FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Portilla, D Crew, MD Grant, D Serrero, G Bates, LM Dai, GH Sasner, M Cheng, J Buonanno, A AF Portilla, D Crew, MD Grant, D Serrero, G Bates, LM Dai, GH Sasner, M Cheng, J Buonanno, A TI cDNA cloning and expression of a novel family of enzymes with calcium-independent phospholipase A(2) and lysophospholipase activities SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RABBIT PROXIMAL TUBULES; CYTOSOLIC PHOSPHOLIPASE-A2; HYPOXIC INJURY; BOVINE BRAIN; PURIFICATION; PROTEIN; ACID; GLYCEROPHOSPHOLIPIDS; IDENTIFICATION; SEQUENCE AB Previous studies have suggested that activation of calcium-independent PLA(2) (CaIPLA(2)) is an early event in cell death after hypoxic injury in proximal tubule cells. An approximately 28-kD CaIPLA(2) with preferential activity toward plasmalogen phospholipids has been recently purified from rabbit kidney cortex (D. Portilla and G. Dal, J Biol Chem 271, 15451-15457, 1996). Their report describes the cloning of a full-length rat cDNA encoding CaIPLA(2), using sequences derived from the purified rabbit kidney cortex enzyme. In addition, cDNA from rabbit kidney that encode the rabbit homologue of the enzyme and a closely related isoform were isolated. The rat cDNA is predicted to encode an approximately 24-kD protein, and each cDNA contains the sequence G-F-S-Q-G, which fits the active site consensus sequence G-X-S-X-G of carboxylesterases. Several lines of evidence (DNA sequence comparison, Southern blot analysis, and examination of the expressed sequence tag database) show that CaIPLA(2) enzymes are encoded by a multigene family in rats, mice, rabbits, and humans. Northern analysis of various tissues from the rat indicated that the CaIPLA(2) gene is ubiquitously expressed, with highest mRNA abundance observed in the kidney and small intestine. The rat CaIPLA(2) cDNA, when expressed in a baculovirus expression system, and the purified rabbit kidney cortex protein exhibit both CaIPLA(2) and lysophospholipase activities. The cloned CaIPLA(2) cDNA are expected to aid in understanding the role of CaIPLA(2) in cell death after hypoxic/ischemic cell injury. C1 Univ Arkansas Med Sci, Dept Internal Med, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Dept Pharmacol, Little Rock, AR 72205 USA. Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NICHHD, Mol Neurobiol Unit, NIH, Bethesda, MD 20892 USA. RP Portilla, D (reprint author), Univ Arkansas Med Sci, Dept Med, Div Nephrol, 4301 W Markham,Slot 501, Little Rock, AR 72205 USA. FU NIDDK NIH HHS [R29 DK46914, R01 DK52926] NR 36 TC 24 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 1998 VL 9 IS 7 BP 1178 EP 1186 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA ZV266 UT WOS:000074287400004 PM 9644627 ER PT J AU Seidman, LJ Stone, WS Jones, R Harrison, RH Mirsky, AF AF Seidman, LJ Stone, WS Jones, R Harrison, RH Mirsky, AF TI Comparative effects of schizophrenia and temporal lobe epilepsy on memory SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE schizophrenia; epilepsy; memory; attention; neuropsychology ID NEUROPSYCHOLOGICAL FUNCTION; DYSFUNCTION; PERFORMANCE; CLASSIFICATION; IMPAIRMENT; PSYCHOSIS; DISORDERS; DEFICIT; RECALL; TASKS AB The goal of this study was to further characterize episodic memory functioning in schizophrenia This study compared verbal and visual learning and memory performance in (1) patients with schizophrenia (N = 35), (2) patients with temporal lobe epilepsy (TLE; N = 30), and (3) normal controls (N = 25). Results indicated significant memory impairments in patients with schizophrenia and TLE. "Savings" score measures of memory decay showed that the loss of information in schizophrenia and TLE was approximately equal, and quantitatively mild compared to that found in most neurologic groups with memory disorders. The severe difficulty shown by the schizophrenia group on a task of incidental recall suggested that the absence of instructional set added to a vulnerability to memory deficit. In contrast, relatively mildly impaired performance on paired associate learning suggested that patients with schizophrenia benefited from retrieval cues, multiple trials, and short (nonsupraspan) informational loads. Because patients with schizophrenia consisted of a relatively nonchronic sample with a mean IQ of 99.7, their memory disorder could not be attributed to schizophrenic dementia, nor was it accounted for by other potential confounds. Patients with schizophrenia, even those relatively early in the course of illness, have a mild episodic memory disorder. C1 Harvard Univ, Sch Med,Massachusetts Mental Hlth Ctr, Harvard Inst Psychiat Epidemiol & Genet, Neuropsychol Lab S530, Boston, MA 02115 USA. Harvard Univ, Sch Med,Massachusetts Mental Hlth Ctr, Dept Psychiat, Commonwealth Res Ctr, Boston, MA 02115 USA. Boston Univ, Dept Psychol, Boston, MA 02215 USA. NIMH, Sect Clin & Expt Neuropsychol, Psychol & Psychopathol Lab, Bethesda, MD 20892 USA. RP Seidman, LJ (reprint author), Harvard Univ, Sch Med,Massachusetts Mental Hlth Ctr, Harvard Inst Psychiat Epidemiol & Genet, Neuropsychol Lab S530, 74 Fenwood Rd, Boston, MA 02115 USA. EM larrys@warren.med.harvard.edu FU NIMH NIH HHS [MH-14915, MH-26183, MH-37156] NR 62 TC 44 Z9 44 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 1998 VL 4 IS 4 BP 342 EP 352 PG 11 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 104ZF UT WOS:000075046600005 PM 9656608 ER PT J AU O'Neil, KM Johnson, BE AF O'Neil, KM Johnson, BE TI Lights flicker on fluorescence bronchoscopy in patients at risk for lung cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CARCINOMA INSITU; DYSPLASIA C1 Natl Naval Med Ctr, Med Branch, Dept Med, Div Pulm, Bethesda, MD 20889 USA. NCI, Lung Canc Biol Sect, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Johnson, BE (reprint author), Natl Naval Med Ctr, Med Branch, Dept Med, Div Pulm, Bldg 8,Rm 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 12 TC 15 Z9 15 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 JUL 1 PY 1998 VL 90 IS 13 BP 953 EP 955 DI 10.1093/jnci/90.13.953 PG 3 WC Oncology SC Oncology GA ZX371 UT WOS:000074508800002 PM 9665138 ER PT J AU Waltregny, D Bellahcene, A Van Riet, I Fisher, LW Young, M Fernandez, P Dewe, W de Leval, J Castronovo, V AF Waltregny, D Bellahcene, A Van Riet, I Fisher, LW Young, M Fernandez, P Dewe, W de Leval, J Castronovo, V TI Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN BREAST-CANCER; RADICAL RETROPUBIC PROSTATECTOMY; ADHESION MOLECULES; CELL-ADHESION; ANTIGEN; ADENOCARCINOMA; SPECIMENS; STAGE-T1C; INTEGRINS; PROTEIN AB Background- Bone sialoprotein (BSP), a bone matrix protein, was recently found to be expressed ectopically in breast cancer and to have a statistically significant association with poor prognosis and the development of bone metastases in that disease. These data prompted us to investigate whether BSP might also be expressed in human prostate cancer, which often metastasizes to bone, and be predictive for progression risk, Methods: Tissue sections from 180 patients who had undergone a radical prostatecomy for localized prostate cancer were analyzed immunohistochemically for BSP expression, Biochemical progression was defined as an increasing serum prostate-specific antigen level of 0.5 ng/mL or more. Statistical analysis was used to assess associations between pathologic findings and level of BSP expression, and a Cox proportional hazards model was used to determine which clinical and histologic parameters, including stage, Gleason score, and BSP expression (immunostaining intensity and extent), were independently associated with biochemical progression, All Pvalues were two-sided. Results: Most of the prostate cancer lesions examined (75.9%) expressed detectable levels of BSP, instability in epithelial borderline pared with no or low expression in the adjacent normal glandular tissue. A statistically sufficient association was found between BSP expression and biochemical progression in both univariate and multivariate analyses. After a follow-up interval of 3 years, the biochemical relapse rate was 36.7% (95% confidence interval [CI] = 23.4%-47.7%) in patients whose tumors expressed high levels of BSP compared with 12.1% (95% CI = 2.3%-20.8%) in patients whose tumors expressed no or a low detectable level of the protein (log-rank test, P =,0014). BSP expression status could identify those patients at higher risk of biochemical progression (log-rank test, P<.05) among patients with moderately differentiated tumors or with pathologically confined tumors. Conclusions: To our knowledge, this study is the first to demonstrate BSP expression in human prostate cancer and to highlight the protein's statistically significant prognostic value in patients with clinically confined prostate adenocarcinomas. C1 Univ Liege, Metastasis Res Lab, B-4000 Liege, Belgium. Univ Liege, Urol Sect, B-4000 Liege, Belgium. Univ Liege, Dept Biostat, B-4000 Liege, Belgium. Univ Liege, Urol Sect, B-4000 Liege, Belgium. Free Univ Brussels, Dept Hematol Immunol, Brussels, Belgium. NIDR, Bone Res Branch, NIH, Bethesda, MD 20892 USA. Univ Barcelona, Hosp Clin Barcelona, Dept Anat Pathol, Inst Invest Biomed Agusti Pi & Su, E-08007 Barcelona, Spain. RP Castronovo, V (reprint author), Univ Liege, Metastasis Res Lab, Tour Pathol 1,Bat B23, B-4000 Liege, Belgium. NR 56 TC 112 Z9 117 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 1 PY 1998 VL 90 IS 13 BP 1000 EP 1008 DI 10.1093/jnci/90.13.1000 PG 9 WC Oncology SC Oncology GA ZX371 UT WOS:000074508800013 PM 9665149 ER PT J AU Hand, M Brown, C Horan, M Simons-Morton, D AF Hand, M Brown, C Horan, M Simons-Morton, D CA Natl Heart Lung Blood Inst TI The National Heart Attack Alert Program: Progress at 5 years in educating providers, patients, and the public and future directions SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE myocardial infarction; patient education; public health; thrombolytic therapy AB The National Heart Attack Alert Program (NHAAP) was launched by the National Heart, Lung, and Blood Institute in 1991 with the goal of reducing morbidity and mortality from acute myocardial infarction (AMI) through the rapid identification and treatment of individuals with symptoms and signs of an AMI. To achieve this goal, the NHAAP established objectives for each of three phases of action where treatment delays can occur: in the hospital, the prehospital setting, and the patient/bystander arena. The NHAAP initially directed its educational efforts toward emergency department professionals. Recommendations for reducing delays in emergency department identification of patients presenting with heart attack symptoms were developed by a working group convened in late 1991. These recommendations were published in February 1994 in a peer-reviewed journal reaching more than 17,000 emergency physicians. The NHAAP worked in a partnership with its coordinating committee, representing 40 health professional, voluntary, and government organizations, to extend the reach of the report's recommendations to their members. Strategies for promoting the emergency department recommendations included publication of excerpts in newsletters and journals of the medical, nursing, and prehospital provider organizations represented on the NHAAP Coordinating Committee, and through symposia at annual meetings. Industry assisted with dissemination efforts and with implementing a continuous quality improvement program based on the paper's recommendations. The NHAAP also developed, with the Joint Committee on Accreditation of Health Care Organizations, a time-to-treatment indicator for thrombolytic therapy to be incorporated into their Indicator Measurement System (IMSystem). To track achievement of the objectives related to the Hospital Action Phase, national data sources for emergency department management of patients with AMI were evaluated at the 5-year point of the NHAAP. Data from a national registry showed that the median time from presentation at the emergency department to receiving thrombolytic therapy declined by about one third between 1992 and the;last half of 1995. The percentage of all Medicare patients receiving thrombolytic therapy within the recommended 30 minutes after emergency department arrival nearly doubled between 1992 and 1995. Based on these and other results presented at the 5-year juncture of the program, the NHAAP Coordinating Committee assessed progress and identified new areas of focus for the next 5 years. Improvements in emergency departments' ability to identify and treat AMI patients progressed during the first 5 years of the NHAAP, when the program was highlighting this as a priority. This model is continuing to be used to address delays in the Prehospital Action Phase. Further research from a National Heart, Lung, and Blood Institute (NHLBI) community intervention Mel will guide the program in its plans for full-scale public education to address the Patient/Bystander Recognition and Action Phase. C1 NHLBI, Interagcy Data Coordinat & Program Evaluat Adviso, Natl Heart Attack Alert Program, Off Prevent Educ & Control,NIH, Bethesda, MD 20892 USA. RP Hand, M (reprint author), NHLBI, Interagcy Data Coordinat & Program Evaluat Adviso, Natl Heart Attack Alert Program, Off Prevent Educ & Control,NIH, 31 Ctr Dr MSC 2480,Bldg 31,Room 4A16, Bethesda, MD 20892 USA. NR 23 TC 17 Z9 18 U1 2 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD JUL PY 1998 VL 6 IS 1 BP 9 EP 17 DI 10.1023/A:1008868020782 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 119UV UT WOS:000075917000002 ER PT J CA Natl Heart Lung Blood Inst TI Access to timely and optimal care of patients with acute coronary syndromes - Community planning considerations: A report by the National Heart Attack Alert Program SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Review DE angina; unstable angina; community health planning; health services accessibility; myocardial infarction ID ACUTE MYOCARDIAL-INFARCTION; AUTOMATIC EXTERNAL DEFIBRILLATORS; EMERGENCY MEDICAL TECHNICIANS; HOSPITAL CARDIAC ARRESTS; TRAUMA CARE; CHEST PAIN; VENTRICULAR-FIBRILLATION; IMMEDIATE ANGIOPLASTY; RAPID DEFIBRILLATION; THROMBOLYTIC THERAPY AB Age-adjusted mortality due to cardiovascular disease (CVD) has declined by more than 50% over the past three decades; however, CVD continues to be the leading cause of death in the United States. In 1994, 1.25 million people experienced an acute myocardial infarction (AMI). Nearly 500,000 Americans died from CVD, and more than half of these deaths occurred suddenly, within 1 hour of symptom onset, outside the hospital setting. The National Heart Attack Alert Program (NHAAP) endorses the view of the American Heart Association that the community should be recognized as the "ultimate coronary care unit." Rapid identification and early treatment are supported by research that demonstrates time is a fundamental factor in reducing morbidity and mortality from AMI and cardiac arrest. A dramatic relationship has been shown between the onset of AMI symptoms, reperfusion treatment, and outcome for patients treated within the first hour after the onset of symptoms. The golden hour has become a widely recognized term in the trauma field, and communities and states are encouraged to develop and implement regional and statewide plans to ensure that trauma patients receive appropriate care within 1 hour of injury. The primary premise of this report - that planning by communities for rapid recognition and triage of patients with symptoms and signs of acute coronary syndromes will result in better outcomes for patients with AMI, including sudden cardiac arrest - is largely based on experience with trauma patients, a population that is benefitting from similar community planning efforts. This NHAAP report reviews community planning considerations and the essential components of an effective community plan (i.e., action plans and protocols, equipment and resources, education and training, and continuous quality improvement evaluation and research) and provides recommendations for each component. The report also presents strategies to guide communities in developing community cardiac emergency action plans. C1 NHLBI, Natl Heart Attack Alert Program, Coordinating Comm,Access Care Subcomm, Off Prevent Educ & Control,NIH, Bethesda, MD 20892 USA. RP Natl Heart Lung Blood Inst (reprint author), NHLBI, Natl Heart Attack Alert Program, Coordinating Comm,Access Care Subcomm, Off Prevent Educ & Control,NIH, 31 Ctr Dr MSC 2480,Bldg 31,Room 4A18, Bethesda, MD 20892 USA. NR 108 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD JUL PY 1998 VL 6 IS 1 BP 19 EP 46 PG 28 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 119UV UT WOS:000075917000003 ER PT J CA Natl Heart Lung Blood Inst TI Educational strategies to prevent prehospital delay in patients at high risk for acute myocardial infarction: A report by the National Heart Attack Alert Program SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE coronary heart disease; myocardial infarction; patient education; thrombolytic therapy ID ACUTE CHEST PAIN; EMERGENCY MEDICAL-SERVICES; PRE-HOSPITAL PHASE; THROMBOLYTIC THERAPY; CORONARY ANGIOPLASTY; UNITED-STATES; DISEASE MORTALITY; PUBLIC-EDUCATION; CREATINE-KINASE; HEALTH-SERVICES AB An estimated 13 million people in the United States have coronary heart disease (CHD), peripheral vascular disease, or cerebrovascular disease. The risk for subsequent myocardial infarction (MI) and death in these patients is fivefold to sevenfold higher than for the general population. Many effective therapies are now available for patients with unstable angina, acute myocardial infarction (AMI), potentially fatal arrhythmias, and cardiogenic shock if they seek and receive care expeditiously. However, delays in accessing and receiving care are a continuing problem, threatening the effectiveness of available treatments. Patients with previously diagnosed CHD, including a previous MI, have the same or greater delay times as those without prior MI or CHD. Because of the high-risk status of these patients, combined with the problem of delay in seeking care, this Working Group of the National Heart Attack Alert Program Coordinating Committee advises physicians and other healthcare providers of their important role in reducing treatment delay in these patients. The Working Group recommends that primary care clinicians in the office and in inpatient settings provide these patients and their family members or significant others with contingency counseling about actions to take in response to symptoms of an AMI. The counseling should address the emotional aspects (e.g., fear and denial) that patients and those around them may experience, as well as barriers that may be associated with the healthcare delivery system. Assistance from other healthcare providers (e.g., nurses) should be solicited to initiate, reinforce, and supplement the counseling. A Patient Advisory Form is offered as an aid to providers in counseling their high-risk patients about these issues. Other materials and aids should be considered as well. Physicians' offices and clinics should devise a system to triage patients rapidly when they call or walk in seeking advice for possible AMI symptoms. Further research is needed to learn more about effective counseling strategies; symptom manifestation in high-risk groups, including the elderly, women, and minorities; and healthcare delivery systems that enhance access to timely care for patients with prior CHD or other clinical atherosclerotic disease. C1 NHLBI, Natl Heart Attack Alert Program, Coordinating Comm,Working Grp Educ Strategies Pre, Off Prevent Educ & Control,NIH, Bethesda, MD 20892 USA. RP NHLBI, Natl Heart Attack Alert Program, Coordinating Comm,Working Grp Educ Strategies Pre, Off Prevent Educ & Control,NIH, 31 Ctr Dr MSC 2480,Bldg 31,Room 4A16, Bethesda, MD 20892 USA. NR 99 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD JUL PY 1998 VL 6 IS 1 BP 47 EP 61 PG 15 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 119UV UT WOS:000075917000004 ER PT J AU Khanna, C Lund, EM Raffe, M Armstrong, PJ AF Khanna, C Lund, EM Raffe, M Armstrong, PJ TI Hypomagnesemia in 188 dogs: A hospital population-based prevalence study SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Article DE dogs; electrolyte; magnesium ID ACUTE MYOCARDIAL-INFARCTION; MAGNESIUM CONCENTRATIONS; HEART-FAILURE; ARRHYTHMIAS; DISEASE; CALCIUM; LETHAL AB Magnesium is a divalent cation involved in more than 300 metabolic processes. Magnesium acts as an intracellular regulator of most energy-demanding pathways. Clinical investigation in the human medical field has determined risk factors for hypomagnesemia and its relationship to a number of disease processes. Experimental studies have established the effects of hypomagnesemia in dogs, but little is known of its prevalence, risk factors, or clinical associations in a hospital population of dogs, To study the prevalence, risk factors, and clinical associations of hypomagnesemia in dogs, a retrospective cross-sectional study of dogs admitted to the University of Minnesota Veterinary Teaching Hospital over a 2.5-year period was undertaken. The prevalence of hypomagnesemia in the study population was 6.1% (188 of 3,102 dogs). Using both categorical and continuous variables in a univariate analysis, significant associations with hypomagnesemia were identified and used to construct a multivariate analysis of the relative risk of hypomagnesemia. Results from evaluation of 3,102 dogs indicate that the most significant predictors of hypomagnesemia were albumin (P less than or equal to .0001; odds ratio [OR] = 0.2), potassium (P less than or equal to .0001; OR = 0.5), total CO2 (P < .05; OR = 0.9), and blood urea nitrogen concentrations (P < .0001; OR = 0.9), a diagnosis of cardiovascular disease (P < .02; OR = 1.9); and being a Collie (P < .02; OR = 3.9) or German Shepherd Dog (P < .002; OR = 2.2). These results can be used to better understand and predict hypomagnesemia in dogs. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Coll Vet Med, Dept Small Anim Clin Sci, St Paul, MN USA. RP Khanna, C (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM khannac@pbmac.nci.nih.gov NR 47 TC 19 Z9 19 U1 0 U2 0 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 JUL-AUG PY 1998 VL 12 IS 4 BP 304 EP 309 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 104CY UT WOS:000074996100008 PM 9686391 ER PT J AU Li, MT Lee, H Guo, J Neipel, F Fleckenstein, B Ozato, K Jung, JU AF Li, MT Lee, H Guo, J Neipel, F Fleckenstein, B Ozato, K Jung, JU TI Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor SO JOURNAL OF VIROLOGY LA English DT Article ID SEQUENCE-BINDING-PROTEIN; TRANSCRIPTIONAL ACTIVATOR; DNA-SEQUENCES; FACTOR FAMILY; GENES; ALPHA; SYSTEM; GAMMA; CELLS; EXPRESSION AB Interferons (IFNs) are a family of multifunctional cytokines with antiviral activities. The K9 open reading frame of Kaposi's sarcoma-associated herpesvirus (KSHV) exhibits significant homology with cellular IFN regulatory factors (IRFs). We have investigated the functional consequence of K9 expression in IFN-mediated signal transduction. Expression of K9 dramatically repressed transcriptional activation induced by IFN-alpha, -beta, and -gamma. Further, it induced transformation of NIH 3T3 cells, resulting in morphologic changes, focus formation, and growth in reduced-serum conditions. The expression of antisense K9 in KSHV-infected BCBL-1 cells consistently increased IFN-mediated transcriptional activation but drastically decreased the expression of certain KSHV genes. Thus, the K9 gene of KSHV encodes the first virus-encoded IRF (v-IRF) which functions as a repressor for cellular IFN-mediated signal transduction. In addition, v-IRF likely plays an important role in regulating KSHV gene expression. These results suggest that KSHV employs an unique mechanism to antagonize IPN-mediated antiviral activity by harboring a functional v-IRF. C1 Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. Univ Erlangen Nurnberg, Inst Klin & Mol Virol, D-8520 Erlangen, Germany. NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. RP Jung, JU (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, 1 Pine Hill Dr, Southborough, MA 01772 USA. EM jjung@warren.med.harvard.edu FU NCI NIH HHS [R01 CA031363, CA31363]; NCRR NIH HHS [P51 RR000168, RR00168, K26 RR000168] NR 39 TC 131 Z9 137 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 5433 EP 5440 PG 8 WC Virology SC Virology GA ZU089 UT WOS:000074160500014 PM 9620998 ER PT J AU Fujisawa, R McAtee, FJ Wehrly, K Portis, JL AF Fujisawa, R McAtee, FJ Wehrly, K Portis, JL TI The neuroinvasiveness of a murine retrovirus is influenced by a dileucine-containing sequence in the cytoplasmic tail of glycosylated Gag SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; C RNA VIRUS; LEUKEMIA-VIRUS; NEURODEGENERATIVE DISEASE; INCUBATION PERIOD; SPONGIFORM NEURODEGENERATION; ENDOCYTIC PATHWAY; WILD MICE; INFECTION; PATHOGENESIS AB The tempo and intensity of retroviral neuropathogenesis are dependent on the capacity of the virus to invade the central nervous system. For murine leukemia viruses, an important determinant of neuroinvasiveness is the virus-encoded protein glycosylated Gag, the function of which in the virus life cycle is not known, While this protein is dispensable for virus replication, mutations which prevent its expression slow the spread of virus in vivo and restrict virus dissemination to the brain. To further explore the function of this protein, we compared two viruses, CasFr(KP) (KP) and CasFr(KP41) (KP41), which differ dramatically in neurovirulence, KP expresses high early viremia titers, is neuroinvasive, and induces clinical neurologic disease in 100% of neonatally inoculated mice, with an incubation period of 18 to 23 days. In contrast, KP41 expresses early viremia titers 100-fold lower than those of KP, exhibits attenuated neuroinvasiveness, and induces clinical neurologic disease infrequently, with a relatively long incubation period. The genomes of these two viruses differ by only 10 nucleotides, resulting in differences at five residues, all located within the N-terminal cytoplasmic tail of glycosylated Gag. In this study, using KP as the parental virus, we systematically mutated each of the five amino acid residues to those of KP41 and found that substitution mutation of two membrane-proximal residues, E-53 and L-56, to K and P, respectively produced the greatest effect on early viremia kinetics and neurovirulence, These mutations disrupted the KP sequence (EFLL56)-F-53, the leucine dipeptide of which suggests the possibility that it may represent a sorting signal for glycosylated Gag. Supporting this idea was the finding that alteration of this sequence motif increased the level of cell surface expression of the protein, which suggests that analysis of the intracellular trafficking of glycosylated Gag may provide further clues to its function. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Portis, JL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. FU PHS HHS [69607] NR 37 TC 19 Z9 19 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 5619 EP 5625 PG 7 WC Virology SC Virology GA ZU089 UT WOS:000074160500036 PM 9621020 ER PT J AU Teng, MN Collins, PL AF Teng, MN Collins, PL TI Identification of the respiratory syncytial virus proteins required for formation and passage of helper-dependent infectious particles SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; DEFECTIVE INTERFERING PARTICLES; RABIES VIRUS; VACCINIA VIRUS; RNA; REPLICATION; GLYCOPROTEIN; CELLS; TRANSCRIPTION; EXPRESSION AB We developed a system to identify the viral proteins required for the packaging acid passage of human respiratory syncytial virus (RSV) by reconstructing these events with cDNA-encoded components. Plasmids encoding individual RSV proteins, each under the control of a T7 promoter, were cotransfected in various combinations together with a plasmid containing a minigenome into cells infected with a vaccinia virus recombinant expressing T7 RNA polymerase. Supernatants from these cells were passaged onto fresh cells which were then superinfected with RSV, Functional reconstitution of RSV-specific packaging and passage was detected by expression of the reporter gene carried on the minigenome, As expected, the four nucleocapsid proteins N, P, L, and M2-1 failed to direct packaging and passage of the minigenome, Passage was achieved by further addition of plasmids expressing three membrane-associated proteins, M, G, and F; inclusion of the fourth envelope-associated protein, SH, did not alter passage efficiency. Passage was reduced 10- to 20-fold by omission of G and was abrogated by omission of either M or F, Coexpression of the nonstructural NS1 or NS2 protein had little effect on packaging and passage except through indirect effects on RNA synthesis in the initial transfection, The M2-1 transcription elongation factor was not required for the generation of passage-competent particles. However, addition of increasing quantities of M2-1 to the transfection mediated a dose-dependent inhibition of passage which,vas alleviated by coexpression of the putative negative regulatory factor M2-2, Omission of the L plasmid reduced passage 10- to 20-fold, most likely due to reduced availability of encapsidated minigenomes for packaging. However, the residual level of passage indicated that neither L protein nor the process of RSV-specific RNA synthesis is required for the production and passage of particles. Omission of N or P from the transfection abrogated passage. Thus, the minimum RSV protein requirements for packaging and passaging a minigenome are N, P, M, and F, although the efficiency is greatly increased by addition of L and G. