Z9 146 U1 2 U2 23 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 1 PY 2001 VL 114 IS 17 BP 7330 EP 7337 DI 10.1063/1.1363668 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 423GT UT WOS:000168168100004 ER PT J AU Christiansen, JS Bengtsson, BA Thorner, MO Hintz, R Sonksen, PH Cohen, P Clemmons, D Strasburger, CJ Carlsson, L Tanaka, T Robinson, I Jorgensen, JO Johannson, G Clayton, PE Cowell, CT Malozowski, SN Hankinson, S Yee, D Baxter, R Swerdlow, A Rosenfeld, R Fradkin, JE Nishi, Y Monson, JP van den Berghe, G Carroll, PV Takala, J van der Lely, AJ Pollak, MN LeRoith, D Tachibana, K Kappelgaard, AM Langbakke, I Lippe, B Wilton, P Stein, P Salazar, DE Maneatis, T Blethen, SL Cutler, GB Blum, WF Svanberg, E Gertner, JM Shimatsu, A Takahashi, H AF Christiansen, JS Bengtsson, BA Thorner, MO Hintz, R Sonksen, PH Cohen, P Clemmons, D Strasburger, CJ Carlsson, L Tanaka, T Robinson, I Jorgensen, JO Johannson, G Clayton, PE Cowell, CT Malozowski, SN Hankinson, S Yee, D Baxter, R Swerdlow, A Rosenfeld, R Fradkin, JE Nishi, Y Monson, JP van den Berghe, G Carroll, PV Takala, J van der Lely, AJ Pollak, MN LeRoith, D Tachibana, K Kappelgaard, AM Langbakke, I Lippe, B Wilton, P Stein, P Salazar, DE Maneatis, T Blethen, SL Cutler, GB Blum, WF Svanberg, E Gertner, JM Shimatsu, A Takahashi, H CA Growth Hormone Soc TI Critical evaluation of the safety of recombinant human growth hormone administration: Statement from the growth hormone research society SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article C1 Aarhus Kommune Hosp, DK-8000 Aarhus, Denmark. Sahlgrens Univ Hosp, Stockholm, Sweden. Univ Virginia, Hlth Sci Ctr, Dept Med, Charlottesville, VA 22908 USA. Stanford Univ, Med Ctr, Stanford, CA 94305 USA. Univ Calif Los Angeles, Matell Childrens Hosp, Los Angeles, CA 90024 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Natl Inst Med Res, London NW7 1AA, England. Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England. US FDA, Rockville, MD 20857 USA. Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. Univ Texas, Hlth Sci Ctr, Austin, TX USA. London Sch Hyg & Trop Med, London WC1, England. Oregon Hlth Sci Univ, Portland, OR 97201 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Hiroshima Redc Cross Hosp, Hiroshima, Japan. Katholieke Univ Leuven, Louvain, Belgium. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. Kanagawa Childrens Med Ctr, Kanagawa, Japan. Novo Nordisk AS, Copenhagen, Denmark. Bristol Myers Squibb Co, New York, NY 10154 USA. Genentech Inc, S San Francisco, CA 94080 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Kyoto Natl Hosp, Kyoto, Japan. Kanazawa Med Univ, Kanazawa, Ishikawa, Japan. RP Thorner, MO (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Med, Box 800466, Charlottesville, VA 22908 USA. RI Pollak, Michael/G-9094-2011; Baxter, Robert/F-3927-2012 OI Pollak, Michael/0000-0003-3047-0604; Baxter, Robert/0000-0001-5061-2142 NR 4 TC 82 Z9 87 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 1868 EP 1870 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600004 ER PT J AU Weyer, C Funahashi, T Tanaka, S Hotta, K Matsuzawa, Y Pratley, RE Tataranni, PA AF Weyer, C Funahashi, T Tanaka, S Hotta, K Matsuzawa, Y Pratley, RE Tataranni, PA TI Hypoadiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADIPOSE-SPECIFIC PROTEIN; CORONARY HEART-DISEASE; NECROSIS-FACTOR-ALPHA; PLASMA-PROTEIN; PIMA-INDIANS; ADIPONECTIN; PATHOGENESIS; MELLITUS; LINK; ADIPOCYTOKINES AB Plasma concentrations of adiponectin, a novel adipose-specific pro tein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 2.6 vs. 10.2 +/- 4.3 mug/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 mug/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance. C1 NIDDK, Clin Diabet & Nutr Sect, NIH, Phoenix, AZ 85016 USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Osaka, Japan. RP Weyer, C (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, 4212 N 16th St,Room 5-41, Phoenix, AZ 85016 USA. EM cweyer@phx.niddk.nih.gov RI sheng, jian/E-9474-2012 NR 31 TC 2234 Z9 2386 U1 13 U2 106 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 1930 EP 1935 DI 10.1210/jc.86.5.1930 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600018 PM 11344187 ER PT J AU Eisenhofer, G Walther, MM Huynh, TT Li, ST Bornstein, SR Vortmeyer, A Mannelli, M Goldstein, DS Linehan, WM Lenders, JWM Pacak, K AF Eisenhofer, G Walther, MM Huynh, TT Li, ST Bornstein, SR Vortmeyer, A Mannelli, M Goldstein, DS Linehan, WM Lenders, JWM Pacak, K TI Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TYROSINE-HYDROXYLASE GENE; N-METHYLTRANSFERASE GENE; CHROMAFFIN CELLS; FAMILIAL PHEOCHROMOCYTOMA; ADRENAL-MEDULLA; DISEASE; EPINEPHRINE; NOREPINEPHRINE; EXPRESSION; PLASMA AB This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TR), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Florence, Dept Clin Pathophysiol, Florence, Italy. Univ Nijmegen St Radboud Hosp, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. RP Eisenhofer, G (reprint author), NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC 1620, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov RI Lenders, J.W.M./L-4487-2015; OI Mannelli, Massimo/0000-0002-8001-9857 NR 43 TC 163 Z9 168 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 1999 EP 2008 DI 10.1210/jc.86.5.1999 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600029 PM 11344198 ER PT J AU Bordi, C Corleto, VD Azzoni, C Pizzi, S Ferraro, G Gibril, F Delle Fave, G Jensen, RT AF Bordi, C Corleto, VD Azzoni, C Pizzi, S Ferraro, G Gibril, F Delle Fave, G Jensen, RT TI The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndromes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VESICULAR MONOAMINE TRANSPORTER-2; GASTRIC CARCINOIDS; CELL TUMORS; CLASSIFICATION; STOMACH; PATHOGENESIS; EXPRESSION; GROWTHS; NEURONS; SURGERY AB Carcinoid tumors were identified in the antro-pyloric mucosa of four patients with multiple endocrine neoplasia type 1 (MEN-1)/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic Zollinger-Ellison syndrome (P < 0.001), indicating a prominent role for the MEN-1 gene defects in tumor development. Immunohistochemically the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, two of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT-2), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In one of these patients a second antral VMAT-2-positive carcinoid was seen 21 months after the first diagnosis. The other two antral carcinoids were unreactive for VMAT-2. Multiple ECL cell tumors were found in the gastric body-fundus mucosa of the two patients with VMAT-2-positive, but not in those with VMAT-2-negative, antral carcinoids. In one case, the former tumors were diagnosed 22 months after the detection of the antral tumor. We conclude that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN-1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least two cases, were identified as ectopic ECL cell carcinoids. C1 Univ Parma, Dept Pathol & Lab Med, Sect Pathol Anat, I-43100 Parma, Italy. Univ La Sapienza, Dept Digest Dis, Sch Med 2, I-00161 Rome, Italy. Univ La Sapienza, Dept Cell Biotechnol & Hematol, I-00161 Rome, Italy. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Bordi, C (reprint author), Univ Parma, Dept Pathol & Lab Med, Sect Pathol Anat, I-43100 Parma, Italy. EM cesare.bordi@unipr.it NR 36 TC 22 Z9 25 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 2236 EP 2242 DI 10.1210/jc.86.5.2236 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600064 PM 11344233 ER PT J AU Path, G Bornstein, SR Gurniak, M Chrousos, GP Scherbaum, WA Hauner, H AF Path, G Bornstein, SR Gurniak, M Chrousos, GP Scherbaum, WA Hauner, H TI Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: Increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LIPOPROTEIN-LIPASE ACTIVITY; TUMOR-NECROSIS-FACTOR; PLASMA INTERLEUKIN-6; 3T3-L1 ADIPOCYTES; ADIPOSE-TISSUE; HUMAN-FIBROBLASTS; PRECURSOR CELLS; MESSENGER-RNA; IN-VIVO; CYTOKINES AB Adipocytes produce the inflammatory cytokine interleukin-6 (IL-6); however, it is not known whether these cells express the IL-6 receptor system, how the secretion of this cytokine is regulated, and whether it has a function within adipose tissue. Using cultured human breast adipocytes, we investigated the expression of IL-6 and its receptor system, the effects of IL-6 on main adipocyte functions, and the regulation of IL-6 secretion by catecholamines and glucocorticoids. In the culture system, immunohistochemistry demonstrated expression of IL-6 and its receptor system, consisting of the ligand-binding IL-6 receptor and the signal-transducing protein gp130, in mature adipocytes, but not in undifferentiated adipocyte precursor cells. In freshly isolated adipocytes, RT-PCR detected messenger ribonucleic acids encoding the above proteins. Chronic incubation of adipocytes with 1 nmol/L IL-6 during adipose differentiation reduced glycero-3-phosphate dehydrogenase (GPDH) activity, a marker of adipocyte differentiation, and triglyceride synthesis to 67 +/- 9% of the basal level (mean +/- SEM; P < 0.05) only on day 21. Incubation of differentiated adipocytes with 10 nmol/L IL-6 for 24 h also resulted in a reduction of GPDH activity to 81 +/- 5% (P < 0.05). On the other hand, 24-h exposure to 10 nmol/L IL-6 increased basal glycerol release by 42 +/- 12% (P < 0.01) and isoproterenol-induced glycerol release by 21 +/- 6% (P < 0.05). The same concentration of IL-6, however, did not alter basal or insulin-stimulated glucose transport. IL-6 secretion was acutely and chronically stimulated by 1 mu mol/L isoproterenol (peak of 6.2-fold after 3 h; P < 0.001) and only moderately suppressed by 100 nmol/L cortisol (-36 +/- 10%; P < 0.001). In conclusion, human breast adipocytes release substantial amounts of IL-6 and express IL-6 receptor and gp130. The secretion of IL-6 by adipocytes is strongly stimulated by beta -adrenergic activation and is modestly suppressed by glucocorticoids. IL-6 reduces GPDH activity and stimulates lipolysis, suggesting an autocrine/paracrine role of this cytokine in human adipose breast tissue. C1 German Diabet Res Inst, D-40552 Dusseldorf, Germany. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Hauner, H (reprint author), German Diabet Res Inst, Hennekamp 65, D-40552 Dusseldorf, Germany. EM hauner@dfi.uni-duesseldorf.de NR 42 TC 110 Z9 117 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 2281 EP 2288 DI 10.1210/jc.86.5.2281 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600071 PM 11344240 ER PT J AU Hirshberg, B Alexander, HR Bartlett, DL Skarulis, MC Libutti, SK Gorden, P AF Hirshberg, B Alexander, HR Bartlett, DL Skarulis, MC Libutti, SK Gorden, P TI Nesidioblastosis in adults: A clinical enigma SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Letter C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hirshberg, B (reprint author), NIDDKD, NIH, Bldg 10,Room 8s235, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2001 VL 86 IS 5 BP 2329 EP 2329 DI 10.1210/jc.86.5.2329 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZV UT WOS:000168731600083 ER PT J AU Mekori, YA Gilfillan, AM Akin, C Hartmann, K Metcalfe, DD AF Mekori, YA Gilfillan, AM Akin, C Hartmann, K Metcalfe, DD TI Human mast cell apoptosis is regulated through Bcl-2 and Bcl-X-L SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE apoptosis; Bcl-2; Bcl-X; c-kit; mast cell ID C-KIT; EXPRESSION; LEUKEMIA; SURVIVAL; LIGAND; LINE AB It is well established that human mast cell proliferation and maturation are regulated by kit ligand (stem cell factor). Little is known, however, about how these two processes are negatively regulated and thus, how mast cell number is controlled in normal and pathologic conditions. We therefore first hypothesized that SCF-dependent human mast cells would undergo programmed cell death (apoptosis) on removal of SCF as has been shown for growth factor-dependent rodent mast cells. We then examined whether SCF acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. As hypothesized, elimination of SCF from primary peripheral blood-derived human mast cell cultures resulted in a significant apoptotic process. During apoptosis, down-regulation of the two apoptosis-regulatory proteins Bcl-2 and Bcl-X-L was observed. Moreover, a deregulated expression of these two proteins was found in two human mast cell lines which are SCF-independent. Thus, SCF functions as a survival factor by repressing apoptosis of human mast cells through Bcl-2 and Bcl-X-L. Deregulated expression of these antiapoptotic proteins may contribute to proliferation and accumulation of mast cells in certain forms of systemic mast cell disorders. C1 Meir Gen Hosp, Dept Med, Kfar Saba, Israel. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Mekori, YA (reprint author), Meir Hosp, Dept Med B, IL-44281 Kefar Sava, Israel. RI Hartmann, Karin/N-4865-2015 OI Hartmann, Karin/0000-0002-4595-8226 NR 12 TC 57 Z9 57 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAY PY 2001 VL 21 IS 3 BP 171 EP 174 DI 10.1023/A:1011083031272 PG 4 WC Immunology SC Immunology GA 441NP UT WOS:000169236700002 PM 11403223 ER PT J AU Demark-Wahnefried, W Peterson, BL Winer, EP Marks, L Aziz, N Marcom, PK Blackwell, K Rimer, BK AF Demark-Wahnefried, W Peterson, BL Winer, EP Marks, L Aziz, N Marcom, PK Blackwell, K Rimer, BK TI Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEALTH TRIAL FEASIBILITY; QUALITY-OF-LIFE; MINORITY POPULATIONS; MEGESTROL-ACETATE; GAIN; WOMEN; DIAGNOSIS; EXERCISE; THERAPY; REHABILITATION AB Purpose: Weight gain is a common problem among breast cancer patients who receive adjuvant chemotherapy (CT). We undertook a study to determine the causes of this energy imbalance. Patients and Methods: Factors related to energy balance were assessed at baseline (within 3 weeks of diagnosis) and throughout 1 year postdiagnosis among 53 premenopausal women with operable breast carcinoma, Thirty-six patients received CT and 17 received only localized treatment (LT). Measures included body composition (dual energy x-ray absorptiometry), resting energy expenditure (REE; indirect calorimetry), dietary intake (2-day dietary recalls and food frequency questionnaires) and physical activity (physical activity records). Results: Mean weight gain in the LT patients was 1.0 kg versus 2.1 kg in the CT group (P = .02), No significant differences between groups in trend over time were observed for REE and energy intake; however, a significant difference was noted for physical activity (P = .01). Several differences between groups in 1-year change scores were detected. The mean change (+/- SE) in LT versus CT groups and P values for uncontrolled/ controlled (age, race, radiation therapy, baseline body mass index, and end point under consideration) analysis are as follows: percentage of body fat (-0.1 +/- 0.4 v +2.2 +/- 0.6%; P = .001/0.04); fat mass (+0.1 +/- 9.3 v +2.3 +/- 0.7 kg; P = .002/0.04); lean body mass (+0.8 +/- 0.2 v +/- 0.4 +/- 0.3 kg; P = .02/0.30); and leg lean mass (+/- 0.5 +/- 0.1 v -0.2 +/- 0. 1 kg; P = .01/0.11). Conclusion: These data do not support overeating as a cause of weight gain among breast cancer patients who receive CT. The data suggest, however, that CT-induced weigh, gain is distinctive and indicative of sarcopenic obesity (weight gain in the presence of lean tissue loss or absence of lean tissue gain). The development of sarcopenic obesity with evidence of reduced physical activity supports the need for interventions focused on exercise, especially resistance training in the lower body, to prevent weight gain. J Clin Oncol 19:2381-2389. (C) 2001 by American Society of Clinical Oncology. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Demark-Wahnefried, W (reprint author), Duke Univ, Med Ctr, Box 2619, Durham, NC 27710 USA. FU NCI NIH HHS [1K07-CA62215] NR 50 TC 225 Z9 227 U1 2 U2 14 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 MAY 1 PY 2001 VL 19 IS 9 BP 2381 EP 2389 PG 9 WC Oncology SC Oncology GA 428WE UT WOS:000168484000003 PM 11331316 ER PT J AU Hamilton, AS Stanford, JL Gilliland, FD Albertsen, PC Stephenson, RA Hoffman, RM Eley, JW Harlan, LC Potosky, AL AF Hamilton, AS Stanford, JL Gilliland, FD Albertsen, PC Stephenson, RA Hoffman, RM Eley, JW Harlan, LC Potosky, AL TI Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: Results from the Prostate Cancer Outcomes study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; RADIOTHERAPY; MEN; CARCINOMA; COMPLICATIONS; IRRADIATION; VALIDATION; MORBIDITY; SYMPTOMS AB Purpose: Studies reporting effects of radiotherapy for prostate cancer on sexual, bower, and urinary function have been conducted primarily in referral centers or academic institutions. Effects of external-beam radiotherapy for prostate cancer among a population-based cohort were assessed. Patients and Methods: The study population included 497 white, Hispanic, and African American men with localized prostate cancer from six US cancer registries who were diagnosed between October 1, 1994, and October 31, 1995, and treated initially with external-beam radiotherapy, They were interviewed at regular intervals, and medical records were reviewed. Distributions of responses for bowel-, urinary-, and sexual-related functions at 6, 12, and 24 months after diagnosis and adjusted mean composite change scores for each domain were analyzed. Results: Declines of 28.9% in the sexual function score and 5.4% in the bower function score occurred by 24 months, whereas at this time, the urinary function score was relatively unchanged, A total of 43% of those who were potent before diagnosis became impotent after 24 months, More than two thirds of the men were satisfied with their treatment and would make the same decision again, Conclusion: Sexual function was the most adversely affected quality-of-life domain, with problems continuing to increase between 12 and 24 months, Bower function problems increased at 6 months, with partial resolution observed by 24 months. Despite the side effects, satisfaction with therapy was high. These results are representative of men in community practice settings and may be of assistance to men and to clinicians when making treatment decisions. J Clin Oncol 19:2517-2526. (C) 2001 by American Society of Clinical Oncology. C1 Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Connecticut, Ctr Hlth, Div Urol, Farmington, CT USA. New Mexico Tumor Registry, Albuquerque, NM USA. Emory Univ, Rollins Sch Publ Hlth, Georgia Ctr Canc Stat, Atlanta, GA USA. NCI, Appl Res Program, Bethesda, MD USA. Dept Vet Affairs Med Ctr, Med Serv, Albuquerque, NM USA. RP Hamilton, AS (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, 1441 Eastlake Ave,Room 3427,MC 9175, Los Angeles, CA 90089 USA. FU NCI NIH HHS [N01-PC-67006, N01-PC-67000, N01-PC-67005, N01-PC-67007, N01-PC-67009, N01-PC-67010] NR 33 TC 83 Z9 83 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2001 VL 19 IS 9 BP 2517 EP 2526 PG 10 WC Oncology SC Oncology GA 428WE UT WOS:000168484000018 PM 11331331 ER PT J AU Berlin, RE Raju, JD Schmidt, PJ Adams, LF Rubinow, DR AF Berlin, RE Raju, JD Schmidt, PJ Adams, LF Rubinow, DR TI Effects of the menstrual cycle on measures of personality in women with premenstrual syndrome: A preliminary study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DISORDERS AB Background: Previous studies suggest that women with premenstrual syndrome (PMS) differ from those without PMS in measures of personality. The purpose of this study was to measure the effect of menstrual cycle phase on personality variables in women with and without PMS. Method: The Personality Diagnostic Questionnaire-Revised (PDQ-R) was administered in both the follicular and luteal phases to women with PMS (according to National Institute of Mental Health PMS Workshop Diagnostic Guidelines) (N = 40). An asymptomatic control group (N = 20) as well as a symptomatic group of women with DSM-IV-diagnosed recurrent, non-menstrual-cycle-related brief depression (N = 20) also completed the questionnaire in both phases. Results: Only women with PMS demonstrated a significant increase in total PDQ-R score (reflecting overall personality disorder) from the follicular to the luteal phase (p < .01). Women with PMS had significantly higher total PDQ-R scores than the asymptomatic controls during both the follicular (p < .05) and luteal (p < .01) phases, whereas there was no significant difference between women with PMS and symptomatic controls during either phase. Subscale scores fit similar patterns, as did the number of women in each group meeting a cutoff score indicative of the presence of personality dysfunction. Conclusion: In this preliminary study, women with PMS were unique in demonstrating a menstrual cycle phase effect on PDQ-R score, while their scores in both phases were closer to symptomatic controls than asymptomatic controls. These findings suggest that personality disorder in women with PMS may have both state- and trait-related components. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Room 3N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. NR 10 TC 16 Z9 18 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2001 VL 62 IS 5 BP 337 EP + PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 440YD UT WOS:000169203500005 PM 11411814 ER PT J AU Summers, RM Choyke, PL Patronas, NJ Tucker, E Wise, B Busse, MK Brewer, HB Shamburek, RD AF Summers, RM Choyke, PL Patronas, NJ Tucker, E Wise, B Busse, MK Brewer, HB Shamburek, RD TI MR virtual angioscopy of thoracic aortic atherosclerosis in homozygous familial hypercholesterolemia SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE magnetic resonance imaging; atherosclerosis; virtual angioscopy; hypercholesterolemia ID ANGIOGRAPHY; TIME; AORTOGRAPHY; BRONCHOSCOPY; DISPLAY; CT AB Purpose: The thoracic aorta is an important site of atherosclerotic disease in patients with homozygous familial hypercholesterolemia (HFH). Thoracic aortic atherosclerosis in patients with HFH was assessed with contrast-enhanced MR angiograms using exoscopic and endoscopic virtual angioscopy reconstructions and maximum intensity projections (MIPs). Method: Contrast-enhanced MR angiograms of the thoracic aorta of 15 patients with HFH and 8 normal volunteers were obtained. Perspective surface reconstructions of the MR angiograms including virtual angioscopy views were evaluated by three radiologists blinded to the diagnosis. Results: Thoracic wall irregularity was depicted on 8 of 15 (53%) patient scans and only 1 of 8 (13%) normal subject scans using surface reconstructions. Wall irregularity scores of patients with HFH were significantly increased compared with controls (2.0 +/- 0.9 vs. 1.0 +/- 0.6; p = 0.008). There was excellent interobserver agreement (weighted kappa = 0.82 +/- 0.12). Virtual endoscopy views added diagnostic confidence compared with exoscopic surface renderings alone. MIP reconstructions were unable to depict wall irregularity. Conclusion: MR angiography with virtual angioscopy of the thoracic aorta depicts nonstenotic wall irregularity of thoracic aortic atherosclerosis in patients with HFH. This may be important For assessing disease progression and response to treatment and may be generalizable to routine (non-HFH) atherosclerosis. C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. 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 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAY-JUN PY 2001 VL 25 IS 3 BP 371 EP 377 DI 10.1097/00004728-200105000-00008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 430KN UT WOS:000168573200008 PM 11351186 ER PT J AU Patwardhan, AJ Eliez, S Warsofsky, IS Glover, GH White, CD Giedd, JN Peterson, BS Rojas, DC Reiss, AL AF Patwardhan, AJ Eliez, S Warsofsky, IS Glover, GH White, CD Giedd, JN Peterson, BS Rojas, DC Reiss, AL TI Effects of image orientation on the comparability of pediatric brain volumes using three-dimensional MR data SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE magnetic resonance imaging; brain; brain, morphology ID RELIABILITY; PHANTOM; PARCELLATION; THICKNESS AB Purpose: The purpose of this study was to examine the comparability of morphometric measurements made on pediatric data sets collected at five scanner locations, each using variations on a 3D spoiled gradient-recalled echo (SPGR) pulse sequence. Method: Archived MR data from 60 typically developing children were collected and separated into seven groups based on the pulse sequence used. A highly automated image-processing procedure was used to segment the brain data into white tissue, gray tissue, and CSF compartments and into various neuroanatomic regions of interest. Results: Volumetric comparisons between groups revealed differences in areas of the temporal and occipital lobes. These differences were observed when comparing data sets with different image orientations and appeared to be due to partial volume averaging (PVA) and susceptibility-induced geometric distortions. Conclusion: Our results indicate that slice selection and image resolution should be controlled in volumetric studies using aggregated data from multiple centers to minimize the effects of PVA and susceptibility-induced geolnetric distortions. C1 Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford Psychiat Neuroimaging Lab, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06520 USA. Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. RP Reiss, AL (reprint author), Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford Psychiat Neuroimaging Lab, 401 Quarry Rd, Stanford, CA 94305 USA. RI Giedd, Jay/A-3080-2008; Rojas, Don/F-4296-2012; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Rojas, Don/0000-0001-6560-9616 FU NICHD NIH HHS [HD31715]; NIMH NIH HHS [MH01142] NR 19 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAY-JUN PY 2001 VL 25 IS 3 BP 452 EP 457 DI 10.1097/00004728-200105000-00020 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 430KN UT WOS:000168573200020 PM 11351198 ER PT J AU Bergwitz, C Bremer, B Soudah, B Mayr, B Brabant, G AF Bergwitz, C Bremer, B Soudah, B Mayr, B Brabant, G TI Familial isolated parathyroid adenoma in a consanguineous family SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Article DE parathyroid adenoma; familial isolated primary hyperparathyroidism; consanguineous; recessive inheritance; dominant germ-cell mutation; otosclerosis; oligodendroglioma ID ENDOCRINE NEOPLASIA TYPE-1; PRIMARY HYPERPARATHYROIDISM; RECEPTOR GENE; MEN1 GENE; MUTATIONS; CARCINOMA; GERMLINE; DISEASE; MAPS AB The 23-year-old Caucasian male propositus presented with symptomatic hypercalcemia, hypophosphatemia and normocalciuria for 2 months. His 29-year-old brother had under-gone an operation for recurrent parathyroid adenoma at age 26 and 28. No other member of the family was affected. His father and mother were second-degree relatives. Laboratory studies showed primary hyperparathyroidism (pHPT), while the remaining endocrine studies and genetic testing for multiple endocrine neoplasia 1 and 2A were normal. Technetium-cardiolite scintigraphy and ultrasound scans revealed a parathyroid mass at the left lower neck. Apart from bilateral hearing loss due to gentamicin treatment as a pre-term child, the patient was in of good health. Signs or symptoms of other endocrinopathies were absent. The patient was referred for parathyroidectomy with subsequent autotransplantation of the remaining glands into his sternocleidomastoid muscle. Histological examination revealed an adenoma with oncocytic differentiation, similar to that seen in his brother. The disease may follow a recessive mode of inheritance or may be due to a dominant germ-cell mutation in one of the parents. The presented case may ultimately help in elucidating the molecular genetic basis of this rare form of pHPT. C1 Hannover Med Sch, Dept Clin Endocrinol, D-3000 Hannover, Germany. Hannover Med Sch, Inst Pathol, D-3000 Hannover, Germany. RP Bergwitz, C (reprint author), NICHD, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. RI Mayr, Bernhard/F-6936-2012 OI Mayr, Bernhard/0000-0002-8973-4494 NR 30 TC 3 Z9 3 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD MAY PY 2001 VL 24 IS 5 BP 349 EP 355 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZR UT WOS:000168731300010 PM 11407655 ER PT J AU Uwaifo, GI Remaley, AT Stene, M Reynolds, JC Yen, PM Snider, RH Becker, KL Sarlis, NJ AF Uwaifo, GI Remaley, AT Stene, M Reynolds, JC Yen, PM Snider, RH Becker, KL Sarlis, NJ TI A case of spurious hypercalcitoninemia: A cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Article DE calcitonin; Hashimoto's thyroiditis; immunoassay; medullary thyroid carcinoma; C-cell hyperplasia ID C-CELL HYPERPLASIA; CHRONIC LYMPHOCYTIC THYROIDITIS; CALCIUM-REGULATING HORMONES; SERUM CALCITONIN; ROUTINE MEASUREMENT; MEDULLARY CARCINOMA; HASHIMOTOS-THYROIDITIS; SYSTEMIC INFLAMMATION; 2-SITE IMMUNOASSAY; ILL CHILDREN AB The measurement of plasma CT has an important role as a screening test for medullary thyroid carcinoma (MTC) in patients with thyroid nodules. However, elevated plasma CT levels should be interpreted within the context of the overall clinical picture in each individual case and carefully validated before therapeutic decisions are made. We present the case of a 17-yr-old girl who was referred to us with a thyroid nodule and elevated plasma CT levels, as measured by a one-site RIA not involving prior plasma extraction. Plasma CT was re-measured using two different methods, a RIA with prior plasma extraction and a two-site immunochemiluminometric assay (ICMA), and was either very low or undetectable. Subsequently, samples were re-assayed using the initially applied CT RIA; plasma CT levels were again found to be elevated. These elevations were of a spurious nature, probably caused by the presence of an unidentified substance in the patient's plasma interfering with the measurement of CT in the initially used RIA. Our patient was eventually diagnosed with Hashimoto's thyroiditis, and had no evidence of MTC. As several conditions can cause either true or spurious hypercalcitoninemia, we suggest that elevated plasma CT levels should be confirmed at least once before other extensive diagnostic investigations are initiated or thyroidectomy is recommended. Finally, the assay selected should detect only the mature CT molecule. C1 NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Clin Pathol, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. NIDDKD, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Esoterix Endocrinol, Peptide Lab, Calabasas Hills, CA USA. VA Med Ctr, Metab Res Dept, Washington, DC USA. RP Sarlis, NJ (reprint author), NIDDK, CEB, NIH, Bldg 10,Rm 8D12C,10 Ctr Dr,MSC 1758, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 NR 58 TC 16 Z9 16 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD MAY PY 2001 VL 24 IS 5 BP 361 EP 369 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZR UT WOS:000168731300012 PM 11407657 ER PT J AU Stratakis, CA AF Stratakis, CA TI Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes SO JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION LA English DT Review DE multiple endocrine neoplasia syndromes; Carney complex; Peutz-Jeghers syndrome; Cowden disease; protein kinase A ID PEUTZ-JEGHERS-SYNDROME; SPOTTY SKIN PIGMENTATION; NODULAR ADRENOCORTICAL DISEASE; PSAMMOMATOUS MELANOTIC SCHWANNOMA; RET PROTOONCOGENE MUTATIONS; INCLUDING CARDIAC MYXOMA; VON-HIPPEL-LINDAU; GERMLINE MUTATIONS; HIRSCHSPRUNG-DISEASE; COWDEN-DISEASE AB The list of multiple endocrine neoplasias (MENs) that have been molecularly elucidated is growing with the most recent addition of Carney complex. MEN type 1 (MEN 1), which affects primarily the pituitary, pancreas, and parathyroid glands, is caused by mutations in the menin gene. MEN type 2 (MEN 2) syndromes, MEN 2A and MEN 2B that affect mainly the thyroid and parathyroid glands and the adrenal medulla, and familial medullary thyroid carcinoma (FMTC), are caused by mutations in the RET oncogene. Finally, Carney complex, which affects the adrenal cortex, the pituitary and thyroid glands, and the gonads, is caused by mutations in the gene that codes for regulatory subunit type 1A of protein kinase A (PKA) (PRKAR1A) in at least half of the known patients. Molecular defects have also been identified in syndromes related to the MENs, like Peutz-Jeghers syndrome (PJS) (the STK11/LKB1 gene), and Cowden (CD; the PTEN gene) and von Hippel-Lindau disease (VHLD; the VHL gene). Although recognition of these syndromes at a young age generally improves prognosis, the need for molecular testing in the diagnostic evaluation of the MENs is less clear. This review presents the newest information on the clinical and molecular genetics of the MENs (MEN 1, MEN 2, and Carney complex), including recommendations for genetic screening, and discusses briefly the related syndromes PJS, CD and VHLD. C1 NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Unit Genet & Endocrinol, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC1862, Bethesda, MD 20892 USA. NR 124 TC 26 Z9 28 U1 0 U2 0 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0391-4097 J9 J ENDOCRINOL INVEST JI J. Endocrinol. Invest. PD MAY PY 2001 VL 24 IS 5 BP 370 EP 383 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 432ZR UT WOS:000168731300013 PM 11407658 ER PT J AU Agostini, HT Deckhut, A Jobes, DV Girones, R Schlunck, G Prost, MG Frias, C Perez-Trallero, E Ryschkewitsch, CF Stoner, GL AF Agostini, HT Deckhut, A Jobes, DV Girones, R Schlunck, G Prost, MG Frias, C Perez-Trallero, E Ryschkewitsch, CF Stoner, GL TI Genotypes of JC virus in east, central and southwest Europe SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID HUMAN POLYOMAVIRUS JC; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; COMPLETE GENOMES; CEREBROSPINAL-FLUID; AFRICAN-AMERICANS; HUMAN MIGRATIONS; VIRAL EVOLUTION; POPULATION; URINE; REARRANGEMENTS AB Distinctive genotypes of JC virus have been described for the major continental landmasses. Studies on European-Americans and small cohorts in Europe showed predominantly Type 1. Types 2 and 7 are found in Asia, and Types 3 and 6 in Africa. These genotypes differ in sequence by about 1-3 %. Each genotype may have several subtypes which differ from each other by about 0.5-1 %. The genotypes can be defined by a distinctive pattern of nucleotides in a typing region of the VP1 gene. This genotyping approach has been confirmed by phylogenetic reconstruction using the entire genome exclusive of the rearranging regulatory region. In this first large European study, we report on the urinary excretion of ICV DNA of 350 individuals from Poland, Hungary, Germany and Spain. We included Gypsy cohorts in Hungary (Roma), Germany (Sinti), and Spain (Gitano), as well as Basques in Spain. We show that while Type 1 predominates in Europe, the proportions of Type 1A and 1B may differ from East to Southwest Europe. Type 4, closely related to the Type 1 sequence (only similar to1% difference) was a minor genotype in Germany, Poland and Spain, but represented the majority in Basques. The Gitanos in Spain showed a variant Type 4 sequence termed 'Rom-1'. Interestingly, neither the Gitanos in Spain, nor Sinti or Roma in Germany or Hungary showed the Type 2 or Type 7 genotype that might be expected if their origins were in an Asian population. C1 NINCDS, Neurotoxicol Sect, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Dept Ophthalmol, D-79106 Freiburg, Germany. Univ Barcelona, Fac Biol, Dept Microbiol, E-08028 Barcelona, Spain. SPKSO, Univ Eye Clin 2, PL-03709 Warsaw, Poland. Hosp Univ Germans Trias & Pujol, Dept Microbiol, E-08916 Badalona, Spain. Donostia Hosp, Dept Microbiol, E-20014 San Sebastian, Spain. RP Stoner, GL (reprint author), NINCDS, Neurotoxicol Sect, NIH, 36 Convent Dr,Room 4A-27, Bethesda, MD 20892 USA. RI Girones, Rosina/B-2975-2009 OI Girones, Rosina/0000-0002-1097-6395 NR 46 TC 70 Z9 70 U1 0 U2 1 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAY PY 2001 VL 82 BP 1221 EP 1231 PN 5 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 425KE UT WOS:000168289100026 PM 11297697 ER PT J AU Lenz, P Day, PM Pang, YYS Frye, SA Jensen, PN Lowy, DR Schiller, JT AF Lenz, P Day, PM Pang, YYS Frye, SA Jensen, PN Lowy, DR Schiller, JT TI Papillomavirus-like particles induce acute activation of dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; EPIDERMAL LANGERHANS CELLS; MAJOR CAPSID PROTEIN; HERPES-SIMPLEX VIRUS; IMMUNE-RESPONSE; T-CELLS; CYTOKINE PRODUCTION; LEISHMANIA-MAJOR; MANNOSE RECEPTOR; CERVICAL-CANCER AB The role of viral structural proteins in the initiation of adaptive immune responses is poorly understood. To address this issue, we focused on the effect of noninfectious papillomavirus-like particles (VLPs) on dendritic cell (DC) activation. We found that murine bone marrow-derived dendritic cells (BMDCs) effectively bound and rapidly internalized bovine papillomavirus VLPs. Exposure to fully assembled VLPs of bovine papillomavirus, human papillomavirus (HPV)16 or HPV18, but not to predominately disordered HPV16 capsomers, induced acute phenotypic maturation of BMDCs. Structurally similar polyomavirus VLPs bound to the DC surface and were internalized, but failed to induce maturation. DCs that had incorporated HPV16 VLPs produced proinflammatory cytokines IL-6 and TNF-alpha however, the release of these cytokines was delayed relative to LPS activation. Production of IL-12p70 by VLP-exposed DCs required the addition of syngeneic T cells or rIFN-gamma. Finally, BMDCs pulsed with HPV16 VLPs induced Th1-dominated primary T cell responses in vitro. Our data provide evidence that DCs respond to intact papillomaviruis capsids and that they play a central role in VLP-induced immunity. These results offer a mechanistic explanation for the striking ability of papillomavirus VLP-based vaccines to induce potent T and B cell responses even in the absence of adjuvant. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NINCDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 36,Room 1D28,36 Convent Dr MSC4040, Bethesda, MD 20892 USA. OI Frye, Stephan/0000-0002-0786-8481 NR 70 TC 180 Z9 188 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5346 EP 5355 PG 10 WC Immunology SC Immunology GA 487YH UT WOS:000171906500004 PM 11313370 ER PT J AU Carta, L Pastorino, S Melillo, G Bosco, MC Massazza, S Varesio, L AF Carta, L Pastorino, S Melillo, G Bosco, MC Massazza, S Varesio, L TI Engineering of macrophages to produce IFN-gamma in response to hypoxia SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCIBLE FACTOR-I; COLONY-STIMULATING FACTOR; OXIDE SYNTHASE PROMOTER; GENE-EXPRESSION; INTERFERON-GAMMA; ADOPTIVE IMMUNOTHERAPY; MURINE MACROPHAGES; PICOLINIC-ACID; BRAIN-TUMORS; SOLID TUMORS AB Activation of murine macrophages (M phi) requires the collaboration of signals derived from the immune system and the environment. In this study, we engineered a murine M phi cell line to become activated in response to an environmental signal, hypoxia, as the sole stimulus. Hypoxia is a condition of low oxygen tension, occurring in several pathological tissues, which acts in synergy with IFN-gamma to induce full M phi activation. We transfected the ANA-1 murine M phi cell line with a construct containing the IFN-gamma gene controlled by a synthetic promoter inducible by hypoxia (HRE3x-Tk), and we characterized the cellular and molecular biology of the engineered M phi under normoxia or hypoxia. Engineered M phi in normoxia expressed basal levels of IFN-gamma mRNA and protein that were strongly augmented by shifting the cells to hypoxia. Furthermore, they responded to the synthesized IFN-gamma with induction of IFN-responsive factor-1 and 2'-5'-oligoadenylate synthase expression. Under normoxic conditions, the engineered M phi had a significant constitutive level of la Ags and Fc receptors. Hypoxia induced further augmentation of Ia and Fe expression. Finally, hypoxia induced inducible NO synthase expression, and subsequent reoxygenation led to the production of NO. In conclusion, the engineered M phi, which produce IFN-gamma in an inducible manner, express new biochemical and functional properties in response to low oxygen environment as the sole stimulus, thereby circumventing the need for costimulation by other immune system-derived signals. C1 Ist Giannina Gaslini, Mol Biol Lab, I-16147 Genoa, Italy. NCI, Dev Therapeut Program, Tumor Hypoxia Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Pastorino, S (reprint author), Ist Giannina Gaslini, Mol Biol Lab, Largo G Gaslini 5, I-16147 Genoa, Italy. RI Bosco, Maria Carla/J-7928-2016; varesio, luigi/J-8261-2016 OI Bosco, Maria Carla/0000-0003-1857-7193; varesio, luigi/0000-0001-5659-2218 FU Telethon [A.075] NR 37 TC 36 Z9 37 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 MAY 1 PY 2001 VL 166 IS 9 BP 5374 EP 5380 PG 7 WC Immunology SC Immunology GA 487YH UT WOS:000171906500007 PM 11313373 ER PT J AU Azzam, HS DeJarnette, JB Huang, K Emmons, R Park, CS Sommers, CL El-Khoury, D Shores, EW Love, PE AF Azzam, HS DeJarnette, JB Huang, K Emmons, R Park, CS Sommers, CL El-Khoury, D Shores, EW Love, PE TI Fine tuning of TCR signaling by CD5 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL ANTIGEN RECEPTOR; T-CELLS; THYMOCYTE SELECTION; NEGATIVE REGULATION; TRANSGENIC MICE; B-CELLS; TYROSINE; TRANSDUCTION; ACTIVATION; COMPLEX AB Current data indicate that CD5 functions as an inhibitor of TCR signal transduction. Consistent with this role, thymocyte selection in TCR transgenic/CD5(-/-) mice is altered in a manner suggestive of enhanced TCR signaling. However, the impact of CD5 deletion on thymocyte selection varies depending on the transgenic TCR analyzed, ranging from a slight to a marked shift from positive toward negative selection. An explanation for the variable effect of CD5 on selection is suggested by the observation that CD5 surface expression is regulated by TCR signal intensity during development and CD5 surface levels on mature thymocytes and T cells parallel the avidity of the positively selecting TCR/MHC/ligand interaction. In this study, we generated mice that overexpress CD5 during thymocyte development (CD5-tg), and then examined the effect of CD5 overexpression or CD5 deletion (CD5(-/-)) on selection of thymocytes that express the same TCR transgenes. The results demonstrate that the effect on thymocyte selection of altering CD5 expression depends on the avidity of the selecting interaction and, consequently, the level of basal (endogenous) CD5 surface expression. Substitution of endogenous CD5 with a transgene encoding a truncated form of the protein failed to rescue the CD5(-/-) phenotype, demonstrating that the cytoplasmic domain of CD5 is required for its inhibitory function. Together, these results indicate that inducible regulation of CD5 surface expression during thymocyte selection functions to fine tune the TCR signaling response. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol Prod, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NR 37 TC 155 Z9 156 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5464 EP 5472 PG 9 WC Immunology SC Immunology GA 487YH UT WOS:000171906500018 PM 11313384 ER PT J AU Herndon, TM Shan, XCC Tsokos, GC Wange, RL AF Herndon, TM Shan, XCC Tsokos, GC Wange, RL TI ZAP-70 and SLP-76 regulate protein kinase C-theta and NF-kappa B activation in response to engagement of CD3 and CD28 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RECEPTOR; VAV PROTOONCOGENE PRODUCT; SYK FAMILY KINASES; TYROSINE PHOSPHORYLATION; MOLECULAR-CLONING; ANTIGEN-RECEPTOR; LYMPHOCYTES-T; PKC-THETA; SIGNAL-TRANSDUCTION; ADAPTER PROTEINS AB The transcription factor NF-KB is a critical regulator of T cell function that becomes strongly activated in response to coengagement of TCR and CD28. Although events immediately proximal to NF-kappaB activation are well understood, uncertainty remains over which upstream signaling pathways engaged by TCR and CD28 lead to NF-kappaB activation. By using Jurkat T cell lines that are deficient or replete for either the protein tyrosine kinase ZAP-70 or the cytosolic adapter molecule SLP-76, the role of these proteins in modulating NF-kappaB activation was examined. NF-kappaB was not activated in response to coengagement of TCR and CD28 in either the ZAP-70- or SLP-76-negative cells, whereas stimuli that bypass these receptors (PMA plus A23187, or TNF-alpha) activated NF-kappaB normally. Protein kinase C (PKC) theta activation, which is required for NF-kappaB activation, also was defective in these cells. Reexpression of ZAP-70 restored PKC theta and NF-kappaB activation in response to TCR and CD28 coengagement. p95(vav) (Vav)-1 tyrosine phosphorylation was largely unperturbed in the ZAP-70-negative cells; however, receptor-stimulated SLP-76/Vav-1 coassociation was greatly reduced. Wild-type SLP-76 fully restored PKC theta and NF-kappaB activation in the SLP-76-negative cells, whereas 3YF-SLP-76, which lacks the sites of tyrosine phosphorylation required for Vav-1 binding, only partially rescued signaling. These data illustrate the importance of the ZAP-70/SLP-76 signaling pathway in CD3/CD28-stimulated activation of PKC theta and NF-kappaB, and suggest that Vav-1 association with SLP-76 may be important in this pathway. C1 NIA, Ctr Gerontol Res, Biol Chem Lab, NIH, Baltimore, MD 21224 USA. Walter Reed Army Med Ctr, Dept Cellular Injury, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. RP Wange, RL (reprint author), NIA, Ctr Gerontol Res, Biol Chem Lab, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 73 TC 55 Z9 55 U1 2 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5654 EP 5664 PG 11 WC Immunology SC Immunology GA 487YH UT WOS:000171906500040 PM 11313406 ER PT J AU Ortmann, R Smeltz, R Yap, G Sher, A Shevach, EM AF Ortmann, R Smeltz, R Yap, G Sher, A Shevach, EM TI A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IFN-GAMMA; INTERLEUKIN-12 DEFICIENCY; TYROSINE PHOSPHORYLATION; CYTOKINE RESPONSES; T-CELLS; IMPAIRMENT; RECEPTOR; JAK2; MYCOBACTERIAL; ACTIVATION AB B10.Q mice are normally susceptible to the induction of collagen-induced arthritis. We noted that one subline of B10.Q mice, B10.Q/J, was completely resistant to disease induction when immunized with collagen in CFA. B10.Q/J mice have a global defect in the generation of Th1 responses, and Ag-specific T cells derived from this strain failed to produce IFN-gamma. Because T cells from these mice could produce normal amounts of IFN-gamma when activated by IL-12/IL-18-independent stimuli, the defect appeared to be a failure to respond to IL-12. This defect extended to NK cells, which also failed to produce IFN-gamma when stimulated by IL-12. The capacity of NK cells, but not activated T cells, to produce IFN-gamma in response to IL-12 could be partially restored by IL-18. The expression of the IL-12R beta1- and beta2-chains on T cells and NK cells from B10.Q/J mice was normal. However, activated T cells from B10.Q/j mice did not signal normally through the IL-12R and manifested a defect in their capacity to phosphorylate Stat4. This defect was partial in that it could be overcome by increasing both the concentration of IL-12 and the incubation times in the Stat4 phosphorylation assays. Because Stat4 function is apparently intact in B10.Q/J mice, the defect in IL-12 signaling can be localized between the IL-12R complex and Stat4. This subtle abnormality in IL-12 responsiveness results in a profound defect in the generation of Th1 cells and the development of autoimmune disease. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N315, Bethesda, MD 20892 USA. NR 24 TC 28 Z9 28 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5712 EP 5719 PG 8 WC Immunology SC Immunology GA 487YH UT WOS:000171906500047 PM 11313413 ER PT J AU Yap, GS Ortmann, R Shevach, E Sher, A AF Yap, GS Ortmann, R Shevach, E Sher, A TI A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IFN-GAMMA PRODUCTION; T-CELLS; INTRACELLULAR PATHOGEN; IL-12-DEFICIENT MICE; RECEPTOR-DEFICIENCY; IMMUNE-RESPONSE; ACUTE INFECTION; INTERLEUKIN-12; MYCOBACTERIAL; TRANSCRIPTION AB This study documents a defect in IL-12-dependent IFN-gamma responses in a substrain (BlO.Q-H2-q/Sgj) of B10.Q mice that manifests as an acute susceptibility to infection by the intracellular protozoan pathogen, Toxoplasma gondii. Despite robust systemic production of IL-12, infected B10.Q/j animals fail to mount an early IFN-gamma response after parasite inoculation. Genetic experiments revealed that the host resistance and IFN-gamma production defects are determined by a single autosomal recessive locus distinct from the Stat4 gene. Nonetheless, a delayed IL-12-mediated IFN-gamma response emerges in later stages of acute infection but is unable to prevent host mortality. IL-18 administration restores, in an IL-12-dependent manner, the early IFN-gamma response and host resistance of B10.Q/j animals. These in vivo studies indicate that the partially impaired IL-12 responsiveness in B10.Q/j mice can result in defective host resistance and demonstrate a therapeutic function for IL-18 in reversing a genetically based immunodeficiency in IL-12-dependent IFN-gamma production. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 126,Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 30 Z9 32 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5720 EP 5725 PG 6 WC Immunology SC Immunology GA 487YH UT WOS:000171906500048 PM 11313414 ER PT J AU Monsurro, V Nielsen, MB Perez-Diez, A Dudley, ME Wang, E Rosenberg, SA Marincola, FM AF Monsurro, V Nielsen, MB Perez-Diez, A Dudley, ME Wang, E Rosenberg, SA Marincola, FM TI Kinetics of TCR use in response to repeated epitope-specific immunization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; MELANOMA ANTIGEN GP100; PEPTIDE VACCINATION; IMMUNE-RESPONSE; IN-VIVO; REPLICATIVE SENESCENCE; METASTATIC MELANOMA; TUMOR-REGRESSION; LYMPHOCYTES; LEAD AB Selection of T cell-directed immunization strategies is based extensively on discordant information derived from preclinical models. We characterized the kinetics of T cell selection in response to repeated antigenic challenge. By enumerating with epitope/HLA tetrameric complexes (tHLA) vaccine-elicited T cell precursor frequencies (Tc-pf) in melanoma patients exposed to the modified gp100 epitope gp100:209-217 (g209-2M) we observed in most patients that the Tc-pf increased with number of immunizations. One patient's kinetics were further characterized. Dissociation kinetics of g209-2M/tHLA suggested enrichment of T cell effector populations expressing TCR with progressively higher affinity. Furthermore, vaccine-elicited T cells maintained the ability to express IFN-gamma ex vivo and proliferate in vitro. Thus, repeated exposure to immunogenic peptides benefited immune competence. These results provide a rationale for immunization strategies. C1 NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Ctr Clin, Dept Transfus Med,HLA Lab, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Div Clin Sci, NIH, Bldg 10,Room 2B42,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. NR 45 TC 48 Z9 50 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2001 VL 166 IS 9 BP 5817 EP 5825 PG 9 WC Immunology SC Immunology GA 487YH UT WOS:000171906500060 PM 11313426 ER PT J AU Restifo, NP AF Restifo, NP TI Hierarchy, tolerance, and dominance in the antitumor T-cell response - Commentary SO JOURNAL OF IMMUNOTHERAPY LA English DT Editorial Material ID MELANOMA ANTIGEN; TUMOR REJECTION; PEPTIDE; INDUCTION; EPITOPES; MICE C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bldg 10,Rm 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 NR 16 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAY-JUN PY 2001 VL 24 IS 3 BP 193 EP 194 DI 10.1097/00002371-200105000-00001 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 436ZY UT WOS:000168966800001 PM 11394495 ER PT J AU Zeng, G AF Zeng, G TI MHC class II-restricted tumor antigens recognized by CD4(+) T cells: New strategies for cancer vaccine design SO JOURNAL OF IMMUNOTHERAPY LA English DT Review DE tumor antigen; helper T lymphocytes; cancer vaccine; peptide vaccine; MHC class II; melanoma ID HLA-DR MOLECULES; INFILTRATING LYMPHOCYTES; HUMAN-MELANOMA; METASTATIC MELANOMA; IMMUNE-RESPONSE; AUTOLOGOUS TUMOR; TYROSINASE GENE; DENDRITIC CELLS; IDENTIFICATION; EPITOPES AB The adoptive transfer of tumor-infiltrating lymphocytes (TIL) can mediate tumor regression in patients with melanoma. This finding has led to the identification and characterization of tumor-associated antigens recognized by CD8(+) TIL. Several clinical trials based on the genes recognized by these CD8(+) T cells have been attempted, but with only limited success. Meanwhile, increasing evidence has demonstrated that CD4(+) T cells play important roles in generating and maintaining antitumor immune responses in animal models. These data suggest that it may be necessary to engage both CD4(+) and CD8(+) T cells for more effective antitumor immunotherapy. In this report, we review emerging molecular approaches in cloning major histocompatibility complex (MHC) class II restricted tumor antigens recognized by CD4(+) T cells as well as approaches to identify new MHC class II-restricted epitopes from known tumor antigens recognized by CD8(+) cytotoxic T lymphocytes and/or antibodies. Progress made in this field has shed light on the roles of tumor antigen-specific CD4(+) T cells in humans; it has also provided new insights into the understanding of tumor genesis and the interaction between tumor and the immune system. More importantly, the discovery of MHC class II-restricted tumor antigens has provided opportunities for developing a new generation of cancer vaccines aimed at eliciting both CD4(+) and CD8(+) T-cell responses against tumor. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Zeng, G (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 24 Z9 24 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAY-JUN PY 2001 VL 24 IS 3 BP 195 EP 204 DI 10.1097/00002371-200105000-00002 PG 10 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 436ZY UT WOS:000168966800002 PM 11394496 ER PT J AU Riley, JP Rosenberg, SA Parkhurst, MR AF Riley, JP Rosenberg, SA Parkhurst, MR TI Identification of a new shared HLA-A2.1 restricted epitope from the melanoma antigen tyrosinase SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE tyrosinase; melanoma; cytotoxic T lymphocytes (CTL; HLA-A2.1; epitope ID CYTOLYTIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; IN-VIVO; METASTATIC MELANOMA; VACCINE DEVELOPMENT; CYSTEINE RESIDUES; PEPTIDE; EXPRESSION; RECOGNIZE; GP100 AB Tyrosinase has many advantages as a target antigen for the immunotherapy of patients with melanoma because it is expressed in nearly all melanoma specimens with a high degree of cellular homogeneity, and its distribution in normal tissues is limited to melanocytes. To broaden our ability to direct cellular immune responses against this protein, we pursued an investigation to identify new shared human leukocyte antigen (HLA)A2.1 restricted epitopes from tyrosinase. Peptides were synthesized that fit a permissive HLA-A2.1 binding motif and did not span common sites of polymorphism. The binding affinity of each peptide to HLA-A2.1 relative to a standard peptide with intermediate binding affinity was evaluated in a competitive inhibition assay. Twelve peptides were selected that had binding affinities within 80% of that of the standard peptide, and these were used to stimulate peripheral blood mononuclear cells (PBMC) in vitro from three HLA-A2.1(+) patients with metastatic melanoma. Cytotoxic T lymphocytes that specifically recognized peptide-pulsed target cells as well as HLA-A2.1(+) tyrosinase(+) melanoma cells were raised from one patient with tyrosinase:8-17 (CLLWSFQTSA). To evaluate further the immunogenicity of this peptide, PBMC from 23 HLA-A2.1(+) patients were stimulated in vitro with tyrosinase:8-17, Eleven bulk T-cell cultures demonstrated specific peptide recognition, and six of these also recognized HLA-A2.1(+) tyrosinase(+) melanoma cells. These data suggest that tyrosinase:8-17 may be clinically useful for the treatment of patients with melanoma. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Parkhurst, MR (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 29 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1053-8550 J9 J IMMUNOTHER JI J. Immunother. PD MAY-JUN PY 2001 VL 24 IS 3 BP 212 EP 220 DI 10.1097/00002371-200105000-00004 PG 9 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 436ZY UT WOS:000168966800004 PM 11394498 ER PT J AU Belshe, RB Stevens, C Gorse, GJ Buchbinder, S Weinhold, K Sheppard, H Stablein, D Self, S McNamara, J Frey, S Flores, J Excler, JL Klein, M El Habib, R Duliege, AM Harro, C Corey, L Keefer, M Mulligan, M Wright, P Celum, C Judson, F Mayer, K McKirnan, D Marmor, M Woody, G AF Belshe, RB Stevens, C Gorse, GJ Buchbinder, S Weinhold, K Sheppard, H Stablein, D Self, S McNamara, J Frey, S Flores, J Excler, JL Klein, M El Habib, R Duliege, AM Harro, C Corey, L Keefer, M Mulligan, M Wright, P Celum, C Judson, F Mayer, K McKirnan, D Marmor, M Woody, G CA Natl Inst Allergy Infect Dis AIDS HIV Network Prevention Trials TI Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus type 1 vaccine with or without gp120: A phase 2 study in higher- and lower-risk volunteers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID GP160 RECOMBINANT VACCINIA; NEUTRALIZING ANTIBODY; RABIES GLYCOPROTEIN; IMMUNE-RESPONSES; NAIVE ADULTS; INFECTION; HIV-1; IMMUNIZATION; TRIAL AB Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study. C1 St Louis Univ, Sch Med, Dept Internal Med, Div Infect Dis, St Louis, MO 63110 USA. Vet Affairs Med Ctr, St Louis, MO USA. New York Blood Ctr, Lab Epidemiol, New York, NY 10021 USA. NYU, Sch Med, Dept Environm Med, New York, NY USA. Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. Dept Publ Hlth, San Francisco AIDS Off, San Francisco, CA USA. Calif Dept Hlth, VRDL, Berkeley, CA USA. Chiron Corp, Emeryville, CA 94608 USA. Fred Hutchinson Canc Res Ctr, HIVNET Stat Ctr, Seattle, WA 98104 USA. Univ Washington, Dept Med, Seattle, WA USA. NIH, Div AIDS, Bethesda, MD 20892 USA. EMMES Corp, Potomac, MD USA. Johns Hopkins Univ, Ctr Immunizat Res, Baltimore, MD USA. Aventis Pasteur, Marcy Letoile, France. Duke Univ, Med Ctr, Cent Immunol Lab, Durham, NC USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Dept Publ Hlth, Denver, CO USA. Fenway Community Hlth, Boston, MA USA. Miriam Hosp, Providence, RI 02906 USA. Mem Hosp, Pawtucket, RI USA. Howard Brown Hlth Ctr, Chicago, IL USA. Univ Penn, Vet Adm Med Ctr, Philadelphia, PA 19104 USA. RP Belshe, RB (reprint author), St Louis Univ, Sch Med, Dept Internal Med, Div Infect Dis, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. OI Marmor, Michael/0000-0001-6605-2661 NR 25 TC 120 Z9 124 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2001 VL 183 IS 9 BP 1343 EP 1352 DI 10.1086/319863 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 420FG UT WOS:000167993400005 PM 11294665 ER PT J AU Straus, S AF Straus, S TI Stephen Straus, MD SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Editorial Material C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Straus, S (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 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 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAY PY 2001 VL 49 IS 3 BP 217 EP 218 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 429QV UT WOS:000168529200001 PM 11352176 ER PT J AU Glaser, M Brown, DJ Law, MP Iozzo, P Waters, SL Poole, K Knickmeier, M Camici, PG Pike, VW AF Glaser, M Brown, DJ Law, MP Iozzo, P Waters, SL Poole, K Knickmeier, M Camici, PG Pike, VW TI Preparation of no-carrier-added [I-124]A(14)-iodoinsulin as a radiotracer for positron emission tomography SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE iodine-124; iodine-125; human insulin; iodoinsulin; specific radioactivity; PET ID PERFORMANCE LIQUID-CHROMATOGRAPHY; INSULIN; I-124; RATS AB A(14)-Iodoinsulin is a close biochemical and pharmacological mimic of insulin. Human insulin was labelled in its A chain tyrosine-14 residue by direct iodination with the positron-emitter iodine-124 (beta (+) = 25.6%; t(1/2) = 4.15 days) to provide a radiotracer for imaging with positron emission tomography (PET). Several reagents were compared for conversion of cyclotron-produced [I-124]iodide into a reactive species for the labelling reaction. Radiochemical yields from the use of Iodo-Gen (R), Chloramine-T, N-bromosuccinimide or lactoperoxidase-hydrogen peroxide were similar [35% (n = 1), 33 +/- 9% (n = 10), 32 +/- 11% (n = 25) or 33% (n = 2), respectively]. [I-124]A(14)-Iodoinsulin was separated from unreacted insulin and radioactive by-products by tandem reverse phase HPLC and rapidly formulated for intravenous injection by adsorption on a Sep-Pak (t)C18-Plus (R) cartridge, followed by elution with 10 mM hydrochloric acid-ethanol (1 : 1 v/v, 1 mi). This radiotracer can now be obtained in useful radioactivities at high effective specific radioactivity and is now being applied to PET studies of its biodistribution in living subjects. Copyright (C) 2001 John Wiley & Sons, Ltd. C1 Hammersmith Hosp, Imaging Res Solut Ltd, London W12 0NN, England. Hammersmith Hosp, MRC, Ctr Clin Sci, London W12 0NN, England. CNR, Inst Clin Physiol, I-56126 Pisa, Italy. Univ Munster, Dept Nucl Med, D-48149 Munster, Germany. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Room B3-20,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. RI Iozzo, Patricia/O-2893-2015 OI Iozzo, Patricia/0000-0001-6443-7074 NR 28 TC 11 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD MAY PY 2001 VL 44 IS 6 BP 465 EP 480 DI 10.1002/jlcr.482.abs PG 16 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 442VG UT WOS:000169305200009 ER PT J AU Yang, D Chertov, O Oppenheim, JJ AF Yang, D Chertov, O Oppenheim, JJ TI Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37) SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE chemotaxis; CCR6; FPRL1; phagocytic leukocytes; dendritic cells; keratinocytes; macrophages ID ANTIBACTERIAL PEPTIDE LL-37; HUMAN NEUTROPHIL DEFENSINS; DENDRITIC CELL MATURATION; INNATE HOST-DEFENSE; BETA-DEFENSIN; ANTIMICROBIAL PEPTIDES; HUMAN BETA-DEFENSIN-1; EPITHELIAL-CELLS; ALPHA-DEFENSINS; CYSTIC-FIBROSIS AB Defensins and cathelicidins are the two major families of mammalian anti-microbial proteins. They contribute to host, innate, anti-microbial defense by disrupting the integrity of the bacterial cell membrane. However, several members of the mammalian anti-microbial proteins including defensins and cathelicidins have been shown recently to have chemotactic effects on host cells, Human neutrophil alpha -defensins are chemotactic for resting, naive CD45RA/CD4 T cells, CD8 T cells, and immature dendritic cells. Human P-defensins are also chemotactic for immature dendritic cells but induce the migration of memory CDP5RO/CD4 T T cells. In contrast, cathelicidin/LL-37 is chemotactic for neutrophils, monocytes, and T cells but not for dendritic cells. Thus, these anti-microbial peptides have distinct, host-target cell spectra. The chemotactic activities of human beta -defensins and cathelicidin/LL-37 are mediated by human CC chemokine receptor 6 and formyl peptide receptor-like 1, respectively. The capacities of defensins and cathelicidins to mobilize various types of phagocytic leukocytes, immature dendritic cells, and lymphocytes, together with their other effects such as stimulating IL-8 production and mast cell degranulation, provide evidence for their participation in alerting, mobilizing, and amplifying innate and adaptive anti-microbial immunity of the host, C1 NCI, Mol Immunoregulat Lab, Div Basic Sci, NIH, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Div Basic Sci, NIH, Bldg 560,Roo, 21-89, Frederick, MD 21702 USA. NR 88 TC 181 Z9 187 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2001 VL 69 IS 5 BP 691 EP 697 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 434GM UT WOS:000168806800002 PM 11358975 ER PT J AU Yamashiro, S Kamohara, H Wang, JM Yang, D Gong, WH Yoshimura, T AF Yamashiro, S Kamohara, H Wang, JM Yang, D Gong, WH Yoshimura, T TI Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE inflammation; chemokine; chemokine receptor; gene expression ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; COLONY-STIMULATING FACTOR; HUMAN POLYMORPHONUCLEAR NEUTROPHILS; DELAYED-TYPE HYPERSENSITIVITY; PROGRAMMED CELL-DEATH; HUMAN DENDRITIC CELLS; COMPLEX CLASS-II; RED-BLOOD-CELLS; BONE-MARROW; IFN-GAMMA AB Polymorphonuclear leukocytes (PMN) are the most abundant leukocytes, comprising about two-thirds of peripheral blood leukocytes, and play major roles in innate immunity. In addition, PMN play critical roles in the development of adaptive immunity. Recently, defensins and other peptides pre-stored in PMN granules were shown to attract monocytes, dendritic cells, and T cells, leading to the hypothesis that the release of PMN granular peptides may link innate and adaptive immunity. During the past several years, we have focused on an alternative hypothesis that activated PMN further differentiate and acquire new phenotypes and functions that enable them to link the two responses. To test our hypothesis, we have taken local and global approaches and have shown several key findings that support the hypothesis. The findings include the requirement for priming PMN by cytokines to induce the delayed expression of MCP-1/CCL2, a signal for mononuclear cells, and the expression of new cell-surface markers by such cytokine-activated PMN, In the present manuscript, we focus on the phenotypic and functional changes that occur during PMN activation with selected cytokines, The results of our study indicate that inflammatory PMN are heterogeneous and play roles in not only innate but also adaptive immunity in response to stimuli released in injured tissues. C1 NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Yoshimura, T (reprint author), NCI, Mol Immunoregulat Lab, Bldg 559,Rm 1, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 61 TC 90 Z9 95 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2001 VL 69 IS 5 BP 698 EP 704 PG 7 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 434GM UT WOS:000168806800003 PM 11358976 ER PT J AU Yao, L Setsuda, J Sgadari, C Cherney, B Tosato, G AF Yao, L Setsuda, J Sgadari, C Cherney, B Tosato, G TI Interleukin-18 expression induced by Epstein-Barr virus-infected cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE Burkitt lymphoma; interferon gamma; angiogenesis; latent membrane protein-1; tumor regression ID IFN-GAMMA PRODUCTION; NECROSIS IN-VIVO; INTERFERON-GAMMA; B-CELLS; T-CELLS; LYMPHOPROLIFERATIVE DISEASE; INDUCIBLE PROTEIN-10; CYTOKINE PRODUCTION; TUMOR-REGRESSION; CXC CHEMOKINES AB Human Epstein-Barr virus (EBV)-negative Burkitt lymphomas cells usually grow as malignant subcutaneous tumors in athymic mice, but these tumors regress when the Burkitt cells are injected in conjunction with EBV-positive lymphoblastoid cells or when the Burkitt cells are transfected with the EBV latent membrane protein-1 (LMP-I) gene. Tumor regression is mediated, in part, by murine interferon gamma (IFN-y) and the IFN-gamma -induced murine chemokine IFN-gamma -inducible protein-10 (IP-10), The mechanisms by which EBV-LIMP-1 promotes the expression of IFN-y has remained unclear. Here we show that murine interleukin (IL)-18 was consistently expressed in regressing Burkitt tumors but was either expressed at low levels or absent from progressively growing Burkitt tumors. By immunohistochemical methods, IL-18 protein was visualized in regressing but not in progressively growing Burkitt tumors, In contrast, IL-12 p35 and IL-12 p40 were only rarely expressed in regressing Burkitt tumors. In splenocyte cultures, EBV-infected lymphoblastoid cells and LMP-1-transfected Burkitt cells promoted the expression of IL-18 but not the expression of IL-12 p35 and IL-12 p40. A neutralizing antibody directed at murine IL-18 reduced murine IP-10 expression induced by EBV-immortalized cells in splenocyte cultures. These results pro,ide evidence for IL-18 expression in response to a viral latency protein and suggest that IL-18 may play an important role as an endogenous inducer of IFN-gamma expression, thereby contributing to tumor regression. C1 NCI, Dept Transplantat Immunol, Med Branch, DCS,NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD USA. Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. RP Yao, L (reprint author), NCI, Dept Transplantat Immunol, Med Branch, DCS,NIH, Bldg 10,Room 12C07, Bethesda, MD 20892 USA. RI Sgadari, Cecilia/H-4302-2016 OI Sgadari, Cecilia/0000-0003-0364-4912 NR 30 TC 12 Z9 12 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2001 VL 69 IS 5 BP 779 EP 784 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 434GM UT WOS:000168806800014 PM 11358987 ER PT J AU Liu, Y Graham, C Parravicini, V Brown, MJ Rivera, J Shaw, S AF Liu, Y Graham, C Parravicini, V Brown, MJ Rivera, J Shaw, S TI Protein kinase C theta is expressed in mast cells and is functionally involved in Fc epsilon receptor I signaling SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE mast cells; kinases; protein; signal transduction; Fc receptors ID HIGH-AFFINITY RECEPTOR; NECROSIS-FACTOR-ALPHA; TYROSINE PHOSPHORYLATION; PKC-THETA; MOLECULAR-CLONING; IMMUNOGLOBULIN-E; RBL-2H3 CELLS; T-LYMPHOCYTES; GAMMA-CHAIN; ACTIVATION AB We investigated possible expression and function in mast cells of protein kinase C (PKC) theta, a member of the PKC family with demonstrated function in a limited range of cell types. We found that PKC theta is expressed in bone marrow-derived mast cells and in the RBL-2H3 mast cell line. PKC theta underwent translocation to the membrane in response to Fc epsilon receptor I(Fc epsilonR I) activation. Receptor activation induced phosphorylation of PKC theta, The tyrosine phosphorylation of PKC theta is delayed relative to PKC delta and coincides temporally with PKC theta association with c-src family members Lyn and Src, Studies of RBL-2H3 cells transduced with PKC theta constructs indicated a role for PKC theta in receptor-induced activation of extracellular regulated kinases, interleukin-3 gene transcription, and degranulation in response to antigen stimulation. These studies extend the known functions of PKC theta to another important immune cell type and indicate the concurrent participation of multiple PKCs in the Fc epsilonR I-mediated response of mast cells. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NIAMSD, Sect Chem Immunol, NIH, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, 9000 Rockville Pike,Bldg 10-4B36, Bethesda, MD 20892 USA. NR 46 TC 44 Z9 47 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2001 VL 69 IS 5 BP 831 EP 840 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 434GM UT WOS:000168806800020 PM 11358993 ER PT J AU Rapoport, SI Chang, MCJ Spector, AA AF Rapoport, SI Chang, MCJ Spector, AA TI Delivery and turnover of plasma-derived essential PUFAs in mammalian brain SO JOURNAL OF LIPID RESEARCH LA English DT Article DE nutrition; phospholipids; metabolism; incorporation; transport; blood-brain barrier ID RADIOLABELED FATTY-ACIDS; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; ACYL-COA CONCENTRATIONS; DOCOSAHEXAENOIC ACID; ARACHIDONIC-ACID; RAT-BRAIN; IN-VIVO; SIGNAL-TRANSDUCTION; AWAKE RATS AB Polyunsaturated fatty acids (PUFAs) are critical to nervous system function and structure, but their rates of incorporation from plasma into brain have not been evaluated. In the adult rat, calculations based on our model show that at least 3-5% of esterified brain arachidonic acid (AA) and 2-8% of esterified brain docosahexaenoic acid (DHA) are replaced daily by unesterified PUFAs in plasma. These rates, when related to unlabeled brain PUFA composition, give half-lives of 1-2 weeks for plasma-brain exchange of AA and DHA, In the human brain, the arachidonate replacement rate is 0.3% per day.j/r Although unesterified plasma PUFA concentrations are low, their rates of incorporation into brain are sufficient to compensate for metabolic and efflux losses, so that PUFA transport from plasma into brain as a component of a lipoprotein is unnecessary. Dietary supplementation, by altering plasma unesterified PUFA. concentrations, can regulate brain PUFA content and may help to treat brain diseases involving PUFA irnbalance.-Rapoport, S. I., M. C.J. Chang, and A A. Spector. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain.. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Rm 6N202, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [HL49264] NR 81 TC 209 Z9 217 U1 1 U2 11 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAY PY 2001 VL 42 IS 5 BP 678 EP 685 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437KK UT WOS:000168990700002 PM 11352974 ER PT J AU Stratakis, CA Turner, ML Lafferty, A Toro, JR Hill, S Meck, JM Blancato, J AF Stratakis, CA Turner, ML Lafferty, A Toro, JR Hill, S Meck, JM Blancato, J TI A syndrome of overgrowth and acromegaloidism with normal growth hormone secretion is associated with chromosome 11 pericentric inversion SO JOURNAL OF MEDICAL GENETICS LA English DT Letter ID AUTOSOMAL-DOMINANT SYNDROME; IN-SITU HYBRIDIZATION; HYPERTROPHIC OSTEOARTHROPATHY; INSULIN-RESISTANCE; FACIAL APPEARANCE; PHYSICAL MAP; PACHYDERMOPERIOSTOSIS; REGION C1 NICHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Inst Mol & Human Genet, Washington, DC 20007 USA. RP Stratakis, CA (reprint author), NICHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 27 TC 5 Z9 5 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD MAY PY 2001 VL 38 IS 5 BP 338 EP 343 DI 10.1136/jmg.38.5.338 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 431KW UT WOS:000168631200015 PM 11403045 ER PT J AU Lyozin, GT Makarova, KS Velikodvorskaja, VV Zelentsova, HS Khechumian, RR Kidwell, MG Koonin, EV Evgen'ev, MB AF Lyozin, GT Makarova, KS Velikodvorskaja, VV Zelentsova, HS Khechumian, RR Kidwell, MG Koonin, EV Evgen'ev, MB TI The structure and evolution of Penelope in the virilis species group of Drosophila: an ancient lineage of retroelements SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE Penelope; non-LTR elements; Drosophila virilis; invasion; horizontal transfer ID HYBRID DYSGENESIS SYNDROME; TRANSPOSABLE ELEMENTS; MOBILE ELEMENTS; SEQUENCES; RETROTRANSPOSON; MELANOGASTER; PHYLOGENIES; CHROMOSOMES; DATABASE; INVASION AB The Penelope element is the key element responsible for mobilization of other transposable elements in the course of hybrid dysgenesis in Drosophila virilis. Penelope has an unusually complex, highly variable organization in all studied species of the virlis group. The BRIDGE1 element from the fish Fugu rubripes is homologous to Penelope, and database searches detected additional homologous sequences among Expressed Sequence Tags from the flatworm Schistosoma mansonii and the nematode Ancylostoma caninum. Phylogenetic analysis shows that the reverse transcriptase of the Penelope group does not belong to any of the characterized major retroelement lineages, but apparently represents a novel branch of non-LTR retroelements. Sequence profile analysis results in the prediction that the C-terminal domain of the Penelope polyprotein is an active endonuclease related to intron-encoded endonucleases and the bacterial repair endonuclease UvrC, which could function as an integrase. No retroelements containing a predicted endonuclease of this family have been described previously. Phylogenetic analysis of Penelope copies isolated from several species of the virilis group reveals two subfamilies of Penelope elements, one of which includes full-length copies whose nucleotide sequences are almost identical, whereas the other one consists of highly diverged defective copies. Phylogenetic analysis of Penelope suggests both vertical transmission of the element and probable horizontal transfers. These findings support the notion that Penelope invasions occurred repeatedly in the evolution of the virilis group. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Inst Cellular Biophys, Pushchino, Russia. VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA. RP Evgen'ev, MB (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NR 45 TC 34 Z9 35 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD MAY PY 2001 VL 52 IS 5 BP 445 EP 456 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 437JP UT WOS:000168988800006 PM 11443348 ER PT J AU Orsini, MA Pannell, LK Erickson, KL AF Orsini, MA Pannell, LK Erickson, KL TI Polychlorinated acetamides from the cyanobacterium Microcoleus lyngbyaceus SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID SPONGE DYSIDEA-HERBACEA; NATURAL-PRODUCTS; METABOLITES; BIOSYNTHESIS; DIVERSITY; BARBAMIDE; ACID AB Several new compounds were isolated from the organic extract of the cyanobacterium Microcolcus lyngbyaceus, and their structures were determined by spectroscopic means. Polychlorinated acetamidoalkynes and alkanes were the major metabolites. 6-Acetamido-1,1,1-trichloroundccane, a positional isomer of the naturally occurring 5-acetamido-1,1,1-trichloroundecane, was synthesized in six steps from 6-decanolactone. C1 Clark Univ, Carlson Sch Chem & Biochem, Worcester, MA 01610 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Erickson, KL (reprint author), Clark Univ, Carlson Sch Chem & Biochem, Worcester, MA 01610 USA. NR 25 TC 8 Z9 8 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAY PY 2001 VL 64 IS 5 BP 572 EP 577 DI 10.1021/np000452p PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 437AG UT WOS:000168967600005 PM 11374946 ER PT J AU Charan, RD McKee, TC Boyd, MR AF Charan, RD McKee, TC Boyd, MR TI Thorectandrols A and B, new cytotoxic sesterterpenes from the marine sponge Thorectandra species SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID LUFFARIELLA-VARIABILIS; (-)-ILIMAQUINONE AB Two new sesterterpenes, thorectandrol A (1) and B (2), were isolated from extracts of the marine sponge Thorectandra sp. The structures were determined by extensive NMR spectral data analysis. NOE correlations were used to define the relative stereochemistry of 1 and 2, while CD data were used to suggest their absolute stereochemistry. Both compounds 1 and 2 inhibited the growth of MALME-3M (melanoma) and MCF-7 (breast) cancer cell lines in the range 30-40 mug/mL. The known compound palauolol (3) was isolated as well and was also cytotoxic. C1 NCI, Ctr Canc Res, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Ctr Canc Res, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. NR 19 TC 16 Z9 16 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAY PY 2001 VL 64 IS 5 BP 661 EP 663 DI 10.1021/np000544e PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 437AG UT WOS:000168967600030 PM 11374971 ER PT J AU Kos, K Fine, L Coulombe, JN AF Kos, K Fine, L Coulombe, JN TI Activin type II receptors in embryonic dorsal root ganglion neurons of the chicken SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE activin; activin receptor; dorsal root ganglion; vasoactive intestinal polypeptide; calcitonin gene related peptide; chicken embryo; in situ hybridization; immunocytochemistry; cell culture ID LEUKEMIA INHIBITORY FACTOR; VASOACTIVE INTESTINAL POLYPEPTIDE; GENE-RELATED PEPTIDE; MESSENGER RIBONUCLEIC-ACIDS; PRIMARY AFFERENT NEURONS; SENSORY NEURONS; SYMPATHETIC NEURONS; DIFFERENTIATION FACTOR; CILIARY GANGLION; CALCITONIN-GENE AB Activin induces neuropeptide expression in thicken ciliary ganglion neurons. To determine if activin might also influence neuropeptide expression in developing sensory neurons, we examined,whether type II activin receptors are expressed during embryonic development of the chicken dorsal root ganglia (DRG), and also examined the effects of activin on neuropeptide! expression in cultured DRG neurons, Using reverse transcription polymerase chain reaction (rtPCR), we detected mRNAs for both the activin receptors type IIA (ActRIIA) and type IIB (ActRIIB) in DRG from embryonic day 7 through posthatch day 1, With bl situ hybridization, we found that morphologically identifiable neurons express mRNAs for both ActRIIA and ActRIIB, With developmental age, a subset of neurons that hybridizes more intensely with riboprobes to these receptor mRNAs becomes evident. A similar pattern of expression is observed with immunocytochemical staining using antisera against activin type II receptors. To examine whether embryonic DRG cells respond to activin we treated dissociated cultures of DRG with activin A and assessed the expression of vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP) mRNAs using semiquantitative rtPCR, Activin treatment results in an increase in VIP mRNA, but does not affect CGRP mRNA levels. These observations indicate that neurons in the embryonic chicken DRG can respond to activin and suggest that activin has the potential to play a role in the development and function of DRG sensory neurons. (C) 2001 John Wiley & Sons, Inc. C1 Uniformed Serv Univ Hlth Sci, Dept Anat & Cell Biol, Bethesda, MD 20814 USA. RP Coulombe, JN (reprint author), NINDS, Neural Dev Sect, NIH, 36 Convent Dr,MSC 4064, Bethesda, MD 20892 USA. NR 83 TC 9 Z9 15 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD MAY PY 2001 VL 47 IS 2 BP 93 EP 108 DI 10.1002/neu.1019 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 421MH UT WOS:000168067800002 PM 11291100 ER PT J AU Chang, MCJ Contreras, MA Rosenberger, TA Rintala, JJO Bell, JM Rapoport, SI AF Chang, MCJ Contreras, MA Rosenberger, TA Rintala, JJO Bell, JM Rapoport, SI TI Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonate; brain; phospholipase A(2); phospholipids; turnover; valproate ID CHRONIC LITHIUM TREATMENT; MANIC-DEPRESSIVE ILLNESS; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; DOCOSAHEXAENOIC ACID; SODIUM VALPROATE; METABOLISM; COA; CORTEX; LIVER AB Both (Li+) and valproic acid (VPA) are effective in treating bipolar disorder, but the pathway by which either works, and whether it is common to both drugs, is not agreed upon. We recently reported, using an in vivo fatty acid model, that Li+ reduces the turnover rate of the second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced AA turnover was accompanied by down-regulation of gene expression and protein levels of an AA-specific cytosolic phospholipase A(2) (cPLA(2)). To see if VPA had the same effect on AA turnover, we used our in vivo fatty acid model in rats chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li+, VPA treatment significantly decreased AA turnover within brain phospholipids (by 28-33%), although it had no effect on cPLA(2) protein levels. Thus, both mood stabilizers, Li+ and VPA have a common action in reducing AA turnover in brain phospholipids, albeit by different mechanisms. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Chang, MCJ (reprint author), NIH, Natl Ctr Res Resources, Div Comparat Med, 6705 Rockledge Dr,Suite 6050,MSC 7965, Bethesda, MD 20892 USA. NR 39 TC 103 Z9 103 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2001 VL 77 IS 3 BP 796 EP 803 DI 10.1046/j.1471-4159.2001.00311.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429WX UT WOS:000168541900009 PM 11331408 ER PT J AU Leavitt, M Setola, V Fishman, PH AF Leavitt, M Setola, V Fishman, PH TI Protein kinase C-mediated down-regulation of beta(2)-adrenergic receptor and gene expression in rat C6 glioma cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE beta(2)-adrenergic receptor; down-regulation; gene transcription; mRNA; protein kinase C ID BETA-ADRENERGIC-RECEPTOR; ADENYLATE-CYCLASE; MESSENGER-RNA; CYCLIC-AMP; DESENSITIZATION; PHOSPHORYLATION; TRANSCRIPTION; AGONIST; ADENYLYLCYCLASE; ERYTHROCYTES AB We investigated the regulation of beta (2)-adrenergic receptors (beta (2)AR) by protein kinase C (PKC) in rat C6 glioma cells at the levels of receptor activity, protein expression and gene expression. Cells exposed to 4 beta -phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, exhibited a time- and concentration-dependent decrease in beta (2)AR binding activity. Maximum down-regulation was similar to 50% by 24 h and western blot analysis revealed a parallel decrease in P,AR protein. In addition, PMA treatment resulted in an acute desensitization of beta (2)AR-stimulated cyclic AMP response prior to any reduction in receptor levels. PMA exposure also affected steady-state beta (2)AR mRNA levels in a time-dependent, biphasic manner. During the first 4 h, levels decreased by similar to 60% and then slowly recovered to similar to 75% of control by 24 h, As the reduction in receptor mRNA was not due to a decrease in its stability, we examined beta (2)AR gene transcription by nuclear run-on assays. Transcriptional activity in nuclei from C6 cells treated with PMA for 2 h was reduced by 70% compared to controls. Thus PKC can regulate beta (2)AR at least two levels: the first being an acute desensitization of receptor function, and the second being a more prolonged repression of receptor gene transcription that in turn results in decreased receptor expression. C1 NINDS, Membrane Biochem Sect, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. RP Fishman, PH (reprint author), NINDS, Membrane Biochem Sect, Lab Mol & Cellular Neurobiol, NIH, Bldg 49,Room 2A28,49 Convent Dr,MSC4440, Bethesda, MD 20892 USA. NR 25 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2001 VL 77 IS 3 BP 823 EP 829 DI 10.1046/j.1471-4159.2001.00279.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429WX UT WOS:000168541900012 PM 11331411 ER PT J AU Sainz, E Korley, JN Battey, JF Sullivan, SL AF Sainz, E Korley, JN Battey, JF Sullivan, SL TI Identification of a novel member of the T1R family of putative taste receptors SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE G protein-coupled receptor; gustation; gustatory system; mouse; Sac locus; taste ID METABOTROPIC GLUTAMATE RECEPTORS; PHEROMONE RECEPTORS; CA2+-SENSING RECEPTOR; OLFACTORY EPITHELIUM; MULTIGENE FAMILY; ODORANT RECEPTOR; MICE; EXPRESSION; TRANSDUCTION; SACCHARIN AB In the gustatory system, the recognition of sugars, amino acids and bitter-tasting compounds is the function of specialized G rotein-coupled receptors. Recently, two members of novel subfamily of G protein-coupled receptors were proposed to function as taste receptors based on their specific expression in taste receptor cells. Here, we report the identification of a third member, T1R3, of this family of receptors. T1R3 maps near the telomere of mouse chromosome 4 rendering it a candidate for the Sac locus, a primary determinant of sweet preference in mice. Consistent with its candidacy for the Sac locus, T1R3 displays taste receptor cell-specific expression. In addition, taster and non-taster strains of mouse harbor different alleles of T1R3. C1 NIDCD, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Sullivan, SL (reprint author), NIDCD, Mol Biol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 39 TC 215 Z9 223 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2001 VL 77 IS 3 BP 896 EP 903 DI 10.1046/j.1471-4159.2001.00292.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429WX UT WOS:000168541900019 PM 11331418 ER PT J AU Berndt, JA Kim, JG Tosic, M Kim, C Hudson, LD AF Berndt, JA Kim, JG Tosic, M Kim, C Hudson, LD TI The transcriptional regulator Yin Yang 1 activates the myelin PLP gene SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE differentiation; myelination; nuclear matrix; oligodendrocyte; proteolipid protein; target genes ID NUCLEAR MATRIX; TARGETED DISRUPTION; BINDING PROTEIN; FACTORS YY1; REPRESSION; ELEMENT; FINGER; CELLS; BRAIN; IDENTIFICATION AB Inauguration of the myelin program in developing oligodendrocytes requires the activation of those genes that encode the myelin proteins and the enzymes responsible for the synthesis and degradation of myelin lipids. An activator of the most abundantly expressed myelin protein, proteolipid protein (PLP), has been identified in a yeast one-hybrid system. The ubiquitously expressed zinc finger protein Yin Yang 1 (YY1) recognizes the myelin PLP promoter in vitro and in vivo. When overexpressed in an oligodendrocyte cell line, YY1 enhances transcription of the PLP promoter. A truncated version of YY1 that includes only the four zinc finger domains has little effect. The binding site for YY1 in the PLP promoter (site 3) fits the YY1 consensus site and DNA-protein complexes containing site 3 can be supershifted with an antibody directed against YY1 protein. Moreover, oligonucleotides with a mutated version of the PLP promoter site 3 are unable to bind to nuclear proteins or to compete for binding in a gel shift system. Finally, mutation of this site greatly reduces the activity of a I-kb PLP promoter region in transfected glial cells. Our results suggest that PLP is a target gene for the transcriptional regulator YY1. This versatile transcription factor and nuclear matrix protein may boost transcription of the PLP gene to meet the demands of actively myelinating oligodendrocytes. C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. Genet Therapy Inc, Gaithersburg, MD USA. CHU Vaudois, Psychiat Neurosci Ctr, CH-1011 Lausanne, Switzerland. RP Hudson, LD (reprint author), 36 Convent Dr,MSC 4160, Bethesda, MD 20892 USA. NR 32 TC 26 Z9 27 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2001 VL 77 IS 3 BP 935 EP 942 DI 10.1046/j.1471-4159.2001.00307.