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, 7 Ctr Dr MSC 0720, Bethesda, MD 20892 USA. RI Teng, Michael/I-5006-2012 OI Teng, Michael/0000-0002-0722-3659 NR 26 TC 81 Z9 83 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 5707 EP 5716 PG 10 WC Virology SC Virology GA ZU089 UT WOS:000074160500045 PM 9621029 ER PT J AU Speck, RF Penn, ML Wimmer, J Esser, U Hague, BF Kindt, TJ Atchison, RE Goldsmith, MA AF Speck, RF Penn, ML Wimmer, J Esser, U Hague, BF Kindt, TJ Atchison, RE Goldsmith, MA TI Rabbit cells expressing human CD4 and human CCR5 are highly permissive for human immunodeficiency virus type 1 infection SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 INFECTION; MOLECULAR CHARACTERIZATION; BIOLOGICAL PHENOTYPE; HUMAN CHROMOSOME-12; SYNCYTIUM FORMATION; CYTOPLASMIC DOMAIN; ANIMAL-MODELS; SURFACE CD4; T-CELL; RECEPTOR AB To evaluate the feasibility of using transgenic rabbits expressing CCR5 and CD4 as a small-animal model of human immunodeficiency virus type 1 (HIV) disease, we examined whether the expression of the human chemokine receptor (CCR5) and human CD4 would render a rabbit cell line (SIRC) permissive to HIV replication. Histologically, SIRC cells expressing CD4 and CCR5 formed multinucleated cells (syncytia) upon exposure to Bat, a macrophagetropic strain of HIV that uses CCR5 for cell entry. Intracellular viral capsid p24 staining showed abundant viral gene expression in Bat-infected SIRC cells expressing CD4 and CCR5. In contrast, neither SIRC cells expressing CD4 alone nor murine 3T3 cells expressing CCR5 and CD4 exhibited significant expression of p24. These stably transfected rabbit cells were also highly permissive for the production of virions upon infection by two other CCR5-dependent strains (JR-CSF and YU-2) but not by a CXCR4-dependent strain (NL4-3). The functional integrity of these virions,vas demonstrated by the successful infection of human peripheral blood mononuclear cells (PBMC) with viral stocks prepared from these transfected rabbit cells. Furthermore, primary rabbit PBMC were found to be permissive for production of infectious virions after circumventing the cellular entry step. These results suggest that a transgenic rabbit model for the study of HN disease may be feasible. C1 Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94141 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94141 USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94141 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Goldsmith, MA (reprint author), Univ Calif San Francisco, Gladstone Inst Virol & Immunol, POB 419100, San Francisco, CA 94141 USA. RI Speck, Roberto/O-2433-2016 FU NIAID NIH HHS [AI28240-09S1, AI42654-01] NR 60 TC 32 Z9 33 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 5728 EP 5734 PG 7 WC Virology SC Virology GA ZU089 UT WOS:000074160500047 PM 9621031 ER PT J AU Cassetti, MC Merchlinsky, M Wolffe, EJ Weisberg, AS Moss, B AF Cassetti, MC Merchlinsky, M Wolffe, EJ Weisberg, AS Moss, B TI DNA packaging mutant: Repression of the vaccinia virus A32 gene results in noninfectious, DNA-deficient, spherical, enveloped particles SO JOURNAL OF VIROLOGY LA English DT Article ID TEMPERATURE-SENSITIVE MUTANTS; ESCHERICHIA-COLI; PSEUDORABIES VIRUS; TERMINAL REPEATS; RNA-POLYMERASE; LAC REPRESSOR; MORPHOGENESIS; PROTEIN; GENOME; TRANSCRIPTION AB The vaccinia virus A32 open reading frame was predicted to encode a protein with a nucleoside triphosphate-binding motif and a mass of 34 kDa, To investigate the role of this protein, we constructed a mutant in which the original A32 gene was replaced by an inducible copy. The recombinant virus, vA32i, has a conditional lethal phenotype: infectious virus formation was dependent on isopropyl-beta-D-thiogalactopyranoside (IPTG), Under nonpermissive conditions, the mutant synthesized early-and late-stage viral proteins, as well as viral DNA that was processed into unit-length genomes, Electron microscopy of cells infected in the absence of IPTG revealed normal-appearing crescents and immature virus particles but very few with nucleoids, Instead of brick-shaped mature particles with defined core structures, there were numerous electron-dense, spherical particles. Some of these spherical particles were wrapped with cisternal membranes, analogous to intracellular and extracellular enveloped virions. Mutant viral particles, purified by sucrose density gradient centrifugation, had low infectivity and transcriptional activity, and the majority were spherical and lacked DNA, Nevertheless, the particle preparation contained representative membrane proteins, cleaved and uncleaved core proteins, the viral RNA polymerase, the early transcription factor and several enzymes, suggesting that incorporation of these components is not strictly coupled to DNA packaging. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. US Food & Drug Adm, Ctr Biol Evaluat & Res, Lab DNA Viruses, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 53 TC 63 Z9 67 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 5769 EP 5780 PG 12 WC Virology SC Virology GA ZU089 UT WOS:000074160500052 PM 9621036 ER PT J AU Michael, NL Nelson, JAE Kewalramani, VN Chang, G O'Brien, SJ Mascola, JR Volsky, B Louder, M White, GC Litman, DR Swanstrom, R O'Brien, TR AF Michael, NL Nelson, JAE Kewalramani, VN Chang, G O'Brien, SJ Mascola, JR Volsky, B Louder, M White, GC Litman, DR Swanstrom, R O'Brien, TR TI Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 Delta 32 SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 INFECTION; CELL-LINE; TROPIC HIV-1; RECEPTOR; AIDS; MIP-1-ALPHA; PROGRESSION; RETROVIRUS; MIP-1-BETA; RANTES AB Individuals who are homozygous for the 32-bp deletion in the gene coding for the chemokine receptor and major human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingly documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5 -/- primary T cells. The recently discovered coreceptors BOB and Bonzo are not used. Although early and persistent SI variants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the caveat that the earliest viruses available from this subject were from approximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruses which exclusively utilize CXCR4. The lack of evolution toward the available minor coreceptors in this subject underscores the dominant biological roles of the major coreceptors CCR5 and CXCR4. This and two similar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart, and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4(+) T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cannot infect macrophages, these data have implications for the relative infection of the T cell compartment versus the macrophage compartment in vivo and for the development of CCR5-based therapeutics. C1 NCI, Viral Epidemiol Branch, NIH, Rockville, MD 20852 USA. NCI, Lab Genom Divers, Rockville, MD 20852 USA. Henry M Jackson Fdn Advancement Mil Med, Rockville, MD USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. USN, Med Res Inst, Dept Infect Dis, Bethesda, MD USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Div Hematol & Oncol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NYU Med Ctr, Skirball Inst, New York, NY 10016 USA. NYU Med Ctr, Howard Hughes Med Inst, New York, NY 10016 USA. RP O'Brien, TR (reprint author), NCI, Viral Epidemiol Branch, NIH, EPN 434,6130 Execut Blvd, Rockville, MD 20852 USA. FU NCI NIH HHS [T32 CA009156, T32-CA-09156, N01-CP-85649] NR 61 TC 135 Z9 138 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 6040 EP 6047 PG 8 WC Virology SC Virology GA ZU089 UT WOS:000074160500083 PM 9621067 ER PT J AU Cohen, OJ Paolucci, S Bende, SM Daucher, M Moriuchi, H Moriuchi, M Cicala, C Davey, RT Baird, B Fauci, AS AF Cohen, OJ Paolucci, S Bende, SM Daucher, M Moriuchi, H Moriuchi, M Cicala, C Davey, RT Baird, B Fauci, AS TI CXCR4 and CCR5 genetic polymorphisms in long-term nonprogressive human immunodeficiency virus infection: Lack of association with mutations other than CCR5-Delta 32 SO JOURNAL OF VIROLOGY LA English DT Article ID CHEMOKINE RECEPTOR GENE; HIV-1 INFECTION; CLONING; 7-TRANSMEMBRANE; PROGRESSION; INDIVIDUALS; RESISTANCE; COFACTOR; ALLELE; ENTRY AB Polymorphisms in the coding sequences of CCR5 and CXCR4 were studied in a group of human immunodeficiency virus (HIV)-infected long-term nonprogressors. Two different point mutations were found in the CXCR4 coding sequence. One of these CXCR4 mutations was silent, and each was unique to two nonprogressors. The well described 32-bp deletion within the CCR5 coding sequence (CCR5-Delta 32) was found in 4 of 13 nonprogressors, and 12 different point mutations were found scattered over the CCR5 coding sequence from 8 nonprogressors. Most of the mutations created either silent or conservative changes in the predicted amino acid sequence: only one of these mutations was found in more than a single nonprogressor. All nonsilent mutations were tested in an HIV envelope-dependent fusion assay, and all functioned comparably to wild-type controls. Polymorphisms in the CXCR4 and CCR5 coding sequences other than CCR5-Delta 32 do not appear to play a dominant mechanistic role in nonprogression among HIV-infected individuals. C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Cohen, OJ (reprint author), NIAID, Immunoregulat Lab, 10 Ctr Dr,MSC 1876,Bldg 10,Rm 11B13, Bethesda, MD 20892 USA. EM OCohen@nih.gov NR 27 TC 53 Z9 56 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 1998 VL 72 IS 7 BP 6215 EP 6217 PG 3 WC Virology SC Virology GA ZU089 UT WOS:000074160500108 PM 9621092 ER PT J AU Larson, EB McCurry, SM Graves, AB Bowen, JD Rice, MM McCormick, WC Zee, N Homma, A Imai, Y White, L Masaki, K Petrovitch, H Ross, W Yamada, M Mimori, Y Sasaki, H AF Larson, EB McCurry, SM Graves, AB Bowen, JD Rice, MM McCormick, WC Zee, N Homma, A Imai, Y White, L Masaki, K Petrovitch, H Ross, W Yamada, M Mimori, Y Sasaki, H TI Standardization of the clinical diagnosis of the dementia syndrome and its subtypes in a cross-national study: The Ni-Hon-Sea experience SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID ALZHEIMERS-DISEASE CERAD; INTERRATER RELIABILITY; VASCULAR DEMENTIA; CRITERIA; CALIFORNIA; PREVALENCE; CONSORTIUM; ESTABLISH; REGISTRY; HAWAII AB Background. Clinical investigators from Seattle, Honolulu, Tokyo, and Hiroshima participated in two standardization exercises in which data were collected on independent assessments. Exercises were conducted to evaluate the interobserver agreement on clinical diagnoses of dementia and dementia subtypes in a cross-national study of dementia prevalence and incidence rates in the United States and Japan. Method. Fifteen clinicians from four participating sites assessed the diagnosis of 85 patients based on standardized summaries of clinical and diagnostic test data on each patient. Diagnostic guidelines and conventions were adopted on the basis of group consensus during standardization exercises. Results. Using DSM-III-R criteria, generally good levels of agreement for all dementia diagnostic categories occurred in both years. For most measures of diagnostic agreement, improvements were observed between the 1995 and 1996 standardization sessions. Interrater agreement was highest for discrimination between dementia and nondementia (1996 overall kappa, kappa =.90). The kappa values fbr dementia subtypes in 1996 ranged from .5 to.85, and for all sites combined the value was .67. For dementia subtypes, percent agreement was highest for vascular dementia and Alzheimer's disease, but was less reliable for other types of dementia. Conclusions. Clinicians from different cultures and medical traditions can reliably use the DSM-III-R criteria to classify dementia cases in cross-national research. The interrater agreement on dementia and its subtypes improved after clear-cut guidelines for interpretation of diagnostic criteria were developed and followed. C1 Univ Washington, Med Ctr, Sch Med, Seattle, WA 98195 USA. Univ S Florida, Tampa, FL USA. Tokyo Metropolitan Inst Gerontol, Tokyo, Japan. St Marianna Univ, Tokyo, Japan. NIA, Honolulu Asia Aging Study, Honolulu, HI USA. Honolulu Vet Affairs, Honolulu, HI USA. Radiat Effects Res Fdn, Hiroshima, Japan. Hiroshima Univ, Hiroshima 730, Japan. RP Larson, EB (reprint author), Univ Washington, Med Ctr, Sch Med, Box 356330, Seattle, WA 98195 USA. FU NIA NIH HHS [AG06781-06, AG09769-03] NR 24 TC 20 Z9 21 U1 1 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 1998 VL 53 IS 4 BP M313 EP M319 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 101QR UT WOS:000074880100022 PM 18314572 ER PT J AU Myers, AM Fletcher, PC Myers, AH Sherk, W AF Myers, AM Fletcher, PC Myers, AH Sherk, W TI Discriminative and evaluative properties of the activities-specific balance confidence (ABC) scale SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID ELDERLY PERSONS; COMMUNITY; MOBILITY; FEAR; GAIT; RISK; FALL AB Background Balance confidence is an important indicator of functional mobility and independence in older adults. Preliminary psychometric evidence for the Activities-specific Balance Confidence (ABC) Scale is promising, with a series of four studies adding information on the discriminative and evaluative properties of this tool. Methods. The original validation sample was reinterviewed one year later. In the second study, the ABC was administered to 475 older adults ranging from home care clients to highly functioning individuals in community exercise programs. The third study compared 31 residents of retirement homes given a 10-week balance control exercise program and fall education with 32 residents who received only fall education. The fourth study examined balance confidence preoperatively and postoperatively for 27 patients undergoing hip or knee replacement. Results, ABC scores remained stable over 12 months in higher functioning elders, bur deteriorated in retirement home residents over 26 weeks. Ten weeks of balance :raining significantly improved balance confidence, as did hip or knee replacement with standard physical therapy. ABC scores lower than 50 indicated a low level of physical functioning characteristic of home care clients. ABC scores above 50 and lower than 80 indicated a moderate level of functioning characteristic of elders in retirement homes and persons with chronic health conditions. ABC scores above 80 are indicative of highly functioning, usually physically active older adults, and are achievable through exercise and rehabilitative therapies. Conclusions. Balance confidence is amenable to change and able to distinguish between elders at various levels of functional mobility. These results provide comparative benchmarks for researchers and clinicians working with different groups of older adults. C1 Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Myers, AM (reprint author), Univ Waterloo, Dept Hlth Studies & Gerontol, Waterloo, ON N2L 3G1, Canada. NR 19 TC 205 Z9 208 U1 2 U2 12 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 1998 VL 53 IS 4 BP M287 EP M294 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 101QR UT WOS:000074880100018 PM 18314568 ER PT J AU Simonsick, EM Kasper, JD Phillips, CL AF Simonsick, EM Kasper, JD Phillips, CL TI Physical disability and social interaction: Factors associated with low social contact and home confinement in disabled older women (The women's health and aging study) SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article ID QUALITY-OF-LIFE; COMMUNITY; POPULATION; MORTALITY; SUPPORT; PREDICTORS; AMERICANS; ADMISSION; PEOPLE; SAMPLE AB Objectives. This study examines the association of disability and social interaction, measured as in-person contact with non-household members and home confinement, and identifies sociodemographic, socioeconomic, and health-related factors that modify this relationship. Methods. Participants were 1,002 moderately to severely disabled community-dwelling women aged 65 and older from the Women's Health and Aging Study, identified by screening an age-stratified random sample of Medicare beneficiaries in Baltimore, Maryland. Logistic regression models were used to estimate the odds of low social interaction associated with disability and each independent modifier. Results. In a typical week, 23% did not visit with anyone residing outside their households and 17% did not leave their homes. In addition to and independent of disability level, older age, not completing high school, having a driver in the home, hearing difficulties and incontinence were associated with low social contact; older age and African American race were related to home confinement. African American women living alone are especially vulnerable to home confinement Discussion. Physical disability is not necessarily socially disabling, as many of the most severely disabled in our study had at least daily social interaction. Improvements in social interaction appear possible through more effective management of certain health conditions and attention to potential sociocultural barriers. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. RP Simonsick, EM (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. EM simonsie@gw.nia.nih.gov FU NIA NIH HHS [N01-AG-1-2112] NR 50 TC 48 Z9 48 U1 2 U2 6 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD JUL PY 1998 VL 53 IS 4 BP S209 EP S217 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 101FD UT WOS:000074858200010 PM 9679522 ER PT J AU Ota, K Stetler-Stevenson, WG Yang, QW Kumar, A Wada, J Kashihara, N Wallner, EI Kanwar, YS AF Ota, K Stetler-Stevenson, WG Yang, QW Kumar, A Wada, J Kashihara, N Wallner, EI Kanwar, YS TI Cloning of murine membrane-type-1-matrix metalloproteinase (MT-1-MMP) and its metanephric developmental regulation with respect to MMP-2 and its inhibitor SO KIDNEY INTERNATIONAL LA English DT Article DE membrane-type matrix; metalloproteinase-1; embryonic kidney; cDNA cloning; gene and protein expression; metanephrogenesis ID MATRIX-DEGRADING METALLOPROTEINASES; IV COLLAGENASE; TISSUE INHIBITOR; EXTRACELLULAR-MATRIX; MESSENGER-RNA; STROMAL CELLS; MT-MMP; BRANCHING MORPHOGENESIS; BASEMENT-MEMBRANE; MOLECULAR-CLONING AB Background. Extracellular matrix macromolecules regulate morphogenesis of embryonic organs, and are developmentally regulated. Their expression and turnover is regulated by matrix metalloproteinases (MMPs). Recently, an epithelial cell "membrane" associated metalloproteinase (MT-1-MMP) has been identified that acts as an activator of a "secreted" MMP-2, and is produced by mesenchymal fibroblasts. The activity of MMP-2 is inhibited by a "soluble" tissue inhibitor of MMP-2, TIMP-2. The role of MT-1-MMP in renal development is unknown. Methods. MT-1-MMP was cloned from embryonic mouse kidney cDNA library, and its spatio-temporal distribution during development in the context of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) was studied. Results. The cloned MT-1-MMP exhibited similar to 86% nucleotide sequence homology with human MT-1-MMP, and had a catalytic domain and a zinc binding site preceded by a RRKR furin recognition motif. A similar to 4.5 Kb MT-1-MMP mRNA transcript was detected, and its expression was developmentally regulated. A parallel developmental regulation of MMP-2 mRNA expression was also observed. TIMP-2 expression was also developmentally regulated, but lagged behind MT-1-MMP and MMP-2. By in situ hybridization, MT-1-RAMP mRNA was seen to be confined to ureteric bud epithelia, and was absent in the mesenchyme, while MMP-2 was confined to the mesenchyme. MT-1-MMP protein expression was seen on ureteric bud epithelia, induced mesenchyme and nascent nephrons, and it was highest during mid gestation. Similar spatio-temporal expressions of MMP-2 and TIMP-2 proteins were observed. Conclusions, mRNAs of MT-MMP-1 and MMP-2 are expressed in the respective epithelial and mesenchymal compartments, while their proteins are co-expressed in the epithelia suggest that MT-1-MMP and MMP-2, in conjunction with TIMP-2, may be involved in paracrine/juxtacrine epithelial:mesenchymal interactions during metanephrogenesis. C1 Northwestern Univ, Sch Med, Dept Pathol & Med, Chicago, IL USA. NCI, Extracellular Matrix Pathol Sect, DCS, NIH, Bethesda, MD 20892 USA. RP Kanwar, YS (reprint author), Northwestern Univ, Sch Med, Dept Pathol, 303 E Chicago Ave, Chicago, IL 60611 USA. RI Yang, Qiwei/C-6154-2011; WADA, Jun/B-2023-2011; Stetler-Stevenson, William/H-6956-2012 OI WADA, Jun/0000-0003-1468-5170; Stetler-Stevenson, William/0000-0002-5500-5808 FU NIDDK NIH HHS [DK28492] NR 66 TC 31 Z9 34 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 1998 VL 54 IS 1 BP 131 EP 142 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA ZV828 UT WOS:000074345400014 PM 9648071 ER PT J AU Fernandez-Llama, P Andrews, P Ecelbarger, CA Nielsen, S Knepper, MA AF Fernandez-Llama, P Andrews, P Ecelbarger, CA Nielsen, S Knepper, MA TI Concentrating defect in experimental nephrotic syndrome: Altered expression of aquaporins and thick ascending limb Na+ transporters SO KIDNEY INTERNATIONAL LA English DT Article DE Na-K-2Cl cotransporter; NHE-3; Na-K-ATPase; adriamycin; aquaporin water channels; TAL; nephrotic syndrome; hypertonicity; transport osmotic equilibration ID WATER CHANNEL EXPRESSION; INDUCED DOWN-REGULATION; RAT-KIDNEY MEDULLA; PROXIMAL TUBULE; VASOPRESSIN; SEGMENTS; EXCRETION; LOCALIZATION; ATPASE; PLASMA AB Background Several pathophysiological states associated with deranged water balance are associated with altered expression and/or intracellular distribution of aquaporin water channels. The possible role of dysregulation of thick ascending limb NaCl transporters, which are responsible for countercurrent multiplication in the kidney, has not been evaluated. Methods. Semiquantitative immunoblotting and immunocytochemistry were carried out in the kidneys of rat with adriamycin induced nephrotic syndrome and in vehicle-injected control rats. Results. Preliminary studies confirmed the presence of a severe concentrating defect. Semiquantitative immunoblotting of outer medullary homogenates demonstrated a marked decrease in the abundance of three thick ascending limb Na+ transporters in nephrotic rats, namely the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), the type 3 Na/H exchanger (NHE-3), and the alpha(1)-subunit of the Na-K-ATPase. These results are predictive of a decrease in the NaCl transport capacity of the medullary thick ascending limb and therefore a decrease in countercurrent multiplication. Immunocytochemistry of outer medullary thin sections demonstrated broad (but highly variable) suppression of BSC-1 expression in the outer medullas of adriamycin-nephrotic rats. There was also a large decrease in outer medullary expression of two collecting duct water channels (aquaporin-2 and -3) and the major water channel of the thin descending limb of Henle's loop (aquaporin-1). Conclusion. The concentrating defect in adriamycin-induced nephrotic syndrome in rats is a consequence of multiple defects in water and solute transporter expression, which would alter both the generation of medullary interstitial hypertonicity and osmotic equilibration in the collecting duct. Whether a similar widespread defect in transporter expression is present in idiopathic nephrotic syndrome in humans is, at this point, untested. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Cell Biol, Washington, DC USA. Univ Aarhus, Inst Anat, Dept Cell Biol, Aarhus, Denmark. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 260,10 Ctr Dr MSC 1603, Bethesda, MD 20892 USA. NR 36 TC 97 Z9 98 U1 0 U2 4 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 1998 VL 54 IS 1 BP 170 EP 179 DI 10.1046/j.1523-1755.1998.00984.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA ZV828 UT WOS:000074345400019 PM 9648076 ER PT J AU Kimmel, PL Phillips, TM Simmens, SJ Peterson, RA Weihs, KL Alleyne, S Cruz, I Yanovski, JA Veis, JH AF Kimmel, PL Phillips, TM Simmens, SJ Peterson, RA Weihs, KL Alleyne, S Cruz, I Yanovski, JA Veis, JH TI Immunologic function and survival in hemodialysis patients SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the American-Society-of-Nephrology CY NOV 02-06, 1997 CL SAN ANTONIO, TEXAS SP Amer Soc Nephrol DE cytokine; interleukin; tumor necrosis factor-alpha; T-cell; survival; dialyzer; chronic kidney failure; hemodialysis ID STAGE RENAL-DISEASE; DIALYSIS; MORTALITY; CYTOKINES; ALPHA AB Background. Although the medical determinants of mortality in patients with end-stage renal disease (ESRD) treated with hemodialysis (HD) are well appreciated, the contribution of immunologic parameters to survival in such patients is unclear, especially when variations in age, medical comorbidity and nutrition are controlled. In addition, although dysregulation of cytokine metabolisn has been appreciated in patients with ESRD, the association of these parameters with outcomes has not been established. Recently, the type of dialyzer used in patients' treatment has been associated with survival, but the mechanisms underlying these findings, including their immune effects, have not been established. We conducted a prospective? cross-sectional, observational multicenter study of urban HD patients to determine the contribution of immunological factors to patient survival. We hypothesized increased proinflammatory cytokines would be associated with increased mortality, and that improved immune function would be associated with survival. Methods. Patients were assessed using demographic and anthropometric indices, Kt/V, protein catabolic rate (PCR) and immunologic variables including circulating cytokine [interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13 and tumor necrosis factor (TNF)-alpha] levels, total hemolytic complement activity (CH50), and T cell number and function. A severity index, previously demonstrated to be a mortality marker, was used to grade medical comorbidity. A Cox proportional hazards model, controlling for patients' age, severity index, level of serum albumin concentration, dialyzer type and dialysis site was used to assess relative survival risk. Results. Two hundred and thirty patients entered the study. The mean (+/- SD) age of the population was 54.4 +/- 14.2 years, mean serum albumin concentration was 3.86 +/- 0.47 g/dl, mean PCR was 1.1 +/- 0.28 g/kg/day, and mean Kt/V 1.2 +/- 0.3. Patients' serum albumin concentration was correlated with levels of Kt/V and PCR, and their circulating IL-13 and TNF-ol levels, but negatively with their circulating IL-2 levels, T-cell number and T-cell antigen recall function. T-cell antigen recall function correlated negatively with PCR, but not Kt/V. There was no correlation of any other immune parameter and medical or demographic factor. Immune parameters, however, were all highly intercorrelated. Mean level of circulating cytokines in HD patients were in all cases greater than those of a normal control group. There were few differences in medical risk factors or immune parameters between patients treated with different types of dialyzers. After an almost three-year mean follow-up period, increased IL-1, TNF-alpha, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, while higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival. The difference in survival between patients treated with unmodified cellulose dialyzers and modified or synthetic dialyzers approached the level of statistical significance, but there were no differences in levels of circulating cytokines between these two groups. Conclusions. Higher levels of circulating proinflammatory cytokines are associated with mortality, while immune parameters reflecting improved T-cell function are associated with survival in ESRD patients treated with HD, independent of other medical risk factors. These factors may serve as markers for outcome. The mechanism underlying the relationship of immune function and survival, and the effect of interventions to normalize immune function in HD patients should be studied. C1 George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Sch Publ Hlth, Washington, DC 20037 USA. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. George Washington Univ, Med Ctr, Dept Psychiat & Behav Sci, Washington, DC 20037 USA. Howard Univ, Med Ctr, Dept Human Dev & Psychoeduc Studies, Washington, DC 20059 USA. Howard Univ, Med Ctr, Dept Med, Washington, DC 20059 USA. NICHD, Sect Womens Hlth, Dev Endocrinol Branch, NIH, Bethesda, MD USA. Washington Hosp Ctr, Dept Med, Washington, DC 20010 USA. RP Kimmel, PL (reprint author), George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. FU NICHD NIH HHS [ZO1-HD-00641-01]; NIDDK NIH HHS [1-RO1-DK 45578] NR 37 TC 334 Z9 348 U1 0 U2 4 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 1998 VL 54 IS 1 BP 236 EP 244 DI 10.1046/j.1523-1755.1998.00981.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA ZV828 UT WOS:000074345400027 PM 9648084 ER PT J AU Groll, AH Muller, FMC Piscitelli, SC Walsh, TJ AF Groll, AH Muller, FMC Piscitelli, SC Walsh, TJ TI Lipid formulations of amphotericin B: Clinical perspectives for the management of invasive fungal infections in children with cancer SO KLINISCHE PADIATRIE LA English DT Article DE cancer; mycoses; amphotericin B; antifungal agents ID FAT EMULSION; CRYPTOCOCCAL MENINGITIS; COLLOIDAL DISPERSION; MARROW TRANSPLANT; NEUTROPENIC PATIENTS; PHARMACOKINETICS; AMBISOME; NEPHROTOXICITY; ANTIFUNGAL; SAFETY AB During the past four decades, amphotericin B deoxycholate has been the cornerstone of systemic chemotherapy for life-threatening fungal infections. Despite a broad spectrum of antifungal activity, its utility is greatly hampered by renal toxicity and limited clinical efficacy, in particular in patients with profound and persistent neutropenia. The novel lipid formulations of amphotericin B have distinct physicochemical properties resulting in different distribution patterns. Nevertheless, they all share a considerable reduction of nephrotoxicity, which allows for the delivery of higher daily dosages of amphotericin B. Preliminary efficacy data indicate that these compounds are overall at least as effective as amphotericin B deoxycholate. However. information for children is limited, and comparative studies for their use as first line agents are only in their beginnings. In this article, we review the clinical pharmacokinetics, safety, and efficacy of the lipid formulations of amphotericin B with special emphasis on pediatric data, and we seek to provide a rational framework for the determination of their current role in patients with cancer and proven or suspected invasive fungal infections. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Pharmacokinet Res Lab, Dept Pharm, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Groll, AH (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 86 TC 20 Z9 24 U1 0 U2 1 PU FERDINAND ENKE VERLAG PI STUTTGART PA POSTFACH 30 03 66, D-70443 STUTTGART, GERMANY SN 0300-8630 J9 KLIN PADIATR JI Klinische Padiatr. PD JUL-AUG PY 1998 VL 210 IS 4 BP 264 EP 273 DI 10.1055/s-2008-1043890 PG 12 WC Pediatrics SC Pediatrics GA 109ZN UT WOS:000075354500021 PM 9743964 ER PT J AU Schelling, JR Nkemere, N Kopp, JB Cleveland, RP AF Schelling, JR Nkemere, N Kopp, JB Cleveland, RP TI Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure SO LABORATORY INVESTIGATION LA English DT Article ID SOLUBLE FORM; EXPRESSION; NECROSIS; ANTIGEN; LIGAND; RECEPTOR; KIDNEY; DEATH; GLOMERULONEPHRITIS; SCLEROSIS AB Renal tubular atrophy predicts a poor prognosis in chronic renal failure, but the molecular mechanisms regulating this process remain unknown. Because the Fas apoptosis pathway has recently been implicated in disease pathogenesis and Fas is expressed in the kidney, we hypothesized that Fas-mediated apoptosis of renal tubule epithelial cells (RTC) contributes to tubular atrophy in chronic renal failure. In vivo, immunohistochemical analyses of renal sections from two murine models of progressive renal disease revealed coordinate increases in RTC Fas expression and apoptosis compared with tissue sections from age-matched control kidneys. Increased RTC apoptosis was not accompanied by compensatory hyperplasia, suggesting that RTC targeted for Fas-dependent apoptotic deletion contribute to tubular atrophy. These data are supported by in vitro studies showing that interleukin-1 alpha and tumor necrosis factor-alpha, cytokines secreted in chronic renal failure, stimulated increases in Fas expression in cultured RTC. Both murine kidney cortex and RTC in culture demonstrated constitutive expression of transmembrane and soluble forms of RTC Fas ligand, features that are primarily restricted to lymphocytes and immune-privileged tissues and that have been previously unrecognized in RTC. Functional studies revealed that interleukin-1 alpha-stimulated RTC Fas expression was accompanied by increased apoptosis, which was inhibited by blocking anti-fas ligand antibodies. In contrast to the conventional paradigm, which holds that Fas-dependent apoptosis is initiated by the binding of lymphocyte Fas ligand to target cell Fas, our data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTC, which then leads to RTC death by fratricide. We propose this pathway as an initiating mechanism of tubular atrophy. C1 Case Western Reserve Univ, Metrohlth Med Ctr, Rammeikamp Ctr Res, Dept Med,Div Nephrol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Div Nephrol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Schelling, JR (reprint author), Case Western Reserve Univ, Metrohlth Med Ctr, Rammeikamp Ctr Res, Dept Med,Div Nephrol, 2500 Metrohlth Dr,G531, Cleveland, OH 44106 USA. OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK NIH HHS [K08 DK02281] NR 52 TC 84 Z9 88 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUL PY 1998 VL 78 IS 7 BP 813 EP 824 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 103XJ UT WOS:000074982900004 PM 9690559 ER PT J AU Epstein, AH Lebovics, RS Van Waes, C Smith, J Okunieff, P Cook, JA AF Epstein, AH Lebovics, RS Van Waes, C Smith, J Okunieff, P Cook, JA TI Intravenous delivery of 5 '-iododeoxyuridine during hyperfractionated radiotherapy for locally advanced head and neck cancers: Results of a pilot study SO LARYNGOSCOPE LA English DT Article DE head; neck; cancer; radiation; sensitizer ID THYMIDINE REPLACEMENT; HALOGENATED PYRIMIDINES; GLIOBLASTOMA-MULTIFORME; RADIATION-THERAPY; PHASE-II; IODODEOXYURIDINE; INFUSIONS; CELLS; RADIOSENSITIZATION; CHEMOTHERAPY AB Objectives: Locally advanced cancers of the head and neck, require aggressive treatment, often with limited effectiveness and significant toxicity and morbidity, This pilot study was designed to assess tolerance using combined hyperfractionated radiotherapy and the halogenated pyrimidine radiosensitizer 5'-iododeoxyuridine (IdUrd), Study Design: This was a prospective single-arm study open to patients with advanced head and neck cancers that had a poor chance of control with conventional radiation therapy. Patients were treated with hyperfractionated radiation therapy at standard doses in combination with an IdUrd infusion and observed for tumor response and normal tissue tolerances. Methods: Radiation therapy was delivered in fractions of 1.2 Gy or 1.5 Gy twice daily to a total dose in the range of 70 to 76 Gy, IdUrd was delivered as an intravenous infusion (1000 mg/m(2) per day) for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. Results: Twelve patients with advanced squamous cell lesions were enrolled and 11 were observed to have complete clinical remissions. Seven patients remained clinically free of local disease at the time of death or most recent follow-up. Acute toxicities, usually hematologic or mucosal, were severe and all patients required treatment modifications and considerable supportive care. Conclusions: Although a high rate of response was achieved using this regimen, the toxicities are prohibitive. The kinetic profile of IdUrd incorporation suggests the need for future studies using repetitive short courses of IdUrd. C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol & Nucl Med, Bethesda, MD 20814 USA. Natl Inst Deafness & Other Commun Disorders, Div Intramural Res, Bethesda, MD USA. Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Epstein, AH (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. NR 29 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD JUL PY 1998 VL 108 IS 7 BP 1090 EP 1094 DI 10.1097/00005537-199807000-00025 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA ZY011 UT WOS:000074577700025 PM 9665262 ER PT J AU Allen, RJ Smith, SD Moldwin, RL Lu, MM Giordano, L Vignon, C Suto, Y Harden, A Tomek, R Veldman, T Ried, T Larson, RA Le Beau, MM Rowley, JD Zeleznik-Le, N AF Allen, RJ Smith, SD Moldwin, RL Lu, MM Giordano, L Vignon, C Suto, Y Harden, A Tomek, R Veldman, T Ried, T Larson, RA Le Beau, MM Rowley, JD Zeleznik-Le, N TI Establishment and characterization of a megakaryoblast cell line with amplification of MLL SO LEUKEMIA LA English DT Article DE cell line; megakaryoblast; MLL amplification ID ACUTE MYELOID-LEUKEMIA; CHROMOSOMAL TRANSLOCATIONS; GENE; 11Q23; REARRANGEMENTS; DIFFERENTIATION; DUPLICATION; EXPRESSION; SEQUENCES; FEATURES AB A new cell line with megakaryoblastic features, designated UoC-M1, was established from the malignant cells of a 68-year-old patient with acute myeloid leukemia. The patient's leukemic cells reacted with cu-naphthyl acetate esterase and acid phosphatase and expressed CD7, CD24, CD34, CD38, CD45, HLA-DR and CD61. Cytogenetic analysis of the patient's malignant cells (and of the UoC-M1 cells) showed a human, male hypodiploid karyotype with many chromosome rearrangements and marker chromosomes. Spectral karyotyping (SKY) analysis complemented the G-banded karyotyping and clarified several chromosomal translocations and identified the marker chromosomes. Fluorescence in site hybridization (FISH) and SKY analysis demonstrated that one marker chromosome contained three segments of chromosome 9 interspersed with three segments of chromosome 11, as well as a portion of chromosome 19. FISH analysis with a probe for MLL revealed that the UoC-M1 cells contained four copies of the MLL gene. Southern blot analysis determined that the MLL gene had a germline profile while Northern and Western analyses showed that the MLL mRNAs and protein were of the appropriate sizes. This is the first report of amplification of the MLL gene which may be an additional mechanism of leukemogenesis or disease progression. C1 Univ Chicago, Sect Pediat Hematol Oncol, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Hematol Oncol Sect, Dept Med, Chicago, IL 60637 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. RP Smith, SD (reprint author), Univ Kansas, Med Ctr, Delp Bldg,Rm 3032,3901 Rainbow Blvd, Kansas City, KS 66160 USA. OI Larson, Richard/0000-0001-9168-3203 FU NCI NIH HHS [CA40046, CA42557] NR 40 TC 37 Z9 39 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 1998 VL 12 IS 7 BP 1119 EP 1127 DI 10.1038/sj.leu.2401002 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA ZY049 UT WOS:000074581500017 PM 9665199 ER PT J AU Everhart, JE Lombardero, M Lake, JR Wiesner, RH Zetterman, RK Hoffnagle, JH AF Everhart, JE Lombardero, M Lake, JR Wiesner, RH Zetterman, RK Hoffnagle, JH TI Weight change and obesity after liver transplantation: Incidence and risk factors SO LIVER TRANSPLANTATION AND SURGERY LA English DT Article ID UNITED-STATES ADULTS; BODY-COMPOSITION; GAIN; COHORT; WOMEN; RACE AB Obesity is a concern in the long-term management of patients following liver transplantation, yet the risk of obesity and the factors that influence its development have not been well defined. We evaluated posttransplantation weight change among a cohort of 774 adults who had their height and weight recorded before liver transplantation at three major centers, Obesity was defined as a body mass index (BMI) of at least 30 kg/m(2). Weight at transplantation was adjusted by the amount of ascites removed. Mean BMI increased from 24.8 kg/m(2) pretransplantation to 27.0 kg/m(2) in the first posttransplantation year, to 28.1 kg/m(2) in the second year, and very little with subsequent observation, Among 320 patients who were not obese before transplantation, 21.6% became obese within 2 years after transplantation. On evaluation of numerous potential donor and pretransplantation risk factors, greater recipient BMI, greater donor BMI, and being married were found to be predictors of subsequent obesity (P <.05), Posttransplantation predictors of obesity included absence of acute cellular rejection, higher cumulative prednisone dose in the second year, and cyclosporine-based immunosuppression, although only rejection and prednisone dose remained predictors on multivariate analysis, Despite the marked weight gain after transplantation, prevalence of obesity at 2 years was only slightly greater than in the general US population. Obesity occurred commonly after liver transplantation, sometimes with a striking gain in weight, In addition to BMI at transplantation, donor BMI, marital status, occurrence of acute rejection, and prednisone dose affected the incidence of obesity, Copyright (C) 1998 by the American Association for the Study of Liver Diseases. C1 NIDDKD, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. Mayo Clin & Mayo Fdn, Dept Med, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Surg, Rochester, MN 55905 USA. Univ Nebraska, Med Ctr, Dept Med, Omaha, NE 68105 USA. Univ Nebraska, Med Ctr, Dept Surg, Omaha, NE USA. RP Everhart, JE (reprint author), Room 6AN-12J,45 Ctr Dr MSC 6600, Bethesda, MD 20892 USA. FU NIDDK NIH HHS [N01-DK-0-2251, N01-DK-0-2252, N01-DK-0-2253] NR 27 TC 96 Z9 98 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 1074-3022 J9 LIVER TRANSPLANT SUR JI Liver Transplant. Surg. PD JUL PY 1998 VL 4 IS 4 BP 285 EP 296 PG 12 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 142DE UT WOS:000077184000007 PM 9649642 ER PT J AU Shrager, RI Basser, PJ AF Shrager, RI Basser, PJ TI Anisotropically weighted MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion; anisotropy; tensor; MRI ID DIFFUSION-TENSOR; SPECTROSCOPY; FEATURES; TISSUES AB The intensity of an isotropically weighted MR image is proportional to a rotationally invariant measure of bulk diffusion, Trace((D) under bar) (where (D) under bar is the effective diffusion tensor). Such images can be acquired from as few as two diffusion-weighted images (DWIs). Analogously, the intensity of an anisotropically weighted MR image is proportional to a rotationally invariant measure of diffusion anisotropy derived from (D) under bar, such as the variance of the principal diffusivities of (D) under bar. By using linear algebra, we show that to produce an anisotropically weighted MR image requires acquiring at least seven DWIs, which is also the minimum number of DWIs sufficient to estimate the entire diffusion tensor, as well as the T-2-weighted amplitude image, A((b) under bar = (O) under bar), in each voxel. A general mathematical framework for constructing isotropically weighted and anisotropically weighted MR images is also provided. C1 NICHHD, Lab Phys Sci, Ctr Technol, NIH, Bethesda, MD 20892 USA. NICHHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), Bldg 13,Room 3N-17,13 South Dr, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 22 TC 20 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn.Reson.Med. PD JUL PY 1998 VL 40 IS 1 BP 160 EP 165 DI 10.1002/mrm.1910400121 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ZV412 UT WOS:000074302000020 PM 9660566 ER PT J AU Roth, KDW Huang, ZH Sadagopan, N Watson, JT AF Roth, KDW Huang, ZH Sadagopan, N Watson, JT TI Charge derivatization of peptides for analysis by mass spectrometry SO MASS SPECTROMETRY REVIEWS LA English DT Review DE mass spectrometry; peptide; derivatization; charge; fragmentation ID FAST-ATOM-BOMBARDMENT; COLLISION-INDUCED DISSOCIATION; TIME-OF-FLIGHT; FIXED POSITIVE CHARGE; AMINO-ACID-SEQUENCE; LASER-DESORPTION; REMOTE FRAGMENTATION; 4-AMINONAPHTHALENESULPHONIC ACID; PROTONATED PEPTIDES; SPECTRA AB The analysis of peptide derivatives by fast atom bombardment, liquid secondary-ionization mass spectrometry, plasma desorption, electrospray ionization, and matrix-assisted laser desorption/ionization is reviewed. The fragmentation patterns of peptides and of charge-derivatized peptides are compared and the proposed fragment ion structures are summarized. A variety of derivatization approaches and the distinguishing features of mass spectra produced from these derivatives are described. The most promising derivatization approaches are evaluated, and the strengths and limitations of these approaches are discussed. (C) 1999 John Wiley & Sons, Inc. C1 Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. Michigan State Univ, Dept Biochem, E Lansing, MI 48824 USA. RP Watson, JT (reprint author), Michigan State Univ, NIH, Mass Spect Facil, Biochem Bldg, E Lansing, MI 48824 USA. NR 73 TC 126 Z9 131 U1 4 U2 18 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0277-7037 J9 MASS SPECTROM REV JI Mass Spectrom. Rev. PD JUL-AUG PY 1998 VL 17 IS 4 BP 255 EP 274 DI 10.1002/(SICI)1098-2787(1998)17:4<255::AID-MAS1>3.0.CO;2-4 PG 20 WC Spectroscopy SC Spectroscopy GA 180MM UT WOS:000079389800001 PM 10224676 ER PT J AU Rost, K Zhang, ML Fortney, J Smith, J Smith, GR AF Rost, K Zhang, ML Fortney, J Smith, J Smith, GR TI Rural-urban differences in depression treatment and suicidality SO MEDICAL CARE LA English DT Article DE depression; services; rural; utilization; suicide; mental health ID DIAGNOSTIC INTERVIEW SCHEDULE; MENTAL-HEALTH-SERVICES; MEDICAL OUTCOMES; UNITED-STATES; PRIMARY CARE; DISORDERS; COMORBIDITY; OUTPATIENTS; PREVALENCE; SYMPTOMS AB OBJECTIVES. Because there are fewer per capita providers trained to deliver mental health services in rural areas, the authors hypothesized that depressed rural individuals would receive less outpatient treatment and report higher rates of hospital admittance and suicide attempts than their urban counterparts. METHODS, The authors recruited 74% of eligible participants (n = 470) from a 1992 telephone survey and followed up 95% of subjects for 1 year. The authors collected data from subjects on psychiatric problems and service use and from insurers/providers on treatment and expenditures. RESULTS. Although there were no rural-urban differences in the rate, type, or quality of outpatient depression treatment, rural subjects made significantly fewer specialty care visits for depression. Depressed rural individuals had 3.05 times the odds of being admitted to the hospital for physical problems (P = 0.02) and 3.06 times the odds of being admitted for mental health problems (P = 0.08) during the year. Elevated rates of hospital admittance disappear in models controlling for number of specialty care depression visits in the previous month. Rural subjects reported significantly more suicide attempts during the period of I year (P = 0.05), CONCLUSIONS, Additional work is warranted to determine how to alter barriers to outpatient specialty care if the rural health care delivery system is to provide cost-effective depression care. C1 VAHSR&D, Field Program Mental Hlth, Little Rock, AR USA. Univ Arkansas Med Sci, Dept Psychiat, NIMH, Ctr Rural Mental Healthcare Res, Little Rock, AR 72205 USA. RP Rost, K (reprint author), Cent Mental Healthcare Res, 5800 W 10th St,Suite 605, Little Rock, AR 72204 USA. FU NIMH NIH HHS [MH49116, MH54444, P50 MH48197] NR 39 TC 71 Z9 72 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 1998 VL 36 IS 7 BP 1098 EP 1107 DI 10.1097/00005650-199807000-00015 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 100UR UT WOS:000074834200015 PM 9674626 ER PT J AU Gannot, I Bonner, RF Gannot, G Fox, PC Smith, PD Gandjbakhche, AH AF Gannot, I Bonner, RF Gannot, G Fox, PC Smith, PD Gandjbakhche, AH TI Optical simulations of a noninvasive technique for the diagnosis of diseased salivary glands in situ SO MEDICAL PHYSICS LA English DT Article DE quantitative imaging; exogenous fluorescent markers; random walk; salivary glands; Sjogren syndrome ID INTERLEUKIN-2 RECEPTOR EXPRESSION; SJOGRENS-SYNDROME; FLUORESCENCE; TISSUE; BIOPSY AB A simulation experiment for three-dimensional (3D) imaging of exogenous fluorescinated antibodies that specifically bind to infiltrating lymphocytes in minor salivary glands was carried out. Small (similar to 1 mm(3) volume) rhodamine targets, which mimic diseased minor salivary glands labeled with fluorescent antibodies to infiltrating lymphocytes in Sjogren's syndrome, were embedded in a highly scattering tissue phantom consisting of a thick Delrin(TM) disk covered by index matched Delrin(TM) slabs of various thickness. In this way the variation of fluorescence profiles on the surface of tissue could be examined corresponding to the range of depths of the salivary glands in vivo. Surface images were obtained for different target depths and radial distances from laser excitation to target fluorophore. These images were analyzed and compared to calculations based on random walk theory in turbid media, using previously determined scattering and absorption coefficients of the Delrin(TM). Excellent agreement between the surface profiles experimentally measured and those predicted by our random walk theory was obtained. Derivation of these theoretical expressions is a necessary step toward devising an inverse algorithm which may have the potential expressions to perform 3D reconstruction of the concentration distribution of fluorescent labels within tissue. (C) 1998 American Association of Physicists in Medicine. C1 Tel Aviv Univ, Fac Engn, Dept Biochem Engn, IL-69978 Tel Aviv, Israel. NICHD, Sect Med Biophys, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NIDR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. ORS, Bioengn & Phys Sci Program, NIH, Bethesda, MD 20892 USA. NICHD, Sect Cell Biophys, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Gannot, I (reprint author), Tel Aviv Univ, Fac Engn, Dept Biochem Engn, IL-69978 Tel Aviv, Israel. EM israel@eob.cdrh.fad.gov RI Bonner, Robert/C-6783-2015 NR 24 TC 15 Z9 15 U1 0 U2 0 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 1998 VL 25 IS 7 BP 1139 EP 1144 DI 10.1118/1.598305 PN 1 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 100FU UT WOS:000074805900008 PM 9682199 ER PT J AU Samuels, J Aksentijevich, I Torosyan, Y Centola, M Deng, ZM Sood, R Kastner, DL AF Samuels, J Aksentijevich, I Torosyan, Y Centola, M Deng, ZM Sood, R Kastner, DL TI Familial Mediterranean fever at the millennium - Clinical spectrum, ancient mutations, and a survey of 100 American - Referrals to the National Institutes of Health SO MEDICINE LA English DT Review ID RECURRENT HEREDITARY POLYSEROSITIS; DOPAMINE-BETA-HYDROXYLASE; TERM COLCHICINE THERAPY; HIGH GENE-FREQUENCY; PERIODIC FEVER; HYPERIMMUNOGLOBULINEMIA-D; DIAGNOSTIC-TEST; DOUBLE-BLIND; SHORT ARM; AMYLOIDOSIS C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. RP Kastner, DL (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, Bldg 10,Room 9N214,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 168 TC 239 Z9 246 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 1998 VL 77 IS 4 BP 268 EP 297 DI 10.1097/00005792-199807000-00005 PG 30 WC Medicine, General & Internal SC General & Internal Medicine GA 109QA UT WOS:000075333400005 PM 9715731 ER PT J AU Simons-Morton, DG AF Simons-Morton, DG TI The context of the Activity Counseling Trial SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article C1 NHLBI, Bethesda, MD 20892 USA. RP Simons-Morton, DG (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 1998 VL 30 IS 7 BP 1084 EP 1085 DI 10.1097/00005768-199807000-00010 PG 2 WC Sport Sciences SC Sport Sciences GA ZY230 UT WOS:000074599300010 PM 9662677 ER PT J AU King, AC Sallis, JF Dunn, AL Simons-Morton, DG Albright, CA Cohen, S Rejeski, WJ Marcus, BH Coday, MC AF King, AC Sallis, JF Dunn, AL Simons-Morton, DG Albright, CA Cohen, S Rejeski, WJ Marcus, BH Coday, MC CA Activity Counseling Trial Res Grp TI Overview of the Activity Counseling Trial (ACT) intervention for promoting physical activity in primary health care settings SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE exercise; physical fitness; primary care; behavioral interventions; clinical trial ID EXERCISE BEHAVIOR; UNITED-STATES; MODEL; MEDICINE; ADVICE; ADULTS; WOMEN; MEN AB Counseling by health care providers has the potential to increase physical activity in sedentary patients, yet few studies have tested interventions for physical activity counseling delivered in health care settings. The Activity Counseling Trial (ACT) is a 5-yr randomized clinical trial to evaluate the efficacy of two primary care, practice-based physical activity behavioral interventions relative to a standard care control condition. A total of 874 sedentary men and women, 35-75 yr of age, have been recruited from primary care physician offices at three clinical centers for 2 yr of participation. They were randomly assigned to one of three experimental conditions that vary, in a hierarchical fashion, by Level of counseling intensity and resource requirements. The interventions, which are based on social cognitive theory and the transtheoretical model, are designed to alter empirically based psychosocial mediators that are known to be associated with physical activity. The present paper describes the theoretical background of the intervention, the intervention methods, and intervention training and quality control procedures. C1 Stanford Univ, Sch Med, Stanford, CA 94305 USA. San Diego State Univ, San Diego, CA 92182 USA. Cooper Inst Aerob Res, Dallas, TX USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27109 USA. Miriam Hosp, Providence, RI 02906 USA. Brown Univ, Sch Med, Providence, RI 02912 USA. Univ Tennessee, Memphis, TN 38163 USA. RP King, AC (reprint author), Stanford Univ, Sch Med, Stanford, CA 94305 USA. FU NHLBI NIH HHS [N01-HC-45136, N01-HC-45137, N01-HC-45135] NR 45 TC 71 Z9 72 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 1998 VL 30 IS 7 BP 1086 EP 1096 DI 10.1097/00005768-199807000-00011 PG 11 WC Sport Sciences SC Sport Sciences GA ZY230 UT WOS:000074599300011 PM 9662678 ER PT J AU Blair, SN Applegate, WB Dunn, AL Ettinger, WH Haskell, WL King, AC Morgan, TM Shih, JH Simons-Morton, DG AF Blair, SN Applegate, WB Dunn, AL Ettinger, WH Haskell, WL King, AC Morgan, TM Shih, JH Simons-Morton, DG CA Activity Counseling Trial Res Grp TI Activity Counseling Trial (ACT): rationale, design, and methods SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE physical activity; physical fitness; behavioral interventions; clinical trial ID CORONARY HEART-DISEASE; ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; UNITED-STATES; PUBLIC-HEALTH; EXERCISE; MEN; FITNESS; INTERVENTION; ASSOCIATION AB The Activity Counseling Trial (ACT) is a multicenter, randomized controlled trial to evaluate the effectiveness of interventions to promote physical activity in the primary health care setting. ACT has recruited, evaluated, and randomized 874 men and women 35-75 yr of age who are patients of primary care physicians. Participants were assigned to one of three educational interventions that differ in amount of interpersonal contact and resources required: standard care control, staff-assisted intervention, or staff-counseling intervention. The study is designed to provide 90% power in both men and women to detect a 1.1 kcal kg(-1) day-l difference in total daily energy expenditure between any two treatment groups, and over 90% power to detect a 7% increase in maximal oxygen uptake. the two primary outcomes. Primary analyses will compare study groups on mean outcome measures at 24 months post-randomization, be adjusted for the baseline value of the outcome measure and for multiple comparisons, and be conducted separately for men and women. Secondary outcomes include comparisons between interventions at 24 months of factors related to cardiovascular disease (blood Iipids/lipoproteins, blood pressure, body composition, plasma insulin, fibrinogen, dietary intake, smoking, heart rate variability), psychosocial effects, and cost-effectiveness, and at 6 months for primary outcome measures. ACT is the first large-scale behavioral intervention study of physical activity counseling in a clinical setting, includes a generalizable sample of adult men and women and of clinical settings, and examines long-term (24 months) effects. ACT has the potential to make substantial contributions to the understanding of how to promote physical activity in the primary health care setting. C1 Cooper Inst Aerob Res, Dallas, TX USA. Univ Tennessee, Memphis, TN 38163 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27103 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. NHLBI, Bethesda, MD 20892 USA. RP Blair, SN (reprint author), Cooper Inst Aerob