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 429WX UT WOS:000168541900023 PM 11331422 ER PT J AU Dalakas, MC AF Dalakas, MC TI Progress in inflammatory myopathies: good but not good enough SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Editorial Material ID INCLUSION-BODY MYOSITIS; CELL RECEPTOR REPERTOIRE; DUCHENNE DYSTROPHY; MUSCLE; DERMATOMYOSITIS; POLYMYOSITIS; EXPRESSION; LYMPHOCYTES; PHENOTYPE; FAMILIES C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 36 TC 22 Z9 25 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAY PY 2001 VL 70 IS 5 BP 569 EP 573 DI 10.1136/jnnp.70.5.569 PG 5 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 426AE UT WOS:000168326200001 PM 11309448 ER PT J AU Ludwin, SK Henry, JM McFarland, H AF Ludwin, SK Henry, JM McFarland, H TI Vascular proliferation and angiogenesis in multiple sclerosis: Clinical and pathogenetic implications SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Queens Univ, Kingston, ON, Canada. NINDS, Bethesda, MD 20892 USA. AFIP, Washington, DC USA. NR 0 TC 17 Z9 17 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2001 VL 60 IS 5 MA 9 BP 505 EP 505 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 433XW UT WOS:000168786800019 ER PT J AU Torres-Munoz, JE Petito, CK Tacoronte, N Stockton, P Maronpot, R AF Torres-Munoz, JE Petito, CK Tacoronte, N Stockton, P Maronpot, R TI Amplified HIV gag and nef gene sequences in microdissected human hippocampal neurons. SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Univ Miami, Dept Pathol, Miami, FL 33136 USA. NIEHS, Div Expt Pathol, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2001 VL 60 IS 5 MA 32 BP 511 EP 511 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 433XW UT WOS:000168786800044 ER PT J AU Wiley, CA Bissel, S Wang, G Capuano, S Murphey-Corb, M Piatek, M Lifson, JD Lopresti, B Mathis, CA AF Wiley, CA Bissel, S Wang, G Capuano, S Murphey-Corb, M Piatek, M Lifson, JD Lopresti, B Mathis, CA TI Positron emission tomography (PET) imaging of macrophage activation in SIV encephalitis. SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Pittsburgh, PA 15260 USA. Natl Canc Inst, Frederick, MD USA. RI Mathis, Chester/A-8607-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2001 VL 60 IS 5 MA 34 BP 511 EP 511 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 433XW UT WOS:000168786800045 ER PT J AU Wong, K Wenger, JB Kaya, B Bouffard, JP Mena, H Schiffmann, R AF Wong, K Wenger, JB Kaya, B Bouffard, JP Mena, H Schiffmann, R TI Glial differentiation of foamy oligodendroglial cells and astrocytic abnormalities in childhood ataxia with diffuse cerebral hypomyelination (CACH). SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Armed Forces Inst Pathol, Washington, DC 20306 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2001 VL 60 IS 5 MA 50 BP 515 EP 515 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 433XW UT WOS:000168786800061 ER PT J AU Li, Y Burke, RE AF Li, Y Burke, RE TI Short-term synaptic depression in the neonatal mouse spinal cord: Effects of calcium and temperature SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PURKINJE-CELL SYNAPSE; DORSAL-ROOT AFFERENTS; GROUP-IA SYNAPSES; POSTSYNAPTIC POTENTIALS; PRESYNAPTIC DEPRESSION; TRANSMITTER RELEASE; EXCITATORY SYNAPSES; CLIMBING FIBER; VISUAL-CORTEX; CALYX SYNAPSE AB We have studied short-term synaptic depression of excitatory postsynaptic potentials (EPSPs) in lumbosacral motoneurons in the isolated, in vitro spinal cord of neonatal mice at 2-4 days postnatal age. We used 2-amino-5-phosphonovaleric acid (AP5; 100 muM) to suppress spontaneous and stimulus-evoked polysynaptic activity. Monosynaptic EPSPs were generated by trains of 10 pulses stimuli delivered to a dorsal root at eight frequencies between 0.125 and 16 Hz. The amplitudes of the second (R2), third (R3), and the average of R8, R9, and R10 (tail) EPSPs, normalized by the first EPSP (R1), defined the shapes of synaptic depression curves. Tail responses were increasingly depressed as stimulation frequency increased but R2 and R3 exhibited relative facilitation at frequencies >1 Hz. Control experiments indicated that the depression curves were not explained by presynaptic activation failure. Lowering external Ca2+ concentration ([Ca2+](o)) from 2.0 to 0.8 mM without changing [Mg2+](o) reduced average R1 amplitudes and R2 depression with little change in tail depression. Conversely, increasing [Ca2+](o) to 4.0 mM increased average R1 amplitude and R2 depression but again did not change tail depression. Increasing the bath temperature from 24 to 32 degreesC produced little change in R1 amplitudes but markedly reduced the depression of all responses at most frequencies. We developed an empirical model, based on mechanisms described in more accessible synaptic systems, that assumes: transmitter is released from a constant fraction, f, of release-ready elements in two presynaptic compartments (N and S) that are subsequently renewed by independent processes with exponential time constants (tau (N) and tau (S)); an activation-dependent facilitation of transmitter release with constant increment and fast exponential decay; and a more slowly decaying, activation-dependent augmentation of the rate of renewal (tau (N)) of N. The model gave satisfactory fits to data from all [Ca2+](o) conditions and implied that f and the increments of the facilitation and augmentation processes were all changed in the same direction as [Ca2+](o), without changing the time constants. In contrast, model fits to the 32 degreesC data implied that the process time constants all decreased by 40-45% while the presumably Ca2+-related weighting factors were unchanged. The model also successfully matched the normalized amplitudes of EPSPs during trains with irregular intervals. C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP Burke, RE (reprint author), NINDS, Neural Control Lab, NIH, Bldg 49,Rm 3A51, Bethesda, MD 20892 USA. NR 59 TC 21 Z9 21 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAY PY 2001 VL 85 IS 5 BP 2047 EP 2062 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 432DC UT WOS:000168675100025 PM 11353021 ER PT J AU Chub, N O'Donovan, MJ AF Chub, N O'Donovan, MJ TI Post-episode depression of GABAergic transmission in spinal neurons of the chick embryo SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SPONTANEOUS RHYTHMIC ACTIVITY; RAT HIPPOCAMPAL-NEURONS; SYNAPTIC TRANSMISSION; GABA(A) RECEPTORS; PATCH-CLAMP; PERSISTENT ACTIVATION; NETWORK ACTIVITY; GRANULE CELLS; CORD; CHANNELS AB Whole cell recordings were obtained from ventral horn neurons in spontaneously active spinal cords isolated from the chick embryo [embryonic days 10 to 11 (E10-E11)] to examine the post-episode depression of GABAergic transmission. Spontaneous activity occurred as recurrent, rhythmic episodes approximately 60 s in duration with 10- to 15-min quiescent inter-episode intervals. Current-clamp recording revealed that episodes were followed by a transient hyperpolarization (7 +/- 1.2 mV, mean +/- SE), which dissipated as a slow (0.5-1 mV/min) depolarization until the next episode. Local application of bicuculline 8 min after an episode hyperpolarized spinal neurons by 6 +/- 0.8 mV and increased their input resistance by 13%, suggesting the involvement of GABAergic transmission. Gramicidin perforated-patch recordings showed that the GABAa reversal potential was above rest potential (E-GABAa = -29 +/- 3 mV) and allowed estimation of the physiological intracellular [Cl-] = 50 mM. In whole cell configuration (with physiological electrode [Cl-]), two distinct types of endogenous GABAergic currents (I-GABAa) were found during the inter-episode interval. The first comprised TTX-resistant, asynchronous miniature postsynaptic currents (mPSCs), an indicator of quantal GABA release (up to 42% of total mPSCs). The second (tonic I-GABAa) was complimentary to the slow membrane depolarization and may arise from persistent activation of extrasynaptic GABAa receptors. We estimate that approximately 10 postsynaptic channels are activated by a single quantum of GABA release during an mPSC and that about 30 extrasynaptic GABAa channels are required for generation of the tonic I-GABAa in ventral horn neurons. We investigated the post-episode depression of I-GABAa by local application of GABA or isoguvacine (100 muM, for 10-30 s) applied before and after an episode at holding potentials (V-hold) -60 mV. The amplitude of the evoked I-GABA was compared after clamping the cell during the episode at one of three different V-hold : -60 mV, below E-GABAa resulting in Cl- efflux; -30 mV, close to E-GABAa with minimal Cl- flux; and 0 mV, above E-GABAa resulting in Cl- influx during the episode. The amplitude of the evoked I-GABA changed according to the direction of Cl- flux during the episode: at -60 mV a 41% decrease, at -30 mV a 4% reduction, and at 0 mV a 19% increase. These post-episode changes were accompanied by shifts of E-GABAa of -10, -1.2, and +7 mV, respectively. We conclude that redistribution of intracellular [Cl-] during spontaneous episodes is likely to be an important postsynaptic mechanism involved in the post-episode depression of GABAergic transmission in chick embryo spinal neurons. C1 NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Chub, N (reprint author), NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Rm 3A50,49 Convent Dr, Bethesda, MD 20892 USA. RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 50 TC 59 Z9 59 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAY PY 2001 VL 85 IS 5 BP 2166 EP 2176 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 432DC UT WOS:000168675100035 PM 11353031 ER PT J AU Takemura, A Inoue, Y Kawano, K Quaia, C Miles, FA AF Takemura, A Inoue, Y Kawano, K Quaia, C Miles, FA TI Single-unit activity in cortical area MST associated with disparity-vergence eye movements: Evidence for population coding SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID OCULAR FOLLOWING RESPONSES; OPTIC FLOW STIMULI; VISUAL-TRACKING NEURONS; SUPERIOR TEMPORAL AREA; PRIMATE MOTOR CORTEX; FREE ARM MOVEMENTS; MACAQUE MONKEY; BINOCULAR DISPARITY; 3-DIMENSIONAL SPACE; STEREOSCOPIC DEPTH AB Single-unit discharges were recorded in the medial superior temporal area (MST) of five behaving monkeys. Brief (230-ms) horizontal disparity steps were applied to large correlated or anticorrelated random-dot patterns (in which the dots had the same or opposite contrast, respectively, at the two eyes), eliciting vergence eye movements at short latencies [65.8 =/- 4.5 (SD) ms]. Disparity tuning curves, describing the dependence of the initial vergence responses (measured over the period 50-110 ms after the step) on the magnitude of the steps, resembled the derivative of a Gaussian, the curves obtained with correlated and anticorrelated patterns having opposite sign. Cells with disparity-related activity were isolated using correlated stimuli, and disparity tuning curves describing the dependence of these initial neuronal responses (measured over the period of 40-100 ms) on the magnitude of the disparity step were constructed (n = 102 cells). Using objective criteria and the fuzzy c-means clustering algorithm, disparity tuning curves were sorted into four groups based on their shapes. A post hoc comparison indicated that these four groups had features in common with four of the classes of disparity-selective neurons in striate cortex, but three of the four groups appeared to be part of a continuum. Most of the data were obtained from two monkeys, and when the disparity tuning curves of all the individual neurons recorded from either monkey were summed together, they fitted the disparity tuning curve for that same animal's vergence responses remarkably well (r(2) : 0.93, 0.98). Fifty-six of the neurons recorded from these two monkeys were also tested with anticorrelated patterns, and all showed significant modulation of their activity (P< 0.005, 1-way ANOVA). Further, when all of the disparity tuning curves obtained with these patterns from either monkey were summed together, they too fitted the disparity tuning curve for that same animal's vergence responses very well (r(2) : 0.93, 0.98). Indeed, the summed activity even reproduced idiosyncratic differences in the vergence responses of the two monkeys. Based on these and other observations on the temporal coding of events, we hypothesize that the magnitude, direction, and time course of the initial vergence velocity responses associated with disparity steps applied to large patterns are all encoded in the summed activity of the disparity-sensitive cells in MST. Latency data suggest that this activity in MST occurs early enough to play an active role in the generation of vergence eye movements at short latencies. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Univ Trieste, Dipartimento Elettr Elettrotecn & Informat, I-34100 Trieste, Italy. NR 105 TC 86 Z9 88 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAY PY 2001 VL 85 IS 5 BP 2245 EP 2266 PG 22 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 432DC UT WOS:000168675100043 PM 11353039 ER PT J AU McGee, AW Topinka, JR Hashimoto, K Petralia, RS Kakizawa, S Kauer, F Aguilera-Moreno, A Wenthold, RJ Kano, M Bredt, DS AF McGee, AW Topinka, JR Hashimoto, K Petralia, RS Kakizawa, S Kauer, F Aguilera-Moreno, A Wenthold, RJ Kano, M Bredt, DS TI PSD-93 knock-out mice reveal that neuronal MAGUKs are not required for development or function of parallel fiber synapses in cerebellum SO JOURNAL OF NEUROSCIENCE LA English DT Article DE PSD-93; Purkinje neuron; MAGUK; cerebellum; synapse; development; knock-out ID POSTSYNAPTIC DENSITY PROTEIN; TUMOR-SUPPRESSOR GENE; GLUTAMATE-RECEPTOR SUBUNIT; NITRIC-OXIDE SYNTHASE; LONG-TERM DEPRESSION; PURKINJE-CELLS; MUTANT MICE; K+ CHANNELS; IN-VIVO; DOMAIN AB Membrane-associated guanylate kinases (MAGUKs) are abundant postsynaptic density (PSD)-95/discs large/zona occludens-1 (PDZ)-containing proteins that can assemble receptors and associated signaling enzymes at sites of cell-cell contact, including synapses. PSD-93, a postsynaptic neuronal MAGUK, has three PDZ domains that can bind to specific ion channels, including NMDA delta2 type glutamate receptors, as well as Shaker and inward rectifier type K+ channels, and can mediate clustering of these channels in heterologous cells. Genetic analyses of Drosophila show that MAGUKs play critical roles in synaptic development because mutations of discs large disrupt the subsynaptic reticulum and block postsynaptic clustering of Shaker K+ channels. It is uncertain whether MAGUKs play an essential role in the development of central synapses. There are four neuronal MAGUKs with overlapping expression patterns in the mammalian brain; however, we find PSD-93 is the only MAGUK expressed in cerebellar Purkinje neurons. Therefore, we targeted disruption of PSD-93 in mouse. Despite the absence of MAGUK immunoreactivity in Purkinje neurons from the knock-outs, these mice have no structural or functional abnormality in cerebellum. Both the dendritic architecture and the postsynaptic localization of PSD-93 interacting proteins remain intact at light and electron microscopic levels in the knock-outs. Postsynaptic Purkinje cell responses, monosynaptic climbing fiber innervation, and cerebellar-dependent behaviors are also normal. Our data demonstrate that MAGUK proteins of the PSD-93/95 family are not essential for development of certain central synapses but may instead participate in specialized aspects of synaptic signaling and plasticity. C1 Univ Calif San Francisco, Sch Med, Dept Physiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Program Biomed Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, Program Neurosci, San Francisco, CA 94143 USA. Kanazawa Univ, Sch Med, Dept Physiol, Kanazawa, Ishikawa 9208640, Japan. Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Kawaguchi, Saitamam 3320012, Japan. NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Bredt, DS (reprint author), Univ Calif San Francisco, Sch Med, Dept Physiol, 513 Parnassus Ave, San Francisco, CA 94143 USA. FU NINDS NIH HHS [NS34822, R01-NS36017] NR 45 TC 78 Z9 82 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 1 PY 2001 VL 21 IS 9 BP 3085 EP 3091 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 423NT UT WOS:000168182900020 PM 11312293 ER PT J AU Grimaldi, M Atzori, M Ray, P Alkon, DL AF Grimaldi, M Atzori, M Ray, P Alkon, DL TI Mobilization of calcium from intracellular stores, potentiation of neurotransmitter-induced calcium transients, and capacitative calcium entry by 4-aminopyridine SO JOURNAL OF NEUROSCIENCE LA English DT Article DE neuron; astrocytes; muscle cell; capacitative calcium entry; intracellular calcium stores; voltage-sensitive K+ potassium channels ID MOTOR EVOKED-POTENTIALS; CYTOSOLIC FREE CALCIUM; POTASSIUM CHANNELS; MULTIPLE-SCLEROSIS; CORTICAL-NEURONS; MECHANISM; ASTROCYTES; MUSCLE; 4-METHYL-2-AMINOPYRIDINE; 3,4-DIAMINOPYRIDINE AB In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca2+](i)) in basal conditions, after stimulation with neurotransmitters, and during capacitative calcium entry. Using fura-2 ratiometric calcium imaging, we found that 4-AP increased [Ca2+](i) in type I astrocytes, neurons, and in skeletal muscle cells. The [Ca2+](i) elevation induced by 4-AP was concentration-dependent and consisted of two phases: the first was dependent on intracellular calcium mobilization, and the second was dependent on extracellular calcium influx. 4-AP also increased the second messenger inositol trisphosphate in both neurons and astrocytes. In astrocytes, 4-AP treatment potentiated the sustained phase of the [Ca2+](i) elevation induced by ATP and bradykinin. In addition, capacitative calcium entry was potentiated severalfold by 4-AP, in astrocytes and muscle cells but not in neurons. These effects of 4-AP were completely and promptly reversible. 4-AP blocked voltage-sensitive K+ currents in astrocytes. However, voltage-sensitive K+ channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca2+](i) were not caused by the blockade of voltage-gated K+ channels. We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca2+](i) to potentiating capacitative calcium entry. The potentiation of capacitative calcium entry in astrocytes or muscle cells may explain some of the therapeutic activities of 4-AP as a neurotransmission enhancer. C1 NINDS, Lab Adapt Syst, Bethesda, MD 20892 USA. Natl Inst Deafness & Commun Disorders, NIH, Bethesda, MD 20892 USA. Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. RP Grimaldi, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Neurol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. OI Grimaldi, Maurizio/0000-0002-7331-7055 NR 40 TC 32 Z9 33 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 1 PY 2001 VL 21 IS 9 BP 3135 EP 3143 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 423NT UT WOS:000168182900025 PM 11312298 ER PT J AU Klapper, W Shin, T Mattson, MP AF Klapper, W Shin, T Mattson, MP TI Differential regulation of telomerase activity and TERT expression during brain development in mice SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE apoptosis; differentiation; hippocampus; neurons; retina; synaptogenesis; TERT; TRF1; TRF2 ID PROGRAMMED CELL-DEATH; CATALYTIC SUBUNIT; REVERSE-TRANSCRIPTASE; PRENATAL-DEVELOPMENT; CEREBRAL-CORTEX; NERVOUS-SYSTEM; DEFICIENT MICE; LIFE-SPAN; MOUSE; PROLIFERATION AB Telomerase is an enzyme activity consisting of a reverse transcriptase called TERT and an RNA component that adds repeats of a DNA sequence (TTAGGG) to the ends of chromosomes, thereby preventing their shortening. Associations between telomerase activity and proliferation and differentiation of neural tumor cells and neural stem cells have been reported, but the role of telomerase in brain development is unknown. We now report analyses of telomerase activity, TERT mRNA levels and levels of mRNAs encoding the telomere-associated proteins TRF1 and TRF2 in three different brain regions (brainstem, hippocampus and cerebral cortex) and the eye of mice at increasing developmental time points. Telomerase activity is high in the brain at embryonic day 13(E13), declines markedly between E13 and E18, remains at a low level until postnatal day 3 (P3) and becomes undetectable by P10. Surprisingly, the temporal pattern of change in telomerase activity is not paralleled by a decrease in levels of TERT mRNA that remain elevated from E13 to P5 (with fluctuations during this time window that vary among brain regions), and then decrease to a lower level that is maintained into adulthood. TRF1 and TRF2 mRNA levels are relatively constant throughout brain development. Our data are consistent with a role for telomerase activity in proliferation of neural progenitor cells, and further suggest that TERT may play roles in neuronal differentiation and survival. The dissociation between TERT expression and telomerase activity is a novel finding that suggests biological functions for TERT in addition to telomere maintenance. Published 2001 Wiley-Liss, Inc. C1 NIA, Neurosci Lab, Gerontol Res Ctr 4F02, 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 4F02, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Klapper, Wolfram/D-2516-2010; Mattson, Mark/F-6038-2012; Klapper, Wolfram/S-6314-2016 NR 41 TC 72 Z9 78 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 1 PY 2001 VL 64 IS 3 BP 252 EP 260 DI 10.1002/jnr.1073 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 428AN UT WOS:000168439100006 PM 11319769 ER PT J AU Krzan, M Wu, VW Schwartz, JP AF Krzan, M Wu, VW Schwartz, JP TI Serotonin regulation of nerve growth factor synthesis in neonatal and adult astrocytes: Comparison to the beta-adrenergic agonist isoproterenol SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE cyclic AMP; adenylate cyclase; cortex; cerebellum; striatum ID FACTOR MESSENGER-RNA; FACTOR NGF SYNTHESIS; CYCLIC-AMP; REACTIVE ASTROCYTES; CULTURED ASTROCYTES; ADENYLYL-CYCLASE; RECEPTORS; BRAIN; NEURONS; SYSTEM AB Although serotonin regulates synthesis of the neurotrophic factor S-100 beta by astrocytes, its ability to affect nerve growth factor (NGF) synthesis has never been examined. We report here that there is a correlation between the effect of serotonin on cyclic adenosine monophosphate (cAMP) content and on NGF content in neonatal astrocytes but not in adult astrocytes. In neonatal striatal astrocytes, serotonin increases both cAMP and NGF, whereas, in neonatal cerebellar astrocytes, serotonin decreases both. The increase in neonatal cortical astrocyte cAMP appeared to be too small (45%) to increase NGF significantly. The P-adrenergic agonist isoproterenol increased cAMP and NGF in both cortical and striatal astrocytes derived from neonatal rats. In contrast, there was a dissociation between cAMP changes and NGF changes in astrocytes derived from adult rats. Both serotonin and isoproterenol increased cAMP in adult cortical astrocytes, without any effect on NGF content. However, adult striatal astrocytes responded to serotonin with an elevation of both cAMP and NGF, whereas isoproterenol could only enhance cAMP, without affecting NGF. Thus, in neonatal astrocytes, a change of sufficient magnitude in cAMP was correlated with a comparable change in NGF, in response to activation of either serotonergic or P-adrenergic receptors; in cerebellar astrocytes, the decrease in cAMP was accompanied by a decrease in NGF. in contrast, adult astrocytes were not responsive: Although cAMP changes were large, NGF synthesis was increased only in striatal astrocytes and only in response to serotonin. Published 2001 Wiley-Liss, Inc. C1 NINDS, NTFS, NIH, Bethesda, MD 20892 USA. RP Schwartz, JP (reprint author), NINDS, NTFS, NIH, Bldg 36,Room 4A31, Bethesda, MD 20892 USA. NR 35 TC 14 Z9 15 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 1 PY 2001 VL 64 IS 3 BP 261 EP 267 DI 10.1002/jnr.1074 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 428AN UT WOS:000168439100007 PM 11319770 ER PT J AU Freedman, N Kurdziel, KA Sundaram, SK Carrasquillo, JA Whatley, M Sellers, D Libutti, SK Yang, JC Bacharach, SL AF Freedman, N Kurdziel, KA Sundaram, SK Carrasquillo, JA Whatley, M Sellers, D Libutti, SK Yang, JC Bacharach, SL TI Comparison of SUV and Patlak slope to monitor cancer therapy using serial PET scans. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. RI Carrasquillo, Jorge/E-7120-2010; Sundaram, Senthil/B-3905-2013 OI Sundaram, Senthil/0000-0002-0382-0536 NR 0 TC 1 Z9 1 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 121 BP 33P EP 33P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900122 ER PT J AU Khin, MM Agyeman, K Arai, AE Panza, JA Carson, J Bacharach, SL Dilsizian, V AF Khin, MM Agyeman, K Arai, AE Panza, JA Carson, J Bacharach, SL Dilsizian, V TI Right ventricular fluorodeoxyglucose uptake in chronic ischemic left ventricular dysfunction correlates with indices of right ventricular function and volumes. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 200 BP 54P EP 54P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900201 ER PT J AU Riddell, C Buvat, I N'Guyen, T Bacharach, SL AF Riddell, C Buvat, I N'Guyen, T Bacharach, SL TI Variable scale reconstruction with nonuniform attenuation for SPECT iterative reconstruction. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 U494 INSERM, Paris, France. SMV Int, Buc, France. NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 215 BP 57P EP 58P PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900216 ER PT J AU Giovacchini, G Chang, MC Bokde, A Connolly, C Channing, MA Herscovitch, P Eckelman, WC Carson, RE Rapoport, SI AF Giovacchini, G Chang, MC Bokde, A Connolly, C Channing, MA Herscovitch, P Eckelman, WC Carson, RE Rapoport, SI TI Brain incorporation of (11)carachidonic (AA) and (11)cpalmitic acid (PA): Human studies with PET. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 0 TC 2 Z9 2 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 243 BP 65P EP 65P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900244 ER PT J AU Carson, RE Lang, L Wu, Y Ma, Y Der, MG Herscovitch, P Eckelman, WC AF Carson, RE Lang, L Wu, Y Ma, Y Der, MG Herscovitch, P Eckelman, WC TI PET evaluation of two F-18-labeled 5-HT1A antagonists with intermediate affinity. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 0 TC 1 Z9 1 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 395 BP 106P EP 106P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900396 ER PT J AU Lee, KS Zhang, L Schieck-Dowd, C Jones, DW Gorey, JG Glennon, RA Weinberger, DR AF Lee, KS Zhang, L Schieck-Dowd, C Jones, DW Gorey, JG Glennon, RA Weinberger, DR TI Estrogen upregulates 5HT2 binding activity in the frontal cortex of rats. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Med Coll Virginia, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 397 BP 106P EP 106P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900398 ER PT J AU Heinz, A Jones, D Gorey, J Weinberger, DR Higley, D AF Heinz, A Jones, D Gorey, J Weinberger, DR Higley, D TI Serotonin transporter availability is associated with alcohol intake in a non-human primate model of alcoholism - A beta-CIT SPECT study SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Cent Inst Mental Hlth, D-6800 Mannheim, Germany. NIMH, Bethesda, MD USA. Natl Inst Alcohol Abuse & Addict, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 401 BP 107P EP 108P PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900402 ER PT J AU Wong, DF Brasic, JR Zhou, Y Gay, O Crabb, AH Kuwabara, H Hilton, J Osman, M Scheffel, UA Rousset, I Fan, H Dannals, RF Musachio, JL AF Wong, DF Brasic, JR Zhou, Y Gay, O Crabb, AH Kuwabara, H Hilton, J Osman, M Scheffel, UA Rousset, I Fan, H Dannals, RF Musachio, JL TI Human imaging of alpha 4 beta 2 nicotinic acetylcholine receptors in vivo using (123)I5-IODO-A-85380. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RI Rousset, Olivier/J-6053-2012; Brasic, James/B-3503-2008 OI Rousset, Olivier/0000-0003-4414-149X; Brasic, James/0000-0002-3948-4853 NR 0 TC 6 Z9 6 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 533 BP 142P EP 142P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900534 ER PT J AU Jagoda, EM Kiesewetter, DO Shimoji, K Yamada, M Gomeza, J Wess, J Eckelman, WC AF Jagoda, EM Kiesewetter, DO Shimoji, K Yamada, M Gomeza, J Wess, J Eckelman, WC TI Regional brain uptake of the muscarinic ligand, (FFP)-F-18-TZTP, is decreased in M2 knockout but not in M3 and M4 knockout mice. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, PET Dept, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 535 BP 143P EP 143P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900536 ER PT J AU Yao, Z Zhang, M Wong, KJ Drumm-Giuseppe, DL Axworthy, DB Mallett, KW Fritzberg, AR Waldmann, TA Brechbiel, MW Pastan, I Paik, CH Carrasquillo, JA AF Yao, Z Zhang, M Wong, KJ Drumm-Giuseppe, DL Axworthy, DB Mallett, KW Fritzberg, AR Waldmann, TA Brechbiel, MW Pastan, I Paik, CH Carrasquillo, JA TI Radioimmunotherapy of A431 xenografted mice with pretargeted B3 antibody/streptavidin and Y-90-biotin. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NeoRx Corp, Seattle, WA USA. NIH, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 567 BP 152P EP 152P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900568 ER PT J AU Khin, MM Panza, JA Ernst, IR Carson, J Bacharach, SL Dilsizian, V AF Khin, MM Panza, JA Ernst, IR Carson, J Bacharach, SL Dilsizian, V TI Right ventricular fluorodeoxyglucose uptake in patients with chronic ischemic heart disease: Relation to severity of left ventricular dysfunction. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 743 BP 171P EP 171P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900644 ER PT J AU Wu, Y Carson, RE AF Wu, Y Carson, RE TI Noise reduction in the simplified reference tissue model for receptor analysis. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 786 BP 182P EP 182P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900687 ER PT J AU Ichise, M Nishizawa, N Burger, C Yonekura, Y AF Ichise, M Nishizawa, N Burger, C Yonekura, Y TI Noninvasive parametric imaging of reversible neuroreceptor binding by linear regression models. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. Fukui Med Univ, Fukui, Japan. Univ Zurich Hosp, CH-8091 Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 801 BP 185P EP 186P PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900701 ER PT J AU Raedler, TJ Dukoff, R Gorey, JG Jones, DW Knable, MB Lee, KS Sunderland, T Weinberger, DR AF Raedler, TJ Dukoff, R Gorey, JG Jones, DW Knable, MB Lee, KS Sunderland, T Weinberger, DR TI Relationship between the in vivo muscarinic cholinergic receptor availability and cerebral blood flow. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Univ Hamburg, Hamburg, Germany. NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 903 BP 211P EP 211P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900802 ER PT J AU Catafau, AM Endres, CJ Gay, O Dogan, AS Hilton, J Cherstniakova, S Rothman, RB Rice, KC Shin, L Cantilena, LR Wong, DF AF Catafau, AM Endres, CJ Gay, O Dogan, AS Hilton, J Cherstniakova, S Rothman, RB Rice, KC Shin, L Cantilena, LR Wong, DF TI C-11-cocaine and C-11-WIN35,428 PET to assess GBR12909 dopamine transporter occupancy in baboons. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDA, IRP, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 927 BP 217P EP 218P PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900826 ER PT J AU Shimoji, K Kiesewetter, DO Esaki, T Itoh, Y Sokoloff, L Eckelman, WC AF Shimoji, K Kiesewetter, DO Esaki, T Itoh, Y Sokoloff, L Eckelman, WC TI Effects of P-TZTP on local cerebral blood flow in rat brain. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIMH, PET Dept, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 936 BP 220P EP 220P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900835 ER PT J AU Garmestani, K Plascjak, PS Brechbiel, MM AF Garmestani, K Plascjak, PS Brechbiel, MM TI A new and convenient method for purification of Y-86 using Sr selective resin. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1084 BP 258P EP 258P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900981 ER PT J AU Kobayashi, H Saga, T Kawamoto, S Sato, N Ishimori, T Haque, TL Mamede, MH Konishi, J Togashi, K Brechbiel, MW AF Kobayashi, H Saga, T Kawamoto, S Sato, N Ishimori, T Haque, TL Mamede, MH Konishi, J Togashi, K Brechbiel, MW TI Synthesis and pharmacokinetics of a novel tumor-targeting and internalizing therapeutic agent, Avidin-dendrimer-1B4M(X), to deliver radiometals emitting Auger electrons into the cell. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Kyoto Univ, Grad Sch Med, Kyoto, Japan. Otsu Municipal Hosp, Otsu, Shiga, Japan. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1087 BP 258P EP 259P PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821900984 ER PT J AU Sato, N Park, CW Shin, BC Wong, KJ Park, LS Yao, Z Carrasquillo, JA Paik, CH AF Sato, N Park, CW Shin, BC Wong, KJ Park, LS Yao, Z Carrasquillo, JA Paik, CH TI Dendrimer-based biotin radiopharmaceutical with enhanced whole-body clearance. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1141 BP 272P EP 272P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821901038 ER PT J AU Waki, A Yoshimoto, M Toyohara, J Obata, A Tsuchida, T Yonekura, Y Eckelman, WC Magata, Y Fujibayashi, Y AF Waki, A Yoshimoto, M Toyohara, J Obata, A Tsuchida, T Yonekura, Y Eckelman, WC Magata, Y Fujibayashi, Y TI Evaluation of (FFLT)-F-18 uptake in tumor cells - Cell lines, mouse and rat studies. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Fukui Med Univ, Biomed Imaging Res Ctr, Fukui, Japan. NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1156 BP 276P EP 276P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821901054 ER PT J AU Kurdziel, KA Kiesewetter, DO Carson, RE Eckelman, WC Herscovitch, P AF Kurdziel, KA Kiesewetter, DO Carson, RE Eckelman, WC Herscovitch, P TI Biodistribution, radiation dose estimates and Pgp modulation studies of (18)FPAClitaxel. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 NIH, PET Dept, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 NR 0 TC 2 Z9 2 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1166 BP 279P EP 279P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821901063 ER PT J AU Scott, AM Lee, FT Hopkins, W Cebon, JS Wheatley, JM Liu, Z Smyth, FE Murone, C Sturrock, S Macgregor, D Hanai, N Inoue, K Brechbiel, MW Davis, I Murphy, R Hannah, A Lim-Joon, M Chan, T Chong, G Hoffman, EW Old, LJ AF Scott, AM Lee, FT Hopkins, W Cebon, JS Wheatley, JM Liu, Z Smyth, FE Murone, C Sturrock, S Macgregor, D Hanai, N Inoue, K Brechbiel, MW Davis, I Murphy, R Hannah, A Lim-Joon, M Chan, T Chong, G Hoffman, EW Old, LJ TI Specific targeting, biodistribution and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma - Results of a phase I trial. SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 Ludwig Inst Canc Res, Austin & Repatriat Med Ctr, Heidelberg, Vic, Australia. Kyowa Hakko Kogyo Co Ltd, Tokyo, Japan. NCI, NIH, Bethesda, MD 20892 USA. Ludwig Inst Canc Res, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 SU S MA 1288 BP 310P EP 310P PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 434NG UT WOS:000168821901185 ER PT J AU Ichise, M Meyer, JH Yonekura, Y AF Ichise, M Meyer, JH Yonekura, Y TI An introduction to PET and SPECT neuroreceptor quantification models SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET; SPECT; neuroreceptors; kinetic modeling; receptor quantification ID POSITRON EMISSION TOMOGRAPHY; REVERSIBLE RADIOLIGAND BINDING; BRAIN TRANSFER CONSTANTS; DOPAMINE D2 RECEPTORS; TIME UPTAKE DATA; GRAPHICAL ANALYSIS; IODINE-123-IBF SPECT; HEALTHY-SUBJECTS; BLOOD; TRANSPORTERS AB PET and SPECT using appropriate radioligands allow imaging of certain critical components of neurotransmission such as presynaptic transporters and postsynaptic receptors in living human brains. PET and SPECT data are commonly analyzed by applying tracer kinetic models. These modeling approaches assume a compartmental system and derive the outcome measure called the binding potential, which reflects the densities of transporters or receptors in a brain region of interest. New models are often noninvasive in that they do not require arterial blood sampling. In this review, the concept and principles of tracer kinetic modeling are introduced and commonly used PET and SPECT neuroreceptor quantification models are discussed. C1 NIMH, MIB, Bethesda, MD 20892 USA. Univ Toronto, Dept Psychiat, PET Imaging Ctr, Toronto, ON, Canada. Fukui Med Univ, Biomed Imaging Res Ctr, Fukui, Japan. RP Ichise, M (reprint author), NIMH, MIB, Room B3-10,Bldg 1,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. NR 30 TC 85 Z9 86 U1 1 U2 5 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2001 VL 42 IS 5 BP 755 EP 763 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 430UX UT WOS:000168594800021 PM 11337572 ER PT J AU Chanock, S AF Chanock, S TI Reflections on events surrounding the time of diagnosis in pediatric oncology SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Editorial Material C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Chanock, S (reprint author), NCI, Pediat Oncol Branch, NIH, 10-13N 240, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD MAY PY 2001 VL 23 IS 4 BP 211 EP 212 DI 10.1097/00043426-200105000-00006 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 432RY UT WOS:000168710500005 PM 11846297 ER PT J AU Dagher, R Pham, TA Sorbara, L Kumar, S Long, L Bernstein, D Mackall, C Raffeld, M Tsokos, M Helman, L AF Dagher, R Pham, TA Sorbara, L Kumar, S Long, L Bernstein, D Mackall, C Raffeld, M Tsokos, M Helman, L TI Molecular confirmation of Ewing sarcoma SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE Ewing sarcoma; polymerase chain reaction; translocation ID POLYMERASE CHAIN-REACTION; CHIMERIC TRANSCRIPTS; EWS GENE; TRANSLOCATION; FAMILY; TUMORS; FUSION; FUSES AB Objective: To analyze retrospectively results of reverse transcription polymerase chain reaction (RT-PCR) testing and demographic information in patients with known or suspected Ewing sarcoma/primitive neuroectodermal tumor family of tumors referred to the National Cancer Institute and to describe factors influencing the determination of molecular marker status. Patients and Methods: Tumor samples from 76 patients from February 1997 to December 1999 were analyzed. In all cases, the diagnosis of this family of tumors was confirmed by histopathologic review. Results: In 58 patients, the presence of a translocation associated with this family of turners was confirmed using RT-PCR. Specifically, there were 45 Ewing sarcoma (EWS)-FLI type 1 translocations, four EWS-FLI type 2 translocations, five EWS-ERG translocations, and four less common EWS-FLI variants. Of patients with a confirmed translocation, four were confirmed only after nested RT-PCR techniques were used. In five patients who initially underwent needle biopsy, the diagnosis was confirmed only after open biopsy or repeat needle biopsy was undertaken. Samples from 18 patients were translocation-negative. Of these, seven samples were deemed inadequate for RT-PCR testing as a result of inappropriate tissue handling or the presence of necrotic material. Five patients were found to have a different diagnosis after complete histopathologic and molecular characterization. Six samples remained, in which adequate tissue was obtained with no evidence of a characteristic translocation. Conclusions: In apparently translocation-negative samples, close attention should be given to the possibility of an alternative diagnosis, the potential need for nested RT-PCR, and the possibility of an inadequate sample. Strong consideration should be given to the use of open biopsy as opposed to needle biopsy to avoid the need for repeat biopsies and the potential for inaccurate assessment of molecular marker status. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Helman, L (reprint author), NCI, Pediat Oncol Branch, NIH, NIH Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 35 Z9 39 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD MAY PY 2001 VL 23 IS 4 BP 221 EP 224 DI 10.1097/00043426-200105000-00009 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 432RY UT WOS:000168710500008 PM 11846300 ER PT J AU Biro, FM McMahon, RP Striegel-Moore, R Crawford, PB Obarzanek, E Morrison, JA Barton, BA Falkner, F AF Biro, FM McMahon, RP Striegel-Moore, R Crawford, PB Obarzanek, E Morrison, JA Barton, BA Falkner, F TI Impact of timing of pubertal maturation on growth in black and white female adolescents: The National Heart, Lung, and Blood Institute Growth and Health Study SO JOURNAL OF PEDIATRICS LA English DT Article ID SECONDARY SEXUAL CHARACTERISTICS; HEIGHT VELOCITY; BODY-SIZE; GIRLS; FATNESS; AGE; STANDARDS; CHILDREN; MENARCHE; INDEXES AB Objectives: To evaluate the impact of early, mid-onset, and late maturation, as assessed by timing of menarche, on height, height velocity weight, body mass index, and sum of skinfolds in a group of white and black girls. Study design: The Growth and Health Study recruited 9- and 10-year-old girls from Richmond, California, Cincinnati, Ohio, and Washington, DC. There were 616 white and 539 black participants recruited at age 9 and 550 white and 674 black participants recruited at age 10. Participants were seen annually for 10 visits. Longitudinal regression models were used to test for. differences in each growth measure by timing of menarche across all ages and to determine whether these differences change with age. Results: Mean age at menarche among white participants was 12.7 years, and among black participants, 12.0 years. According to race-specific 20th and 80th percentiles, early maturers were tallest at early ages and shortest after adult stature had been attained. Peak height velocity and post-menarche increment in stature were greatest in early maturers and least in late maturers. weight was greatest in early and least in late maturers, as was body mass index. Sum of skinfolds was also greatest in early and least in late maturers. There was no impact of timing of maturation on two common measures of regional fat distribution. Conclusions: Girls who matured early were shorter in early adulthood, despite having greater peak height velocity and post-menarchal increment in height. Throughout puberty early maturers had greater ponderosity and adiposity, although there was no association with regional distribution of fat. C1 Childrens Hosp, Med Ctr, Div Adolescent Med, Cincinnati, OH 45229 USA. Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. Wesleyan Univ, Middletown, CT USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. NHLBI, Bethesda, MD 20892 USA. Maryland Med Res Inst, Baltimore, MD 21210 USA. RP Biro, FM (reprint author), Childrens Hosp, Med Ctr, Div Adolescent Med, 3333 Burnet Ave, Cincinnati, OH 45229 USA. RI McMahon, Robert/C-5462-2009; OI Barton, Bruce/0000-0001-7878-8895 FU NHLBI NIH HHS [N01-HL-55023, N01-HL-55024, N01-HL-55025, N01-HL-55026, U01-HL-48941] NR 31 TC 154 Z9 162 U1 4 U2 7 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 MAY PY 2001 VL 138 IS 5 BP 636 EP 643 DI 10.1067/mpd.2001.114476 PG 8 WC Pediatrics SC Pediatrics GA 431LY UT WOS:000168633800006 PM 11343036 ER PT J AU Zhang, HP Ford, H Roth, JS Kelley, JA AF Zhang, HP Ford, H Roth, JS Kelley, JA TI Evaluation of a fluorogenic derivatization method for the reversed-phase HPLC analysis of 2 '-beta-fluoro-2 ',3 '-dideoxyadenosine, a new anti-AIDS drug SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE high-performance liquid chromatography; 2 '-beta-fluoro-2 ',3 '-dideoxyadenosine; lodenosine; fluorescence detection; nucleoside; chloroacetaldehyde derivatization ID HUMAN-IMMUNODEFICIENCY-VIRUS; PERFORMANCE LIQUID-CHROMATOGRAPHY; HUMAN PLASMA; FLUORESCENCE DETECTION; ADENINE-NUCLEOTIDES; CHLOROACETALDEHYDE; ADENOSINE; INFECTION; HIV; PHARMACOKINETICS AB High sensitivity (10(-7) to 10(-9) M) reversed-phase high-performance liquid chromatography (HPLC) analysis of adenine nucleosides acid nucleotides, especially in a biological matrix, is difficult using only ultraviolet detection. Derivatization coupled with fluorescence detection has been investigated as a means of enhancing sensitivity for the reversed-phase HPLC analysis of 2 '-beta -fluoro-2 ' ,3 ' -dideuxyadenosine (F-ddA), an experimental, acid-stable, anti-AIDS drug. The reaction of chloroacetaldehyde: with the adenine base has been employed to form fluorescent 1,N-6-etheno derivatives of F-ddA and 5 ' -deoxyadenosine, which is used as an internal standard. These derivatives give an analytically useful fluorescence emission at 416 nm after excitation at 230, 265, or 275 nm. Derivatization, fluorescence detection and reversed-phase chromatography have been optimized for the analysis of nanomolar concentrations of F-ddA in human plasma. This method has potential for the measurement of F-ddA at low concentration and in limited volume samples from in vivo biological studies. Q Published by Elsevier Science B.V. C1 NCI, Med Chem Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Roth, JS (reprint author), NIH, Lab Neurotoxicol, Bldg 10,Room 3D-42,MSC1262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 28 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAY PY 2001 VL 25 IS 2 BP 285 EP 297 DI 10.1016/S0731-7085(00)00496-9 PG 13 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 423YB UT WOS:000168204400012 PM 11275436 ER PT J AU Baumann, MH Rothman, RB Pablo, JP Mash, DC AF Baumann, MH Rothman, RB Pablo, JP Mash, DC TI In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID INDUCED LOCOMOTOR-ACTIVITY; NUCLEUS-ACCUMBENS; ALKALOID IBOGAINE; SEROTONIN; MORPHINE; DOPAMINE; BRAIN; FENFLURAMINE; MECHANISMS; IDENTIFICATION AB Ibogaine is a naturally occurring compound with purported antiaddictive properties. When administered to primates, ibogaine is rapidly o-demethylated to form the metabolite 12-hydroxyibogamine (noribogaine). Peak blood levels of noribogaine exceed those of ibogaine, and noribogaine persists in the bloodstream for at least 1 day. Very few studies have systematically evaluated the neurobiological effects of noribogaine in vivo. In the present series of experiments, we compared the effects of i.v. administration of ibogaine and noribogaine (1 and 10 mg/kg) on motor behaviors, stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. Ibogaine caused dose-related increases in tremors, whereas noribogaine did not. Both ibogaine and noribogaine produced significant elevations in plasma corticosterone and prolactin, but ibogaine was a more potent stimulator of corticosterone secretion. Neither drug altered extracellular DA levels in the nucleus accumbens. However, both drugs increased extracellular 5-HT levels, and noribogaine was more potent in this respect. Results from in vitro experiments indicated that ibogaine and noribogaine interact with 5-HT transporters to inhibit 5-HT uptake. The present findings demonstrate that noribogaine is biologically active and undoubtedly contributes to the in vivo pharmacological profile of ibogaine in rats. Noribogaine is approximately 10 times more potent than ibogaine as an indirect 5-HT agonist. More importantly, noribogaine appears less apt to produce the adverse effects associated with ibogaine, indicating the metabolite may be a safer alternative for medication development. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 43 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2001 VL 297 IS 2 BP 531 EP 539 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422FM UT WOS:000168107900010 PM 11303040 ER PT J AU Shenoy, SR O'Keefe, BR Bolmstedt, AJ Cartner, LK Boyd, MR AF Shenoy, SR O'Keefe, BR Bolmstedt, AJ Cartner, LK Boyd, MR TI Selective interactions of the human immunodeficiency virus-inactivating protein cyanovirin-N with high-mannose oligosaccharides on gp120 and other glycoproteins SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ENVELOPE GLYCOPROTEINS; CONCANAVALIN-A; HIV-1 GP120; CD4; COMPLEX; BINDING; FUSION; SITE; GP41 AB The virucidal protein cyanovirin-N (CV-N) mediates its highly potent anti-human immunodeficiency virus activity, at least in part, through interactions with the viral envelope glycoprotein gp120. Here we dissect in further detail the mechanism of CV-N's glycosylation-dependent binding to gp120. Isothermal titration calorimetry (ITC) binding studies of CV-N with endoglycosidase H-treated gp120 showed that binding was completely abrogated by removal of high-mannose oligosaccharides from the glycoprotein. Additional ITC and circular dichroism spectral studies with CV-N and other glycoproteins as well showed that CV-N discriminately bound only glycoproteins that contain high-mannose oligosaccharides. Binding experiments with RNase B indicated that the single high-mannose oligosaccharide on that enzyme mediated all of its binding with CV-N (K-d = 0.602 muM). A finer level of oligosaccharide selectivity of CV-N was revealed in affinity chromatography-liquid chromatography-mass spectrometry experiments, which showed that CV-N preferentially bound only oligomannose-8 (Man-8) and oligomannose-9 isoforms of RNase B. Finally, we biophysically characterized the interaction of CV-N with a purified, single oligosaccharide, Man-8. The binding affinity of Man-8 for CV-N is unusually strong (K-d = 0.488 muM), several hundredfold greater than observed for oligosaccharides and their protein lectins (K-d = 1 muM-1 mM), further establishing a critical role of high-mannose oligosaccharides in CV-N binding to glycoproteins. C1 NCI, Lab Drug Discovery Res & Dev, Ctr Canc Res, Frederick, MD 21702 USA. Univ Gothenburg, Dept Clin Virol, Gothenburg, Sweden. SAIC Frederick, Frederick, MD USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Ctr Canc Res, Bldg 1052,Room 121, Frederick, MD 21702 USA. NR 24 TC 76 Z9 79 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2001 VL 297 IS 2 BP 704 EP 710 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422FM UT WOS:000168107900031 PM 11303061 ER PT J AU Spong, CY Abebe, DT Gozes, I Brenneman, DE Hill, JM AF Spong, CY Abebe, DT Gozes, I Brenneman, DE Hill, JM TI Prevention of fetal demise and growth restriction in a mouse model of fetal alcohol syndrome SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID DEPENDENT NEUROTROPHIC FACTOR; VASOACTIVE-INTESTINAL-PEPTIDE; ACTING NEUROPROTECTIVE PEPTIDE; EMBRYONIC GROWTH; CELL-DEATH; ETHANOL; NEURONS; CONSUMPTION; EXPOSURE; GLUTATHIONE AB Two peptides [NAPVSIPQ (NAP) and SALLRSIPA (ADNF-9)], that are associated with novel glial proteins regulated by vasoactive intestinal peptide, are shown now to provide protective intervention in a model of fetal alcohol syndrome. Fetal demise and growth restrictions were produced after intraperitoneal injection of ethanol to pregnant mice during midgestation (E8). Death and growth abnormalities elicited by alcohol treatment during development are believed to be associated, in part, with severe oxidative damage. NAP and ADNF-9 have been shown to exhibit antioxidative and antiapoptotic actions in vitro. Pretreatment with an equimolar combination of the peptides prevented the alcohol-induced fetal death and growth abnormalities. Pretreatment with NAP alone resulted in a significant decrease in alcohol-associated fetal death; whereas ADNF-9 alone had no detectable effect on fetal survival after alcohol exposure, indicating a pharmacological distinction between the peptides. Biochemical assessment of the fetuses indicated that the combination peptide treatment prevented the alcohol-induced decreases in reduced glutathione. Peptide efficacy was evident with either 30-min pretreatment or with 1-h post-alcohol administration. Bioavailability studies with [H-3] NAPVSIPQ indicated that 39% of the total radioactivity comigrated with intact peptide in the fetus 60 min after administration. These studies demonstrate that fetal death and growth restriction associated with prenatal alcohol exposure were prevented by combinatorial peptide treatment and suggest that this therapeutic strategy be explored in other models/diseases associated with oxidative stress. C1 NICHHD, Sect Dev & Mol Pharmacol, LDN, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Spong, CY (reprint author), NICHHD, Sect Dev & Mol Pharmacol, LDN, NIH, BLdg 49,5A-38,MSC 4480,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 37 TC 132 Z9 136 U1 1 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2001 VL 297 IS 2 BP 774 EP 779 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422FM UT WOS:000168107900039 PM 11303069 ER PT J AU Krug, K Cumming, BG Parker, AJ AF Krug, K Cumming, BG Parker, AJ TI Stimulus-dependent alteration of interneuronal correlations in V5 (MT) of the awake behaving macaque SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract ID RESPONSES C1 Univ Oxford, Physiol Lab, Oxford OX1 3PT, England. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RI Parker, Andrew/I-7867-2013 OI Parker, Andrew/0000-0001-5800-0407 NR 4 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY PY 2001 VL 533 SU S BP 72P EP 73P PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 441HE UT WOS:000169224300089 ER PT J AU Bridge, H Cumming, BG Parker, AJ AF Bridge, H Cumming, BG Parker, AJ TI Gaze angle has little effect on the orientation tuning of V1 neurons in the awake behaving macaque SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract C1 Univ Oxford, Physiol Lab, Oxford OX1 3PT, England. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RI Parker, Andrew/I-7867-2013 OI Parker, Andrew/0000-0001-5800-0407 NR 3 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY PY 2001 VL 533 SU S BP 73P EP 73P PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 441HE UT WOS:000169224300090 ER PT J AU Foulkes, AJM Cumming, BG AF Foulkes, AJM Cumming, BG TI Human stereoscopic depth perception in an anticorrelated single-edge stimulus SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Meeting Abstract ID BINOCULAR DISPARITY C1 Univ Oxford, Physiol Lab, Oxford OX1 3PT, England. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY PY 2001 VL 533 SU S BP 73P EP 74P PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 441HE UT WOS:000169224300091 ER PT J AU Miao, FJP Janig, W Jasmin, L Levine, JD AF Miao, FJP Janig, W Jasmin, L Levine, JD TI Spino-bulbo-spinal pathway mediating vagal modulation of nociceptive-neuroendocrine control of inflammation in the rat SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID ANTERIOR PRETECTAL NUCLEUS; SYNOVIAL PLASMA EXTRAVASATION; DORSAL HORN NEURONS; ROSTRAL VENTROMEDIAL MEDULLA; I PROJECTION NEURONS; LAMINA-I; INTRATHECAL NICOTINE; SYMPATHETIC OUTFLOW; BIPHASIC MODULATION; INHIBITION AB 1. Stimulation of nociceptors by intradermal capsaicin produces depression of bradykinin (BK)-induced synovial plasma extravasation (PE) that is markedly enhanced by subdiaphragmatic vagotomy. This depression is mediated by the adrenal medullae, a propriospinal pathway between the afferent nociceptive input and preganglionic neurones projecting to the adrenal medullae, and a spino-bulbo-spinal pathway. Here we investigated the role of spinal ascending and descending pathways in the interaction between noxious and vagal afferent inputs, leading to inhibition of BK-induced PE mediated by the adrenal medullae. Nociceptors in the paw were activated by capsaicin and depression of BK-induced PE was measured in rats with intact or cut subdiaphragmatic vagus nerves. 2. After cutting the dorsolateral funiculus (DLF) contralateral to the stimulated hindpaw (segment;al level C-5/C-6 and T-8/T-9), depression of BK-induced PE was weak or absent both in rats with intact vagus nerves and in vagotomised rats, suggesting that an ascending excitatory pathway was interrupted. 3. After cutting the DLF ipsilateral to the stimulated hindpaw, depression of BK-induced PE was already markedly enhanced, even in the absence of vagotomy. Ipsilateral DLF lesion (L-2/L-3) below the level of the spinal output to the adrenal medullae produced the same effect, suggesting interruption of a descending inhibitory pathway that relays the effect of vagal activity to the level of the capsaicin-induced nociceptive input. 4. Contralateral and ipsilateral hemisection of the spinal cord (C-5/C-6) produced the same changes as the corresponding DLF lesions. 5. Ipsi- or contralateral lesion of the dorsal funiculus at the spinal level T-8/T-9 had no effect on depression of BK-induced PE generated by cutaneous noxious stimulation of the forepaw. 6. We suggest that noxious stimulation activates an ascending pathway of the spino-bulbo-spinal excitatory circuit which projects through the DLF contralateral to the nociceptive input, and that the inhibitory pathway which is activated by vagal afferent activity projects through the DLF ipsilateral to the nociceptive input. C1 Univ Calif San Francisco, NIH Pain Ctr, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH Pain Ctr, Dept Neurol Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, NIH Pain Ctr, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Kiel, Inst Physiol, D-24098 Kiel, Germany. RP Miao, FJP (reprint author), Univ Calif San Francisco, NIH Pain Ctr, Dept Med, Box 0440,521 Parnassus Ave,Room C-522, San Francisco, CA 94143 USA. FU NIAMS NIH HHS [AR-32634, R01 AR032634] NR 38 TC 20 Z9 20 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY 1 PY 2001 VL 532 IS 3 BP 811 EP 822 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 432ED UT WOS:000168678500020 PM 11313448 ER PT J AU Huber, AM Hicks, JE Lachenbruch, PA Perez, MD Zemel, LS Rennebohm, RM Wallace, CA Lindsley, CB Passo, MH Ballinger, SH Bowyer, SL Reed, AM White, PH Katona, IM Miller, FW Rider, LG Feldman, BM AF Huber, AM Hicks, JE Lachenbruch, PA Perez, MD Zemel, LS Rennebohm, RM Wallace, CA Lindsley, CB Passo, MH Ballinger, SH Bowyer, SL Reed, AM White, PH Katona, IM Miller, FW Rider, LG Feldman, BM CA Juvenile Dermatomyositis Dis Activ TI Validation of the childhood health assessment questionnaire iu the juvenile idiopathic myopathies SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE juvenile idiopathic inflammatory myopathy; juvenile dermatomyositis; outcome assessment; physical function assessment; validation; measurement ID INFLAMMATORY MYOPATHIES; DISEASE-ACTIVITY; DAMAGE INDEXES; DERMATOMYOSITIS; RESPONSIVENESS; CHILDREN; MYOSITIS AB Objective. To examine the validity of the Childhood Health Assessment Questionnaire (CHAQ) in patients with juvenile idiopathic inflammatory myopathy (IIM). Methods. One hundred fifteen patients were enrolled in a multicenter collaborative study, during which subjects were assessed twice, 7-9 months apart. Physical function was measured using the CHAQ. Internal reliability was assessed using adjusted item-total correlations and item endorsement rates. Construct validity was assessed by comparing predicted and actual correlations of the CHAQ with other measures of physical function and disease activity. Responsiveness was assessed by calculating effect size (ES) and standardized response mean (SRM) in a group of a priori defined "improvers." Results. Item-total correlations were high (r(s) range = 0.35-0.81), suggesting all items were related to overall physical function. Manual muscle testing and the Childhood Myositis Assessment Scale correlated moderate to strongly with the CHAQ (r(s) = -0.64 and -0.75. both p < 0.001). Moderate correlations were also seen with the physician global assessment of disease activity (r(s) = 0.58, p < 0.001). parent global assessment of overall health (r(s) = -0.65, p < 0.001). Steinbrocker function class (r(s) = 0.69, p < 0.001), and global skin activity (r(s) = 0.40, p < 0.001), while global disease damage and skin damage had low correlations (r(s) = 0.13 and 0.07, p 0.17). Responsiveness of the CHAQ was high. with ES = 1.05 and SRM = 1.20. Conclusion. In this large cohort of patients with juvenile IIM, the CHAQ exhibited internal reliability, construct validity and strong responsiveness. We conclude that the CHAQ is a valid measure of physical function in juvenile IIm, appropriate for use in therapeutic trials, and potentially in the clinical carl of these patients. C1 Hosp Sick Children, Div Rheumatol, Dept Pediat, Toronto, ON M5G 2X8, Canada. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. NIAMSD, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIAMSD, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. US FDA, Div Biostat, Bethesda, MD 20014 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Baylor Coll Med, Texas Childrens Hosp, Houston, TX 77030 USA. Univ Connecticut, Connecticut Childrens Med Ctr, Hartford, CT 06112 USA. Ohio State Univ, Columbus Childrens Hosp, Columbus, OH 43210 USA. Univ Washington, Childrens Hosp, Seattle, WA 98195 USA. Univ Kansas, Kansas City, KS 66103 USA. Univ Cincinnati, Childrens Hosp, Cincinnati, OH USA. Indiana Univ, James Whitcomb Riley Hosp Children, Indianapolis, IN USA. Univ N Carolina, Chapel Hill, NC USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Feldman, BM (reprint author), Hosp Sick Children, Div Rheumatol, Dept Pediat, 555 Univ Ave, Toronto, ON M5G 2X8, Canada. RI Feldman, Brian/A-8586-2011; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 19 TC 75 Z9 75 U1 0 U2 0 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 MAY PY 2001 VL 28 IS 5 BP 1106 EP 1111 PG 6 WC Rheumatology SC Rheumatology GA 428XX UT WOS:000168487900032 PM 11361197 ER PT J AU Kajava, AV AF Kajava, AV TI Review: Proteins with repeated sequence - Structural prediction and modeling SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE classification; molecular modeling; prediction; tandem repeats; structural bioinformatics ID LEUCINE-RICH-REPEAT; SECONDARY STRUCTURE PREDICTION; PARALLEL BETA-HELIX; CRYSTAL-STRUCTURE; COILED-COIL; 3-DIMENSIONAL STRUCTURE; CIRCUMSPOROZOITE PROTEIN; PLASMODIUM-FALCIPARUM; TRINUCLEOTIDE REPEATS; FUNCTIONAL DIVERSITY AB The relationship between the amino acid sequence and the three-dimensional structure of proteins with internal repeats is discussed. In particular, correlations between the amino acid composition and the ability to fold in a unique structure, as well as classification of the structures based on their repeat length, are described. This analysis suggests rules that can be used for the structural prediction of repeat-containing proteins. The paper is focused on prediction and modeling of solenoid-like proteins with the repeat length ranging between 5 and 40 residues. The models of leucine-rich repeat proteins and bacterial proteins with pentapeptide repeats are examined in light of the recently solved structures of the related molecules. (C) 2001 Academic Press. C1 NIH, Ctr Mol Modeling, CIT, Bethesda, MD 20892 USA. RP Kajava, AV (reprint author), NIH, Ctr Mol Modeling, CIT, Bldg 12A,Room 2011, Bethesda, MD 20892 USA. RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 NR 92 TC 75 Z9 77 U1 1 U2 4 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY-JUN PY 2001 VL 134 IS 2-3 BP 132 EP 144 DI 10.1006/jsbi.2000.4328 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 475BT UT WOS:000171142300005 PM 11551175 ER PT J AU Saremi, A Hanson, RL Williams, DE Roumain, J Robin, RW Long, JC Goldman, D Knowler, WC AF Saremi, A Hanson, RL Williams, DE Roumain, J Robin, RW Long, JC Goldman, D Knowler, WC TI Validity of the CAGE questionnaire in an American Indian population SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID ALCOHOL DEPENDENCE; LIKELIHOOD RATIOS; PIMA-INDIANS; DRINKING; ABUSE; DISORDERS; MORTALITY; TESTS; WOMEN AB Objective: This study evaluated the performance of the CAGE questionnaire (a set of four questions about alcoholism) in an American Indian population. Method: We analyzed data from a cross-sectional study of 275 individuals (179 women) aged 21 years or older. Alcohol dependence was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R), based on a detailed psychiatric interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. Accuracy of the CAGE questionnaire was quantified as sensitivity, specificity, likelihood ratios and the area under receiver operating characteristics (ROC) curves, using the DSM-III-R diagnosis as the reference. Results: Of participants interviewed 85% of men and 53% of women had a diagnosis of alcohol dependence by DSM-III-R. A CAGE score of greater than or equal to 2 had a sensitivity and specificity of 68% and 93%, respectively, in men and 62% and 79% in women, for the diagnosis of alcohol dependence. CAGE scores of 0, 1 and greater than or equal to 2 were associated with likelihood ratios of 0.3, 0.3 and 9.5, respectively, in men and 0.4, 0.7 and 1.5 in women. The area under the ROC curve was 81% for men and 75% for women. Conclusions: These findings suggest that the CAGE questionnaire is a valid screening method, in this population, for identifying people likely to have alcohol dependence. C1 NIDDK, Diabet & Arthritis Epidemiol Sect, Phoenix, AZ 85014 USA. RP Knowler, WC (reprint author), NIDDK, Diabet & Arthritis Epidemiol Sect, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Hanson, Robert/O-3238-2015; Goldman, David/F-9772-2010 OI Hanson, Robert/0000-0002-4252-7068; Goldman, David/0000-0002-1724-5405 NR 32 TC 14 Z9 17 U1 1 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD MAY PY 2001 VL 62 IS 3 BP 294 EP 300 PG 7 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 441NG UT WOS:000169236000003 PM 11414338 ER PT J AU Hain, TC Burnett, TA Larson, CR Kiran, S AF Hain, TC Burnett, TA Larson, CR Kiran, S TI Effects of delayed auditory feedback (DAF) on the pitch-shift reflex SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID RESPONSES AB Changes in voice pitch auditory feedback to vocalizing subjects elicit compensatory changes in voice fundamental frequency (FO). The neural mechanisms responsible for this behavior involve the auditory and vocal-motor systems, collectively known as the audio-vocal system. Previous work [Burnett er nl., J. Acoust. Sec. Am. 103, 3153-3161 (1998); Hain rt al., Exp. Brain Res. 130, 133-141 (2000): Larson et nl., J. Acoust. Sec. Am. 107, 559-564 (2000)] indicated that this system operates using negative feedback to cancel out low-level errors in voice FO output. By introducing delays in the auditory feedback pathway, we hoped to transiently "open" the feedback loop and learn which components of the response are most closely related to the timing of the auditory feedback signal. Subjects were presented with pitch-shift stimuli that were paired with a delay of 0, 50, 100, 200, 300, or 500 ms. Delayed auditory feedback did not affect voice FO response latency or magnitude, but it delayed the timing of later parts of the response. As a further test of the audio-vocal control system, a second experiment was conducted in which delays of 100, 200, or 300 ms were combined with stimuli having onset velocities of 1000 or 330 cents/s. Results confirmed earlier reports that the system is sensitive to velocity of stimulus onset. A simple feedback model reproduced most features of both experiments. These results strongly support previous suggestions that the audio-vocal system monitors auditory feedback and, through closed-loop negative feedback incorporating a delay, adjusts voice FO so as to cancel unintentional small magnitude fluctuations in FO. (C) 2001 Acoustical Society of America. C1 Northwestern Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Neurol, Chicago, IL 60611 USA. NINDS, Laryngeal & Speech Sect, MNB, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Dept Commun Sci & Disorders, Evanston, IL 60208 USA. RP Northwestern Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60611 USA. EM clarson@northwestern.edu RI Kiran, S/B-1892-2013 FU NIDCD NIH HHS [DC02764-01] NR 11 TC 26 Z9 26 U1 0 U2 2 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD MAY PY 2001 VL 109 IS 5 BP 2146 EP 2152 DI 10.1121/1.1366319 PN 1 PG 7 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 431AC UT WOS:000168608700037 PM 11386566 ER PT J AU Martin, A Koenig, K Scahill, L Tierney, E Porter, FD Nwokoro, NA AF Martin, A Koenig, K Scahill, L Tierney, E Porter, FD Nwokoro, NA TI Smith-Lemli-Opitz syndrome SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter C1 Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06510 USA. Kennedy Krieger Inst, Baltimore, MD USA. NICHHD, Herritable Disorders Branch, Bethesda, MD 20892 USA. RP Martin, A (reprint author), Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT 06510 USA. NR 2 TC 11 Z9 11 U1 0 U2 0 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 MAY PY 2001 VL 40 IS 5 BP 506 EP 507 DI 10.1097/00004583-200105000-00008 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 425UE UT WOS:000168309400008 PM 11349693 ER PT J AU Weissman, NJ Panza, JA Tighe, JF Perras, ST Kushner, H Gottdiener, JS AF Weissman, NJ Panza, JA Tighe, JF Perras, ST Kushner, H Gottdiener, JS TI Specificity of Doppler echocardiography for the assessment of changes in valvular regurgitation: Comparison of side-by-side versus serial interpretation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID AORTIC REGURGITATION; REGRESSION; VARIABILITY AB OBJECTIVES We sought to determine the specificity of two different methods for assessing change in aortic (AR), mitral (MR) and tricuspid (TR) valvular regurgitation. BACKGROUND Echocardiographic imaging with Doppler is the standard noninvasive diagnostic tool for assessing valvular structure and function. Change can be assessed using either independent evaluations (serial) or using a side-by-side comparison, METHODS Subjects were from the placebo arm of a randomized, double-blind, clinical trial. Three echocardiograms over 10 months were performed. An initial and three-month echocardiogram were read as independent groups, blinded to all parameters except sequence. The initial and 10-month echocardiograms were read side-by-side, blinded to all parameters including sequence, RESULTS Two hundred nineteen predominantly healthy, obese, white, middle-aged women had initial and three-month echocardiograms (acquisition interval 105 +/- 28 days) evaluated by the serial method (mean 167 +/- 61 days between interpretations), The same subjects had the initial and 10-month studies (acquisition interval 303 +/- 27 days) compared side-by-side. The specificity of the serial versus side-bu-side method for determining change in MR grade nas 55.8% versus 93.2% (p < 0.001); TR: 63.8% versus 97.6% (p < 0.001) and AR: 93.7% versus 97.6 (p = 0.08). Notably, most of the change occurred in a range (none versus physiologic/mild) that has limited clinical significance. Furthermore, the percentage of echocardiograms interpreted as nonevaluable was lower with the side-by-side method for MR (5.0% vs. 16.0%, p = 0.06), TR (4.6% vs. 15.5%, p < 0.001) and AR (4.1% vs. 12.3%, p = 0.002), CONCLUSIONS The side-by-side method of assessing change in valvular regurgitation appears to be the more reliable method with a higher specificity and minimal data loss. (J Am Coll Cardiol 2001;37:1614-21) (C) 2001 by the American College of Cardiology. C1 Washington Hosp Ctr, Cardiovasc Res Inst, Washington, DC 20010 USA. NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. Cardiovasc Res Inst, New Windsor, NY USA. Wyeth Ayerst Res, Dept Clin Res, Philadelphia, PA USA. St Francis Hosp, Div Cardiol, Roslyn, NY USA. RP Weissman, NJ (reprint author), Washington Hosp Ctr, Cardiovasc Res Inst, Suite 4B-1,110 Irving St NW, Washington, DC 20010 USA. NR 16 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY PY 2001 VL 37 IS 6 BP 1614 EP 1621 DI 10.1016/S0735-1097(01)01222-0 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 427UN UT WOS:000168424000019 PM 11345374 ER PT J AU Bedford, S Melzer, D Guralnik, J AF Bedford, S Melzer, D Guralnik, J TI Problem behavior in the last year of life: Prevalence, risks, and care receipt in older Americans SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE problem behavior; older; care receipt; dementia; behavioral symptoms; mental disorders ID OBSTRUCTIVE PULMONARY-DISEASE; COGNITIVE IMPAIRMENT; DEMENTIA PATIENTS; NURSING-HOME; COMMUNITY; DEPRESSION; RESIDENTS; ANXIETY; QUALITY; PEOPLE AB OBJECTIVES: To estimate the prevalence of problem behavior in the last year of life in older people and to explore risk factors and assess the effect of behaviors on access to care. DESIGN: Retrospective analysis of data from the 1993 National Mortality Followback Survey, conducted by the National Center for Health Statistics (NCHS). SETTING: Persons who resided and died in the United States (except South Dakota) in 1993. PARTICIPANTS: Seven thousand six hundred and eighty-four deaths in people age 65 and older were included, from which full informant interview data were available for 6,748 decedents (88%). MEASUREMENTS: Informant data were collected on frequency of complaints about behavior from family members, complaints from others in the community, bizarre behavior, destroying property, violent threats or attempts, and temper tantrums. RESULTS: Overall, 20% of decedents were reported as having any of the problem behaviors sometimes or often in the last year of life. Rates differed little by age at death or gender. Risks of having problem behaviors were higher for those with clinically diagnosed dementia, mental illness, alcohol abuse, and bronchitis or emphysema. A diagnosis of dementia had been made in 27% of those with behavior problems. Nursing homes or healthcare facilities were the usual residence of 32% of people with any behavior problems sometimes or often during their last year of life. In formants for decedents who had destroyed property or made violent threats were 2.3 times (95% confidence interval (CI) = 1.2-1.4) more likely to report that the subject had not received the care they had needed during the last year of life. CONCLUSION: Problem behavior is relatively common in older people in the last year of life and is not confined to nursing home residents or people suffering from dementia. C1 Inst Publ Hlth, Cambridge CB2 2SR, England. Addenbrookes NHS Trust, Cambridge CB2 2QQ, England. NIA, Epidemiol Demog & Biometry Off, Bethesda, MD 20892 USA. RP Melzer, D (reprint author), Inst Publ Hlth, Forvie Site,Robinson Way, Cambridge CB2 2SR, England. OI Melzer, David/0000-0002-0170-3838 NR 23 TC 13 Z9 13 U1 0 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2001 VL 49 IS 5 BP 590 EP 595 DI 10.1046/j.1532-5415.2001.49119.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 436DV UT WOS:000168922000012 PM 11380752 ER PT J AU Weeber, M Klein, H de Jong-van den Berg, LTW Vos, R AF Weeber, M Klein, H de Jong-van den Berg, LTW Vos, R TI Using concepts in literature-based discovery: Simulating Swanson's Raynaud-fish oil and migraine-magnesium discoveries SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID SCIENTIFIC DISCOVERY; MEDICAL LITERATURES; CONNECTIONS; ARROWSMITH; KNOWLEDGE; IMPLICIT; SYSTEM AB Literature-based discovery has resulted in new knowledge. In the biomedical context, Don R. Swanson has generated several literature-based hypotheses that have been corroborated experimentally and clinically. In this paper, we propose a two-step model of the discovery process in which hypotheses are generated and subsequently tested. We have implemented this model in a Natural Language Processing system that uses biomedical Unified Medical Language System (UMLS) concepts as its unit of analysis. We use the semantic information that is provided with these concepts as a powerful filter to successfully simulate Swanson's discoveries of connecting Raynaud's disease with fish oil and migraine with a magnesium deficiency. C1 Univ Groningen, Inst Drug Explorat, NL-9713 AV Groningen, Netherlands. Univ Maastricht, Fac Hlth Sci, NL-6200 MD Maastricht, Netherlands. Ctr Language & Cognit Groningen, Dept Humanities Comp, NL-9700 AS Groningen, Netherlands. RP Weeber, M (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. NR 29 TC 99 Z9 108 U1 2 U2 14 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD MAY PY 2001 VL 52 IS 7 BP 548 EP 557 DI 10.1002/asi.1104.abs PG 10 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 427VP UT WOS:000168426400004 ER PT J AU Brouwers, P van Engelen, M Lalonde, F Perez, L de Haan, E Wolters, P Martin, A AF Brouwers, P van Engelen, M Lalonde, F Perez, L de Haan, E Wolters, P Martin, A TI Abnormally increased semantic priming in children with symptomatic HIV-1 disease: Evidence for impaired development of semantics? SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE HIV-1; AIDS; neuropsychological tests; pediatrics; reaction times; semantic development ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; QUINOLINIC ACID; CEREBROSPINAL-FLUID; BASAL GANGLIA; NEUROLOGIC MANIFESTATIONS; ALZHEIMERS-DISEASE; PEDIATRIC AIDS; INFECTION; KNOWLEDGE AB Language deficits are a major characteristic of neurobehavioral dysfunction in pediatric HIV disease. An object decision task, which assessed reaction time facilitation following a semantic or identical prime in comparison to an unrelated prime, was used to investigate whether semantic processing abnormalities could be responsible, in part, for these deficits. Thirty children with vertically acquired HIV infection (M age 9.0 years; range 6-13) participated. Either a picture of the same object (repetition prime), a semantically related object (semantic prime), a semantically unrelated object, or a nonsense object preceded a target picture, which in 50% of the cases was a real object. Brain scans of children were rated and used together with neurobehavioral functioning to classify children as having HIV-related CNS abnormalities (n = 13) or not (n = 17). increased semantic priming but not repetition priming was associated with a greater degree of cortical atrophy. Furthermore, CNS compromised children had significantly faster reaction times following a semantic prime compared to an unrelated prime than non-compromised patients. This facilitation following semantic priming for the CNS compromised patients (13.3%) almost equaled the facilitation following repetition priming (15.3%) while for the non-compromised patients facilitation following semantic priming (7.9%) was clearly smaller than following repetition priming (14.6%). These data suggest that HIV infection in children may result in a reduced neural network leading to impoverished semantic representations characterized by poor differentiation between closely related objects. C1 NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Univ Utrecht, Psychol Lab, NL-3508 TC Utrecht, Netherlands. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Med Illness Counseling Ctr, Chevy Chase, MD USA. RP Brouwers, P (reprint author), Baylor Coll Med, Texas Childrens Canc Ctr, 6621 Fannin St,MC 3-3320, Houston, TX 77030 USA. RI martin, alex/B-6176-2009; OI de Haan, Edward/0000-0003-0312-3674 NR 64 TC 5 Z9 7 U1 4 U2 4 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD MAY PY 2001 VL 7 IS 4 BP 491 EP 501 DI 10.1017/S1355617701744050 PG 11 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 436RE UT WOS:000168948600006 PM 11396551 ER PT J AU Sairanen, TR Lindsberg, PJ Brenner, M Carpen, O Siren, AL AF Sairanen, TR Lindsberg, PJ Brenner, M Carpen, O Siren, AL TI Differential cellular expression of tumor necrosis factor-alpha and Type I tumor necrosis factor receptor after transient global forebrain ischemia SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE rat; TNF-alpha; experimental ischemia; cytokines; immunohistochemistry; in situ hybridization ID FOCAL CEREBRAL-ISCHEMIA; TNF-ALPHA; GENE-EXPRESSION; BRAIN-INJURY; RAT-BRAIN; GERBIL HIPPOCAMPUS; PROTECT NEURONS; NERVOUS-SYSTEM; MICE LACKING; INHIBITION AB We examined the expression of tumor necrosis factor-alpha (TNF-alpha) and the Type I tumor necrosis factor receptor, (TNFR1), in relation to c-fos, a known regulator gene of immediate cellular responses, after an extended period of global ischemia. The number of TNF-alpha mRNA expressing cells peaked in most brain areas after 8 h of reperfusion. Significant increases in TNFR1 mRNA expression were evident in the cortex at 2 and 8 h of reperfusion and after 8 h of reperfusion in the CA3/CA4 region of the hippocampus. Transient neuronal c-fos mRNA expression preceded these responses. TNF-alpha immunoreactivity was seen in neurons >>> oligodendrocytes = perivascular cells = ependymal cells = vessel wall structures. After ischemia/reperfusion, increased TNF-alpha immunoreactivity was evident only in oligodendrocytes. TNFR1 immunoreactivity in sham brains manifested in bundles of cellular fibers of variable length and thickness. In post-ischemic brains, immunoreactivity in these cellular processes representing mainly astroglial extensions was suppressed at 2 h but recovered partially by 8 and 24 h of reperfusion. In contradiction, transient ischemia-induced TNFR1 immunoreactivity was observed in somas of large cortical neurons, in activated microglia/macrophages, perivascular and endothelial cells. Taken together, the increase in neuronal TNF-alpha mRNA appeared not to be followed by substantial translation to protein in the cerebral tissue after an extended period of global ischemia. However, there was increased neuronal TNFR1 immunostaining in conjunction with increased immunostaining for TNF-alpha in oligoglial elements, which suggests signaling to neurons by enhanced oligoglial TNF-alpha. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Helsinki, Dept Neurol, FIN-00290 Helsinki, Finland. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. Haartman Inst, Dept Pathol, FIN-00290 Helsinki, Finland. Biomedicum Helsinki, Program Neurosci, Helsinki 00029, Finland. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Max Planck Inst Expt Med, D-37075 Gottingen, Germany. RP Sairanen, TR (reprint author), Univ Helsinki, Dept Neurol, Haartmaninkatu 4, FIN-00290 Helsinki, Finland. EM tiina_sairanen@hotmail.com RI Lindsberg, Perttu/F-1271-2010 FU NINDS NIH HHS [NS-28225] NR 47 TC 52 Z9 57 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X EI 1878-5883 J9 J NEUROL SCI JI J. Neurol. Sci. PD MAY 1 PY 2001 VL 186 IS 1-2 BP 87 EP 99 DI 10.1016/S0022-510X(01)00508-1 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 448WN UT WOS:000169653100014 PM 11412877 ER PT J AU Pavlovich, CP Battiwalla, M Rick, ME Walther, MM AF Pavlovich, CP Battiwalla, M Rick, ME Walther, MM TI Antibody induced coagulopathy from bovine thrombin use during partial nephrectomy SO JOURNAL OF UROLOGY LA English DT Article DE antibodies; kidney; thrombin ID TOPICAL THROMBIN C1 NCI, Urol Oncol Branch, Hematol Branch, NHLBI, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Pavlovich, CP (reprint author), NCI, Urol Oncol Branch, Hematol Branch, NHLBI, Bethesda, MD 20892 USA. NR 3 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2001 VL 165 IS 5 BP 1617 EP 1617 DI 10.1016/S0022-5347(05)66362-8 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 426CP UT WOS:000168321500065 PM 11342931 ER PT J AU Chernoff, A Choyke, PL Linehan, WM Walther, MM AF Chernoff, A Choyke, PL Linehan, WM Walther, MM TI Parenchymal sparing surgery in a patient with multiple bilateral papillary renal cancer SO JOURNAL OF UROLOGY LA English DT Article DE kidney; kidney neoplasms ID TUMORS C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Chernoff, A (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 3 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2001 VL 165 IS 5 BP 1623 EP 1624 DI 10.1016/S0022-5347(05)66366-5 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 426CP UT WOS:000168321500069 PM 11342935 ER PT J AU Gavazza, A Presciuttini, S Barale, R Lubas, G Gugliucci, B AF Gavazza, A Presciuttini, S Barale, R Lubas, G Gugliucci, B TI Association between canine malignant lymphoma, living in industrial areas, and use of chemicals by dog owners SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Article DE case-control study; environmental pollution; hemopoietic neoplasm ID NON-HODGKINS-LYMPHOMA; 2,4-DICHLOROPHENOXYACETIC ACID; PET DOGS; PASSIVE SMOKING; LUNG-CANCER; EXPOSURE; MESOTHELIOMA; ASBESTOS; BENZENE; RISK AB A case-control study was carried out to determine whether residential exposure to environmental pollutants increased risk for canine lymphoma in pet dugs. One hundred one cases with cyctologically or histologically confirmed lymphoma diagnosed at a veterinary teaching hospital between the middle of 1996 and the middle of 1998 were examined. Controls were obtained by choosing twice the number of dogs without neoplastic disease. with overlapping distributions of province of residence, age, sex. and breed. Information regarding animal management. residence type, professional or hobby use of chemicals by owners, and treatment with herbicides or other pesticides in the area li frequently visited by the dogs was obtained with a multiple-choice questionnaire by telephone interview. Two variables were positively and independently associated with the disease. namely residency in industrial areas (odds ratio [OR]: = 8.5: 95% confidence interval [CI]. 2.3-30.9) and use of chemicals by owners, specifically paints or solvents (OR = 4.6: 95% CI. 1.7-12.6). A significantly lower value of the mean apr of disease onset was found in the group of dogs at risk in comparison with the group of all other dogs (6.1 +/- 0.4 years, n = 36 versus 7.5 +/- 0.4 years. n = 65, respectively; P = .008). Variables describing animal care and pesticide use were either not associated with the disease or were uninformative. We suggest that canine lymphoma may be considered a sentinel of potentially hazardous situations for humans, because of the relatively short latency between exposure and disease onset. C1 Univ Pisa, Dipartimento Clin Vet, Pisa, Italy. Univ Pisa, Dipartimento Sci Uomo & Ambiente, Pisa, Italy. NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. RP Lubas, G (reprint author), Univ Pisa, Dipartimento Clin Vet, Vle delle Piagge 2, Pisa, Italy. OI BARALE, Roberto/0000-0003-4161-2241 NR 27 TC 27 Z9 28 U1 3 U2 13 PU AMER COLL VETERINARY INTERNAL MEDICINE PI LAKEWOOD PA 7175 W JEFFERSON AVE, STE 2125, LAKEWOOD, CO 80235 USA SN 0891-6640 J9 J VET INTERN MED JI J. Vet. Intern. Med. PD MAY-JUN PY 2001 VL 15 IS 3 BP 190 EP 195 DI 10.1892/0891-6640(2001)015<0190:ABCMLL>2.3.CO;2 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 432DW UT WOS:000168677800005 PM 11380026 ER PT J AU Bukh, J Apgar, CL Govindarajan, S Emerson, SU Purcell, RH AF Bukh, J Apgar, CL Govindarajan, S Emerson, SU Purcell, RH TI Failure to infect rhesus monkeys with hepatitis C virus strains of genotypes 1a, 2a or 3a SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE genotype; hepatitis C virus; macaque; rhesus monkeys ID SEQUENCE-ANALYSIS; RNA; CHIMPANZEES; PRIMATES; ANTIBODY AB The chimpanzee is the only recognized animal model for the study of hepatitis C virus (HCV). However, recently it was reported that rhesus monkeys were susceptible to HCV and developed hepatitis during infection. In the present study, we inoculated two rhesus monkeys each with HCV strain H77 (genotype 1a), strain HC-J6 (genotype 2a) or strain S52 (genotype 3a). Weekly serum samples were tested for liver enzyme values, HCV antibodies and HCV RNA. We did not find evidence of HCV infection in any of the monkeys during 24 weeks of follow-up. Our study demonstrates that rhesus monkeys are not readily infected with HCV and apparently do not represent a useful animal model for the study of HCV. C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ So Calif, Rancho Los Amigos Med Ctr, Liver Res Lab, Downey, CA 90242 USA. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bldg 7,Room 201,7 Ctr Dr MSC 0740, Bethesda, MD 20892 USA. FU NIAID NIH HHS [N01-AI-45180, N01-AI-52705] NR 15 TC 11 Z9 14 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD MAY PY 2001 VL 8 IS 3 BP 228 EP 231 DI 10.1046/j.1365-2893.2001.00284.x PG 4 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 443QF UT WOS:000169351300011 PM 11380802 ER PT J AU Kovacs, GR Vasilakis, N Moss, B AF Kovacs, GR Vasilakis, N Moss, B TI Regulation of viral intermediate gene expression by the vaccinia virus B1 protein kinase SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSCRIPTION INITIATION-FACTOR; DNA-REPLICATION; RNA-POLYMERASE; CAPPING ENZYME; STAGE GENES; IN-VITRO; ENCODES; IDENTIFICATION; H5R; PURIFICATION AB The B1 gene of vaccinia virus encodes a serine/threonine protein kinase that is expressed early after infection. Under nonpermissive conditions, temperature-sensitive mutants (ts2 and ts25) that map to B1 fail to efficiently replicate viral DNA, Our goal was to extend studies on the function of B1 by determining if the kinase is required for intermediate or late gene expression, two events that ordinarily depend on viral DNA replication. First, we established that early viral gene expression occurred at the nonpermissive temperature. By using a transfection procedure that circumvents the viral DNA replication requirement, we found that reporter genes regulated by an intermediate promoter were transcribed only under conditions permissive for expression of active BI, To assay late gene expression, the T7 RNA polymerase gene was inserted into the genome of ts25 to form ts25/T7, A DNA replication-independent late gene transcription system was established by cotransfecting plasmids containing T7 promoter-driven late gene transcription factors and a late promoter reporter gene into ts25/T7-infected cells. Late genes, unlike intermediate genes, were expressed at the nonpermissive temperature. Last, we showed that overexpression of B1 stimulated intermediate but inhibited late gene expression in tells infected with wild-type virus. C1 Wyeth Lederle Vaccines, Dept Viral Vaccine Res, Pearl River, NY 10965 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kovacs, GR (reprint author), Wyeth Lederle Vaccines, Dept Viral Vaccine Res, Pearl River, NY 10965 USA. NR 38 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2001 VL 75 IS 9 BP 4048 EP 4055 DI 10.1128/JVI.75.9.4048-4055.2001 PG 8 WC Virology SC Virology GA 421PN UT WOS:000168072900004 PM 11287554 ER PT J AU Wilson, CC Palmer, B Southwood, S Sidney, J Higashimoto, Y Appella, E Chesnut, R Sette, A Livingston, BD AF Wilson, CC Palmer, B Southwood, S Sidney, J Higashimoto, Y Appella, E Chesnut, R Sette, A Livingston, BD TI Identification and antigenicity of broadly cross-reactive and conserved human immunodeficiency virus type 1-derived helper T-lymphocyte epitopes SO JOURNAL OF VIROLOGY LA English DT Article ID HLA-DR MOLECULES; REVERSE-TRANSCRIPTASE; CELL RESPONSES; SEROPOSITIVE INDIVIDUALS; ANTIRETROVIRAL THERAPY; NATURAL INFECTION; HIV-1 INFECTION; PEPTIDE MOTIFS; IN-VIVO; SUPPRESSION AB Human immunodeficiency virus (HIV)-specific helper T lymphocytes (HTL) play a key role in the immune control of HN type I (HIV-1) infection, and as such are an important target of potential HIV-I vaccines. In order to identify HTL epitopes in HIV-1 that might serve as vaccine targets, conserved HN-l-derived peptides bearing an HLA-DR binding supermotif were tested for binding to a panel of the most representative HLA-DR molecules. Eleven highly cross-reactive binding peptides were identified: three in Gag and eight in Pol. Lymphoproliferative responses to this panel of peptides, as well as to the HIV-1 p24 and p66 proteins, were evaluated with a cohort of 31 HIV-l-infected patients. All 11 peptides were recognized by peripheral blood mononuclear cells from multiple HIV-infected donors. Many of the responsive HIV-infected subjects showed recognition of multiple peptides, indicating that HIV-l-specific T-helper responses may be broadly directed in certain individuals. A strong association existed between recognition of the parental recombinant HIV-1 protein and the corresponding HTL peptides, suggesting that these peptides represent epitopes that are processed and presented during the course of HIV-I infection. Lastly, responses to the supermotif peptides were mediated by CD4(+) T cells and were restricted by major histocompatibility complex class II molecules. The epitopes described herein are potentially important components of HIV-1 therapeutic and prophylactic vaccines. C1 Univ Colorado, Hlth Sci Ctr, Div Clin Immunol, Dept Med, Denver, CO 80262 USA. Epimmune Inc, San Diego, CA 92121 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wilson, CC (reprint author), Univ Colorado, Hlth Sci Ctr, Div Clin Immunol, Dept Med, Campus Box B-164,4200 E 9th Ave, Denver, CO 80262 USA. FU NIAID NIH HHS [AI01459, AI43664, P01 AI043664] NR 53 TC 79 Z9 79 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 MAY PY 2001 VL 75 IS 9 BP 4195 EP 4207 DI 10.1128/JVI.75.9.4195-4207.2001 PG 13 WC Virology SC Virology GA 421PN UT WOS:000168072900019 PM 11287569 ER PT J AU Nees, M Geoghegan, JM Hyman, T Frank, S Miller, L Woodworth, CD AF Nees, M Geoghegan, JM Hyman, T Frank, S Miller, L Woodworth, CD TI Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kappa B-responsive genes in cervical keratinocytes SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; MAMMARY EPITHELIAL-CELLS; REGULATORY FACTOR-I; TRANSCRIPTION FACTORS; E7 PROTEIN; IMMORTALIZED KERATINOCYTES; E6; GROWTH; APOPTOSIS; P53 AB Infection with high-risk human papillomaviruses (HPV) is a major risk factor for development of cervical cancer. Expression of the HPV E6 and E7 oncoproteins increases in differentiating keratinocytes, resulting in inactivation of the p53 and retinoblastoma proteins, two important transcriptional regulators. We used cDNA microarrays to examine global alterations in gene expression in differentiating cervical keratinocytes after infection with retroviruses encoding HPV type 16 (HPV-16) E6 and E7, Expression of 80 cellular genes (approximately 4% of the genes on the array) was altered reproducibly by E6 and/or E7, Cluster analysis classified these genes into three Functional groups: (i) interferon (IFN)-responsive genes, (ii) genes stimulated by NF-kappaB, and (iii) genes regulated in cell cycle progression and DNA synthesis. HPV-16 E6 or a dominant negative p53 protein downregulated multiple IFN-responsive genes. E6 decreased expression of IFN-alpha and -beta, downregulated nuclear STAT-I protein, and decreased binding of STAT-I to the IFN-stimulated response element. E7 alone was less effective; however, coexpression of E6 and E7 downregulated IFN-responsive genes more efficiently than E6, The HPV-16 E6 protein also stimulated expression of multiple genes known to be inducible by NF-kappaB and AP-I, E6 enhanced expression of functional components of the NF-kappaB signal pathway, including p50, NIK, and TRAF-interacting protein, and increased binding to NF-kappaB and AP-I DNA consensus binding sites. Secretion of interleukin-8, RANTES, macrophage inflammatory protein la, and 10-kappa Da IFN gamma -inducible protein were increased in differentiating keratinocytes by E6, Thus, high-level expression of the HPV-16 E6 protein in differentiating keratinocytes directly alters expression of genes that influence host resistance to infection and immune function. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NINDS, Bethesda, MD 20892 USA. Ctr Adv Technol, NCI Array Fac, Gaithersburg, MD USA. RP Woodworth, CD (reprint author), Clarkson Univ, Dept Biol, Potsdam, NY 13699 USA. NR 60 TC 216 Z9 226 U1 1 U2 11 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 MAY PY 2001 VL 75 IS 9 BP 4283 EP 4296 DI 10.1128/JVI.75.9.4283-4296.2001 PG 14 WC Virology SC Virology GA 421PN UT WOS:000168072900028 PM 11287578 ER PT J AU Okun, MM Day, PM Greenstone, HL Booy, FP Lowy, DR Schiller, JT Roden, RBS AF Okun, MM Day, PM Greenstone, HL Booy, FP Lowy, DR Schiller, JT Roden, RBS TI L1 interaction domains of papillomavirus L2 necessary for viral genome encapsidation SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; MINOR CAPSID PROTEIN; BOVINE PAPILLOMAVIRUS; IN-VITRO; MONOCLONAL-ANTIBODIES; DNA; TYPE-16; E2; NEUTRALIZATION; PSEUDOVIRIONS AB BPHE-1 cells, which harbor 50 to 200 viral episomes, encapsidate viral genome and generate infectious bovine papillomavirus type 1 (BPV1) upon coexpression of capsid proteins L1 and L2 of BPV1, but not coexpression of BPV1 L1 and human papillomavirus type 16 (HPV16) L2, BPV1 L2 bound in vitro via its C-terminal 85 residues to purified LI capsomers, but not with intact LI virus-like particles in vitro. However, when the efficiency of BPV1 L1 coimmunoprecipitation with a series of BPV1 L2 deletion mutants was examined in vivo, the results suggested that residues 129 to 246 and 384 to 460 contain independent L1 interaction domains. An L2 mutant lacking the C-terminal L1 interaction domain was impaired for encapsidation of the viral genome, Coexpression of BPV1 L1 and a chimeric L2 protein composed of HPV16 L2 residues 1 to 98 fused to BPV1 L2 residues 99 to 469 generated infectious virions. However, inefficient encapsidation was seen when L1 was coexpressed with either BPV1 L2 with residues 91 to 246 deleted or with BPV1 U with residues I to 225 replaced with HPV16 L2, Impaired genome encapsidation did not correlate closely with impairment of the LL proteins either to localize to promyelocytic leukemia oncogenic domains (PODs) or to induce localization of L1 or E2 to PODs, We conclude that the L1-binding domain located near the C terminus of L2 may bind L1 prior to completion of capsid assembly, and that both L1-binding domains of L2 are required for efficient encapsidation of the viral genome. C1 Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. NCI, Cellular Oncol Lab, Div Basic Sci, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, Wolfson Lab, Dept Biochem, London SW7 2AY, England. RP Roden, RBS (reprint author), Johns Hopkins Univ, Dept Pathol, Room 656,Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. NR 38 TC 38 Z9 42 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 MAY PY 2001 VL 75 IS 9 BP 4332 EP 4342 DI 10.1128/JVI.75.9.4332-4342.2001 PG 11 WC Virology SC Virology GA 421PN UT WOS:000168072900032 PM 11287582 ER PT J AU McGettigan, JP Foley, HD Belyakov, IM Berzofsky, JA Pomerantz, RJ Schnell, MJ AF McGettigan, JP Foley, HD Belyakov, IM Berzofsky, JA Pomerantz, RJ Schnell, MJ TI Rabies virus-based vectors expressing human immunodeficiency virus type 1 (HIV-1) envelope protein induce a strong, cross-reactive cytotoxic T-lymphocyte response against envelope proteins from different HIV-1 isolates SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODIES; CYNOMOLGUS MONKEYS; ATTENUATED SIV; DNA VACCINES; NEF GENE; LIVE; MACAQUES; IMMUNIZATION; PROTECTION; INFECTION AB Novel viral vectors that are able to induce both strong and long-lasting immune responses may be required as effective vaccines for human immunodeficiency virus type I (HIV-1) infection. Our previous experiments with a replication-competent vaccine strain-based rabies virus (RV) expressing HIV-1 envelope protein from a laboratory-adapted HIV-1 strain (NL4-3) and a primary HIV-1 isolate (89.6) shelved that RV-based vectors are excellent for B-cell priming. Here we report that cytotoxic T-Lymphocyte (CTL) responses against HIV-I gp160 are induced by recombinant RVs. Our results indicated that a single inoculation of mice with an RV expressing HIV-1 gp160 induced a solid and long-lasting memory CTL response specific for HIV-1 envelope protein. Moreover, CTLs from immunized mice were not restricted to the homologous HIV-I envelope protein and were able to cross-kill target cells expressing HIV-1 gp160 from heterologous HIV-1 strains. These studies further suggest promise for RV-based vectors to elicit a persistent immune response against HIV-1 and their potential utility as efficacious anti-HIV-1 vaccines. C1 Thomas Jefferson Univ, Jefferson Med Coll, Ctr Human Virol, Dorrance H Hamilton Labs, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Biochem & Mol Pharmacol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Philadelphia, PA 19107 USA. NCI, Metab Branch, Mol Immunogenet & Vaccine Res Sect, Bethesda, MD 20892 USA. RP Schnell, MJ (reprint author), 1020 Locust St,Suite 335, Philadelphia, PA 19107 USA. FU NIAID NIH HHS [AI44340] NR 38 TC 46 Z9 53 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2001 VL 75 IS 9 BP 4430 EP 4434 DI 10.1128/JVI.75.9.4430-4434.2001 PG 5 WC Virology SC Virology GA 421PN UT WOS:000168072900045 PM 11287595 ER PT J AU Veldman, T Horikawa, I Barrett, JC Schlegel, R AF Veldman, T Horikawa, I Barrett, JC Schlegel, R TI Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein SO JOURNAL OF VIROLOGY LA English DT Article ID CATALYTIC SUBUNIT HTERT; REVERSE-TRANSCRIPTASE; HUMAN KERATINOCYTES; EPITHELIAL-CELLS; CANCER-CELLS; C-MYC; P53; PROTEIN; EXPRESSION; IDENTIFICATION AB The E6 and E7 oncogenes of human papillomavirus type 16 (HPV 16) are sufficient for the immortalization of human genital keratinocytes in vitro. The products of these viral genes associate with p53 and pRb tumor suppressor proteins, respectively, and interfere with their normal growth-regulatory functions. The HPV-16 E6 protein has also been shown to increase the telomerase enzyme activity in primary epithelial cells by an unknown mechanism, We report here that a study using reverse transcription-PCR and RNase protection assays in transduced primary human foreskin keratinocytes (HFKs) shows that the E6 gene (but not the E7 gene) increases telomerase hTERT gene transcription coordinately with E6-induced telomerase activity. In these same cells, the E6 gene induces a 6.5-fold increase in the activity of a 1,165-bp 5 ' promoter/regulatory region of the hTERT gene, and this induction is attributable to a minimal 251-bp sequence (-211 to +40), Furthermore, there is a 35-bp region (+5 to +40) within this minimal E6-responsive promoter that is responsible for 60% of E6 activity. Although the minimal hTERT promoter contains Myc-responsive E-box elements and recent studies have suggested a role for Myc protein in hTERT transcriptional control, we found no alterations in the abundance of either c-Myc or c-Mad in E6-transduced HFKs, suggesting that there are other or additional transcription factors critical for regulating hTERT expression. C1 Georgetown Univ, Sch Med, Dept Pathol, Washington, DC 20007 USA. Georgetown Univ, Sch Med, Dept Oncol, Washington, DC 20007 USA. NCI, Lab Biosyst & Canc, Canc & Aging Sect, NIH, Bethesda, MD 20892 USA. RP Schlegel, R (reprint author), Georgetown Univ, Sch Med, Dept Pathol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. FU NCI NIH HHS [1F31 CA90203-01, F31 CA090203, R01 CA 53371, R01 CA053371] NR 46 TC 173 Z9 191 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 MAY PY 2001 VL 75 IS 9 BP 4467 EP 4472 DI 10.1128/JVI.75.9.4467-4472.2001 PG 6 WC Virology SC Virology GA 421PN UT WOS:000168072900052 PM 11287602 ER PT J AU Taraporewala, ZF Patton, JT AF Taraporewala, ZF Patton, JT TI Identification and characterization of the helix-destabilizing activity of rotavirus nonstructural protein NSP2 SO JOURNAL OF VIROLOGY LA English DT Article ID SINGLE-STRANDED RNA; DNA-BINDING-PROTEIN; TEMPERATURE-SENSITIVE MUTANTS; BLUETONGUE VIRUS; INCLUSION-BODIES; INFECTED CELLS; MESSENGER-RNA; SIGMA-NS; REPLICATION; BACULOVIRUS AB The rotavirus nonstructural protein NSP2 self-assembles into homomultimers, hinds single-stranded RNA nonspecifically, possesses a Mg2+-dependent nucleoside triphosphatase (NTPase) activity, and is a component of replication intermediates. Because these properties are characteristics of known viral helicases, we examined the possibility that this was also an activity of NSP2 by using a strand displacement assay and purified bacterially expressed protein, The results revealed that, under saturating concentrations, NSP2 disrupted both DNA-RNA and RNA-RNA duplexes; hence, the protein possesses helix-destabilizing activity. However, unlike typical helicases, NSP2 required neither a divalent cation nor a nucleotide energy source for helix destabilization. Further characterization showed that NSP2 displayed no polarity in destabilizing a partial duplex, In addition, helix destabilization by NSP2 was found to proceed cooperatively and rapidly. The presence of Mg2+ and other divalent cations inhibited by approximately one-half the activity of NSP2, probably due to the increased stability of the duplex substrate brought on by the cations, In contrast, under conditions where NSP2 functions as an NTPase, its helix-destabilizing activity was less sensitive to the presence of Mg2+, suggesting that in the cellular environment the two activities associated with the protein, helix destabilization and NTPase, may function together. Although distinct from typical helicases, the helix-destabilizing activity of NSP2 is quite similar to that of the sigma NS protein of reovirus and to the single-stranded DNA-binding proteins (SSBs) involved in double-stranded DNA replication. The presence of SSB-like nonstructural proteins in two members of the family Reoviridae suggests a common mechanism of unwinding viral mRNA prior to packaging and subsequent minus-strand RNA synthesis. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 7 Ctr Dr,MSC 0720,Room 117, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 NR 42 TC 59 Z9 62 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2001 VL 75 IS 10 BP 4519 EP 4527 DI 10.1128/JVI.75.10.4519-4527.2001 PG 9 WC Virology SC Virology GA 425UD UT WOS:000168309300006 PM 11312322 ER PT J AU Nappi, F Schneider, R Zolotukhin, A Smulevitch, S Michalowski, D Bear, J Felber, BK Pavlakis, GN AF Nappi, F Schneider, R Zolotukhin, A Smulevitch, S Michalowski, D Bear, J Felber, BK Pavlakis, GN TI Identification of a novel posttranscriptional regulatory element by using a rev- and RRE-mutated human immunodeficiency virus type 1 DNA proviral clone as a molecular trap SO JOURNAL OF VIROLOGY LA English DT Article ID MESSENGER-RNA EXPORT; CONSTITUTIVE TRANSPORT ELEMENT; SIMIAN RETROVIRUS TYPE-1; A-PARTICLE ELEMENT; ROUS-SARCOMA VIRUS; NUCLEAR EXPORT; NUCLEOCYTOPLASMIC TRANSPORT; FUNCTIONAL-ANALYSIS; MOUSE PLASMACYTOMA; GENE TRANSCRIPTS AB Human immunodeficiency virus (HN) and all other lentiviruses utilize the essential viral protein Rev, which binds to RRE RNA, to export their unspliced and partially spliced mRNAs from the nucleus. We used a rev-and RRE-defective HIV type 1 (HIV-1) molecular clone in complementation experiments to establish a method for the rapid isolation of posttranscriptional regulatory elements from the mammalian genome by selecting for rescue of virus replication. Viruses rescued by this method contained a novel element with homology to rodent intracisternal A-particle (IAP) retroelements. A functional element was contained within a 247-nucleotide fragment named RNA transport element (RTE), which was able to promote replication of the Rev- and RRE-defective HIV-1 in both human lymphoid cell lines and primary lymphocytes, demonstrating its potent posttranscriptional function. RTE was functional in many cell types, indicating that the cellular factors that recognize RTE are widely expressed and evolutionarily conserved. RTE also promoted RNA export from Xenopus oocyte nuclei. RTE-mediated RNA transport was CRM1 independent, and RTE did not show high affinity for binding to mRNA export factor TAP/NXF1, Since CRM1 and TAP/NXF1 are critical export receptors associated,vith the two recognized mRNA export pathways, these results suggest that RTE functions via a distinct export mechanism. Taken together, our results identify a novel posttranscriptional control element that uses a conserved cellular export mechanism. C1 NCI, Frederick Canc Res & Dev Ctr, BRL, Human Retrovirus Sect, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, BRL, Human Retrovirus Pathogenesis Sect, Frederick, MD 21702 USA. RP Pavlakis, GN (reprint author), NCI, Frederick Canc Res & Dev Ctr, BRL, Human Retrovirus Sect, Bldg 535,Room 210, Frederick, MD 21702 USA. NR 74 TC 38 Z9 38 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 MAY PY 2001 VL 75 IS 10 BP 4558 EP 4569 DI 10.1128/JVI.75.10.4558-4569.2001 PG 12 WC Virology SC Virology GA 425UD UT WOS:000168309300010 PM 11312326 ER PT J AU Schmidt, AC McAuliffe, JM Murphy, BR Collins, PL AF Schmidt, AC McAuliffe, JM Murphy, BR Collins, PL TI Recombinant bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the respiratory syncytial virus (RSV) G and F proteins can be used to achieve simultaneous mucosal immunization against RSV and HPIV3 SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINIA VIRUS; HEMAGGLUTININ-NEURAMINIDASE; T-CELLS; PARA-INFLUENZA; COTTON RATS; FUSION GLYCOPROTEINS; REASSORTANT VIRUSES; M2 PROTEIN; A VIRUS; L-GENE AB Recombinant bovine/human parainfluenza virus type 3 (rB/HPIV3), a recombinant bovine PIV3 (rBPIV3) in which the F and HN genes were replaced with their HPIV3 counterparts, was used to express the major protective antigens of respiratory syncytial virus (RSV) in order to create a bivalent mucosal vaccine against RSV and HPIV3, The attenuation of rB/HPIV3 is provided by the host range restriction of the BPIV3 backbone in primates. RSV G and F open reading frames (ORFs) were placed under the control of PIV3 transcription signals and inserted individually into the rB/HPIV3 genome in the promoter-proximal position preceding the nucleocapsid protein gene. The recombinant PIV3 expressing the RSV G ORF (rB/HPIV3-G1) was not restricted in its replication in vitro, whereas the virus expressing the RSV F ORF (rB/HPIV3-F1) was eightfold restricted compared to its rB/HPIV3 parent. Both viruses replicated efficiently in the respiratory tract of hamsters, and each induced RSV serum antibody titers similar to those induced by RSV infection and anti-HPIV3 titers similar to those induced by HPIV3 infection. Immunization of hamsters with rB/HPIV3-G1, rB/HPIV3-F1, or a combination of both viruses resulted in a high level of resistance to challenge with RSV or HPIV3 28 days later. These results describe a vaccine strategy that obviates the technical challenges associated with a live attenuated RSV vaccine, providing, against the two leading viral agents of pediatric respiratory tract disease, a bivalent vaccine whose attenuation phenotype is based on the extensive host range sequence differences of BPIV3. C1 NIAID, LID, NIH, Bethesda, MD 20892 USA. RP Schmidt, AC (reprint author), NIAID, LID, NIH, Bldg 7,Rm 130,7 Ctr Dr,MSC 0720, Bethesda, MD 20892 USA. FU NIAID NIH HHS [AI-000030, AI-000087] NR 62 TC 61 Z9 64 U1 2 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 MAY PY 2001 VL 75 IS 10 BP 4594 EP 4603 DI 10.1128/JVI.75.10.4594-4603.2001 PG 10 WC Virology SC Virology GA 425UD UT WOS:000168309300013 PM 11312329 ER PT J AU Priola, SA Chabry, J Chan, KM AF Priola, SA Chabry, J Chan, KM TI Efficient conversion of normal prion protein (PrP) by abnormal hamster PrP is determined by homology at amino acid residue 155 SO JOURNAL OF VIROLOGY LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; SCRAPIE-ASSOCIATED FORM; CHRONIC WASTING DISEASE; NEURO-BLASTOMA CELLS; IN-VITRO CONVERSION; TRANSGENIC MICE; SPECIES-BARRIER; SPONGIFORM ENCEPHALOPATHY; NEUROBLASTOMA-CELLS; RESISTANT FORMS AB In the transmissible spongiform encephalopathies, disease is closely associated with the conversion of the normal proteinase K-sensitive host prion protein (PrP-sen) to the abnormal proteinase K-resistant form (PrP-res). Amino acid sequence homology between PrP-res and PrP-sen is important in the formation of new PrP-res and thus in the efficient: transmission of infectivity across species barriers. It was previously shown that the generation of mouse PrP-res was strongly influenced by homology between PrP-sen and PrP-res at amino acid residue 138, a residue located in a region of loop structure common to PrP molecules from many different species. In order to determine if homology at residue 138 also affected the formation of PrP-res in a different animal species, we assayed the ability of hamster PrP-res to convert a panel of recombinant PrP-sen molecules to protease-resistant PrP in a cell-free conversion system. Homology at amino acid residue 138 was not critical for the formation of protease resistant hamster PrP, Rather, homology between PrP-sen and hamster PrP-res at amino acid residue 155 determined the efficiency of formation of a protease-resistant product induced by hamster PrP-res. Structurally, residue 155 resides in a turn at the end of the first alpha helix in hamster PrP-sen; this feature is not present in mouse PrP-sen. Thus, our data suggest that PrP-res molecules isolated from scrapie-infected brains of different animal species have different PrP-sen structural requirements for the efficient formation of protease-resistant PrP. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. CNRS, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RI Chabry, Joelle/O-2101-2016 NR 52 TC 47 Z9 48 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 MAY PY 2001 VL 75 IS 10 BP 4673 EP 4680 DI 10.1128/JVI.75.10.4673-4680.2001 PG 8 WC Virology SC Virology GA 425UD UT WOS:000168309300022 PM 11312338 ER PT J AU Banks, WA Freed, EO Wolf, KM Robinson, SM Franko, M Kumar, VB AF Banks, WA Freed, EO Wolf, KM Robinson, SM Franko, M Kumar, VB TI Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: Role of envelope proteins and adsorptive endocytosis SO JOURNAL OF VIROLOGY LA English DT Article ID CAPILLARY ENDOTHELIAL-CELLS; CENTRAL-NERVOUS-SYSTEM; HUMAN CHOROID-PLEXUS; HIV-INFECTION; TRANSFER CONSTANTS; ENTRY; RAT; DEMENTIA; ALBUMIN; MOUSE AB Blood-borne human immunodeficiency virus type 1 (HIV-1) crosses the blood-brain barrier (BBB) to induce brain dysfunction. How HIV-1 crosses the BBB is unclear. Most work has focused on the ability of infected immune cells to cross the BBB, with less attention devoted to the study of free virus. Since the HIV-1 coat glycoprotein gp120 can cross the BBB, we postulated that. gp120 might be key in determining whether free virus can cross the BBB. We used radioactive virions which do (Env(+)) or do not (Env(-)) bear the envelope proteins to characterize the ability of HIV-1 to be taken up by the murine BBB. In vivo and in vitro studies showed that the envelope proteins are key to the uptake of free virus and that uptake was enhanced by wheat germ agglutinin, strongly suggesting that the envelope proteins induce viral adsorptive endocytosis and transcytosis in brain endothelia. Capillary depletion showed that Env(+) virus completely crossed the vascular BBB to enter the parenchyma of the brain. Virus also entered the cerebrospinal fluid, suggesting passage across the choroid plexus as well. About 0.22% of the intravenously injected dose was taken up per g of brain. In vitro studies showed that postinternalization membrane cohesion (membrane binding not reversed with acid wash or cell lysis) was a regulated event. Intact virus was recovered from the brain endothelial cytosol and was effluxed from the endothelial cells. These results show that free HIV-1 can cross the BBB by an event related to adsorptive endocytosis and mediated by the envelope proteins. C1 VAMC, GRECC, St Louis, MO 63106 USA. St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr, St Louis, MO 63104 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Banks, WA (reprint author), VAMC, GRECC, 915 N Grand Blvd, St Louis, MO 63106 USA. FU NIMH NIH HHS [R0-1 MH54979]; NINDS NIH HHS [R0-1 NS41863, R01 NS041863] NR 69 TC 68 Z9 69 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 MAY PY 2001 VL 75 IS 10 BP 4681 EP 4691 DI 10.1128/JVI.75.10.4681-4691.2001 PG 11 WC Virology SC Virology GA 425UD UT WOS:000168309300023 PM 11312339 ER PT J AU Ward, BM Moss, B AF Ward, BM Moss, B TI Visualization of intracellular movement of vaccinia virus virions containing a green fluorescent protein-B5R membrane protein chimera SO JOURNAL OF VIROLOGY LA English DT Article ID EXTRACELLULAR ENVELOPED VIRUS; ACTIN-CONTAINING MICROVILLI; TO-CELL SPREAD; TAIL FORMATION; GOLGI NETWORK; LIVING CELLS; A33R GENE; MICROTUBULE; TRANSPORT; PARTICLES AB We produced an infectious vaccinia virus that expressed the B5R envelope glycoprotein fused to the enhanced green fluorescent protein (GFP), allowing us to visualize intracellular virus movement in real time. Previous transfection studies indicated that fusion of GFP to the C-terminal cytoplasmic domain of B5R did not interfere with Golgi localization of the viral protein. To determine whether B5R-GFP was fully functional, we started with a B5R deletion mutant that made small plaques and inserted the B5R-GFP gene into the original B5R locus. The recombinant virus made normal-sized plaques and acquired the ability to form actin tails, indicating reversal of the mutant phenotype, Moreover, immunogold electron microscopy revealed that both intracellular enveloped virions (IEV) and extracellular enveloped virions contained B5R-GFP. By confocal microscopy of live infected cells, we visualized individual fluorescent particles, corresponding to IEV in size and shape, moving from a juxtanuclear location to the periphery of the cell, where they usually collected Drier to association,vith actin tails. The fluorescent particles could be seen emanating from cells at the tips of microvilli. Using a digital camera attached to an inverted fluorescence microscope, we acquired images at 1 frame/s, At this resolution, IEV movement appeared saltatory; in some frames there was no net movement, whereas in others movement exceeded 2 mum/s. Further studies indicated that IEV movement was reversibly arrested by the microtubule-depolymerizing drug nocodazole, This result, together with the direction, speed, and saltatory motion of IEV, was consistent with a role for microtubules in intracellular transport of IEV. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 46 TC 116 Z9 118 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 MAY PY 2001 VL 75 IS 10 BP 4802 EP 4813 DI 10.1128/JVI.75.10.4802-4813.2001 PG 12 WC Virology SC Virology GA 425UD UT WOS:000168309300036 PM 11312352 ER PT J AU Boyer, PL Sarafianos, SG Arnold, E Hughes, SH AF Boyer, PL Sarafianos, SG Arnold, E Hughes, SH TI Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED DNA; 3'-AZIDO-3'-DEOXYTHYMIDINE AZT; ANGSTROM RESOLUTION; STERIC HINDRANCE; 3TC RESISTANCE; TYPE-1; MUTATIONS; POLYMERASE; MECHANISM; COMPLEX AB Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated, It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient, So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region ground the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT, Steric constraints involving the azido group cause the end of an AZT 5 ' -monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Ft Detrick, MD 21702 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, FCRDC, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Ft Detrick, MD 21702 USA. OI Sarafianos, Stefan G/0000-0002-5840-154X NR 24 TC 208 Z9 213 U1 0 U2 8 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 MAY PY 2001 VL 75 IS 10 BP 4832 EP 4842 DI 10.1128/JVI.75.10.4832-4842.2001 PG 11 WC Virology SC Virology GA 425UD UT WOS:000168309300039 PM 11312355 ER PT J AU Paulose-Murphy, M Ha, NK Xiang, CS Chen, YD Gillim, L Yarchoan, R Meltzer, P Bittner, M Trent, J Zeichner, S AF Paulose-Murphy, M Ha, NK Xiang, CS Chen, YD Gillim, L Yarchoan, R Meltzer, P Bittner, M Trent, J Zeichner, S TI Transcription program of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) SO JOURNAL OF VIROLOGY LA English DT Article ID VIRAL GENE-EXPRESSION; LYMPHOMA CELL-LINE; DNA MICROARRAY; CDNA MICROARRAYS; IDENTIFICATION; KSHV; INTERLEUKIN-6; ENCODES; GENOME; SEQUENCES AB Human herpesvirus 8 (HHV-8), a gammaherpesvirus implicated in Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease, encodes several pathogenically important cellular homologs. To define the HHV-8 transcription program, RNA obtained from latently infected body cavity-based lymphoma 1 cells induced to undergo lytic replication was used to query a custom HHV-8 DNA microarray containing nearly every known viral open reading frame. The patterns of viral gene expression offer insights into the replication and pathogenic strategies of HHV-8. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Zeichner, S (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Room 10S255,MSC 1868, Bethesda, MD 20892 USA. NR 46 TC 155 Z9 158 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2001 VL 75 IS 10 BP 4843 EP 4853 DI 10.1128/JVI.75.10.4843-4853.2001 PG 11 WC Virology SC Virology GA 425UD UT WOS:000168309300040 PM 11312356 ER PT J AU Huang, Y Kong, WP Nabel, GJ AF Huang, Y Kong, WP Nabel, GJ TI Human immunodeficiency virus type 1-specific immunity after genetic immunization is enhanced by modification of Gag and Pol expression SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; REVERSE-TRANSCRIPTASE; MAMMALIAN-CELLS; HIV-1 PROTEASE; RESPONSES; PARTICLES; VIREMIA; DNA; PR160GAG-POL; REPLICATION AB Immunity to human immunodeficiency virus virion-like structures or a polyprotein has been examined after DNA immunization with Rev-independent expression vectors. A Gag-Pol fusion protein stimulated cytotoxic T lymphocyte and antibody responses to Gag and Pol, while a Gag-Pol pseudoparticle did not elicit substantial Pol responses. This fusion protein may be useful for AIDS vaccines. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC-3005, Bethesda, MD 20892 USA. NR 29 TC 98 Z9 101 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 MAY PY 2001 VL 75 IS 10 BP 4947 EP 4951 DI 10.1128/JVI.75.10.4947-4951.2001 PG 5 WC Virology SC Virology GA 425UD UT WOS:000168309300054 PM 11312370 ER PT J AU Smith, JA AF Smith, JA TI Sjogren's syndrome: Looking women in their dry eyes SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Meeting Abstract C1 NIH, NEI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD MAY PY 2001 VL 10 IS 4 BP 390 EP 390 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 441JY UT WOS:000169228300019 ER PT J AU Van Dyke, T Ryder, M Cordero, R Gallagher, A Griffiths, G Offenbacher, S Cizza, G Kimberlin, M Lombardi, A Meng, L Shih, W AF Van Dyke, T Ryder, M Cordero, R Gallagher, A Griffiths, G Offenbacher, S Cizza, G Kimberlin, M Lombardi, A Meng, L Shih, W CA Alendronate Periodontal Study Grp TI Safety of once-weekly alendronate 70 mg in periodontal disease. SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Meeting Abstract C1 Boston Univ, Boston, MA 02215 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Hilltop Res, W Palm Beach, FL USA. Hilltop Res, Miamiville, OH USA. Scott & White Mem Hosp & Clin, Temple, TX 76508 USA. Univ N Carolina, Chapel Hill, NC USA. NIH, Bethesda, MD 20892 USA. Merck Res Labs, Rahway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD MAY PY 2001 VL 10 IS 4 BP 404 EP 404 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 441JY UT WOS:000169228300070 ER PT J AU Sternin, E Nizza, D Gawrisch, K AF Sternin, E Nizza, D Gawrisch, K TI Temperature dependence of DMPC/DHPC mixing in a bicellar solution and its structural implications SO LANGMUIR LA English DT Article ID LIQUID-CRYSTALLINE MEDIUM; HIGH-RESOLUTION NMR; MAGNETIC-RESONANCE; ORIENTATIONAL ORDER; BIOLOGICAL-MEMBRANES; BILAYERED MICELLES; LIPID BILAYERS; POWDER SPECTRA; SPECTROSCOPY; PHASE AB Bicelle-forming mixtures of short-chain 1,2-dicaproyl-sn-glycero-3-phosphocholin (DHPC) and long-chain 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) exhibit complicated phase behavior. We studied chain-melting and morphological phase changes in mixtures of DMPC/DHPC of 4.5:1 molar ratio in the temperature range of 0-60 degreesC. The phase state of both lipids and the alignment of lipid monolayers in the magnetic field were determined by solid-state H-2 and P-31 NMR. DMPC and DHPC mix in a micellar state at 0-10 degreesC but separate upon heating to 15 degreesC into gel-phase DMPC bilayers and DHPC micelles. Near the gel-to-liquid-crystalline phase transition of DMPC, at 24 degreesC, the DHPC spectra become anisotropic suggesting arrangement of DHPC in a mixed DMPC/DHPC phase. DMPC in this structure possesses the chain order typical of liquid crystalline bilayers, but DHPC chain order remains much lower, with lipid aggregates oriented mostly at random. In the bicelle phase, at 32-36 degreesC, highly anisotropic lipid particles with their DMPC monolayer normal oriented perpendicular to the magnetic field are formed. The angular distribution function of bilayer normals has significant mosaic spread and tails with surprisingly high intensity that is caused by the monolayers that are oriented at random. In the bicelle phase, magic angle spinning nuclear Overhauser effect H-1 NMR spectrometry revealed intensive intermolecular cross-relaxation among DMPC and among DHPC molecules but no detectable magnetization exchange between DMPC and DHPC, confirming that DHPC and DMPC experience limited physical contact. Above 36 degreesC, chain order of DMPC decreased, in particular for the bonds near the terminal methyl groups, while order parameters of DHPC increased, both indicative for DMPC/DHPC mixing in the same monolayer. The degree of this mixed monolayer orientation at temperatures above the bicelle state is significantly lower. Near 60 degreesC a fraction of DHPC converts to a micellar phase that also dissolves a trace of DMPC. Thus, a highly aligned bicelle phase exists only in a narrow range of temperatures. Complex orientational distributions arise at other temperatures, driven by lipid mixing and structural phase changes. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Brock Univ, St Catharines, ON L2S 3A1, Canada. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. NR 34 TC 68 Z9 69 U1 4 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD MAY 1 PY 2001 VL 17 IS 9 BP 2610 EP 2616 DI 10.1021/la001199w PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 426XD UT WOS:000168373000014 ER PT J AU Kellman, P Epstein, FH McVeigh, ER AF Kellman, P Epstein, FH McVeigh, ER TI Adaptive sensitivity encoding incorporating temporal filtering (TSENSE) SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE SENSE; SMASH; UNFOLD; rapid imaging; cardiac imaging; parallel MRI ID SENSE; SMASH AB A number of different methods have been demonstrated which increase the speed of MR acquisition by decreasing the number of sequential phase encodes. The UNFOLD technique is based on time interleaving of k-space lines in sequential images and exploits the property that the outer portion of the field-of-view is relatively static. The differences in spatial sensitivity of multiple receiver coils may be exploited using SENSE or SMASH techniques to eliminate the aliased component that results from undersampling k-space, In this article, an adaptive method of sensitivity encoding is presented which incorporates both spatial and temporal filtering. Temporal filtering and spatial encoding may be combined by acquiring phase encodes in an interleaved manner. In this way the aliased components are alternating phase. The SENSE formulation is not altered by the phase of the alias artifact; however, for imperfect estimates of coil sensitivities the residual artifact will have alternating phase using this approach. This is the essence of combining temporal filtering (UNFOLD) with spatial sensitivity encoding (SENSE), Any residual artifact will be temporally frequency-shifted to the band edge and thus may be further suppressed by temporal low-pass filtering. By combining both temporal and spatial filtering a high degree of alias artifact rejection may be achieved with less stringent requirements on accuracy of coil sensitivity estimates and temporal low-pass filter selectivity than would be required using each method individually. Experimental results that demonstrate the adaptive spatiotemporal filtering method (adaptive TSENSE) with acceleration factor R = 2, for real-time nonbreath-held cardiac MR imaging during exercise induced stress are presented. Published 2001 Wiley-Liss, Inc. 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. FU Intramural NIH HHS [Z01 HL004608-08] NR 12 TC 274 Z9 279 U1 0 U2 6 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAY PY 2001 VL 45 IS 5 BP 846 EP 852 DI 10.1002/mrm.1113 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 428CR UT WOS:000168444000015 PM 11323811 ER PT J AU Konda, SD Aref, M Wang, S Brechbiel, M Wiener, EC AF Konda, SD Aref, M Wang, S Brechbiel, M Wiener, EC TI Specific targeting of folate-dendrimer MRI contrast agents to the high affinity fo late receptor expressed in ovarian tumor xenografts SO MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE LA English DT Article DE folate; dendrimer; ovarian cancer; targeted contrast agents; MRI; gadolinium ID BINDING-PROTEIN; MONOCLONAL-ANTIBODY; IRON-OXIDE; IN-VIVO; CANCER; CELLS; CARCINOMA; CYTOTOXICITY; ENDOCYTOSIS; TRANSPORT AB The need to develop target-specific MRI contrast agents, to aid in disease characterization remains highly essential. In this study, we present a generation four polyamidoamine (PAMAM) folate-dendrimer that specifically targets the high affinity folate receptor (hFR) overexpressed on more than 80% of ovarian tumors. In vitro, mouse erythroleukemia cells expressing the hFR bind the radiolabeled folate-dendrimer chelate resulting in over 2700% increase in binding compared with untreated cells. The binding was inhibited by free folic acid to levels observed on folate-receptor-negative cells. In vivo, ovarian tumor xenografts resulted in a 33% contrast enhancement, following the folate-dendrimer chelate administration, that was significantly different compared with results obtained with a non-specific, extracellular fluid space agent, Gd-HP-DO3A. In addition, this contrast enhancement was, absent in saline-treated animals, folate-receptor-negative tumors, and was inhibited by free folic acid. Results suggest that a macromolecular, dendrimeric; MRI agent with high molecular relaxivities (1646 mM(-1) s(-1)) can be used in specifically targeting the hFR on tumor cells, and ovarian tumors. (C) 2001 Elsevier Science B.V. All rights reserved. C1 Univ Illinois, Coll Med, Biomed Magnet Resonance Lab, Urbana, IL 61801 USA. Univ Illinois, Beckman Inst, Urbana, IL 61801 USA. Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. Univ Illinois, Dept Nucl Plasma & Radiol Engn, Urbana, IL 61801 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Wiener, EC (reprint author), 1710 Beckman Inst,405 N Mathews, Urbana, IL 61801 USA. FU NCI NIH HHS [1R29-CA61918, T32 CA09067]; NCRR NIH HHS [1S10-RR06243, 5P41-RR05964]; NIGMS NIH HHS [T32 GM07143] NR 44 TC 157 Z9 169 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1352-8661 J9 MAGN RESON MATER PHY JI Magn. Reson. Mat. Phys. Biol. Med. PD MAY PY 2001 VL 12 IS 2-3 BP 104 EP 113 DI 10.1007/BF02668091 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 486JT UT WOS:000171815200007 PM 11390265 ER PT J AU DiGiovanna, JJ AF DiGiovanna, JJ TI Retinoid chemoprevention in patients at high risk for skin cancer SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article; Proceedings Paper CT 6th International Conference on the Long-Term Complications of Treatment of Children and Adolescents for Cancer CY JUN 23-24, 2000 CL ONTARIO, CANADA DE skin cancer; ratinoid chemoprevention; xeroderma pigmentosum ID RENAL-TRANSPLANT RECIPIENTS; XERODERMA PIGMENTOSUM; ORAL ISOTRETINOIN; PREVENTION; ACITRETIN; THERAPY AB Patients who develop large numbers of skin cancers suffer increased morbidity and mortality. A high skin cancer risk can result from inherited disorders such as xeroderma pigmentosum (abnormal repair of UV-induced DNA damage) or the nevoid basal cell carcinoma syndrome (tumor suppressor gene abnormality). The efficacy of systemic retinoid skin cancer chemoprevention was first demonstrated in these disorders. Since the mechanism of cancer prevention was not thought to involve correction of the underlying defect causing the disorder, individuals at high risk For new skin cancers from other causes may also benefit from this approach. With the success of organ transplantation, there is a growing population of transplant recipients living long, active lives who also have sustained chronic UV damage. This population is at high risk for developing aggressive squamous cell carcinomas. In this population, extensive skin involvement with human papilloma virus induced warts and actinic keratoses results in difficulty with diagnosis and monitoring for these dangerous malignancies. Patients who have received treatment with agents that cause DNA damage, such as X-radiation, may also have a high skin cancer risk. Retinoid chemoprevention may also be of benefit in the management of selected patients with these iatrogenic conditions. This evolving therapeutic role has heightened the need for the development of new retinoids, with more efficacy and less toxicity, for cancer chemoprevention, Med. Pediatr. Oncol. 36:564-567, 2001. (C) 2001 Wiley-Liss, Inc. C1 Brown Univ, Rhode Isl Hosp, Sch Med, Dept Dermatol, Providence, RI 02903 USA. Brown Univ, Sch Med, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02903 USA. NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD USA. RP DiGiovanna, JJ (reprint author), Brown Univ, Rhode Isl Hosp, Sch Med, Dept Dermatol, JBS-1,593 Eddy St, Providence, RI 02903 USA. NR 15 TC 34 Z9 37 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD MAY PY 2001 VL 36 IS 5 BP 564 EP 567 DI 10.1002/mpo.1131 PG 4 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 426VB UT WOS:000168368100011 PM 11340613 ER PT J AU Inskip, PD AF Inskip, PD TI Thyroid cancer after radiotherapy for childhood cancer SO MEDICAL AND PEDIATRIC ONCOLOGY LA English DT Article; Proceedings Paper CT 6th International Conference on the Long-Term Complications of Treatment of Children and Adolescents for Cancer CY JUN 23-24, 2000 CL ONTARIO, CANADA DE thyroid neoplasms; radiotherapy; second cancers; epidemiologic studies ID HODGKINS-DISEASE; EPIDEMIOLOGIC EVIDENCE; MOLECULAR-GENETICS; UNITED-STATES; 2ND CANCERS; RADIATION; IRRADIATION; CARCINOMA; NEOPLASMS; THERAPY AB The thyroid gland in children is among the most sensitive organs to the carcinogenic effects of ionizing radiation, and Very young children are at especially high risk. Risk associated with exposure to external X- or gamma -radiation increases linearly with increasing dose to the thyroid gland at low-to-moderate doses, but the dose-response relationship appears to flatten at the very high doses characteristic of cancer radiotherapy. Because of the extreme sensitivity of the thyroid gland in children, there is a risk of radiation-induced thyroid cancer even when the thyroid gland is outside of the irradiated field. increased incidence of thyroid cancer has been noted following radiotherapy For childhood Hodgkin disease, non-Hodgkin lymphoma, neuroblastoma, Wilms tumor, acute lymphocytic leukemia and tumors of the central nervous system. Radiation-induced tumors begin to appear 5-10 years after irradiation and excess risk persists for decades, perhaps for the remainder of life. The background incidence of thyroid cancer is two- to threefold higher among females than mates, and the absolute increase in risk due to irradiation is higher in females as well. Most of the thyroid cancers that occur in association with irradiation are of the papillary type, for which the cure rate is high if tumors are detected early. This highlights the importance of long-term surveillance of persons irradiated during childhood. Important areas for research include the possibility that children with certain types of first cancer are especially susceptible, the basis of the greater female susceptibility, the joint effects of radiation and other factors, and genetic mechanisms in radiation-induced and spontaneously occurring thyroid cancer. Med. Pediatr. Oncol. 36:568-573, 2001. (C) 2001 Wiley-Liss, Inc. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Inskip, PD (reprint author), Execut Plaza S,Room 7052, Bethesda, MD 20892 USA. NR 50 TC 57 Z9 59 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 0098-1532 J9 MED PEDIATR ONCOL JI Med. Pediatr. Oncol. PD MAY PY 2001 VL 36 IS 5 BP 568 EP 573 DI 10.1002/mpo.1132 PG 6 WC Oncology; Pediatrics SC Oncology; Pediatrics GA 426VB UT WOS:000168368100012 PM 11340614 ER PT J AU Krystal, JH D'Souza, DC Sanacora, G Goddard, AW Charney, DS AF Krystal, JH D'Souza, DC Sanacora, G Goddard, AW Charney, DS TI Current perspectives on the pathophysiology of schizophrenia, depression, and anxiety disorders SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Review ID POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; MAGNETIC-RESONANCE SPECTROSCOPY; OBSESSIVE-COMPULSIVE DISORDER; CORTICOTROPIN-RELEASING FACTOR; MEDIODORSAL THALAMIC NUCLEUS; SUBGENUAL PREFRONTAL CORTEX; NATIONAL-COMORBIDITY-SURVEY; PITUITARY-ADRENAL AXIS; PANIC DISORDER AB This article reviews the rapidly changing concepts related to the pathophysiology of major psychiatric disorders. The current era is an exciting one for psychiatric research, and the rapidity with which advances are being made is a source of hope to patients with these disorders and for society. C1 Vet Affairs Connecticut Hlthcare Syst, Psychiat Serv, W Haven, CT 06576 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, Clin Neurosci Res Unit, New Haven, CT 06519 USA. Connecticut Mental Hlth Ctr, Anxiety Disorders Res Clin, New Haven, CT 06519 USA. Schizophrenia Biol Res Ctr, W Haven, CT USA. NIMH, Anxiety & Affect Disorders Program, Bethesda, MD USA. RP Krystal, JH (reprint author), Vet Affairs Connecticut Hlthcare Syst, Psychiat Serv, 950 Campbell Ave, W Haven, CT 06576 USA. FU NIAAA NIH HHS [KO2 AA 00261-01] NR 129 TC 14 Z9 15 U1 3 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0025-7125 J9 MED CLIN N AM JI Med. Clin. N. Am. PD MAY PY 2001 VL 85 IS 3 BP 559 EP + DI 10.1016/S0025-7125(05)70329-1 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 431BA UT WOS:000168611000002 PM 11349473 ER PT J AU Roy, PK Venzon, DJ Feigenbaum, KM Koviack, PD Bashir, S Ojeaburu, JV Gibril, F Jensen, RT AF Roy, PK Venzon, DJ Feigenbaum, KM Koviack, PD Bashir, S Ojeaburu, JV Gibril, F Jensen, RT TI Gastric secretion in Zollinger-Ellison syndrome - Correlation with clinical expression, tumor extent and role in diagnosis - A prospective NIH study of 235 patients and a review of 984 cases in the literature SO MEDICINE LA English DT Review ID MULTIPLE ENDOCRINE NEOPLASIA; LONG-TERM TREATMENT; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; G-CELL HYPERFUNCTION; ACID SECRETION; SERUM GASTRIN; HELICOBACTER-PYLORI; DUODENAL GASTRINOMAS; INJECTION TEST; H2-RECEPTOR ANTAGONISTS C1 NIDDK, DDB, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, 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. RI Venzon, David/B-3078-2008 NR 318 TC 71 Z9 74 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD MAY PY 2001 VL 80 IS 3 BP 189 EP 222 DI 10.1097/00005792-200105000-00005 PG 34 WC Medicine, General & Internal SC General & Internal Medicine GA 434LL UT WOS:000168816400005 PM 11388095 ER PT J AU Lu, LJW Tice, JA Bellino, FL AF Lu, LJW Tice, JA Bellino, FL TI Phytoestrogens and healthy aging: gaps in knowledge - A workshop report SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Review DE phytoestrogens; isoflavones; cardiovascular disease; lipids; osteoporosis; bone metabolism; cancer; menopausal symptom; endocrine; aging; health claims ID LOW-DENSITY-LIPOPROTEIN; ESTROGEN REPLACEMENT THERAPY; SOY PROTEIN ISOLATE; BREAST-CANCER RISK; OVARIECTOMIZED CYNOMOLGUS MONKEYS; OVARIAN HORMONE DEFICIENCY; SUPPRESSES MAMMARY-CANCER; PROSTATE-RELATED CANCERS; NUTRITION FACTS PANEL; LARGE-BOWEL-CANCER AB There is an increasing public interest in foods and dietary supplements containing phytoestrogens for the maintenance of health. A workshop was convened to assess evidence for the potential benefits of phytoestrogen-containing foods or supplements on diseases or conditions affecting older populations. Preclinical, clinical, and epidemiologic data on the cardiovascular system, various cancers, bone diseases, and menopausal symptoms were the focus of the discussions. Research on the basis of consumer food choices as well as a presentation from the FDA regarding approval of the use of soy foods to reduce the risk of cardiovascular disease were also presented. Based on the information presented, isoflavone-containing soy foods may have favorable effects on the cardiovascular system, but major knowledge gaps still exist regarding effects of phytoestrogen supplements on bone diseases, various cancers, menopausal symptoms, and cognitive function. C1 Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. Univ Calif San Francisco, Dept Gen Internal Med, San Francisco, CA 94143 USA. NIA, Biol Aging Program, Bethesda, MD 20892 USA. RP Lu, LJW (reprint author), Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, 2-102 Ewing Hall,700 Harborside Dr, Galveston, TX 77555 USA. NR 179 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD MAY-JUN PY 2001 VL 8 IS 3 BP 157 EP 170 DI 10.1097/00042192-200105000-00004 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 428UU UT WOS:000168480700003 PM 11355037 ER PT J AU Hsieh, YH Bobo, LD Quinn, TC West, SK AF Hsieh, YH Bobo, LD Quinn, TC West, SK TI Determinants of trachoma endemicity using Chlamydia trachomatis ompA DNA sequencing SO MICROBES AND INFECTION LA English DT Article DE trachoma; Chlamydia trachomatis; major outer membrane protein; molecular epidemiology; persisting infection; multi-genotype infection ID OUTER-MEMBRANE PROTEIN; POLYMERASE CHAIN-REACTION; ENZYME-IMMUNOASSAY; RISK-FACTORS; CORE GROUP; T-HELPER; INFECTION; TANZANIA; SEROVAR; GENE AB A six-year prospective study of Chlamydia trachomdtis infection and ocular disease in Tanzanian village children was conducted to identify the determinants of trachoma endemicity using sequencing of ompA. Overall, 749 conjunctival samples were obtained, with 176 children sampled in both 1989 and 1995. 31.1% (233/749) were positive by PCR-enzyme immunoassay, and 76% (176/ 233) of the positives were sequenced in variable domains (VD) 1 to 4 (22 children in both 1989 and 1995). Twenty-six ompA genotypes of serovar A, and w19 of B/Ba were identified, and only 20% of genotypes identified in 1995 matched those found in 1983. Tn particular, B/Ba genotypes exhibited a 15-base region in VD 2 with increased nucleotide substitution, and these types were associated with age load did predict subsequent severe trachoma (odds ratio (OR) = 10.14, 95% confidence interval (CI): 1.71, 60.23; OR = 6.40, 95% CI: 0.75, 54.41; OR = 6.74, 95% CI: 0.82, 55.38, respectively). And, multitypic infection was clustered with residence of village and associated with familial cattle ownership. In conclusion, high ompA polymorphism and the inability of some hosts to clear infection with the same ompA genotype suggest two distinct but converging mechanisms of endemic severe trachoma. (C) 2001 Editions scientifiques et medicales Elsevier SAS. C1 Johns Hopkins Univ, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. NIAID, NIH, Bethesda, MD 20814 USA. Johns Hopkins Univ, Dana Ctr Invest Ophthalmol, Baltimore, MD 21287 USA. RP Hsieh, YH (reprint author), Johns Hopkins Univ, Dept Med, Div Infect Dis, 720 Rutland Ave, Baltimore, MD 21205 USA. NR 52 TC 16 Z9 16 U1 0 U2 1 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD MAY PY 2001 VL 3 IS 6 BP 447 EP 458 DI 10.1016/S1286-4579(01)01400-9 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 440GK UT WOS:000169167400002 PM 11377206 ER PT J AU DasGupta, SF Rapoport, SI Gerschenson, M Murphy, E Fiskum, G Russell, SJ Chandrasekaran, K AF DasGupta, SF Rapoport, SI Gerschenson, M Murphy, E Fiskum, G Russell, SJ Chandrasekaran, K TI ATP synthesis is coupled to rat liver mitochondrial RNA synthesis SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE in organello; mitochondria; transcription; ATP; regulation; respiration ID CYTOCHROME-OXIDASE; NEURONAL-ACTIVITY; GENE-EXPRESSION; CELL-DEATH; DNA; TRANSCRIPTION; APOPTOSIS; EVENTS AB Rat liver mitochondria respond to changes in energy demand by modulating the amount of RNA synthesized. Coupled rat liver mitochondria were used to determine the relationship between mitochondrial respiration, ATP levels, and mitochondrial transcription. This system included oxidizable substrates (malate and glutamate) and constituents that could support both mitochondrial respiration and transcription. The respiratory inhibitor rotenone, phosphorylation inhibitor oligomycin, and the uncoupler of oxidative phosphorylation carbonyl-cyanide p-triflouromethoxyphehylhydrazone inhibited RNA synthesis. Addition of ADP stimulated mitochondrial transcription and peak RNA synthesis was observed at 1-2 mM ADP. At ADP concentrations above 2 mM, RNA synthesis decreased. These results demonstrate that mitochondrial transcription is tightly coupled to ATP levels. C1 Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. NHLBI, Div Heart & Vascular Dis, NIH, Bethesda, MD 20892 USA. NIA, Sect Brain Physiol & Metab, NIH, Bethesda, MD 20892 USA. RP Chandrasekaran, K (reprint author), Univ Maryland, Sch Med, Dept Anesthesiol, MSTF 5-34,685 W Baltimore St, Baltimore, MD 21201 USA. FU NIA NIH HHS [AG16966A]; NINDS NIH HHS [NS34152] NR 30 TC 7 Z9 7 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD MAY PY 2001 VL 221 IS 1-2 BP 3 EP 10 DI 10.1023/A:1010812128765 PG 8 WC Cell Biology SC Cell Biology GA 448JP UT WOS:000169624000002 PM 11506183 ER PT J AU Harlin, H Reffey, SB Duckett, CS Lindsten, T Thompson, CB AF Harlin, H Reffey, SB Duckett, CS Lindsten, T Thompson, CB TI Characterization of XIAP-deficient mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID APOPTOSIS INHIBITORY PROTEIN; X-LINKED IAP; CELL-DEATH; BACULOVIRAL-INHIBITOR; BIR DOMAIN; GENE; CLEAVAGE; CASPASES; FAMILY; OVEREXPRESSION AB The inhibitor of apoptosis protein (IAP) family consists of a number of evolutionarily conserved proteins that function to inhibit programmed cell death. S-linked L-IP (SL-IP) was clotted due to its sequence homolog with other family members and has previously been shown to prevent apoptosis by binding to active caspases 3, 7, and 9 in vitro. XIAP transcripts can be found in a variety of tissues, anti the protein levels are regulated both transcriptionally and posttranscriptionally. To better understand the function of XIAP in normal cells, tr;e generated mice deficient in XIAP through homologous gene targeting. The resulting mice were viable, and histopathological analysis did not reveal any differences between XIAP-deficient and wild-type mice. We were unable to detect any defects in induction of caspase-dependent or -independent apoptosis in cells from the gene-targeted mice. One change was observed in cells derived from XIAP-deficient mice: the levels of c-IAP1 and c-IAP2 protein were increased. This suggests that there exists a compensatory mechanism that leads to upregulation of other family members when XIAP expression is lost. The changes in c-IAP1 and c-IAP2 expression may provide functional compensation for loss of XIAP during development or in the induction of apoptosis. C1 Univ Penn, Abramson Family Canc Res Inst, Dept Canc Biol, Philadelphia, PA 19104 USA. Univ Penn, Abramson Family Canc Res Inst, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Chicago, Dept Med, Comm Immunol, Chicago, IL 60637 USA. NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Thompson, CB (reprint author), Univ Penn, Abramson Family Canc Res Inst, Dept Canc Biol, Room 450,BRB 2-3,421 Curie Bldg, Philadelphia, PA 19104 USA. RI Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 NR 31 TC 301 Z9 311 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2001 VL 21 IS 10 BP 3604 EP 3608 DI 10.1128/MCB.21.10.3604-3608.2001 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 425TA UT WOS:000168306700033 PM 11313486 ER PT J AU Kachko, AV Cheusova, TB Sorokin, AV Kazachinskaya, EI Cheshenko, IO Belanov, EF Bukreev, AA Ivanova, AV Razumov, IA Ryabchikova, EI Netesov, SV AF Kachko, AV Cheusova, TB Sorokin, AV Kazachinskaya, EI Cheshenko, IO Belanov, EF Bukreev, AA Ivanova, AV Razumov, IA Ryabchikova, EI Netesov, SV TI Morphology and antigenic properties of recombinant analogs of the Marburg virus nucleoprotein SO MOLECULAR BIOLOGY LA English DT Article DE filovirus; Marburg virus; nucleoprotein; recombinant protein; expression system; morphology ID NUCLEOCAPSID-LIKE STRUCTURES; EBOLA-VIRUS; PROTEIN; CELLS AB The full-length gene for Marburg virus (MV) nucleoprotein (NP) was cloned in prokaryotic pQE32 under the control of the T5 promoter and in eukaryotic pTM1 under the control of the T7 RNA polymerase promoter Recombinant NP was synthesized in Escherichia coli and in human kidney cell line 293 cotransfected with recombinant vaccinia virus vTF7-3 expressing T7 RNA polymerase. On evidence of electron microscopy with immune detection, recombinant NP formed tubules of two types in E. roll and of a single type in cell line 293. ELISA and immunoblotting with polyclonal and monoclonal antibodies revealed common antigenic determinants in recombinant NP and natural MV NP. C1 VECTOR State Res Ctr Virol & Biotechnol, Inst Mol Biol, Koltsov 630559, Novosibirsk Reg, Russia. NIAID, NCI, Bethesda, MD 20892 USA. RP VECTOR State Res Ctr Virol & Biotechnol, Inst Mol Biol, Koltsov 630559, Novosibirsk Reg, Russia. EM a_kachko@chat.ru RI Belanov, Evgenij/B-7051-2012; Netesov, Sergey/A-3751-2013; Ryabchikova, Elena /G-3089-2013 OI Netesov, Sergey/0000-0002-7786-2464; Ryabchikova, Elena /0000-0003-4714-1524 NR 20 TC 0 Z9 0 U1 1 U2 3 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0026-8933 EI 1608-3245 J9 MOL BIOL+ JI Mol. Biol. PD MAY-JUN PY 2001 VL 35 IS 3 BP 417 EP 422 DI 10.1023/A:1010487131381 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 449KK UT WOS:000169683600020 ER PT J AU Torgan, CE Daniels, MP AF Torgan, CE Daniels, MP TI Regulation of myosin heavy chain expression during rat skeletal muscle development in vitro SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SLOW MYOSIN; FIBER-TYPE; TRANSCRIPTION FACTORS; CONTRACTILE ACTIVITY; PROTEIN PHOSPHATASE; GENE-EXPRESSION; BINDING-PROTEIN; CYCLOSPORINE-A; NF-AT; CALCINEURIN AB Signals that determine fast- and slow-twitch phenotypes of skeletal muscle fibers are thought to stem from depolarization, with concomitant contraction and activation of calcium-dependent pathways. We examined the roles of contraction and activation of calcineurin (CN) in regulation of slow and fast myosin heavy chain (MHC) protein expression during muscle fiber formation in vitro. Myotubes formed from embryonic day 21 rat myoblasts contracted spontaneously, and similar to 10% expressed slow MHC after 12 d in culture, as seen by immunofluorescent staining. Transfection with a constitutively active form of calcineurin (CN*) increased slow MHC by 2.5-fold as determined by Western blot. This effect was attenuated 35% by treatment with tetrodotoxin and 90% by administration of the selective inhibitor of CN, cyclosporin A. Conversely, cyclosporin A alone increased fast MHC by twofold. Cotransfection with VIVIT, a peptide that selectively inhibits calcineurin-induced activation of the nuclear factor of activated T-cells, blocked the effect of CN* on slow MHC by 70% but had no effect on fast MHC. The results suggest that contractile activity-dependent expression of slow MHC is mediated largely through the CN-nuclear factor of activated T-cells pathway, whereas suppression of fast MHC expression may be independent of nuclear factor of activated T-cells. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Daniels, MP (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 46 TC 37 Z9 37 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAY PY 2001 VL 12 IS 5 BP 1499 EP 1508 PG 10 WC Cell Biology SC Cell Biology GA 461DR UT WOS:000170350100024 PM 11359938 ER PT J AU Kropachev, KY Kaledin, VI Kobzev, VF Plisov, SY Levashova, ZB Merkulova, TI AF Kropachev, KY Kaledin, VI Kobzev, VF Plisov, SY Levashova, ZB Merkulova, TI TI Involvement of transcription factor HNF3 gamma in the effect of o-aminoazotoluene on glucocorticoid induction of tyrosine aminotransferase in mice sensitive to its hepatocarcinogenic action SO MOLECULAR CARCINOGENESIS LA English DT Article DE carcinogenesis; epigenetic; o-aminoazotoluene; tyrosine aminotransferase; hepatocyte nuclear factor-3 ID GENE-EXPRESSION; DAWLEY RATS; LIVER; CELL; DNA; INHIBITION; PROTEINS; ELEMENT; BINDING; FAMILY AB in the rodent liver, hepatocarcinogens inhibit the glucocorticoid induction of several liver-specific genes, including tyrosine aminotransferase (TAT). A distinct positive correlation exists in mice between the extent of inhibition of TAT induction after acute administration of o-aminoazotoluene (OAT) and the frequency of liver tumors after chronic exposure to the carcinogen. To elucidate the mechanism of the carcinogenic action, the effects of OAT on the DNA-binding activity of several transcription factors participating in the glucocorticoid regulation of TAT gene expression were studied. The experimental inbred male mice were sensitive (A/He and SWR/J, tumor induction frequency of 75-100%, TAT induction inhibition of 35-50%) and resistant (CC57BR/Mv and AKR/J, 0-6% and 10-15%, respectively) to OAT. Gel retardation experiments showed that hepatocyte nuclear factor 3 (HNF3)gamma DNA-binding activity was strongly reduced in nuclear extracts from the livers of OAT-treated A/He and SWR/J mice but only slightly reduced in CC57Br/Mv and AKR/J mice. The DNA-binding activities of Ets, AP1 family members, and GME binding proteins were unaffected. HNF3 gamma DNA-binding activity was reduced by 1 h after OAT administration and remained tow for 1 mo, as did inhibition of TAT induction in the liver. These results suggested that the inhibitory effect of OAT on the glucocorticoid induction of TAT is mediated by reduced HNF3 gamma DNA-binding activity. (C) 2001 Wiley-Liss. Inc. C1 Russian Acad Sci, Inst Cytol & Genet, Lab Gene Express Control, Novosibirsk 630090, Russia. Russian Acad Sci, Inst Cytol & Genet, Sect Nucle Acids Chem, Novosibirsk 630090, Russia. Natl Canc Inst, Lab Comparat Carcinogenesis, Frederick, MD USA. RP Merkulova, TI (reprint author), Russian Acad Sci, Inst Cytol & Genet, Lab Gene Express Control, Lavrentiev Prospect 6, Novosibirsk 630090, Russia. RI Merkulova, Tatyana/R-9163-2016 NR 38 TC 9 Z9 17 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2001 VL 31 IS 1 BP 10 EP 15 DI 10.1002/mc.1035 PG 6 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 439QM UT WOS:000169128600002 PM 11398193 ER PT J AU Sen, RJ King, RA Weisberg, RA AF Sen, RJ King, RA Weisberg, RA TI Modification of the properties of elongating RNA polymerase by persistent association with nascent antiterminator RNA SO MOLECULAR CELL LA English DT Article ID ESCHERICHIA-COLI; EARLY TRANSCRIPTION; LAC REPRESSOR; PHAGE-HK022; RESOLUTION; LAMBDA; SITE AB Nascent RNA encoded by putt, a cia-acting antitermination site of bacteriophage HK022, increases readthrough of terminators by directly modifying the transcript elongation complex. To characterize the interaction between the antiterminator RNA and RNA polymerase, we stalled the elongation complex downstream of putt and determined the sensitivity of the transcript to ribonuclease cleavage. Part of PutL RNA was protected from cleavage by wild-type polymerase, but not by a mutant with a defect in put-dependent antitermination. We also exposed the stalled complex to oligonucleotides complementary to putt RNA, restarted transcription, and measured antitermination. Some, but not all, complementary oligonucleotides inhibited antitermination. Finally, cleavage of the RNA between putL and the 3 ' -end released putL RNA from the stalled complex and prevented antitermination. C1 NICHHD, Mol Genet Lab, Sect Microbial Genet, NIH, Bethesda, MD 20892 USA. RP Weisberg, RA (reprint author), NICHHD, Mol Genet Lab, Sect Microbial Genet, NIH, Bethesda, MD 20892 USA. NR 18 TC 22 Z9 22 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY PY 2001 VL 7 IS 5 BP 993 EP 1001 DI 10.1016/S1097-2765(01)00243-X PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 438EA UT WOS:000169039700008 PM 11389846 ER PT J AU Maizels, ET Mukherjee, A Sithanandam, G Peters, CA Cottom, J Mayo, KE Hunzicker-Dunn, M AF Maizels, ET Mukherjee, A Sithanandam, G Peters, CA Cottom, J Mayo, KE Hunzicker-Dunn, M TI Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and-3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID OVARIAN GRANULOSA-CELLS; ENDOTHELIAL GROWTH-FACTOR; ELEMENT-BINDING PROTEIN; P38 MAP KINASE; LUTEINIZING-HORMONE SURGE; NECROSIS-FACTOR-ALPHA; HEAT-SHOCK PROTEINS; GENE-EXPRESSION; MESSENGER-RNA; PHOSPHORYLATION SITES AB The current study investigates the activation in vivo and regulation of the expression of components of the p38 mitogen-activated protein kinase (MAPK) pathway during gonadotropin-induced formation and development of the rat corpus luteum, employing a sequential PMSG/human CG (hCG) treatment paradigm. We postulated that the p38 MAPK pathway could serve to promote phosphorylation of key substrates during luteal maturation, since maturing luteal cells, thought to be cAMP-nonresponsive, nevertheless maintain critical phosphoproteins. Both p38 MAPK and its upstream activator MAPK kinase-6 (MKKG) were found to be chronically activated during the luteal maturation phase, with activation detected by 24 h post hCG and maintained through 4 days post hCG. The p38 MAPK downstream protein kinase target termed MAPK-activated protein kinase-3 (MAPKAPK-3) was newly induced at both mRNA and protein levels during luteal formation and maturation, while mRNA and protein expression of the closely related MAPKAPK-2 diminished. Two potential substrates for MAPKAPKs, the small heat shock protein HSP-27 and the cAMP regulatory element binding protein CREB, were monitored in vivo for phosphorylation. HSP-27 phosphorylation was not modulated during luteal maturation. In contrast, we observed sustained luteal-phase CREB phosphorylation in vivo, consistent with upstream MKK6/p38 MAPK activation and MAPKAPK-3-induction. MAPKAPK-3-specific immune complex kinase assays provided direct evidence that MAPKAPK-3 was in an activated state during luteal maturation in vivo. Cellular inhibitor studies indicated that an intact p38 MAPK path was required for CREB phosphorylation in a cellular model of luteinization, as treatment of luteinized granulosa cells with the p38 MAPK inhibitor SE 203580 strongly inhibited CREB phosphorylation. Transient transfection studies provided direct evidence that MAPKAPK-3 was capable of signaling to activate CREB transcriptional activity, as assessed by means of GAL4-CREB fusion protein construct coexpressed with GAL4-luciferase reporter construct. Introduction of wild-type, but not kinase-dead mutant, MAPKAPK-3 cDNA, into a mouse ovarian cell line stimulated GAL4-CREB-dependent transcriptional activity approximately 3-fold. Thus MAPKAPK-3 is indeed uniquely poised to support luteal maturation through the phosphorylation and activation of the nuclear transcription factor CREB. C1 Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC, Frederick, MD 21702 USA. RP Northwestern Univ, Sch Med, Dept Cell & Mol Biol, 303 E Chicago Ave, Chicago, IL 60611 USA. EM mhd@northwestern.edu FU NCI NIH HHS [N01-CO-56000]; NICHD NIH HHS [P30 HD-28048, T32 HD-07068, P01 HD-21921]; NIDDK NIH HHS [T32 DK-07169] NR 96 TC 37 Z9 38 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2001 VL 15 IS 5 BP 716 EP 733 DI 10.1210/me.15.5.716 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427FB UT WOS:000168393200004 PM 11328854 ER PT J AU Hovey, RC Goldhar, AS Baffi, J Vonderhaar, BK AF Hovey, RC Goldhar, AS Baffi, J Vonderhaar, BK TI Transcriptional regulation of vascular endothelial growth factor expression in epithelial and stromal cells during mouse mammary gland development SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PERMEABILITY FACTOR EXPRESSION; TUMOR ANGIOGENESIS; FACTOR FAMILY; FAT-CELLS; VEGF; MICE; RECEPTOR; ESTROGEN; GENE; DIFFERENTIATION AB Accompanying changes in the development and function of the mammary gland is the establishment of a vascular network of critical importance for lactogenesis and tumorigenesis. A potent angiogenic and permeability factor that regulates vascular development in association with epithelial-stromal interactions is vascular endothelial growth factor (VEGF), Analysis of VEGF transcription by RT-PCR revealed mRNA for all three VEGF isoforms (VEGF(120), (164), (188)) within the mammary gland of nulliparous females. During pregnancy the level of VEGF(188) declined and became undetectable during lactation in association with the increased abundance of VEGF(120) and VEGF(164) mRNAs, All three isoforms were expressed at consistent levels within the cleared mammary fat pad throughout development. Furthermore, the presence of VEGF(188) mRNA in omental adipose tissue at various stages established that VEGF(188) is expressed specifically in adipose tissue within the mammary gland, Using 3T3-L1 preadipocytes it was demonstrated that VEGF(188) mRNA transcription occurs as a late event during lipogenesis distinct from earlier induction of VEGF(120) and VEGF(164) mRNA during differentiation. In contrast, HC11 mammary epithelial cells only expressed mRNA for VEGF(120) and VEGF(164). Localization of VEGF mRNA and protein revealed that VEGF is expressed in stromal cells of the mammary gland in nulliparous females and then undergoes a transition to epithelial expression during lactation. By contrast, mRNA for the VEGF receptors, Flk-1 and Flt-1, localized to stromal cells within the mammary fat pad during virgin and gestational development and was expressed in the interstitial tissue basal to epithelial cells during lactation. Taken together, these results support the conclusion that VEGF is differentially transcribed by specific cell types within the mammary gland, and that under hormonal regulation it functions in an autocrine/paracrine manner. C1 Natl Canc Inst, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Vonderhaar, BK (reprint author), Natl Canc Inst, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B47,10 Ct Dr, Bethesda, MD 20892 USA. NR 43 TC 43 Z9 46 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2001 VL 15 IS 5 BP 819 EP 831 DI 10.1210/me.15.5.819 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 427FB UT WOS:000168393200011 PM 11328861 ER PT J AU Wolford, JK Hanson, RL Kobes, S Bogardus, C Prochazka, M AF Wolford, JK Hanson, RL Kobes, S Bogardus, C Prochazka, M TI Analysis of linkage disequilibrium between polymorphisms in the KCNJ9 gene with type 2 diabetes mellitus in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE KCNKJ9; type 2 diabetes; 1q21; Pima Indians; association analysis; single nucleotide polymorphism. ID SUSCEPTIBILITY GENES; ASSOCIATION; SEARCH; LOCUS; POWER AB The KCNJ9 gene encodes a G-protein-coupled inwardly rectifying potassium channel and is located within a region on human chromosome 1 that has been linked with type 2 diabetes mellitus in Pima Indians and Caucasians. To assess the potential contribution of genetic alterations within KCNJ9 to diabetes susceptibility in the Pimas, we have genotyped 11 single nucleotide polymorphisms (SNPs) in 50 Pimas with diabetes and 50 Pimas over the age of 45 without diabetes and in 51 sib pairs, discordant for the disease, who were characterized by decreased allele sharing at the chromosomal location of the maximum LOD score, We detected three SNP clusters exhibiting distinct linkage disequilibria, Polymorphisms in intron 2, exon 3, and the 3'-UTR were in statistically significant linkage disequilibrium with diabetes in the case-control group (P = 0.006), but not the sibling pairs (P = 0.097). A weak association with diabetes was also found in the original linkage set comprising 1150 Pimas (odds ratio = 0.64/ P = 0.079 for a dominant model and OR = 0.67/P = 0.005 for a recessive model), However, no effect on linkage was detected following adjustment for one of the most strongly associated SNPs in the entire original linkage set. Our results indicate that variants in KCNJ9 are associated with diabetes in Pimas but do not account for the linkage of 1q with diabetes in this population. (C) 2001 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, NIH, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 21 TC 17 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAY PY 2001 VL 73 IS 1 BP 97 EP 103 DI 10.1006/mgme.2001.3167 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 433LR UT WOS:000168761300013 PM 11350189 ER PT J AU Yang, XL Pratley, RE Baier, LJ Horikawa, Y Bell, GI Bogardus, C Permana, PA AF Yang, XL Pratley, RE Baier, LJ Horikawa, Y Bell, GI Bogardus, C Permana, PA TI Reduced skeletal muscle calpain-10 transcript level is due to a cumulative decrease in major isoforms SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE type 2 diabetes; Pima Indians; Calpain-10; isoforms; skeletal muscle ID INSULIN-RESISTANCE; DIABETES-MELLITUS; PIMA-INDIANS AB The DNA polymorphism SNP-43 in the calpain-10 gene is associated with insulin resistance and reduced skeletal muscle transcript in Pima Indians. Alternative splicing generates transcript isoforms calpain-10a to -10h. We determined the contribution of calpain-10 mRNA isoforms to the decreased total skeletal muscle calpain-10 mRNA levels observed in the G/G homozygotes. The expression levels of the major isoforms, calpain-10a and -10f, were positively correlated with the total calpain-10 mRNA levels, indicating a cumulative effect. (C) 2001 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Pheonix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA. Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA. Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA. RP Permana, PA (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Pheonix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. NR 7 TC 28 Z9 29 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAY PY 2001 VL 73 IS 1 BP 111 EP 113 DI 10.1006/mgme.2001.3171 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 433LR UT WOS:000168761300016 PM 11350192 ER PT J AU Sawitzke, J Austin, S AF Sawitzke, J Austin, S TI An analysis of the factory model for chromosome replication and segregation in bacteria SO MOLECULAR MICROBIOLOGY LA English DT Review ID ESCHERICHIA-COLI; BACILLUS-SUBTILIS; CELL-CYCLE; BIDIRECTIONAL MIGRATION; BIPOLAR LOCALIZATION; POLAR LOCALIZATION; DNA; PROTEIN; SMC; ORIGIN AB Recent advances in microscopy have given us important clues as to the nature of chromosome segregation in bacteria. Most current observations favour the view that the process is co-replicational: DNA replication forks are anchored at the cell centre, and the newly replicated DNA is moved towards the cell poles, This scheme can account for orderly segregation even at high growth rates where multiple replication cycles overlap, We argue that there are five distinct activities directly involved in co-replicational segregation dynamics, These we refer to as Push, Direct, Condense, Hold and Clear. We attempt to assign one of these roles to each protein implicated in chromosome segregation. The proposed process is very different from mitosis in eukaryotic cells and perhaps more closely resembles the formation of separate sister chromatids during DNA replication. C1 NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Frederick, MD 21702 USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Div Basic Sci, Frederick, MD 21702 USA. NR 40 TC 61 Z9 63 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2001 VL 40 IS 4 BP 786 EP 794 DI 10.1046/j.1365-2958.2001.02350.x PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 441JG UT WOS:000169226800002 PM 11401686 ER PT J AU Bolmstedt, AJ O'Keefe, BR Shenoy, SR Mcmahon, JB Boyd, MR AF Bolmstedt, AJ O'Keefe, BR Shenoy, SR Mcmahon, JB Boyd, MR TI HIV-inhibitory natural products part 71 - Cyanovirin-N defines a new class of antiviral agent targeting N-linked, high-mannose glycans in an oligosaccharide-specific manner SO MOLECULAR PHARMACOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN GP120; INACTIVATING PROTEIN; NEUTRALIZING ANTIBODIES; ACETYLGLUCOSAMINIDASE-H; GLYCOSYLATION SITES; DISULFIDE BONDS; TYPE-1 GP120; CD4; CYANOBACTERIUM AB Herein we report that the novel HIV-inactivating protein cyanovirin-N (CV-N) targets specific, N-linked high-mannose oligosaccharides found on the viral envelope of HIV-1. First, we released the oligosaccharides by PnGase-treatment of HIV-gp120 (containing high-mannose, hybrid-type and complex-type oligosaccharides) or HSV-1 gC (containing only complex-type). Then, in an affinity chromatographic system, we found that CV-N bound to the free oligosaccharides from gp120 but not from gC-1, suggesting that high-mannose oligosaccharides constitute a target structure for CV-N. This was supported by the affinity of CV-N for high-mannose glycans released from gp120 by endo-H as well as high-mannose glycans released from castanospermine-treated HSV-1 gC. Furthermore, free Man-8 or Man-9 oligosaccharides partially inhibited the binding of CV-N to gp120, although neither oligosaccharides smaller than Man-7 nor monosaccharides interfered with CV-N/gp120 interaction, thereby establishing the oligosaccharide-specific affinity of CV-N to high-mannose glycans. This affinity for high-mannose oligosaccharides may explain the broad antiviral activity of CV-N against human and primate immunodeficiency retroviruses as well as certain other viruses that carry these oligosaccharides. C1 NCI, Lab Drug Discovery Res & Dev, Div Basic Sci, Frederick, MD 21702 USA. Gothenburg Univ, Dept Clin Virol, S-41124 Gothenburg, Sweden. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Div Basic Sci, Bldg 1052,Rm 121, Frederick, MD 21702 USA. NR 25 TC 115 Z9 130 U1 1 U2 7 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 MAY PY 2001 VL 59 IS 5 BP 949 EP 954 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422HP UT WOS:000168112700001 PM 11306674 ER PT J AU Molteni, R Lipska, BK Weinberger, DR Racagni, G Riva, MA AF Molteni, R Lipska, BK Weinberger, DR Racagni, G Riva, MA TI Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE brain derived neurotrophic factor; fibroblast growth factor-2; brain plasticity; ibotenic acid; hippocampus; stress ID FIBROBLAST-GROWTH-FACTOR; EXCITOTOXIC HIPPOCAMPAL DAMAGE; FACTOR MESSENGER-RNA; RAT CORTICAL ASTROCYTES; CENTRAL-NERVOUS-SYSTEM; PREFRONTAL CORTEX; CEREBRAL-CORTEX; FACTOR-II; KINDLING EPILEPTOGENESIS; SYNAPTIC PLASTICITY AB The neonatal (PND 7) lesion of the ventral hippocampus (VH) with ibotenic acid represents a well-established experimental paradigm that recapitulates many schizophrenia-like phenomena. In order to investigate molecular changes that could contribute to long lasting consequences on brain function, we have investigated the effects of the VH lesion on the expression for the trophic factors FGF-2 and BDNF, We used RNase protection assay to measure their mRNA levels in cortical regions of prepubertal (PND 35) and young adult (PND 56) animals, both under basal condition as well as in response to an acute restraint stress. The expression of BDNF was not altered by the VH lesion in prefrontal (PFC) and frontal cortex (FC) of PND 35 or PND 56 rats. An acute restraint stress at PND 35 produced a significant increase of the neurotrophin expression in PFC of sham as well as lesioned animals. However in young adult animals a significant elevation of BDNF expression was observed only in sham rats. We also found that the VH lesion produced a significant reduction of basal BDNF mRNA levels in the cingulate cortex of young adult, but not prepubertal rats. This effect was not accompanied by changes in the acute modulation of the neurotrophin, which was up-regulated by stress in both experimental groups. Conversely the expression of FGF-2 at PND 35 and PND 56 was not altered by early postnatal VH lesion, and there were no major differences between sham and lesioned animals in response to the acute stress. The changes in trophic factor expression may be relevant for the long-term effects of VH lesion on synaptic plasticity and may determine an increased vulnerability of the brain under challenging situations. C1 Univ Milan, Dept Pharmacol Sci, Ctr Neuropharmacol, I-20133 Milan, Italy. NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. IRCCS San Giovanni Diofatebenefratelli, Brescia, Italy. RP Riva, MA (reprint author), Univ Milan, Dept Pharmacol Sci, Ctr Neuropharmacol, Via Balzaretti 9, I-20133 Milan, Italy. RI Racagni, Giorgio/B-5826-2011; Lipska, Barbara/E-4569-2017; OI Molteni, Raffaella/0000-0002-5481-7572; Riva, Marco Andrea/0000-0002-1699-5060 NR 64 TC 57 Z9 57 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAY PY 2001 VL 6 IS 3 BP 285 EP 292 DI 10.1038/sj.mp.4000865 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 412HJ UT WOS:000167548700008 PM 11326296 ER PT J AU Akyurek, LM Nallamshetty, S Aoki, K San, H Yang, ZY Nabel, GJ Nabel, EG AF Akyurek, LM Nallamshetty, S Aoki, K San, H Yang, ZY Nabel, GJ Nabel, EG TI Coexpression of guanylate kinase with thymidine kinase enhances prodrug cell killing in vitro and suppresses vascular smooth muscle cell proliferation in vivo SO MOLECULAR THERAPY LA English DT Article DE thymidine kinase; ganciclovir; acyclovir; vascular smooth muscle cells ID IN-VIVO; GENE-THERAPY; EXPRESSION; TUMOR; INJURY; COMBINATION; GENERATION; RESTENOSIS; VACCINES; VECTOR AB Herpes simplex virus-thymidine kinase (HSV-TK) phosphorylates the prodrugs ganciclovir (GCV) and acyclovir (ACV), leading to disruption of DNA synthesis and inhibition of cell proliferation. HSV-TK vectors have been successfully employed in cardiovascular and cancer gene therapy. Activation of GCV and ACV, after an initial phosphorylation step by the viral thymidine kinase, is carried out by guanylate kinase. We reasoned that coexpression of guanylate kinase (CK) with HSV-TK would augment phosphorylation of CCV or ACV, leading to increased cell killing. To test this hypothesis, a vector expressing TK with CK (TKciteGK) was developed and tested on vascular smooth muscle cells (vsmcs) in vitro and in vivo. Compared to HSV-TK vectors, killing of vascular cells transduced with TKciteGK and exposed to GCV was significantly increased (P = 0.03). The TKciteGK construct was evaluated with three promoters: CMV, EF1 alpha, and SM22 alpha. TKciteGK expression driven by a CMV promoter induced cell killing more effectively than SM22 alpha or EF1 alpha promoters in primary vsmcs. Based upon these in vitro findings, TKciteGK vectors with a CMV promoter were tested in two animal models of cardiovascular disease: balloon angioplasty and stent deployment in pig arteries. Following vascular injury, expression of CMV-TKciteGK with GCV significantly reduced vsmc proliferation and intimal lesion formation compared to control vectors with GCV, In the angioplasty model, there was an 80% reduction in intima-to-media area ratio (P = 0.0002). These findings were paralleled in a stent model with 66% reduction in intimal lesions (P = 0.006). Coexpression of GK with TK increases cell killing and permits administration of CCV at lower doses. These modifications in TKciteGK vectors and GCV showed enhanced efficacy at lower prodrug doses, leading to improved safety for cardiovascular gene therapy. C1 NHLBI, Vasc Biol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Vasc Biol Branch, NIH, Bldg 10,Room 8C103, Bethesda, MD 20892 USA. NR 33 TC 16 Z9 17 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2001 VL 3 IS 5 BP 779 EP 786 DI 10.1006/mthe.2001.0315 PN 1 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 436EW UT WOS:000168924400016 PM 11356082 ER PT J AU Hutton, JT Metman, LV Chase, TN Juncos, JL Koller, WC Pahwa, R LeWitt, PA Samii, A Tsui, JKC Calne, DB Waters, CH Calabrese, VP Bennett, JP Barrett, R Morris, JL AF Hutton, JT Metman, LV Chase, TN Juncos, JL Koller, WC Pahwa, R LeWitt, PA Samii, A Tsui, JKC Calne, DB Waters, CH Calabrese, VP Bennett, JP Barrett, R Morris, JL TI Transdermal dopaminergic D-2 receptor agonist therapy in parkinson's disease with n-0923 TDS: A double-blind, placebo-controlled study SO MOVEMENT DISORDERS LA English DT Article DE N-0923 transdermal; Parkinson's disease; dopaminergic D-2 agonist ID IONTOPHORETIC DELIVERY; INTRAVENOUS-INFUSION; LEVODOPA; FLUCTUATIONS; PHNO; (+)-4-PROPYL-9-HYDROXYNAPHTHOXAZINE; PATHOPHYSIOLOGY; MONKEYS; POTENT AB N-0923 is a non-ergot, dopaminergic D-2 agonist designed to be transdermally available. It has anti-parkinsonian effects when infused int ravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated. (C) 2001 Movement Disorder Society. C1 Covenant Med Ctr Lakeside, Neurol Res & Educ Ctr, Lubbock, TX 79410 USA. NINDS, NIH, Bethesda, MD 20892 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Univ Miami, Med Ctr, Dept Neurol, Miami, FL 33152 USA. Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. Wayne State Univ, Sch Med, Dept Neurol Psychiat & Behav Neurosci, Detroit, MI USA. Clin Neurosci Ctr, Southfield, MI USA. Univ British Columbia, Vancouver Hosp & Hlth Sci Ctr, Vancouver, BC V5Z 1M9, Canada. Univ So Calif, Los Angeles, CA USA. McGuire VA Hosp, Dept Neurol, Richmond, VA USA. Univ Virginia, Med Ctr, Dept Neurol, Charlottesville, VA USA. Discovery Therapeut Inc, Richmond, VA USA. RP Hutton, JT (reprint author), Covenant Med Ctr Lakeside, Neurol Res & Educ Ctr, 4102 24th St,Suite 500, Lubbock, TX 79410 USA. NR 27 TC 42 Z9 46 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAY PY 2001 VL 16 IS 3 BP 459 EP 463 DI 10.1002/mds.1085 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 438HZ UT WOS:000169048700008 PM 11391739 ER PT J AU Del Dotto, P Pavese, N Gambaccini, G Bernardini, S Metman, LV Chase, TN Bonuccelli, U AF Del Dotto, P Pavese, N Gambaccini, G Bernardini, S Metman, LV Chase, TN Bonuccelli, U TI Intravenous amantadine improves levadopa-induced dyskinesias: An acute double-blind placebo-controlled study SO MOVEMENT DISORDERS LA English DT Article DE amantadine; levodopa; dyskinesia; Parkinson's disease ID LEVODOPA-INDUCED DYSKINESIAS; PARKINSONS-DISEASE; ANTAGONIST AMANTADINE; NMDA ANTAGONIST; PHOSPHORYLATION; BLOCKADE; MODEL; BRAIN AB Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different: days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous arnantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations. (C) 2001 Movement Disorder Society. C1 Univ Pisa, Dept Neurosci, Neurol Sect, I-56100 Pisa, Italy. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Bonuccelli, U (reprint author), Univ Pisa, Dept Neurosci, Neurol Sect, Via Roma 67, I-56100 Pisa, Italy. RI Bonuccelli, Ubaldo/K-8681-2016 OI Bonuccelli, Ubaldo/0000-0001-6218-6312 NR 28 TC 95 Z9 98 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAY PY 2001 VL 16 IS 3 BP 515 EP 520 DI 10.1002/mds.1112 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 438HZ UT WOS:000169048700017 PM 11391748 ER PT J AU Boroojerdi, B Ziemann, U Chen, R Buterfisch, CM Cohen, LG AF Boroojerdi, B Ziemann, U Chen, R Buterfisch, CM Cohen, LG TI Mechanisms underlying human motor system plasticity SO MUSCLE & NERVE LA English DT Review DE cortical maps; functional relevance; modulation; motor cortex; plasticity; transcranial magnetic stimulation ID TRANSCRANIAL MAGNETIC STIMULATION; LONG-TERM POTENTIATION; UPPER-LIMB AMPUTATION; HUMAN VISUAL-CORTEX; ADULT OWL MONKEYS; REORGANIZATION FOLLOWING MOTOR; FREQUENCY-DISCRIMINATION TASK; CROSS-MODAL PLASTICITY; ISCHEMIC NERVE BLOCK; SPINAL-CORD INJURY AB There has been increased interest in the ability of the adult human nervous system to reorganize and adapt to environmental changes throughout life. This ability has been termed "plasticity." Plastic changes in the cerebral cortex have been studied: ia) as modifications of sensory or motor cortical representation of specific body parts (cortical maps, body representation level); and (b) as changes in the efficacy of existing synapses or generation of new synapses (neuronal or synaptic level), In this review, we describe paradigms used to study mechanisms of plasticity in the intact human motor system, the functional relevance of such plasticity and possible ways to modulate it. (C) 2001 John Wiiey & Sons, Inc.* C1 Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. Univ Frankfurt, Neurol Clin, Frankfurt, Germany. Univ Toronto, Univ Hlth Network, Div Neurol, Toronto, ON, Canada. RP Cohen, LG (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N 234,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Winstein, Carolee/A-8375-2008; Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 146 TC 44 Z9 47 U1 1 U2 7 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD MAY PY 2001 VL 24 IS 5 BP 602 EP 613 DI 10.1002/mus.1045 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 426UQ UT WOS:000168367100002 PM 11317269 ER PT J AU Schmid, TE Lowe, X Marchetti, F Bishop, J Haseman, J Wyrobek, AJ AF Schmid, TE Lowe, X Marchetti, F Bishop, J Haseman, J Wyrobek, AJ TI Evaluation of inter-scorer and inter-laboratory reliability of the mouse epididymal sperm aneuploidy (m-ESA) assay SO MUTAGENESIS LA English DT Article ID IN-SITU HYBRIDIZATION; BONE-MARROW CELLS; CHROMOSOME-ABNORMALITIES; MULTICOLOR FISH; FLUORESCENCE; MICE; MEN; INDUCTION; OOCYTES; ORIGIN AB The mouse epididymal sperm aneuploidy (mESA) assay using 3-chromosome fluorescence in situ hybridization (FISH) was recently developed for assessing the aneugenic potential of chemicals on male germ cells. This study was designed to identify the major technical factors that affect inter-scorer and inter-laboratory variability of the mESA assay. Two laboratories participated in this study (GSF and Lawrence Livermore National Laboratory, LLNL), Mice (102/E1xC3H/E1) F-1 were exposed in one laboratory (GSF) to vinblastine (VBL; single intraperitoneal injection of 0, 0,5, 1.0 or 2.0 mg/kg), one of the 10 priority compounds of the Commission of the European Communities (CEC) Aneuploidy Program. Twenty-two days later the mESA assay was applied to analyze sperm aneuploidy, In the initial evaluation, small but statistically significant differences were found between the two laboratories in baseline frequencies and there was also disagreement in the determination of a VBL aneuploid effect. Therefore, experiments were conducted to identify the sources of the inter-laboratory differences and technical factors that affected assay reliability and the VBL study was repeated. A harmonization experiment was conducted by bringing the microscope scorers from both laboratories to the same site (LLNL) for a cross-training exercise. Following this exercise, a second group of VBL-treated and control mice were evaluated, and we concluded that VBL is not a sperm aneugen, Our research has identified scoring criteria as the major source of inter-laboratory variation and emphasizes the importance of strict technical controls for the mESA assay, including controlling slide preparations for treatment-induced reductions in sperm count, coding of slides and selection of statistical tests. These considerations are particularly important for the interpretation of small effects (less than or equal to2-fold) on sperm aneuploidy, Our findings suggest that 2-fold differences in frequencies can result from differences among scorers, samples and treatment groups, and are readily within the normal variation for the mESA assay. Such small differences should be viewed with caution until independently confirmed. C1 Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. GSF Forschungszentrum Umwelt & Gesundheit GMBH, Inst Saugetiergenet, D-85764 Neuherberg, Germany. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Wyrobek, AJ (reprint author), Univ Calif Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, POB 808,7000 East Ave, Livermore, CA 94550 USA. OI Marchetti, Francesco/0000-0002-9435-4867 FU NIEHS NIH HHS [Y01-ES-10203] NR 42 TC 13 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD MAY PY 2001 VL 16 IS 3 BP 189 EP 195 DI 10.1093/mutage/16.3.189 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 432EA UT WOS:000168678200002 PM 11320142 ER PT J AU Penta, JS Johnson, FM Wachsman, JT Copeland, WC AF Penta, JS Johnson, FM Wachsman, JT Copeland, WC TI Mitochondrial DNA in human malignancy SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE mitochondrial DNA mutations; mitochondrial disease; reactive oxygen species (ROS); cancer ID RENAL-CELL CARCINOMA; LEUKEMIC HL-60 CELLS; STEADY-STATE LEVELS; CONTROL REGION DNA; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; GENE-EXPRESSION; GASTRIC TUMORS; CANCER-CELLS; HELA-CELLS AB Alterations in expression of mitochondrial DNA (mtDNA)-encoded polypeptides required for oxidative phosphorylation and cellular ATP generation may be a general characteristic of cancer cells. Mitochondrial DNA has been proposed to be involved in carcinogenesis because of high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. Since mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences and subsequent accumulation of mutations may lead to tumor formation. The mitochondrial genome is dependent upon the nuclear genome for transcription. translation, replication and repair, but precise mechanisms for how the two genomes interact and integrate with each other are poorly understood. In solid tumors, elevated expression of mtDNA-encoded subunits of the mitochondrial electron respiratory chain may reflect mitochondrial adaptation to perturbations in cellular energy requirements. In this paper, we review mitochondrial genomic aberrations reported in solid tumors of the breast, colon, stomach, liver, kidney, bladder, head/neck and lung as well as for hematologic diseases such as leukemia, myelodysplastic syndrome and lymphoma. We include data for elevated expression of mtDNA-encoded electron respiratory chain subunits in breast, colon and liver cancers and also the mutations reported in cancers of the colon, stomach, bladder, head/neck and lung. Finally, we examine the role of reactive oxygen species (ROS) generated by mitochondria in the process of carcinogenesis. Published by Elsevier Science B.V. C1 NIEHS, Off Clin Res, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Penta, JS (reprint author), NIEHS, Off Clin Res, NIH, POB 12233,MD A2-05, Res Triangle Pk, NC 27709 USA. NR 134 TC 318 Z9 359 U1 5 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD MAY PY 2001 VL 488 IS 2 BP 119 EP 133 DI 10.1016/S1383-5742(01)00053-9 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 427LK UT WOS:000168405500003 PM 11344040 ER PT J AU Kargul, GJ Dudekula, DB Qian, Y Lim, MK Jaradat, SA Tanaka, TS Carter, MG Ko, MSH AF Kargul, GJ Dudekula, DB Qian, Y Lim, MK Jaradat, SA Tanaka, TS Carter, MG Ko, MSH TI Verification and initial annotation of the NIA mouse 15K cDNA clone set SO NATURE GENETICS LA English DT Letter ID DATABASE; GENOME; MAP C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RI Carter, Mark/B-5089-2010; Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Dudekula, Dawood/0000-0002-4054-1827 NR 16 TC 91 Z9 92 U1 0 U2 1 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2001 VL 28 IS 1 BP 17 EP 18 DI 10.1038/ng0501-17 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 427NW UT WOS:000168413300008 PM 11326268 ER PT J AU Yoshikawa, H Matsubara, K Qian, GS Jackson, P Groopman, JD Manning, JE Harris, CC Herman, JG AF Yoshikawa, H Matsubara, K Qian, GS Jackson, P Groopman, JD Manning, JE Harris, CC Herman, JG TI SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity SO NATURE GENETICS LA English DT Article ID CONSTITUTIVE ACTIVATION; PROMOTER HYPERMETHYLATION; SIGNAL-TRANSDUCTION; LIVER-REGENERATION; DNA METHYLATION; GENE; PROTEIN; CELLS; INACTIVATION; LEUKEMIA AB Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490. a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490. C1 Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. Nara Inst Sci & Technol, Nara, Japan. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. Shanghai Canc Inst, Shanghai, Peoples R China. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Herman, JG (reprint author), Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21205 USA. FU NCI NIH HHS [P50 CA58184] NR 44 TC 490 Z9 516 U1 0 U2 19 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 MAY PY 2001 VL 28 IS 1 BP 29 EP 35 DI 10.1038/ng0501-29 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 427NW UT WOS:000168413300011 PM 11326271 ER PT J AU Cho, C Willis, WD Goulding, EH Haesook, JH Choi, YC Hecht, NB Eddy, EM AF Cho, C Willis, WD Goulding, EH Haesook, JH Choi, YC Hecht, NB Eddy, EM TI Haploinsufficiency of protamine-1 or-2 causes infertility in mice SO NATURE GENETICS LA English DT Article ID MAMMALIAN SPERM NUCLEI; MALE GERM-CELLS; MOUSE PROTAMINE-1; PROTEINS; SEQUENCE; FERTILITY; DEFICIENT; GENES; CDNA AB Protamines are the major DNA-binding proteins in the nucleus of sperm in most vertebrates(1-5) and package the DNA in a volume less than 5% of a somatic cell nucleus(6). Many mammals have one protamine, but a few species, including humans and mice, have two(7-13). Here we use gene targeting to determine if the second protamine provides redundancy to an essential process, or if both protamines are necessary. We disrupted the coding sequence of one allele of either Prm1 or Prm2 in embryonic stem (ES) cells derived from 129-strain mice, and injected them into blastocysts from C57BL/6-strain mice. Male chimeras produced 129-genotype sperm with disrupted Prm1 or Prm2 alleles, but failed to sire offspring carrying the 129 genome. We also found that a decrease in the amount of either protamine disrupts nuclear formation, processing of protamine-2 and normal sperm function. Our studies show that both protamines are essential and that haploinsufficiency caused by a mutation in one allele of Prm1or Prm2 prevents genetic transmission of both mutant and wild-type alleles. C1 NIEHS, Gamet Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Penn, Med Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. RP Eddy, EM (reprint author), NIEHS, Gamet Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 28 TC 294 Z9 306 U1 5 U2 17 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 MAY PY 2001 VL 28 IS 1 BP 82 EP 86 DI 10.1038/ng0501-82 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 427NW UT WOS:000168413300022 PM 11326282 ER PT J AU Fan, QR Long, EO Wiley, DC AF Fan, QR Long, EO Wiley, DC TI Crystal structure of the human natural killer cell inhibitory receptor KIR2DLI-HLA-Cw4 complex SO NATURE IMMUNOLOGY LA English DT Article ID MHC CLASS-I; LEUKOCYTE ANTIGEN (HLA)-CW4; HLA-C; DIRECT BINDING; GROWTH-HORMONE; PEPTIDE; RECOGNITION; MOLECULES; LIGANDS; SPECIFICITIES AB Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells.We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DLI (KIR2DLI) bound to its class I MHC ligand, HLA-Cw4,The KIR2DLI-HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DLI that hosts the Lys(80) residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DLI-HLA-Cw4 and in a previously reported KIR2DLI-HLA-Cw3 complex. A dimeric aggregate of KIR-HLA-C complexes was observed in one KIR2DLI-HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee hips with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by hips. C1 Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA. NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. RP Wiley, DC (reprint author), Harvard Univ, Dept Mol & Cell Biol, 7 Divin Ave, Cambridge, MA 02138 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 53 TC 175 Z9 181 U1 0 U2 2 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 MAY PY 2001 VL 2 IS 5 BP 452 EP 460 PG 9 WC Immunology SC Immunology GA 429ZZ UT WOS:000168549800019 PM 11323700 ER PT J AU Guo, LY Hu-Li, J Zhu, JF Pannetier, C Watson, C McKenzie, GJ McKenzie, ANJ Paul, WE AF Guo, LY Hu-Li, J Zhu, JF Pannetier, C Watson, C McKenzie, GJ McKenzie, ANJ Paul, WE TI Disrupting III3 impairs production of IL-4 specified by the linked allele SO NATURE IMMUNOLOGY LA English DT Article ID INTERLEUKIN-4 RECEPTOR; T-CELLS; IMMUNE-RESPONSES; BINDING SUBUNIT; GAMMA-CHAIN; B-CELLS; COMPONENT; SEQUENCE; REGION; GENE AB Interleukin 13-deficient (IL-13(-/-)) mice express a defect in priming for IL-4 production that is not corrected by adding IL-13 to the priming culture. This is partly accounted for by the consumption of IL-4 without endogenous replacement during culture of IL-13(-/-) CD4(+) T cells. We examined cells from mice in which disrupted Il13 was linked to wild-type Il4 on one chromosome and wild-type Il13 was linked to a "knocked-in" green fluorescent protein (GfP) gene in the Il4 locus. Our results show that the deficit in IL-4 production was due, at least in part, to a cis effect, in which disrupted Il13 diminished IL-4 production from the linked Il14 gene. C1 NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Lorantis, Cambridge, England. RP Paul, WE (reprint author), NIAID, NIH, Immunol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Zhu, Jinfang/B-7574-2012 NR 18 TC 11 Z9 11 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAY PY 2001 VL 2 IS 5 BP 461 EP 466 PG 6 WC Immunology SC Immunology GA 429ZZ UT WOS:000168549800020 PM 11323701 ER PT J AU McCampbell, A Fischbeck, KH AF McCampbell, A Fischbeck, KH TI Polyglutamine and CBP: Fatal attraction? SO NATURE MEDICINE LA English DT Editorial Material ID CREB-BINDING PROTEIN; HUNTINGTONS-DISEASE; EXPANDED POLYGLUTAMINE; TRANSCRIPTION; SEQUESTRATION; RECRUITMENT; RECEPTORS; FORM AB The mutant proteins that cause polyglutamine disease bind CREB-binding protein (CBP), a key transcriptional coactivator for neuronal survival factors. This results in a loss of CBP-dependent transcription and may account for the neuronal degeneration associated with these diseases. C1 NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. RP McCampbell, A (reprint author), NINDS, Neurogenet Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 15 TC 66 Z9 69 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2001 VL 7 IS 5 BP 528 EP 530 DI 10.1038/87842 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 454FE UT WOS:000169961100020 PM 11329046 ER PT J AU Manji, HK Drevets, WC Charney, DS AF Manji, HK Drevets, WC Charney, DS TI The cellular neurobiology of depression SO NATURE MEDICINE LA English DT Review ID MOOD-DISORDERS; SYNAPTIC PLASTICITY; NEUROPSYCHIATRIC DISORDERS; HIPPOCAMPAL NEUROGENESIS; N-ACETYLASPARTATE; BIPOLAR DISORDER; CUSHINGS-DISEASE; HUMAN BRAIN; IN-VIVO; LITHIUM AB Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression. C1 NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. NIMH, Sect Neuroimaging, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. EM manjih@intra.nimh.nih.gov NR 72 TC 714 Z9 748 U1 7 U2 83 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2001 VL 7 IS 5 BP 541 EP 547 DI 10.1038/87865 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 454FE UT WOS:000169961100031 PM 11329053 ER PT J AU Geanacopoulos, M Vasmatzis, G Zhurkin, VB Adhya, S AF Geanacopoulos, M Vasmatzis, G Zhurkin, VB Adhya, S TI Gal repressosome contains an antiparallel DNA loop SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; LAC REPRESSOR; B-DNA; PROTEIN; COMPLEX; HU AB Gal repressosome assembly and repression of the gal operon in Escherichia coli occurs when two dimeric GalR proteins and the histone-like HU protein bind to cognate sites causing DNA looping. Structure-based genetic analysis defined the GalR surfaces interacting to form a stacked, V-shaped, tetrameric structure. Stereochemical models of the four possible DNA loops compatible with the GalR tetramer configuration were constructed using the sequence-dependent structural parameters of the interoperator DNA and conformation changes caused by GalR and asymmetric HU binding. Evaluation of their DNA elastic energies gave unambiguous preference to a loop structure in which the two gal operators adopt an antiparallel orientation causing undertwisting of DNA. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Expt & Computat Biol, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Div Expt Pathol, Rochester, MN 55905 USA. Mayo Clin Canc Ctr, Rochester, MN 55905 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 32 TC 70 Z9 73 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD MAY PY 2001 VL 8 IS 5 BP 432 EP 436 DI 10.1038/87595 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 425WU UT WOS:000168315300016 PM 11323719 ER PT J AU Wlodawer, A Li, M Dauter, Z Gustchina, A Uchida, K Oyama, H Dunn, BM Oda, K AF Wlodawer, A Li, M Dauter, Z Gustchina, A Uchida, K Oyama, H Dunn, BM Oda, K TI Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; SUBSTRATE-SPECIFICITY; SERINE-PROTEASE; STRUCTURE REFINEMENT; CRYSTAL-STRUCTURE; PEPTIDASE-I; RESOLUTION; IDENTIFICATION; PURIFICATION; INHIBITOR AB The crystal structure of a pepstatin-insensitive carboxyl proteinase from Pseudomonas sp. 101 (PSCP) has been solved by single-wavelength anomalous diffraction using the absorption peak of bromide anions. Structures of the uninhibited enzyme and of complexes with an inhibitor that was either covalently or noncovalently bound were refined at 1.0-1.4 Angstrom resolution. The structure of PSCP comprises a single compact domain with a diameter of similar to 55 Angstrom, consisting of a seven-stranded parallel beta -sheet flanked on both sides by a number of helices. The fold of PSCP is a superset of the subtilisin fold, and the covalently bound inhibitor is linked to the enzyme through a serine residue. Thus, the structure of PSCP defines a novel family of serine-carboxyl proteinases (defined as MEROPS S53) with a unique catalytic triad consisting of Glu 80, Asp 84 and Ser 287. C1 NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. Brookhaven Natl Lab, Natl Canc Inst, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Brookhaven Natl Lab, NSLS, Upton, NY 11973 USA. Teikyo Univ, Sch Sci & Engn, Dept Biosci, Utsunomiya, Tochigi 3208551, Japan. Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov NR 35 TC 78 Z9 79 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD MAY PY 2001 VL 8 IS 5 BP 442 EP 446 DI 10.1038/87610 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 425WU UT WOS:000168315300018 PM 11323721 ER PT J AU Ishii, K Lippa, C Tomiyama, T Miyatake, F Ozawa, K Tamaoka, A Hasegawa, T Fraser, PE Shoji, S Nee, LE Pollen, DA St George-Hyslop, PH Ii, K Ohtake, T Kalaria, RN Rossor, MN Lantos, PL Cairns, NJ Farrer, LA Mori, H AF Ishii, K Lippa, C Tomiyama, T Miyatake, F Ozawa, K Tamaoka, A Hasegawa, T Fraser, PE Shoji, S Nee, LE Pollen, DA St George-Hyslop, PH Ii, K Ohtake, T Kalaria, RN Rossor, MN Lantos, PL Cairns, NJ Farrer, LA Mori, H TI Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; aging; A beta; plaque; Presenilin-1; APP (amyloid precursor protein); APOE; immunohistochemistry ID FAMILIAL ALZHEIMERS-DISEASE; PRECURSOR PROTEIN GENE; BETA-PROTEIN; MUTANT PRESENILIN-1; MISSENSE MUTATIONS; TRANSGENIC MICE; SENILE PLAQUES; A-BETA; ONSET; CHROMOSOME-14 AB Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral A beta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of A beta 40 and A beta 42. A beta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of A beta 42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of A beta 42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of A beta 40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of A beta burden in a different fashion from APP717 mutations in their familial AD brains. (C) 2001 Elsevier Science Inc. All rights reserved. C1 Tokyo Inst Psychiat, Dept Mol Biol, Tokyo, Japan. Univ Tsukuba, Dept Neurol, Tsukuba, Ibaraki 305, Japan. Med Coll Penn & Hahnemann Univ, Dept Neurol, Philadelphia, PA 19102 USA. Osaka City Univ, Sch Med, Dept Neurosci, Osaka 5458585, Japan. Univ Tokushima, Sch Med, Dept Pathol, Tokushima 770, Japan. Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Dept Neurol, Worcester, MA 01655 USA. Tokyo Metropolitan Neurol Hosp, Dept Neurol, Tokyo, Japan. Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. UCL Natl Hosp Neurol & Neurosurg, Dept Neurol, London WC1N 3BG, England. Inst Psychiat, Dept Neuropathol, London SE5 8AF, England. Boston Univ, Sch Med, Dept Med, Genet Program, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Med, Genet Program, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA. RP Mori, H (reprint author), Tokyo Inst Psychiat, Dept Mol Biol, Tokyo, Japan. EM mori@med.osaka-cu.ac.jp OI Farrer, Lindsay/0000-0001-5533-4225 FU NIA NIH HHS [AG09029, AG13623, AG95004] NR 73 TC 12 Z9 13 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAY-JUN PY 2001 VL 22 IS 3 BP 367 EP 376 DI 10.1016/S0197-4580(01)00216-0 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 437YK UT WOS:000169026800008 PM 11378241 ER PT J AU Turkheimer, FE Smith, CB Schmidt, K AF Turkheimer, FE Smith, CB Schmidt, K TI Estimation of the number of "true" null hypotheses in multivariate analysis of neuroimaging data SO NEUROIMAGE LA English DT Article DE PET; autoradiography; multiple comparisons; P plot ID MULTIPLE TESTS; IMAGES; ANESTHESIA; ACTIVATION; VALUES; SPACE; RAT AB The repeated testing of a null univariate hypothesis in each of many sites (either regions of interest or voxels) is a common approach to the statistical analysis of brain functional images. Procedures, such as the Bonferroni, are available to maintain the Type I error of the set of tests at a specified level. An initial assumption of these methods is a "global null hypothesis," i.e., the statistics computed on each site are assumed to be generated by null distributions. This framework may be too conservative when a significant proportion of the sites is affected by the experimental manipulation. This report presents the development of a rigorous statistical procedure for use with a previously reported graphical method, the P plot, for estimation of the number of "true" null hypotheses in the set. This estimate can then be used to sharpen existing multiple comparison procedures. Performance of the P plot method in the multiple comparison problem is investigated in simulation studies and in the analysis of autoradiographic data. (C) 2001 Academic Press. C1 NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. Hammersmith Hosp, MRC, Cyclotron Unit, London W12 0NN, England. RP NIMH, Cerebral Metab Lab, Bldg 36, Bethesda, MD 20892 USA. RI Turkheimer, Federico/B-9485-2012 OI Turkheimer, Federico/0000-0002-3766-3815 NR 37 TC 48 Z9 48 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD MAY PY 2001 VL 13 IS 5 BP 920 EP 930 DI 10.1006/nimg.2001.0764 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 429CA UT WOS:000168497400014 PM 11304087 ER PT J AU Dawid, IB Chitnis, AB AF Dawid, IB Chitnis, AB TI LIM homeobox genes and the CNS: A close relationship SO NEURON LA English DT Editorial Material ID IN-VIVO; PROTEIN; ZEBRAFISH; DOMAINS C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NR 11 TC 13 Z9 14 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY PY 2001 VL 30 IS 2 BP 301 EP 303 DI 10.1016/S0896-6273(01)00307-5 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 436XW UT WOS:000168962000001 PM 11394990 ER PT J AU Sato, T Murthy, A Thompson, KG Schall, JD AF Sato, T Murthy, A Thompson, KG Schall, JD TI Search efficiency but not response interference affects visual selection in frontal eye field SO NEURON LA English DT Article ID SACCADE TARGET SELECTION; SUPERIOR COLLICULUS; NEURONAL-ACTIVITY; INTRACORTICAL MICROSTIMULATION; NEURAL MECHANISMS; PREFRONTAL CORTEX; SQUIRREL-MONKEYS; MENTAL PROCESSES; MACAQUE MONKEYS; CORTICAL AREAS AB Two manipulations of a visual search task were used to test the hypothesis that the discrimination of a target from distracters by visually responsive neurons in the frontal eye field (FEF) marks the outcome and conclusion of visual processing instead of saccade preparation. First, search efficiency was reduced by increasing the similarity of the distracters to the target. Second, response interference was introduced by infrequently changing the location of the target in the array. Both manipulations increased reaction time, but only the change in search efficiency affected the time needed to select the target by visually responsive neurons. This result indicates that visually responsive neurons In FEF form an explicit representation of the location of the target in the image. C1 Vanderbilt Univ, Dept Psychol, Vanderbilt Vis Res Ctr, Nashville, TN 37240 USA. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Schall, JD (reprint author), Vanderbilt Univ, Dept Psychol, Vanderbilt Vis Res Ctr, 111 21st Ave S,301 Wilson Hall, Nashville, TN 37240 USA. FU NEI NIH HHS [R01-EY08890, P30-EY08126] NR 59 TC 104 Z9 105 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY PY 2001 VL 30 IS 2 BP 583 EP 591 DI 10.1016/S0896-6273(01)00304-X PG 9 WC Neurosciences SC Neurosciences & Neurology GA 436XW UT WOS:000168962000027 PM 11395016 ER PT J AU Bokde, ALW Tagamets, MA Friedman, RB Horwitz, B AF Bokde, ALW Tagamets, MA Friedman, RB Horwitz, B TI Functional interactions of the inferior frontal cortex during the processing of words and word-like stimuli SO NEURON LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; PREFRONTAL CORTEX; WORKING-MEMORY; HUMAN BRAIN; SENTENCE COMPREHENSION; TEMPORAL-LOBE; PET-RCBF; SPEECH; RETRIEVAL AB The hypothesis that ventral/anterior left inferior frontal gyrus (LIFG) subserves semantic processing and dorsal/posterior LIFG subserves phonological processing was tested by determining the pattern of functional connectivity of these regions with regions in left occipital and temporal cortex during the processing of words and word-like stimuli. In accordance with the hypothesis, we found strong functional connectivity between activity in ventral LIFG and activity in occipital and temporal cortex only for words, and strong functional connectivity between activity in dorsal LIFG and activity in occipital and temporal cortex for words, pseudowords, and letter strings, but not for false font strings. These results demonstrate a task-dependent functional fractionation of the LIFG in terms of its functional links with posterior brain areas. C1 Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD 21228 USA. NIMH, Geriatr Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Funct Neuroimaging Lab, Baltimore, MD 21201 USA. Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. NRH Res Ctr, Washington, DC 20007 USA. RP Horwitz, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD 21228 USA. FU NICHD NIH HHS [R01 HD36019] NR 53 TC 157 Z9 158 U1 3 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTES AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY PY 2001 VL 30 IS 2 BP 609 EP 617 DI 10.1016/S0896-6273(01)00288-4 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 436XW UT WOS:000168962000029 PM 11395018 ER PT J AU Baumann, MH Ayestas, MA Dersch, CM Rothman, RB AF Baumann, MH Ayestas, MA Dersch, CM Rothman, RB TI 1-(m-chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin (5-HT) release; 5-HT depletion; d-fenfluramine; m-chlorophenylpiperazine; neurotoxicity ID INCREASES EXTRACELLULAR SEROTONIN; PRIMARY PULMONARY-HYPERTENSION; BIOGENIC-AMINE TRANSPORTERS; D-FENFLURAMINE; M-CHLOROPHENYLPIPERAZINE; META-CHLOROPHENYLPIPERAZINE; PARA-CHLOROAMPHETAMINE; P-CHLOROAMPHETAMINE; MEDIATED OXIDATION; INDAN ANALOGS AB Serotonin (5-HT) releasing agents such as d-fenfluramine are known to cause long-term depletion of forebrain 5-HT in animals, but the mechanism of this effect is unknown. In the present study, we examined the relationship between drug-induced 5-HT release and long-term 5-HT depletion in rat brain. The 5-HT-releasing actions of d-fenfluramine and a non-amphetamine 5-HT drug, 1-(m-chlorophenyl)piperazine (mCPP), were compared using in vivo microdialysis in the nucleus accumbens. The ability of d-fenfluramine and mCPP to interact with 5-HT transporters was tested using in vitro assays for T [H-3]5-HT uptake and radioligand binding. Local infusion of d-fenfluramine or mCPP (1-100 muM) increased extracellular 5-HT, with elevations in dopamine occurring at high doses. Intravenous injection of either drug (1-10 mu mol/kg) produced dose-related increases in 5-HT without affecting dopamine. d-Fenfluramine and mCPP exhibited similar potency in their ability to stimulate 5-HT efflux in vivo and interact with 5-HT transporters in vitro. When rats received high-dose d-fenfluramine or mCPP (10 or 30 mu mol/kg, i.p., every 2 h, 4 doses), only d-fenfluramine-treated rats displayed long-term 5-HT depletions. Thus, mCPP is a 5-HT releaser that does not appear to cause 5-HT depletion. Our data support the notion that 5-HT release per se may not be sufficient to produce the long-term 5-HT deficits associated with d-fenfluramine and other amphetamines. (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 58 TC 51 Z9 52 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2001 VL 24 IS 5 BP 492 EP 501 DI 10.1016/S0893-133X(00)00221-9 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 421KZ UT WOS:000168064700003 PM 11282249 ER PT J AU Holmes, A AF Holmes, A TI Targeted gene mutation approaches to the study of anxiety-like behavior in mice SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Neuroscience CY OCT 23-28, 1999 CL MIAMI BEACH, FLORIDA SP Soc Neurosci DE anxiety; behavior; transgenic; knockout; gene; mouse; genetic background; GABA(A) receptor; 5-HT receptors; corticotropin-releasing hormone ID ELEVATED PLUS-MAZE; CORTICOTROPIN-RELEASING-FACTOR; INBRED MOUSE STRAINS; RECEPTOR MUTANT MICE; GAMMA-AMINOBUTYRIC-ACID; DEFENSE TEST BATTERY; INCREASED EXPLORATORY ACTIVITY; IMPAIRED STRESS-RESPONSE; TRAIT LOCI ANALYSES; DEFICIENT MICE AB Studying the behavioral phenotypes of transgenic and gene knockout mice is a powerful means to better understand the pathophysiology of neuropsychiatric disorders and ultimately improve their treatment. This paper provides an overview of the methods and findings of studies that have tested for anxiety-related behavioral phenotypes in gene mutant mice. In the context of improving the side effect burden of benzodiazepines, gene targeting has been valuable for dissociating the functional roles (i.e., anxiolytic, sedative, amnestic) of individual GABAA receptor subunits. Supporting the link between abnormalities in CRH function and anxiety, CRH overexpressing transgenic mice and CRH-R2 receptor knockout mutants have displayed significantly increased anxiety-like behavior, while CRH-RI receptor knockout mice have shown an anxiolytic-like phenotype. Consistent with an important role for the serotonergic system in anxiety, 5-HTIA receptor deficient mice have consistently exhibited heightened anxiety-like behavior, while the evidence from 5-HT1(B) and 5-HT2(C) deficient mice remains somewhat equivocal. Mutant mice lacking either of the monoamine degrading enzymes, MAOA or COMT, have shown a number of behavioral and neurological effects, including alterations in anxiety-like behavior. With enhanced spatial and temporal control over gene mutations, in combination with an improved battery of behavioral tests, gene mutant mice will provide an increasingly valuable tool for understanding the neural substrates of anxiety. (C) 2001 Elsevier Science Ltd. All rights reserved. C1 NIMH, Sect Behav Pharmacol, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Holmes, A (reprint author), NIMH, Sect Behav Pharmacol, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NR 151 TC 135 Z9 137 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD MAY PY 2001 VL 25 IS 3 BP 261 EP 273 DI 10.1016/S0149-7634(01)00012-4 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 451EU UT WOS:000169788800005 PM 11378180 ER PT J AU Donovan, DM Nguyen, J Revay, R Liu, ZY Rowley, DL Barrett, T AF Donovan, DM Nguyen, J Revay, R Liu, ZY Rowley, DL Barrett, T TI Murine dopamine transporter proximal promoter sequences do not direct lacZ transgene expression to ventral midbrain. SO NEUROSCIENCE RESEARCH COMMUNICATIONS LA English DT Article DE dopamine transporter; promoter; lacZ; transgenic; murine; midbrain ID TYROSINE-HYDROXYLASE GENE; CENTRAL-NERVOUS-SYSTEM; TISSUE-SPECIFIC EXPRESSION; MESSENGER-RNA EXPRESSION; RAT-BRAIN; 5'-FLANKING REGION; RECEPTOR GENE; SUBUNIT GENE; HIGH-LEVEL; MICE AB Dopamine is an important neurotransmitter involved in a variety of central nervous system functions including locomotion, cognition and emotions. The dopamine transporter is uniquely expressed on dopamine neurons, where it's uptake of dopamine constitutes the primary mechanism for terminating dopamine neurotransmission. Although dopamine transporter (DATI) sequences have been isolated from several organisms, little is known about the genomic regulatory elements required for expression. This work describes transgenic analysis of a series of murine DATI promoter fusions to the lacZ reporter gene to localize putative promoter elements. Despite lacZ expression from these constructs in cultured cells, no expression was observed in any dopaminergic loci from either adult or embryonic mouse brains, for any of the four constructs described. Thus, the murine DAT gene sequences sufficient for activating expression are not located within 2.8 kb 5' to the transcription start site, or within the first eight kb of transcribed sequences. C1 NIA, Transgen & Knockout Facil Sect, IRP, NIH, Baltimore, MD 21224 USA. NIDA, IRP, NIH, Baltimore, MD 21224 USA. RP Donovan, DM (reprint author), NIA, Transgen & Knockout Facil Sect, IRP, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 68 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0893-6609 J9 NEUROSCI RES COMMUN JI Neurosci. Res. Commun. PD MAY-JUN PY 2001 VL 28 IS 3 BP 151 EP 163 DI 10.1002/nrc.1016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 447UR UT WOS:000169591300002 ER PT J AU Garmestani, K Yao, Z Zhang, M Wong, K Park, CW Pastan, I Carrasquillo, JA Brechbiel, MW AF Garmestani, K Yao, Z Zhang, M Wong, K Park, CW Pastan, I Carrasquillo, JA Brechbiel, MW TI Synthesis and evaluation of a macrocyclic bifunctional chelating agent for use with bismuth radionuclides SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE bismuth; Bi-205,Bi-206; radioimmunotherapy; bifunctional chelating agent; alpha-therapy ID EPIDERMOID CARCINOMA XENOGRAFTS; MONOCLONAL-ANTIBODY THERAPY; ALPHA-PARTICLE-EMITTER; B-CELL LYMPHOMA; SPECTROPHOTOMETRIC METHOD; ANTI-CD20 ANTIBODY; IN-VIVO; RADIOIMMUNOTHERAPY; DTPA; BIODISTRIBUTION AB The detailed synthesis of the bifunctional chelating agent 2-(p-isothiocyanatobenzyl)-1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N"',N""-pentaacetic acid (BF_PEPA) is reported. This ligand was conjugated to monoclonal antibody B3 and the resultant immunoconjugate radiolabeled with Bi-205,Bi-206. The in vivo stability of the radiolabeled immunoconjugate, and targeting characteristics were determined by biodistribution studies in A431 xenograft tumor-bearing mice sacrificed at 0.5, 1, 2, 4, and 24 hr. Results indicate that BF_PEPA appears to not be a suitable bifunctional chelating agent for sequestering isotopes of Bi(III) for radioimmunotherapy applications. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NCI, Radioimmune & Inorgan Chem Sect, ROB, DCS, Bethesda, MD 20892 USA. NCI, Ctr Clin, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NCI, DCS, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, DBS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, ROB, DCS, Bldg 10,Room B3B69,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 47 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAY PY 2001 VL 28 IS 4 BP 409 EP 418 DI 10.1016/S0969-8051(00)00203-1 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 440ZH UT WOS:000169206200008 PM 11395314 ER PT J AU Channing, MA Huang, BX Eckelman, WC AF Channing, MA Huang, BX Eckelman, WC TI Analysis of residual solvents in 2-[F-18]FDG by GC SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE residual solvents; 2-[F-18]FDG; gas chromatography ID KRYPTOFIX 2.2.2 AB A gas chromatography method has been developed for the measurement of the residual acetone, ethanol and acetonitrile in 2-deoxy-2-[F-18] fluoro-D-glucose (2-[F-18]FDG), in accordance with the pending FDA revision on the drug. The detections limits were 0.1 ppm for all three solvents. Good precision and linearity were obtained over ranges spanning the allowable concentration levels proposed by FDA. The amounts of the three solvents in our routine 2-[F-18]FDG products have been found well below the maximum permissible levels. The method is very amenable to quality control testing for the radiopharmaceutical. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Huang, BX (reprint author), NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. NR 7 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAY PY 2001 VL 28 IS 4 BP 469 EP 471 DI 10.1016/S0969-8051(00)00213-4 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 440ZH UT WOS:000169206200015 PM 11395321 ER PT J AU Queimado, L Rao, M Schultz, RA Koonin, EV Aravind, L Nardo, T Stefanini, M Friedberg, EC AF Queimado, L Rao, M Schultz, RA Koonin, EV Aravind, L Nardo, T Stefanini, M Friedberg, EC TI Cloning the human and mouse MMS19 genes and functional complementation of a yeast mms19 deletion mutant SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEOTIDE-EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; FACTOR TFIIH; NUCLEAR TRANSPORT; HEAT REPEATS; DNA-REPAIR; PSI-BLAST; TRANSCRIPTION; PROTEIN; TRICHOTHIODYSTROPHY AB The MMS19 gene of the yeast Saccharomyces cerevisiae encodes a polypeptide of unknown function which is required for both nucleotide excision repair (NER) and RNA polymerase II (RNAP II) transcription. Here we report the molecular cloning of human and mouse orthologs of the yeast MMS19 gene. Both human and Drosophila MMS19 cDNAs correct thermosensitive growth and sensitivity to killing by UV radiation in a yeast mutant deleted for the MMS19 gene, indicating functional conservation between the yeast and mammalian gene products. Alignment of the translated sequences of MMS19 from multiple eukaryotes, including mouse and human, revealed the presence of several conserved regions, including a HEAT repeat domain near the C-terminus, The presence of HEAT repeats, coupled with functional complementation of yeast mutant phenotypes by the orthologous protein from higher eukaryotes, suggests a role of Mms19 protein in the assembly of a multiprotein complex(es) required for NER and RNAP II transcription. Both the mouse and human genes are ubiquitously expressed as multiple transcripts, some of which appear to derive from alternative splicing. The ratio of different transcripts varies in several different tissue types. C1 Univ Texas, SW Med Ctr, Dept Pathol, Lab Mol Pathol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Genome Sci & Technol Ctr, Dallas, TX 75390 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Texas A&M Univ, Dept Biol, College Stn, TX USA. Ist Genet Biochim & Evoluzionist, I-27100 Pavia, Italy. RP Friedberg, EC (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, Lab Mol Pathol, Room NB6-212A,6000 Harry Hines Blvd, Dallas, TX 75390 USA. RI Queimado, Lurdes/L-7465-2013 OI Queimado, Lurdes/0000-0002-1106-4873 FU NCI NIH HHS [CA44247] NR 37 TC 11 Z9 14 U1 0 U2 1 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 MAY 1 PY 2001 VL 29 IS 9 BP 1884 EP 1891 DI 10.1093/nar/29.9.1884 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 430ZF UT WOS:000168605800007 PM 11328871 ER PT J AU Orren, DK Machwe, A Karmakar, P Piotrowski, J Cooper, MP Bohr, VA AF Orren, DK Machwe, A Karmakar, P Piotrowski, J Cooper, MP Bohr, VA TI A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID REPLICATION PROTEIN-A; WRN PROTEIN; HELICASE; CELLS; REPAIR; MICE; PHENOTYPE; DELETION; GROWTH AB Werner syndrome (WS) is a premature aging disorder where the affected individuals appear much older than their chronological age. The single gene that is defective in WS encodes a protein (WRN) that has ATPase, helicase and 3'-->5' exonuclease activities. Our laboratory has recently uncovered a physical and functional interaction between WRN and the Ku heterodimer complex that functions in double-strand break repair and V(D)J recombination. Importantly, Ku specifically stimulates the exonuclease activity of WRN. We now report that Ku enables the Werner exonuclease to digest through regions of DNA containing 8-oxoadenine and 8-oxoguanine modifications, lesions that have previously been shown to block the exonuclease activity of WRN alone. These results indicate that Ku significantly alters the exonuclease function of WRN and suggest that the two proteins function concomitantly in a DNA damage processing pathway. In support of this notion we also observed co-localization of WRN and Ku, particularly after DNA damaging treatments. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40536 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 31 TC 71 Z9 72 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 MAY 1 PY 2001 VL 29 IS 9 BP 1926 EP 1934 DI 10.1093/nar/29.9.1926 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 430ZF UT WOS:000168605800012 PM 11328876 ER PT J AU Morrison, JA Barton, BA Obarzanek, E Crawford, PB Guo, SS Schreiber, GB AF Morrison, JA Barton, BA Obarzanek, E Crawford, PB Guo, SS Schreiber, GB TI Racial differences in the sums of skinfolds and percentage of body fat estimated from impedance in black and white girls, 9 to 19 years of age: The National Heart, Lung, and Blood Institute Growth and Health Study SO OBESITY RESEARCH LA English DT Article DE girls; race; adiposity; impedance; skinfolds; puberty ID X-RAY ABSORPTIOMETRY; CARDIOVASCULAR-DISEASE; ADOLESCENT GIRLS; VISCERAL FAT; FREE MASS; OBESITY; CHILDREN; ANTHROPOMETRY; OVERWEIGHT; EQUATIONS AB Objectives: This National Heart, Lung, and Blood Institute Growth and Health Study report assesses racial differences in fat patterning in black and white girls ages 9 to 19 years, comparing the sum of triceps and subscapular skinfolds (SSFs) and percentage of body fat (%BF) from impedance as two indices of adiposity. It is hypothesized that racial differences in fat patterning manifest during puberty. Research Methods and Procedures: SSF and %BF were measured annually. Racial differences in SSF and %BF were evaluated by age. Associations between %BF and SSF were evaluated using the Pearson's correlations coefficient. Classification agreement was evaluated using the kappa-statistic. Effects of pubertal stage and race on classification agreement were examined using multivariate models. Results: White girls had a greater mean %BF at 9 to 12 years of age; black girls had a greater %BF thereafter. Black girls had a greater mean SSF at every age. The correlation coefficient between SSF and %BF was 0.79, and there was good agreement between %BF and SSF in separating high (> 85th percentile) from not high (kappa = 0.60 for whites and 0.66 for blacks). SSF associated more with %BF in prepuberty and early puberty than in late puberty. Discussion: Despite good correlations between %BF and SSF, the two methods indicate different fat patterns in black and white girls. C1 Childrens Hosp, Med Ctr, Div Cardiol, Cincinnati, OH 45229 USA. Maryland Med Res Inst, Baltimore, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Wright State Univ, Sch Med, Dept Community Hlth, Dayton, OH 45435 USA. Wright State Univ, Sch Med, Dept Math & Stat, Div Human Biol, Dayton, OH 45435 USA. WESTAT Corp, Rockville, MD 20850 USA. RP Morrison, JA (reprint author), Childrens Hosp, Med Ctr, Div Cardiol, OSB 4,3333 Burnet Ave, Cincinnati, OH 45229 USA. OI Barton, Bruce/0000-0001-7878-8895 FU NHLBI NIH HHS [HC-55023-26, HL 48941] NR 28 TC 25 Z9 26 U1 0 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI ROCHESTER PA C/O DR MICHAEL JENSEN, MAYO MEDICAL CENTER, MAYO CLIN 200 FIRST ST, SW, ROCHESTER, MN 55905 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD MAY PY 2001 VL 9 IS 5 BP 297 EP 305 DI 10.1038/oby.2001.37 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 432HC UT WOS:000168685300004 PM 11346671 ER PT J AU Chou, CJ Cha, MC Jung, DW Boozer, CN Hashim, SA Pi-Sunyer, FX AF Chou, CJ Cha, MC Jung, DW Boozer, CN Hashim, SA Pi-Sunyer, FX TI High-fat diet feeding elevates skeletal muscle uncoupling protein 3 levels but not its activity in rats SO OBESITY RESEARCH LA English DT Article DE high-fat diet; uncoupling protein 3; mitochondrial swelling; Western blot; energy expenditure; rats ID THYROID-HORMONE; EXPRESSION; MICE; THERMOGENESIS; MITOCHONDRIA; METABOLISM; MECHANISM; OBESITY; LEPTIN; ACIDS AB Objective: The objective of this study is to test the impact of high-fat diet (HFD) feeding on skeletal muscle (SM) uncoupling protein 3 (UCP3) expression and its association with mitochondrial ion permeability and whole-body energy homeostasis. Research Methods and Procedures: Sprague-Dawley rats were fed ad libitum either a HFD (60% of energy from fat, n = 6) or a low-fat diet (12% of energy from fat, n = 6) for 4 weeks. Twenty-four-hour energy expenditure was measured by indirect calorimetry in the last week of the dietary treatment. Blood samples were collected for plasma leptin and free fatty acid assays, and mitochondria were isolated from hindlimb SM for subsequent determinations of UCP3 levels and mitochondrial ion permeability. Results: Plasma leptin levels were higher in rats fed the HFD despite the same body weight in two groups. The same dietary treatment also rendered a 2-fold increase in plasma free fatty acid and SM UCP3 protein levels (Western blot) compared with the group fed the low-fat diet. However, the elevated UCP3 protein levels did not correlate with mitochondrial swelling rates, a measure of mitochondrial chloride, and proton permeability, or with 24-hour energy expenditure. Discussion: The high correlation between the levels of plasma free fatty acid levels and SM UCP3 suggests that circulating free fatty acid may play an important role in UCP3 expression during the HFD feeding. However, the dissociation between the UCP3 protein levels and 24-hour energy expenditure as well as mitochondrial ion permeability suggests that mitochondrial proton leak mediated by muscle UCP3 may not be a major contributor in energy balance in HFD feeding, and other regulatory mechanisms independent of gene regulation may be responsible for the control of UCP3-mediated uncoupling activity. C1 St Lukes Roosevelt Hosp Ctr, Obes Res Ctr, New York, NY USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Ohio State Univ, Dept Med Biochem, Columbus, OH 43210 USA. RP Chou, CJ (reprint author), NIDDKD, NIH, Bldg10,Room 8N-252,10 Ctr Dr, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [DK49853, P30DK26687, R01 DK40414] NR 25 TC 18 Z9 18 U1 0 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI ROCHESTER PA C/O DR MICHAEL JENSEN, MAYO MEDICAL CENTER, MAYO CLIN 200 FIRST ST, SW, ROCHESTER, MN 55905 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD MAY PY 2001 VL 9 IS 5 BP 313 EP 319 DI 10.1038/oby.2001.39 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 432HC UT WOS:000168685300006 PM 11346673 ER PT J AU Syme, SE Drury, TF Horowitz, AM AF Syme, SE Drury, TF Horowitz, AM TI Maryland dental hygienists' knowledge and opinions of oral cancer risk factors and diagnostic procedures SO ORAL DISEASES LA English DT Article DE dental hygienists; oral cancer; knowledge; risk factors; diagnostic procedures ID PHARYNGEAL CANCER; UNITED-STATES; ALCOHOL-DRINKING; TOBACCO SMOKING; PREVENTION; CAVITY; OROPHARYNX AB OBJECTIVES: To examine Maryland dental hygienists' (DHs) knowledge of oral cancer risk factors and diagnostic procedures, as well as opinions about the currency and adequacy of their oral cancer knowledge, educational preparation, interest in, and preferred types of, continuing education courses. METHODS: Seven hundred DHs were randomly selected from a registry of 2677 Maryland licensed dental hygienists. A mailed survey instrument provided baseline data on 331 (RR = 60%) DHs, Stratified tabular and logistic analytical techniques were employed (alpha level less than or equal to0.05). RESULTS: Most correctly identified tobacco use (99.7%) and alcohol use (89%) as risk factors; however, 31% incorrectly identified poor oral hygiene as a risk factor. 64% of DHs correctly identified older age as a risk factor, yet only 16% identified that the majority of oral cancers are diagnosed in the 60+ year old age group. Nearly 91% correctly identified the examination procedures of the tongue for oral cancer detection; while only 16% of DHs correctly identified erythroplakia and leukoplakia as the conditions most likely associated with oral cancer. CONCLUSIONS: Gaps in knowledge exist and strongly suggest the need for continuing education courses to clarify risk factors and diagnostic procedures associated with earlier oral cancer detection and prevention. C1 Univ Maryland, Baltimore Sch Dent, Dept Dent Hyg, Baltimore, MD 21201 USA. NIDCR, Off Sci Policy & Anal, NIH, Bethesda, MD 20892 USA. RP Syme, SE (reprint author), Univ Maryland, Baltimore Sch Dent, Dept Dent Hyg, 666 W Baltimore St,Room 3-G-31, Baltimore, MD 21201 USA. NR 37 TC 17 Z9 17 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1354-523X J9 ORAL DIS JI Oral Dis. PD MAY PY 2001 VL 7 IS 3 BP 177 EP 184 DI 10.1034/j.1601-0825.2001.0070307.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 444BA UT WOS:000169377000007 PM 11495194 ER PT J AU Battey, JF AF Battey, JF TI News from the National Institute on Deafness and Other Communication Disorders SO OTOLOGY & NEUROTOLOGY LA English DT Editorial Material C1 NIDOCD, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), NIDOCD, NIH, 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 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAY PY 2001 VL 22 IS 3 BP 287 EP 290 DI 10.1097/00129492-200105000-00003 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 428DP UT WOS:000168446300003 PM 11347628 ER PT J AU Paget-McNicol, S Saul, A AF Paget-McNicol, S Saul, A TI Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum SO PARASITOLOGY LA English DT Article DE dihydrofolate reductase; mutation rate; malaria; mathematical modelling; Plasmodium falciparum ID THYMIDYLATE SYNTHASE GENE; DRUG-RESISTANCE; MALARIA PARASITES; PYRIMETHAMINE RESISTANCE; SEQUENCE-ANALYSIS; INVITRO; DNA; FREQUENCIES; EVOLUTION; SELECTION AB A new method has been established to define the limits on a spontaneous mutation rate for a gene in Plasmodium falciparum. The method combines mathematical modelling and large-scale in vitro culturing and calculates the difference in mutant frequencies at 2 separate time-points. We measured the mutation rate at 2 positions in the dihydrofolate reductase (DHFR) gene of 3D7, a pyrimethamine-sensitive line of P. fulciparum. This line was re-cloned and an effectively large population was treated with a selective pyrimethamine concentration of 40 nM. We detected point mutations at codon-46 (TTA to TCA) and codon-108 (ACC to AAC), resulting in serine replacing leucine and asparagine replacing serine respectively in the corresponding gene product. The substitutions caused a decrease in pyrimethamine sensitivity. By mathematical modelling we determined that the mutation rate at a given position in DHFR was low and occurred at less than 2(.)5 x 10(-9) mutations/DHFR gene/replication. This result has important implications for Plasmodium genetic diversity and antimalarial drug therapy by demonstrating that even with lon mutation rates anti-malarial resistance will inevitably arise when mutant alleles are selected under drug pressure. C1 Univ Queensland, St Lucia, Qld 4029, Australia. Queensland Inst Med Res, Malaria & Arbovirus Unit, St Lucia, Qld 4029, Australia. NIAID, Malaria Vaccine Dev Unit, LPD, NIH, Rockville, MD 20852 USA. RP Paget-McNicol, S (reprint author), Univ Queensland, St Lucia, Qld 4029, Australia. RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 38 TC 41 Z9 41 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI PORT CHESTER PA 110 MIDLAND AVE, PORT CHESTER, NY 10573-9863 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD MAY PY 2001 VL 122 BP 497 EP 505 DI 10.1017/S0031182001007739 PN 5 PG 9 WC Parasitology SC Parasitology GA 436AE UT WOS:000168913700002 PM 11393822 ER PT J AU Ahmed, F Ansaruzzaman, M Haque, E Rao, MR Clemens, JD AF Ahmed, F Ansaruzzaman, M Haque, E Rao, MR Clemens, JD TI Epidemiology of postshigellosis persistent diarrhea in young children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE antibiotic resistance; diarrhea; persistent; diarrhea; dysentery; bacillary; epidemiology; Shigella ID MEDIATED IMMUNE-DEFICIENCY; URBAN BRAZILIAN SLUM; BANGLADESHI CHILDREN; RURAL BANGLADESH; DEVELOPING-COUNTRIES; ESCHERICHIA-COLI; PHYSICAL GROWTH; NALIDIXIC-ACID; RISK-FACTORS; DOUBLE-BLIND AB Background, Dysentery accounts for 20% of the 4.6 million diarrhea-associated deaths among children in developing countries, with the risk from death in dysenteric persistent diarrhea 10-fold higher than that in acute dysentery, Although Shigella accounts for the majority of dysenteric episodes, very little is known about the epidemiology of postshigellosis persistent diarrhea, Methods. Rural Bangladeshi children younger than 5 years of age (n = 1756) were followed for 1 month after exposure to sentinel cases of Shigella dysentery, The likelihood of an acute diarrheal episode becoming persistent was assessed. Results. Diarrhea caused by Shigella was significantly associated with an increased risk of persistent diarrhea (age-adjusted relative risk, 1.83; 95% confidence interval, 1.19 to 2.81). Despite the use of nalidixic acid in dysenteric episodes, persistent diarrhea occurred in 23% of children with shigellosis, Infection by multiply antibiotic-resistant Shigella isolates (age-adjusted relative risk, 3.76; 95% confidence interval, 1.51 to 9.36) and occurrence of shigellosis during infancy were observed to be risk factors for initiation of Shigella diarrhea persistence. However, 88% of the persistent shigellosis episodes occurred in older children, 50% were associated with nondysenteric shigellosis and 79% were caused by Shigella species other than Shigella dysenteriae 1. Conclusions. These data demonstrate the importance of Shigella as a cause of persistent diarrhea and indicate that strategies to prevent postshigellosis persistent diarrhea must be broad-based, with a focus on older children as well as infants, management of nondysenteric as well as dysenteric disease and prevention of diarrhea caused by multiple Shigella species. C1 Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. Int Vaccine Inst, Seoul, South Korea. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Ahmed, F (reprint author), Ctr Dis Control & Prevent, Div Prevent Res & Analyt Methods, Mail Stop K-73,4770 Buford Highway, Atlanta, GA 30341 USA. NR 37 TC 15 Z9 15 U1 1 U2 1 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 MAY PY 2001 VL 20 IS 5 BP 525 EP 530 DI 10.1097/00006454-200105000-00011 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 431VZ UT WOS:000168653600010 PM 11368112 ER PT J AU Levy, HL Guldberg, P Guttler, F Hanley, WB Matalon, R Rouse, BM Trefz, E Azen, C Allred, EN de la Cruz, F Koch, R AF Levy, HL Guldberg, P Guttler, F Hanley, WB Matalon, R Rouse, BM Trefz, E Azen, C Allred, EN de la Cruz, F Koch, R TI Congenital heart disease in maternal phenylketonuria: Report from the Maternal PKU Collaborative Study SO PEDIATRIC RESEARCH LA English DT Article ID PHENYLALANINE-HYDROXYLASE DEFICIENCY; UNITED-STATES; FACTOR NKX2-5; MUTATIONS; PHENOTYPE; GENOTYPE; DEFECTS; GENE; HYPERPHENYLALANINEMIA; FEMALES AB The frequency and types of congenital heart disease in offspring from pregnancies in women with hyperphenylalaninemia were examined in the international prospective Maternal Phenylketonuria Collaborative Study. Relationships of congenital heart disease in offspring to the basal blood phenylalanine level in the mother, metabolic control through diet during pregnancy, and phenylalanine hydroxylase mutations in mother and offspring were determined. The 416 offspring from 412 maternal phenylketonuria pregnancies that produced live births and 100 offspring from the 99 control pregnancies were included in this examination. Thirty-four of the 235 offspring (14%; 95% CI. 10.2 to 19.6%) from pregnancies in phenylketonuric women with a basal phenylalanine level greater than or equal to 900 muM (15 mg/dL) [normal blood phenylalanine < 120 M (2 mg/dL)] and not in metabolic control [phenylalanine level less than or equal to 600 muM (10 mg/dL)] by the eighth gestational week had congenital heart disease compared with one control offspring (1%) with congenital heart disease. One offspring among the 50 (2%) from mothers with non-phenylketonuria mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented compared with expected percentages among those with congenital heart disease in the general population. A basal maternal phenylalanine level > 1800 muM (30 mg/dL) significantly increased the risk for bearing a child with congenital heart disease (p = 0.003). Phenylalanine hydroxylase mutations in the mothers and offspring did not have an independent relationship to congenital heart disease but were related through the basal maternal phenylalanine levels. The data in this study indicate that a basal maternal phenylalanine level of 900 muM may be a threshold for congenital heart disease, that women with the most severe degree of phenylketonuria are at highest risk for bearing such a child, and that prevention of the congenital heart disease requires initiation of the low phenylalanine diet before conception or early in pregnancy with metabolic control no later than the eighth gestational week. C1 Childrens Hosp, Div Genet, Boston, MA 02115 USA. Childrens Hosp, Neuroepidemiol Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. John F Kennedy Inst, DK-2600 Glostrup, Denmark. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Univ Texas, Med Branch, Galveston, TX 77550 USA. Childrens Hosp Reutlingen, Reutlingen, Germany. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. NICHHD, Bethesda, MD 20892 USA. RP Levy, HL (reprint author), Childrens Hosp, Div Genet, 300 Longwood Ave,IC-106, Boston, MA 02115 USA. FU NCRR NIH HHS [MO1-RR02172]; NICHD NIH HHS [N01-HD-2-3149] NR 31 TC 36 Z9 38 U1 0 U2 2 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 MAY PY 2001 VL 49 IS 5 BP 636 EP 642 DI 10.1203/00006450-200105000-00005 PG 7 WC Pediatrics SC Pediatrics GA 425VU UT WOS:000168313000005 PM 11328945 ER PT J AU Aguilera, G Rabadan-Diehl, C Nikodemova, M AF Aguilera, G Rabadan-Diehl, C Nikodemova, M TI Regulation of pituitary corticotropin releasing hormone receptors SO PEPTIDES LA English DT Article DE corticotropin releasing hormone receptor type-1 pituitary; CRH receptor binding; CRH receptor mRNA; CRH receptor regulation ID MESSENGER-RIBONUCLEIC-ACID; FACTOR CRF RECEPTORS; HOMOLOGOUS DESENSITIZATION; GLUCOCORTICOID REGULATION; ARGININE-VASOPRESSIN; ACTH-SECRETION; DEFICIENT MICE; CHRONIC STRESS; RAT PITUITARY; ADRENAL AXIS AB Corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through type-1 CRH (CRH1) receptors. Stimulation of the hypothalamic pituitary adrenal (HPA) axis as well as increased corticotroph responsiveness during stress and adrenalectomy are associated with marked pituitary CRH binding downregulation. The presence of CRH1 receptors in the pituitary are essential to maintain ACTH secretion. Downregulation of CRH binding is associated with normal or elevated levels of CRH1 receptor mRNA and this may contribute to the maintainence of permissive levels of CRH I receptors in the pituitary. Injection of either CRH or glucocorticoids in rats in vivo induces CRH binding and CRH1 receptor mRNA downregulation, whereas their simultaneous administration causes only transient CRH1 receptor mRNA loss. Vasopressin increases CRH1 receptor mRNA levels. This suggest that interactions between CRH, vasopressin and glucocorticoids accounts for CRH1 receptor mRNA upregulation during stress. The lack of correlation between CRH binding and CRH1 receptor mRNA indicates that the major sites for pituitary CRH1 receptor regulation are at the post-transcriptional level. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NICHD, Dev Endocrinol Branch, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NICHD, Dev Endocrinol Branch, Sect Endocrine Physiol, NIH, Bethesda, MD 20892 USA. NR 49 TC 49 Z9 51 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD MAY PY 2001 VL 22 IS 5 SI SI BP 769 EP 774 DI 10.1016/S0196-9781(01)00390-4 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 430CU UT WOS:000168556600009 PM 11337090 ER PT J AU Kuo, GM Boumpas, DT Illei, GG Yarboro, C Pucino, F Burstein, AH AF Kuo, GM Boumpas, DT Illei, GG Yarboro, C Pucino, F Burstein, AH TI Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis SO PHARMACOTHERAPY LA English DT Article; Proceedings Paper CT American-College-of-Clinical-Pharmacy Spring Practice and Research Forum CY APR 02, 2000 CL MONTEREY, CALIFORNIA SP Amer Coll Clin Pharm ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LOW-DOSE FLUDARABINE; CYCLOPHOSPHAMIDE THERAPY; RHEUMATOID-ARTHRITIS; OVARIAN FAILURE; ERYTHEMATOSUS; PHOSPHATE; TRIAL; RISK AB Study Objective. To compare the pharmaco kinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis. Design. Open-label, randomized, crossover trial conducted with a phase I-II trial. Setting. Government research hospital. Patients. Five patients with lupus nephritis. Intervention. Fludarabine 30 mg/m(2)/day was administered either subcutaneously or as a 0.5-hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m(2) on the first day of each cycle. Measurements and Main Results. Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6-hour intervals for 24 hours. Plasma and urine were analyzed for fluoroarabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using, a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (038-0.56) and 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concentration-time curves from 0-24 hours of 4.65 (4.17-4.98) and 4.55 (3.5-4.94) mg(.)hour/L, respectively. Bioavailability of F-ara-A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing. Conclusion. Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration. C1 NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. NIAMSD, Clin Invest Sect, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. RP Burstein, AH (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Ctr Clin, Bldg 10,Room 1N257, Bethesda, MD 20892 USA. NR 32 TC 7 Z9 9 U1 0 U2 2 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD MAY PY 2001 VL 21 IS 5 BP 528 EP 533 DI 10.1592/phco.21.6.528.34549 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 470AW UT WOS:000170849100002 PM 11349741 ER PT J AU Bogan, JA Grimwade, JE Thornton, M Zhou, P Denning, GDC Helmstetter, CE AF Bogan, JA Grimwade, JE Thornton, M Zhou, P Denning, GDC Helmstetter, CE TI P1 and NR1 plasmid replication during the cell cycle of Escherichia coli SO PLASMID LA English DT Article DE plasmid; replication; Escherichia coli; cell cycle; temperature shift; minichromosome; oriC ID DNA-REPLICATION; DIVISION CYCLE; B-R; INITIATION; CHROMOSOME; ORIGIN; TRANSCRIPTION; METHYLATION; REGION; SEQA AB Replication patterns of the miniP1 plasmid pZC176, the miniNR1 plasmid pRR933, and the high copy miniNR1 derivative pRR942 were examined during the Escherichia coli cell division cycle and compared to the cycle-specific replication pattern of a minichromosome and the cycle nonspecific pattern of pBR322. In E. coli cells growing with doubling times of 40 and 60 min, the miniP1 plasmid was found to replicate with a slight periodicity during the division cycle. The periodicity was not nearly as pronounced as that of the minichromosome, was not affected by the presence of a minichromosome, and was not evident in cells growing more rapidly with a doubling time of min. Both miniNR1 plasmids, pRR933 and pRR942, replicated with patterns indistinguishable from that of pBR322 and clearly different from that of the minichromosome. It is concluded that both P1 and NR1 plasmids can replicate at all stages of the cell cycle but that pi displays a slight periodicity in replication prob ability in the cycle of slower growing cells. This periodicity does not appear to be coupled to a specific age in the cycle, but could be associated with the achievement of a specifics cell mass per plasmid. During temperature shifts of a dnaC(Ts) mutant, the miniP1 plasmid and pBR322 replicated with similar patterns that differed from that of the minichromosome, but were consistent with a brief eclipse between rounds of replication. (C) 2001 Academic Press. C1 Florida Inst Technol, Dept Biol Sci, Melbourne, FL 32901 USA. RP Bogan, JA (reprint author), NICHHD, NIH, Bldg 6,Room 416, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM26429] NR 47 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0147-619X J9 PLASMID JI Plasmid PD MAY PY 2001 VL 45 IS 3 BP 200 EP 208 DI 10.1006/plas.2000.1512 PG 9 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA 445YN UT WOS:000169486300003 PM 11407915 ER PT J AU Liu, XF Olsson, P Wolfgang, CD Bera, TK Duray, P Lee, B Pastan, I AF Liu, XF Olsson, P Wolfgang, CD Bera, TK Duray, P Lee, B Pastan, I TI PRAC: A novel small nuclear protein that is specifically expressed in human prostate and colon SO PROSTATE LA English DT Article DE EST; novel gene; LNCaP; prostate cancer cell line ID DNA-SEQUENCE; GENE; CANCER; REGION; TRANSLATION; INFORMATION; DISCOVERY; EVOLUTION; HOXB-13; CELLS AB BACKGROUND. The database of human Expressed Sequence Tags (dbEST) provides a potential source for identification of tissue-specific genes. This database contains sequences that originate from cDNA libraries from particular tumors, organs or cell typos. In this report, we have used the EST database to identify PRAC, a novel gene specifically expressed in human Prostate, prostate cancer, Rectum And distal Colon. METHODS. Using a computer based analysis, a cluster of sequence homologous ESTs was identified which contained ESTs derived only from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The PRAC transcript and protein Mas identified using Northern blot analysis, RACE-PCR, primer extension, and western blot. RESULTS. PRAC encode a 382 nucleotide RNA found in prostate, rectum, distal colon, and in three prostate cancer cell lines; LNCaP, PC-3 and DU145. This transcript encodes a 6 kDa nuclear protein. The PRAC gene is located on chromosome 17 at position 17q21, about 4 kbp downstream from the homeodomain Hoxb-13 gene. CONCLUSIONS. Our data proves that the EST database can be a useful tool for discovery of prostate-specific genes. The nuclear localization, identification of potential phosphorylation sites, and possible cotranscription with the Hoxb-13 gene suggest that PRAC may have a regulatory role in the nucleus. Prostate 47:125-131, 2001. (C) 2001 Wiley-Liss, Inc. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E16,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 26 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 0270-4137 J9 PROSTATE JI Prostate PD MAY 1 PY 2001 VL 47 IS 2 BP 125 EP 131 DI 10.1002/pros.1055 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 426FE UT WOS:000168338500007 PM 11340635 ER PT J AU Iyer, LM Koonin, EV Aravind, L AF Iyer, LM Koonin, EV Aravind, L TI Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE START; aromatase; cyclase; lipid binding; birch allergen ID PROTEIN SECONDARY STRUCTURE; PSI-BLAST; POLYKETIDE SYNTHASE; CRYSTAL-STRUCTURE; DATABASE; SEQUENCE; PREDICTION; MECHANISM; SEARCHES; MATRICES AB With a protein structure comparison, an iterative database search with sequence profiles, and a multiple-alignment analysis, we show that two domains with the helix-grip fold, the star-related lipid-transfer (START) domain of the MLN64 protein and the birch allergen, are homologous. They define a large, previously underappreciated superfamily that we call the START superfamily. In addition to the classical START domains that are primarily involved in eukaryotic signaling mediated by lipid binding and the birch antigen family that consists of plant proteins implicated in stress/pathogen response, the START superfamily includes bacterial polyketide cyclases/aromatases (e.g., TcmN and WhiE VI) and two families of previously uncharacterized proteins, The identification of this domain provides a structural prediction of an important class of enzymes involved in polyketide antibiotic synthesis and allows the prediction of their active site. It is predicted that all START domains contain a similar ligand-binding pocket, Modifications of this pocket determine the ligand-binding specificity and may also be the basis for at least two distinct enzymatic activities, those of a cyclase/aromatase and an RNase. Thus, the START domain superfamily is a rare case of the adaptation of a protein fold with a conserved ligand-binding mode for both a broad variety of catalytic activities and noncatalytic regulatory functions. Published 2001 Wiley-Liss, Inc.(dagger) 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. NR 45 TC 130 Z9 136 U1 1 U2 15 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 MAY 1 PY 2001 VL 43 IS 2 BP 134 EP 144 DI 10.1002/1097-0134(20010501)43:2<134::AID-PROT1025>3.3.CO;2-9 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 413XX UT WOS:000167637800007 PM 11276083 ER PT J AU Buzas, Z Chang, HT Vieira, NE Yergey, AL Stastna, M Chrambach, A AF Buzas, Z Chang, HT Vieira, NE Yergey, AL Stastna, M Chrambach, A TI Direct vertical electroelution of protein from a PhastSystem band for mass spectrometric identification at the level of a few picomoles SO PROTEOMICS LA English DT Article DE vertical electroelution; picomolar protein identification; mass spectrometry ID GEL-ELECTROPHORESIS APPARATUS; SUBCELLULAR-SIZED PARTICLES; POLYACRYLAMIDE GELS; SEPARATED PROTEINS; SDS-PROTEIN; RECOVERY; SENSITIVITY AB An electroelution apparatus prototype of a new design was constructed. In that design, the electric field passes vertically through the protein band located on a horizontal (PhastSystem) minigel polymerized on a net of Gel-Fix (Serva). A simple, home-made apparatus allows for electroelution of protein bands at the level of a few picomoles and their identification, after concentration, by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The technique is applicable to one-dimensional (I-D) or two-dimensional (2-D) gels of any size, but has been exemplified only by application to I-D minigels to demonstrate the lower limits of protein load of the method. When in the course of further development of the prototype it will be combined with a modification to two dimensions of the electroelution mechanism under computer control of the high-performance gel electrophoresis apparatus**** (formerly of LabIntelligence), the new design appears uniquely qualified for an automated spot elution from 2-D gels under avoidance of gel sectioning. C1 NICHD, Macromol Anal Sect, NIH, Bethesda, MD 20892 USA. NICHD, Sect Mass Spectrometry & Metab, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHD, Macromol Anal Sect, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. RI Chang, Huan-Tsung/C-1183-2011; Stastna, Miroslava/G-9266-2014; OI Chang, Huan-Tsung/0000-0002-5393-1410 NR 26 TC 10 Z9 12 U1 1 U2 2 PU WILEY-V C H VERLAG GMBH PI BERLIN PA PO BOX 10 11 61, D-69451 BERLIN, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD MAY PY 2001 VL 1 IS 5 BP 691 EP 698 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 452YP UT WOS:000169887500005 PM 11678038 ER PT J AU Lilenfeld, LRR Devlin, B Bacanu, S Kaye, WH Bulik, CM Strober, M Berrettini, WH Fichter, MM Goldman, D Halmi, KA Kaplan, A Woodside, DB Treasure, J AF Lilenfeld, LRR Devlin, B Bacanu, S Kaye, WH Bulik, CM Strober, M Berrettini, WH Fichter, MM Goldman, D Halmi, KA Kaplan, A Woodside, DB Treasure, J CA Price Fdn Collaborative Grp TI Deriving behavioural phenotypes in an international, multi-centre study of eating disorders SO PSYCHOLOGICAL MEDICINE LA English DT Article ID TRIDIMENSIONAL PERSONALITY QUESTIONNAIRE; TERM WEIGHT RESTORATION; ANOREXIA-NERVOSA; BULIMIA-NERVOSA; SEROTONIN ACTIVITY; ANXIETY DISORDERS; TEMPERAMENT; RECOVERY; WOMEN; PERFECTIONISM AB Background. An international, multi-site study funded by the Price Foundation has collected 237 affected relative pairs to identify potential genetic factors that may contribute to the pathogenesis of anorexia nervosa (AN), The current report utilized this sample to derive phenotypes from the personality and behavioural traits assessed in a large number of individuals with eating disorders. Methods. Multivariate analytical techniques were used to characterize the relationships among personality (e,g, trait anxiety, perfectionism, harm avoidance, novelty seeking) and behavioural traits (obsessions and compulsions) in individuals with eating disorders (primarily AN; N = 348) and assess the effectiveness of these traits in classifying subjects into diagnostic subtypes, Results. Factor analysis revealed that the most influential factor was one of trait anxiety, harm avoidance, perfectionism, obsessive-compulsive behaviours, and diminished self-directedness, although the precise nature of this factor differed slightly across sites. Discriminant analysis was used to evaluate the utility of these personality/behavioural factors in predicting subdiagnosis, Overall, the misclassification rate was 34%; however, there was an 80% rate of accurate classification of those individuals with a diagnosis of restricting-type AN. Conclusions. Trait anxiety, harm avoidance, perfectionism, obsessive-compulsive behaviours and diminished self-directedness may best be conceptualized as parts of the same underlying construct among individuals with eating disorders, particularly AN. These personality and behavioural traits were also found to be of some utility in classifying eating disordered individuals into diagnostic subgroups, particularly those with restricting-type AN. We expect these phenotypic findings to benefit our ongoing search for genetic loci underlying the liability to eating disorders. C1 Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. Univ Calif Los Angeles, Sch Med, Neuropsychiat Inst & Hosp, Los Angeles, CA USA. Univ Penn, Sch Med, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. Hosp Behav Med, Klin Roseneck, Munich, Germany. NIAAA, NIH, Bethesda, MD 20034 USA. Cornell Univ, Weill Med Coll, New York Presbyterian Hosp Westchester, White Plains, NY USA. Toronto Hosp, Dept Psychiat, Toronto, ON, Canada. Bethlem Royal & Maudsley Hosp, Inst Psychiat, London, England. RP Kaye, WH (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, 3811 OHara St,E-724, Pittsburgh, PA 15213 USA. RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Treasure, Janet/0000-0003-0871-4596 NR 59 TC 23 Z9 24 U1 4 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD MAY PY 2001 VL 31 IS 4 BP 635 EP 645 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 433TY UT WOS:000168776900008 ER PT J AU Scuteri, A Parsons, D Chesney, MA Anderson, DE AF Scuteri, A Parsons, D Chesney, MA Anderson, DE TI Anger inhibition potentiates the association of high end-tidal CO2 with blood pressure in women SO PSYCHOSOMATIC MEDICINE LA English DT Article DE anger; breathing; blood pressure; end-tidal CO2; hypertension; women ID ESSENTIAL-HYPERTENSION; ADULTS; HYPOVENTILATION; PERSONALITY; EXPRESSION; DISORDERS; GENDER; STRESS AB Objective: High resting end-tidal CO2 (PetCO(2)) has been shown to be an independent predictor of systolic blood pressure (SBP) in women, particularly older women. The study reported in this article investigated whether the tendency to experience, express, and/or suppress anger contributes to the association of PetCO(2) and SEP in women and in men. Methods: The Spielberger Anger Expression Inventory was administered to 403 healthy male and female participants in the Baltimore Longitudinal Study on Aging. Resting PetCO(2) was obtained by means of a respiratory gas monitor, and resting blood pressure was obtained with an oscillometric device. The associations of resting PetCO(2) and the anger scales with SEP and diastolic blood pressure (DBP) were investigated using multivariate regression analyses. Results: PetCO(2), as well as age and body mass index, was an independent predictor of SEP in women with low, but not high, trait anger and in women with low, but not high, anger-out. PetCO(2) was not an independent predictor of SEP in men with either high or low anger. In addition, PetCO(2) was not an independent predictor of DBP in either men or women. Conclusions: The results of this study indicate that inhibition of anger potentiates the relationship of high PetCO(2) with SEP in women but not men. Additional studies are needed to determine the origins of the observed gender differences and the psychophysiological pathways by which high resting PetCO(2) contributes to elevated resting blood pressure in women. C1 NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. RP Anderson, DE (reprint author), NIA, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD MAY-JUN PY 2001 VL 63 IS 3 BP 470 EP 475 PG 6 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 432ZN UT WOS:000168731000016 PM 11382275 ER PT J AU Newbold, RR Jefferson, WN Padilla-Banks, E Walker, VR Pena, DS AF Newbold, RR Jefferson, WN Padilla-Banks, E Walker, VR Pena, DS TI Cell response endpoints enhance sensitivity of the immature mouse uterotropic assay SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE risk assessment; estrogens; endocrine disrupters; uterotropic bioassay; environmental estrogens; xenoestrogens; lactoferrin; complement C3; PCNA ID ESTROGEN; DIETHYLSTILBESTROL; METABOLITES; ONTOGENY; EXPOSURE; INVITRO; MARKERS; INVIVO; UTERUS AB Outbred immature CD-I mice were subcutaneously (s.c.) injected once on postnatal day 17 or on postnatal days 17, 18, and 19 with 17 beta -estradiol, diethylstilbestrol, tamoxifen, 4-hydroxytamoxifen, methoxychlor, the methoxychlor metabolite HPTE, nonylphenol, o,p ' -DDT, endosulfan, or kepone over a wide dose range (0.1 to 1,000,000 mug/kg). On the day following the last injection, uterine weight/body weight ratios were determined and uterine tissues processed for histologic examination. All compounds except endosulfan and kepone increased uterine wet weight compared to vehicle controls; however, the dose response curve and magnitude of response varied depending on the compound. Choosing the maximum wet weight dose for each compound, uterine tissue was evaluated for epithelial cell height, epithelial and stromal cell proliferation, endometrial gland number, and induction of estrogen-inducible proteins lactoferrin and complement C3. All compounds elicited estrogen-responsive changes in these endpoints that were individually more sensitive than uterine weight alone. We conclude that these endpoints enhance the sensitivity of the uterotropic bioassay. (C) 2001 Elsevier Science Inc. All rights reserved. C1 NIEHS, Dev endocrinol Studies Grp, Toxicol Lab, Environm Toxicol Program,Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Off Director, Nihon Univ, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), NIEHS, Dev endocrinol Studies Grp, Toxicol Lab, Environm Toxicol Program,Div Intramural Res,NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 41 Z9 44 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD MAY-JUN PY 2001 VL 15 IS 3 BP 245 EP 252 DI 10.1016/S0890-6238(01)00130-7 PG 8 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 441QW UT WOS:000169241900004 PM 11390168 ER PT J AU Zheng, G Gastwirth, JL AF Zheng, G Gastwirth, JL TI On the Fisher information in randomly censored data SO STATISTICS & PROBABILITY LETTERS LA English DT Article DE hazard rate; Koziol-Green model; loss of Fisher information ID KOZIOL-GREEN MODEL; SURVIVAL FUNCTION; KAPLAN-MEIER AB After expressing the Fisher information in randomly censored data in terms of hazard rates, we examine the loss of Fisher information under the Koziol-Green random censoring model. Because the same parameter enters both the survival and censoring distributions in this model, the censored data may contain more Fisher information than the uncensored data. (C) 2001 Elsevier Science B.V. All rights reserved. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. NR 13 TC 11 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD MAY 1 PY 2001 VL 52 IS 4 BP 421 EP 426 DI 10.1016/S0167-7152(01)00025-6 PG 6 WC Statistics & Probability SC Mathematics GA 442KZ UT WOS:000169285900011 ER PT J AU Hunt, KJ Evans, GW Folsom, AR Sharrett, AR Chambless, LE Tegeler, CH Heiss, G AF Hunt, KJ Evans, GW Folsom, AR Sharrett, AR Chambless, LE Tegeler, CH Heiss, G TI Acoustic shadowing on B-mode ultrasound of the carotid artery predicts ischemic stroke - The atherosclerosis risk in communities (ARIC) study SO STROKE LA English DT Article DE carotid arteries; cerebral infarction; incidence; risk factors; ultrasonography ID BEAM COMPUTED-TOMOGRAPHY; TISSUE CHARACTERIZATION; ATHEROMATOUS PLAQUES; CORONARY-ARTERIES; FOLLOW-UP; DISEASE; CALCIFICATION; HEMORRHAGE; STENOSIS; ENDARTERECTOMY AB Background and Purpose-We examined the relationship of carotid artery lesions (CALs), with and without acoustic shadowing (AS), to incident ischemic stroke events in the Atherosclerosis Risk in Communities study cohort. Methods-The study population consisted of 13 123 men and women aged 45 to 64 years, and free of stroke, examined during 1986-1989. Over an average follow-up time of 8.0 years, 226 incident ischemic stroke cases (thromboembolic brain infarctions) were identified and classified by a standardized protocol. Three levels of exposure were defined on the basis of the presence of B-mode ultrasound-detected CALs and AS in a 3-cm Segment of the carotid arteries centered at the bifurcation. Results-The hazard ratio for ischemic stroke adjusted fur age, ethnicity, and study site for women with a CAL without AS, compared with those without a GAL, was 1.92 (95% CI, 1.23, 3.01), and the hazard ratio comparing those with a CAL with AS with those without a CAL was 4.01 (95% CI, 2.28, 7.06). The corresponding hazard ratios fur men were 1.99 (95% CI, 1.36, 2.91) and 2.23 (95% CI, 1.32, 3.79). Although adjustment for diabetes, hypertension medication, systolic blood pressure, left ventricular hypertrophy score, fibrinogen, von Willebrand factor antigen, and smoking status attenuated these associations somewhat, when compared with no evidence of CALs, CALs with AS remained statistically significant predictors of ischemic stroke in women, while CALs without AS were predictive of ischemic stroke in men. Conclusions-B-mode ultrasound-detected CALs and AS serve as markers of atherosclerosis and thus are predictive of ischemic stroke. C1 Univ N Carolina, Dept Epidemiol, CVD Program, Bank Amer, Chapel Hill, NC 27514 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. Wake Forest Univ, Baptist Med Ctr, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Wake Forest Univ, Baptist Med Ctr, Dept Neurol, Winston Salem, NC 27109 USA. Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Bethesda, MD 20892 USA. RP Heiss, G (reprint author), Univ N Carolina, Dept Epidemiol, CVD Program, Bank Amer, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55017, 5-T32-HL07055, N01-HC-55018, N01-HC-55016, N01-HC-55020, N01-HC-55019, N01-HC-55021] NR 60 TC 30 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2001 VL 32 IS 5 BP 1120 EP 1126 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 430MG UT WOS:000168577200017 PM 11340220 ER PT J AU Pluta, RM AF Pluta, RM TI Endothelin-1 in vasospasm after SAH SO STROKE LA English DT Editorial Material ID ANEURYSMAL SUBARACHNOID HEMORRHAGE; ET(A) RECEPTOR ANTAGONIST; CEREBRAL VASOSPASM; CEREBROSPINAL-FLUID; RELEASE; CELLS; DOGS C1 NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Pluta, RM (reprint author), NINDS, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2001 VL 32 IS 5 BP 1189 EP 1190 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 430MG UT WOS:000168577200030 ER EF