Res, Dallas, TX USA. FU NHLBI NIH HHS [N01-HC-45135, N01-HC-45136, N01-HC-45137] NR 48 TC 66 Z9 67 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 1998 VL 30 IS 7 BP 1097 EP 1106 DI 10.1097/00005768-199807000-00012 PG 10 WC Sport Sciences SC Sport Sciences GA ZY230 UT WOS:000074599300012 PM 9662679 ER PT J AU Player, MR Wondrak, EM Bayly, SF Torrence, PF AF Player, MR Wondrak, EM Bayly, SF Torrence, PF TI Ribonuclease L, a 2-5A-Dependent enzyme: Purification to homogeneity and assays for 2-5A binding and catalytic activity SO METHODS-A COMPANION TO METHODS IN ENZYMOLOGY LA English DT Article ID INTERFERON ACTION; TARGETING RNA; ACTIVATION; CLEAVAGE; ENDONUCLEASE; PPP(A2'P)NA; APOPTOSIS; SYSTEM; CELLS AB RNase L is a latent endonuclease found in reptiles, birds, and mammals. It is activated by the 2',5'-phosphodiester-linked oligoadenylates called 2-5A and has been implicated in the mechanism of action of interferon, as well as in a variety of other biological phenomena such as apoptosis. Covalent linkage of 2-5A to antisense oligonucleotides permits recruitment of RNase L for enhancement of antisense action. The purification of RNase L described herein and the assays for its detection and activation will help to provide further mechanistic details on how this unique nuclease functions and what its biochemical roles may be. In addition, such assays will facilitate the screening of 2-5A-antisense congeners for exploration of the potential therapeutic applications of RNase L, (C) 1998 Academic Press. C1 NIDDKD, Sect Biomed Chem, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Torrence, PF (reprint author), NIDDKD, Sect Biomed Chem, Med Chem Lab, NIH, Bldg 8,Room B2A02, Bethesda, MD 20892 USA. EM torrence@helix.nih.gov NR 31 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD JUL PY 1998 VL 15 IS 3 BP 243 EP 253 DI 10.1006/meth.1998.0628 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 118AG UT WOS:000075814600009 PM 9735309 ER PT J AU Stevenson, B Casjens, S Rosa, P AF Stevenson, B Casjens, S Rosa, P TI Evidence of past recombination events among the genes encoding the Erp antigens of Borrelia burgdorferi SO MICROBIOLOGY-SGM LA English DT Article DE Borrelia burgdorferi; Lyme disease; erp genes; recombination; plasmids ID LYME-DISEASE AGENT; SURFACE PROTEIN-C; UNIT-COPY MINIPLASMIDS; CIRCULAR PLASMIDS; IMMUNOCOMPETENT MICE; NUCLEOTIDE-SEQUENCE; MOLECULAR ANALYSIS; LINEAR CHROMOSOME; DAUGHTER CELLS; F-PLASMID AB A single Borrelia burgdorferi bacterium may contain six or more different 32 kb circular plasmids (cp32s). Although these plasmids are homologous throughout much of their sequences, two loci have been identified at which they can vary significantly. The cp32 plasmids and their relatives each contain two adjacent genes, orfC and orf3, that vary in sequence between plasmids found within clones of individual bacteria. The orfC gene product is homologous to proteins involved in partitioning of bacterial plasmids. and the differences at this locus between plasmids may account for their compatibility. The orfC-orf3 loci are located approximately 5 kb from another variable locus called erp. The orfC-orf3 loci were used as physically linked markers to assess genetic rearrangements in the erp loci; this revealed examples of recombination involving both individual genes and entire erp loci. Recombination of the genes encoding the ErP antigens might contribute to the evasion of the mammalian immune response and could play roles in the establishment and persistence of B. burgdorferi infections in mammalian hosts. C1 NIAID, Lab Microbial Struct & Funct, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Utah, Div Mol Biol & Genet, Dept Oncol Sci, Salt Lake City, UT 84132 USA. RP Stevenson, B (reprint author), Univ Kentucky, Med Ctr, Dept Microbiol & Immunol, MS 415 UKMC, Lexington, KY 40536 USA. EM lkspic00@pop.uky.edu NR 56 TC 57 Z9 57 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD JUL PY 1998 VL 144 BP 1869 EP 1879 PN 7 PG 11 WC Microbiology SC Microbiology GA 103KR UT WOS:000075000100019 PM 9695920 ER PT J AU Templeton, TJ Kaslow, DC AF Templeton, TJ Kaslow, DC TI An amino terminal intron indicates that transcripts for the Plasmodium falciparum Golgi network marker Rab6 do not encode alternative amino termini SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE rab6H; Plasmodium; genome; cDNA ID GENE; IDENTIFICATION; PROTEINS; FAMILY C1 NIAID, Malaria Vaccines Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Templeton, TJ (reprint author), NIAID, Malaria Vaccines Sect, Parasit Dis Lab, NIH, Bldg 4,Room B1-31, Bethesda, MD 20892 USA. NR 14 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD JUL 1 PY 1998 VL 94 IS 1 BP 149 EP 153 DI 10.1016/S0166-6851(98)00038-3 PG 5 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 109EQ UT WOS:000075308600015 PM 9719520 ER PT J AU Hansford, RG Zorov, D AF Hansford, RG Zorov, D TI Role of mitochondrial calcium transport in the control of substrate oxidation SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Review DE mitochondrial dehydrogenases; mitochondrial matrix free calcium; cardiac myocytes; cardiomyopathy; oxidative phosphorylation ID GLYCEROL-PHOSPHATE DEHYDROGENASE; ISOLATED VENTRICULAR MYOCYTES; RAT-HEART MITOCHONDRIA; CARDIOMYOPATHIC HAMSTERS; SARCOPLASMIC-RETICULUM; CA2+ TRANSIENTS; DIABETIC RATS; FURA-2-LOADED HEPATOCYTES; MAMMALIAN MITOCHONDRIA; ADENINE-NUCLEOTIDES AB This paper reviews the model of the control of mitochondrial substrate oxidation by Ca2+ ions. The mechanism is the activation by Ca2+ of four mitochondrial dehydrogenases, viz. glycerol 3-phosphate dehydrogenase, the pyruvate dehydrogenase multienzyme complex (PDH), NAD-linked isocitrate dehydrogenase (NAD-IDH) and 2-oxoglutarate dehydrogenase (OGDH). This results in the increase, or near-maintenance, of mitochondrial NADH/NAD ratios in the activated state, depending upon the tissue and the degree of 'downstream' activation by Ca2+, likely at the level of the F1 Fo ATPase. Higher values of the redox span of the respiratory chain allow for greatly increased fluxes through oxidative phosphorylation with a minimal drop in protonmotive force and phosphorylation potential. As PDH, NAD-IDH and OGDH are all located within the inner mitochondrial membrane, it is changes in matrix free Ca2+ [Ca2+](m) which act as a signal to these activities. In this article, we review recent work in which [Ca2+](m) is measured in cells and tissues, using different techniques, with special emphasis on the question of the degree of damping of [Ca2+](m) relative to changes in cytosol free Ca2+ in cells with rapid transients in cytosol Ca2+, e.g. cardiac myocytes. Further, we put forward the point of view that the failure of mitochondrial energy transduction to keep pace with cellular energy needs in some forms of heart failure may involve a failure of [Ca2+](m) to be raised adequately to allow the activation of the dehydrogenases. We present new data to show that this is so in cardiac myocytes isolated from animals suffering from chronic, streptozocin-induced diabetes. This raises the possibility of therapy based upon partial inhibition of mitochondrial Ca2+ efflux pathways, thereby raising [Ca2+](m) at a given, time-average value of cytosol free Ca2+. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Hansford, RG (reprint author), NIA, Gerontol Res Ctr, NIH, Hopkins Bayview, Baltimore, MD 21224 USA. NR 113 TC 133 Z9 138 U1 0 U2 6 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 JUL PY 1998 VL 184 IS 1-2 BP 359 EP 369 DI 10.1023/A:1006893903113 PG 11 WC Cell Biology SC Cell Biology GA 113DG UT WOS:000075534200024 PM 9746330 ER PT J AU Sera, T Wolffe, AP AF Sera, T Wolffe, AP TI Role of histone H1 as an architectural determinant of chromatin structure and as a specific repressor of transcription on Xenopus oocyte 5S rRNA genes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID RIBOSOMAL-RNA GENES; POLYMERASE-II TRANSCRIPTION; DIRECTS SPECIFIC INITIATION; INTERNAL CONTROL REGION; LINKER HISTONES; DNA-BINDING; GLOBULAR DOMAIN; NUCLEOTIDE-SEQUENCE; NUCLEOSOMAL TEMPLATES; CRYSTAL-STRUCTURE AB We explore the role of histone H1 as a DNA sequence-dependent architectural determinant of chromatin structure and of transcriptional activity in chromatin. The Xenopus laevis oocyte- and somatic-type 5S rRNA genes are differentially transcribed in embryonic chromosomes in vivo depending on the incorporation of somatic histone H1 into chromatin. We establish that this effect can be reconstructed at the level of a single nucleosome. H1 selectively represses oocyte-type 5S rRNA genes by directing the stable positioning of a nucleo some such that transcription factors cannot hind to the gene. This effect does not occur on the somatic-type genes. Histone H1 binds to the 5' end of the nucleosome core on the somatic 5S rRNA gene, leaving key regulatory elements in the promoter accessible, while histone H1 binds to the 3' end of the nucleosome core on the oocyte 5S rRNA genes, specifically blocking access to a key promoter element (the C box). TFIIIA can bind to the somatic 5S rRNA gene assembled into a nucleosome in the presence of H1. Because H1 binds with equivalent affinities to nucleosomes containing either gene, we establish that it is the sequence-selective assembly of a specific repressive chromatin structure on the oocyte 5S rRNA genes that accounts for differential transcriptional repression. Thus, general components of chromatin can determine the assembly of specific regulatory nucleoprotein complexes. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. NR 124 TC 76 Z9 76 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1998 VL 18 IS 7 BP 3668 EP 3680 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW151 UT WOS:000074380100003 PM 9632749 ER PT J AU Ryan, KM Vousden, KH AF Ryan, KM Vousden, KH TI Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID WILD-TYPE P53; P53-MEDIATED TRANSCRIPTIONAL REPRESSION; P53-DEPENDENT APOPTOSIS; G(1) ARREST; PROTEIN; ACTIVATION; GROWTH; INDUCTION; PROMOTERS; GENE AB Suppression of tumor cell growth by p53 results from the activation of both apoptosis and cell cycle arrest, functions which have been shown to be separable activities of p53. We have characterized a series of p53 mutants with amino acid substitutions at residue 175 and show that these mutants fall into one of three classes: class I, which is essentially wild type for apoptotic and cell cycle arrest functions; class II, which retains cell cycle arrest activity but is impaired in the induction of apoptosis; and class III, which is defective in both activities. Several residue 175 mutants which retain cell cycle arrest function have been detected in cancers, and we show that these have lost apoptotic function. Furthermore, several class II mutants have been found to be temperature sensitive for apoptotic activity while showing constitutive cell cycle arrest function. Taken together, these mutants comprise an excellent system with which to investigate the biochemical nature of p53-mediated apoptosis, the function of principal importance in tumor suppression. All of the mutants that showed loss of apoptotic function also showed defects in the activation of promoters from the potential apoptotic targets Bax and the insulin-like growth factor-binding protein 3 gene (IGF-BP3), and a correlation between full apoptotic activity and activation of both of these promoters was also seen with the temperature-sensitive mutants. However, a role for additional apoptotic activities of p53 was suggested by the observation that some mutants retained significant apoptotic function despite being impaired in the activation of Bax- and IGF-BP3-derived promoters. In contrast to the case of transcriptional activation, a perfect correlation between transcriptional repression of the c-fos promoter and the ability to induce apoptosis was seen, although the observation that Bax expression induced a similar repression of transcription from this promoter suggests that this may be a consequence, rather than a cause, of apoptotic death. C1 NCI, ABL Basic Res Program, FCRDC, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, ABL Basic Res Program, FCRDC, Bldg 560,Room 22-96,W 7th St, Frederick, MD 21702 USA. NR 43 TC 154 Z9 156 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1998 VL 18 IS 7 BP 3692 EP 3698 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW151 UT WOS:000074380100005 PM 9632751 ER PT J AU Jacobs-Helber, SM Wickrema, A Birrer, MJ Sawyer, ST AF Jacobs-Helber, SM Wickrema, A Birrer, MJ Sawyer, ST TI AP1 regulation of proliferation and initiation of apoptosis in erythropoietin-dependent erythroid cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; RAT EMBRYO CELLS; C-JUN; TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; DELETION MUTANT; DNA-BINDING; RECEPTOR; ACTIVATION; EXPRESSION AB The transcription factor AP1 has been implicated in the induction of apoptosis in cells in response to stress factors and growth factor withdrawal. We report here that AP1 is necessary for the induction of apoptosis following hormone withdrawal in the erythropoietin (EPO)-dependent erythroid cell line HCD57. AP1 DNA binding activity increased upon withdrawal of HCD57 cells from EPO. A dominant negative AP1 mutant rendered these cells resistant to apoptosis induced by EPO withdrawal and blocked the downregulation of Bcl-X-L. JunB is a major binding protein in the API complex observed upon EPO withdrawal; JunB but not c-Jun was present in the AP1 complex 3 h after EPO withdrawal in HCD57 cells, with a concurrent increase in junB message and protein. Furthermore, analysis of API DNA binding activity in an apoptosis-resistant subclone of HCD57 revealed a lack of induction in AP1 DNA binding activity and no change in junB mRNA levels upon EPO withdrawal. In addition, we determined that c-Jun and AP1 activities correlated with EPO-induced proliferation and/or protection from apoptosis. AP1 DNA binding activity increased over the first 3 h following EPO stimulation of HCD57 cells, and suppression of AP1 activity partially inhibited EPO-induced proliferation. c-Jun but not JunB was present in the AP1 complex 3 h after EPO addition. These results implicate AP1 in the regulation of proliferation and survival of erythroid cells and suggest that different API factors may play distinct roles in both triggering apoptosis (JunB) and protecting erythroid cells from apoptosis (c-Jun). C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol Toxicol, Richmond, VA 23298 USA. Univ Illinois, Hematol Oncol Sect, Chicago, IL 60607 USA. NCI, Dept Cell & Canc Biol, Med Branch, NIH, Rockville, MD 20850 USA. RP Sawyer, ST (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol Toxicol, POB 980613, Richmond, VA 23298 USA. EM SSAWYER@GEMS.VCU.EDU FU NIDDK NIH HHS [R01DK39781, R01 DK039781] NR 73 TC 74 Z9 76 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1998 VL 18 IS 7 BP 3699 EP 3707 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW151 UT WOS:000074380100006 PM 9632752 ER PT J AU Mittelstadt, PR Ashwell, JD AF Mittelstadt, PR Ashwell, JD TI Cyclosporin A-sensitive transcription factor Egr-3 regulates Fas ligand expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID IMMEDIATE-EARLY GENE; ZINC-FINGER PROTEIN; T-CELL HYBRIDOMAS; NGFI-A; MEDIATED CYTOTOXICITY; INDUCED APOPTOSIS; LYMPHOPROLIFERATIVE SYNDROME; FAMILY; ACTIVATION; GROWTH AB Activation-induced transcriptional upregulation of the ligand for Fas (FasL) and the resulting apoptosis of Fas-bearing cells constitute essential steps in a host of normal and pathological processes. Here we describe an activation-inducible cis acting regulatory element in the fasL promoter that is required for gene expression. Oligonucleotide competition and antibody supershift analyses identified two activation-induced DNA binding species: Egr-1 (NGFI-A, krox-24, zif268, TIS-I), a transcription factor that has been implicated in growth, differentiation, and apoptosis; and Egr-3 (PILOT), a transcription factor of no previously known function, Activation-induced expression of Egr-3, like that of FasL, was inhibited by cyclosporin A, whereas expression of Egr-1 was unaffected, Transient expression of Egr-3 alone increased fasL promoter activity in a cyclosporin A-insensitive manner, whereas expression of Egr-1 had little effect. Moreover, endogenous fast mRNA was induced in nonlymphoid cells by forced expression of Egr-3 in the absence of any other stimulus. These studies identify a critical Egr family-binding site in the fasL promoter and demonstrate that activation-induced Egr-3, but not Egr-1, directly upregulates fast transcription in response to activating stimuli. C1 NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 10,Room 1B-40, Bethesda, MD 20892 USA. NR 67 TC 135 Z9 141 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1998 VL 18 IS 7 BP 3744 EP 3751 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW151 UT WOS:000074380100011 PM 9632757 ER PT J AU Harris, ME Gontarek, RR Derse, D Hope, TJ AF Harris, ME Gontarek, RR Derse, D Hope, TJ TI Differential requirements for alternative splicing and nuclear export functions of equine infectious anemia virus rev protein SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL MESSENGER-RNA; MENTAL-RETARDATION PROTEIN; SITE-SPECIFIC MUTAGENESIS; TYPE-1 REV; HIV-1 REV; ACTIVATION DOMAIN; RESPONSE ELEMENT; TARGET SEQUENCE; PHENOTYPIC SELECTION AB The Rev protein of equine infectious anemia virus (ERev) exports unspliced and partially spliced viral RNAs from the nucleus. Like several cellular proteins, ERev regulates its own mRNA by mediating an alternative splicing event. To determine the requirements for these functions, we have identified ERev mutants that affect RNA export or both export and alternative splicing. Mutants were further characterized for subcellular localization, nuclear-cytoplasmic shuttling, and multimerization. None of the nuclear export signal (NES) mutants are defective for alternative splicing; Furthermore, the NES of ERev is similar in composition but distinct in spacing from other leucine-rich NESs. Basic residues at the C terminus of ERev are involved in nuclear localization, and disruption of the C-terminal residues affects both functions of ERev. ERev forms multimers, and no mutation disrupts this activity. In two mutants with substitutions of charged residues in the middle of ERev, RNA export is affected. One of these mutants is also defective for ERev-mediated alternative splicing but is identical to wild-type ERev in its localization, shuttling, and multimerization. Together, these results demonstrate that the two functions of ERev both require nuclear import and at least one other common activity, but RNA export can be separated from alternative splicing based on its requirement for a functional NES. C1 Salk Inst Biol Studies, Infect Dis Lab, La Jolla, CA 92037 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Frederick, MD 21702 USA. RP Hope, TJ (reprint author), Salk Inst Biol Studies, Infect Dis Lab, POB 85800, San Diego, CA 92186 USA. EM hope@salk.edu FU NIAID NIH HHS [AI35477] NR 57 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 1998 VL 18 IS 7 BP 3889 EP 3899 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW151 UT WOS:000074380100027 PM 9632773 ER PT J AU Lavrik, OI Zakharenko, AL Prasad, R Vlasov, VA Bogachev, VS Favre, A AF Lavrik, OI Zakharenko, AL Prasad, R Vlasov, VA Bogachev, VS Favre, A TI Deoxynucleoside triphosphates covalently linked to DNA polymerases through a base are active in reactions of nucleotidyl transfer SO MOLECULAR BIOLOGY LA English DT Article DE DNA polymerase beta of higher eukaryotes; photoactivatable dNTP analogs; photoaffine modification; nucleotidyl transfer ID REVERSE-TRANSCRIPTASE; AFFINITY MODIFICATION; ESCHERICHIA-COLI; BETA; DERIVATIVES; TEMPLATE; ANALOG; ALPHA AB Interaction of DNA polymerases [EC 2.7.7.7], namely, mammalian DNA polymerase beta and Klenow fragment of Escherichia coli DNA polymerase I, with deoxynucleoside 5'-triphosphates was investigated using photoaffinity labeling. For catalytically competent labeling of the dNTP-binding site of DNA polymerases, 5-[N-(2-nitro-5-azidobenzoyl)-trans-3-aminopropenyl-1]-deoxyuridine 5'-triphosphate (NABdUTP), 4-thiothymidine 5'-triphosphate (sTTP), and 5-iododeoxyuridine 5'-triphosphate (IdUTP), which are substrates for DNA polymerases, were covalently linked to the enzymes using UV irradiation and used for extension of a 5'-P-32-labeled primer in duplexes containing a dNTP-complementary or noncomplementary base in the template, and in a "blunt-end" duplex (without the coding template base). Efficient primer extension with a covalently bound dNTP requires conformational mobility of the dNTP, which is provided by its attachment through a long linker. The transfer of the nucleotidyl residue onto the blunt end only occurred after covalent fixation of dNTP and was more effective in the presence of Mn2+ than of Mg2+ ions. The dNTP binding by DNA polymerases as well as the subsequent nucleotidyl transfer may occur in the absence of the "coding" base of the template. This base determines the choice of dNTP, interacting with DNA polymerases as a cofactor forming a specific complex for the dNTP selection at every elongation step. C1 Russian Acad Sci, Novosibirsk Bioorgan Chem Inst, Novosibirsk 630090, Russia. NIEHS, Res Triangle Pk, NC 27709 USA. Russian Acad Sci, Novosibirsk Inst Cytol & Genet, Novosibirsk 630090, Russia. CNRS, Inst Jacques Monod, Paris 05, France. RP Lavrik, OI (reprint author), Russian Acad Sci, Novosibirsk Bioorgan Chem Inst, Novosibirsk 630090, Russia. EM lavrik@modul.bioch.nsk.su RI Lavrik, Olga /G-4641-2013 NR 24 TC 1 Z9 1 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA CONSULTANTS BUREAU, 233 SPRING ST, NEW YORK, NY 10013 USA SN 0026-8933 J9 MOL BIOL+ JI Mol. Biol. PD JUL-AUG PY 1998 VL 32 IS 4 BP 510 EP 517 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 122PL UT WOS:000076080600007 ER PT J AU Presley, JF Smith, C Hirschberg, K Miller, C Cole, NB Zaal, KJM Lippincott-Schwartz, J AF Presley, JF Smith, C Hirschberg, K Miller, C Cole, NB Zaal, KJM Lippincott-Schwartz, J TI Golgi membrane dynamics SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID 3-DIMENSIONAL ARCHITECTURE; ENDOPLASMIC-RETICULUM; ELECTRON-MICROSCOPY; PROTEIN; APPARATUS; TRANSPORT; COAT C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Presley, JF (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NR 31 TC 63 Z9 64 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA PUBL OFFICE, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL PY 1998 VL 9 IS 7 BP 1617 EP 1626 PG 10 WC Cell Biology SC Cell Biology GA 100UV UT WOS:000074834500005 PM 9658158 ER PT J AU Sidorenkov, I Komissarova, N Kashlev, M AF Sidorenkov, I Komissarova, N Kashlev, M TI Crucial role of the RNA : DNA hybrid in the processivity of transcription SO MOLECULAR CELL LA English DT Article ID TERNARY COMPLEXES; CHAIN ELONGATION; BUBBLE DUPLEXES; POLYMERASE; INITIATION; TRANSLOCATION; BINARY; ENZYME; VIEW AB We present an approach for studying the role of complementary nucleic acid interactions in transcription elongation by E. coli RNA polymerase (RNAP). The method involves in vitro reconstitution of a catalytically active elongation complex (EC) by the addition of RNAP to a single-strand DNA oligonucleotide containing the preannealed RNA primer, followed by incorporation of the complementary nontemplate DNA oligonucleotide. In all parameters tested, the reconstituted complex is indistinguishable from normal EC obtained by promoter-specific initiation. Using RNA primers of different lengths, which were fully or partially complementary to the DNA, we determined the minimal transcript length and the degree of its template pairing that is required to stabilize protein/nucleic acid interactions in EC to the high level characteristic of normal transcription, Our data show that a hybrid at least 9 nt long, formed between the template DNA and 3'-proximal RNA transcript, is necessary for the high processivity of EC during RNA chain elongation. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Kashlev, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NR 28 TC 138 Z9 139 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUL PY 1998 VL 2 IS 1 BP 55 EP 64 DI 10.1016/S1097-2765(00)80113-6 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106WR UT WOS:000075174500006 PM 9702191 ER PT J AU Cho, RJ Campbell, MJ Winzeler, EA Steinmetz, L Conway, A Wodicka, L Wolfsberg, TG Gabrielian, AE Landsman, D Lockhart, DJ Davis, RW AF Cho, RJ Campbell, MJ Winzeler, EA Steinmetz, L Conway, A Wodicka, L Wolfsberg, TG Gabrielian, AE Landsman, D Lockhart, DJ Davis, RW TI A genome-wide transcriptional analysis of the mitotic cell cycle SO MOLECULAR CELL LA English DT Article ID SACCHAROMYCES-CEREVISIAE; DEPENDENT KINASES; CDK INHIBITORS; HO GENE; YEAST; PROTEIN; CANCER; REGULATORS; ACTIVATION; ROUGHEX AB Progression through the eukaryotic cell cycle is known to be both regulated and accompanied by periodic fluctuation in the expression levels of numerous genes. We report here the genome-wide characterization of mRNA transcript levels during the cell cycle of the budding yeast S. cerevisiae. Cell cycle-dependent periodicity was found for 416 of the 6220 monitored transcripts. More than 25% of the 416 genes were found directly adjacent to other genes in the genome that displayed induction in the same cell cycle phase, suggesting a mechanism for local chromosomal organization in global mRNA regulation. More than 60% of the characterized genes that displayed mRNA fluctuation have already been implicated in cell cycle period-specific biological roles. Because more than 20% of human proteins display significant homology to yeast proteins, these results also link a range of human genes to cell cycle period-specific biological functions. C1 Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. Affymetrix, Santa Clara, CA 95051 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Campbell, MJ (reprint author), Mol Applicat, 607 Hansen Way,Bldg 1, Palo Alto, CA 94304 USA. RI Landsman, David/C-5923-2009; OI Steinmetz, Lars/0000-0002-3962-2865; Landsman, David/0000-0002-9819-6675; Winzeler, Elizabeth/0000-0002-4049-2113 NR 45 TC 1402 Z9 1451 U1 3 U2 35 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUL PY 1998 VL 2 IS 1 BP 65 EP 73 DI 10.1016/S1097-2765(00)80114-8 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106WR UT WOS:000075174500007 PM 9702192 ER PT J AU Zhong, M Orosz, A Wu, C AF Zhong, M Orosz, A Wu, C TI Direct sensing of heat and oxidation by Drosophila heat shock transcription factor SO MOLECULAR CELL LA English DT Article ID ISOLATED POLYTENE NUCLEI; DNA-BINDING ACTIVITY; COILED-COIL; IN-VIVO; ACTIVATION; PROTEIN; INDUCTION; HSP70; GENE; PHOSPHORYLATION AB The heat shock transcription factor HSF activates expression of its target genes in response to elevated temperatures and chemical or physiological stress. A key step in the activation process involves the formation of HSF homotrimers, leading to high-affinity DNA binding. The mechanism by which HSF trimerization and DNA binding is regulated by stress signals has remained elusive. Here, we report that trimerization and DNA binding of purified Drosophila HSF can be directly and reversibly induced in vitro by heat shock temperatures in the physiological range and by an oxidant, hydrogen peroxide. Other inducers of the heat shock response, including salicylate, dinitrophenol, ethanol, and arsenite, have no effect on HSF trimerization in vitro, indicating that these inducers act by indirect mechanisms. C1 NCI, Mol Cell Biol Lab, Bethesda, MD 20892 USA. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, Bethesda, MD 20892 USA. EM carlwu@helix.nih.gov RI yu, yan/C-2322-2012 NR 53 TC 120 Z9 125 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUL PY 1998 VL 2 IS 1 BP 101 EP 108 DI 10.1016/S1097-2765(00)80118-5 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106WR UT WOS:000075174500011 PM 9702196 ER PT J AU Koshimizu, T Tomic, M Van Goor, F Stojilkovic, SS AF Koshimizu, T Tomic, M Van Goor, F Stojilkovic, SS TI Functional role of alternative splicing in pituitary P2X(2) receptor-channel activation and desensitization SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GATED ION CHANNELS; MESSENGER-RNA; P-2X RECEPTOR; CALCIUM OSCILLATIONS; EXTRACELLULAR ATP; SENSORY NEURONS; CELLS; GONADOTROPHS; INTEGRATION; EXPRESSION AB Although ATP-gated ion channel (P2XR) expression is high among anterior pituitary cells, identification of the receptor subtypes and their selective expression within subpopulations of cell types, as well as their physiological role(s), are incompletely characterized. In this study, we focused on the expression and activity of the P2X(2)R subtype in anterior pituitary cells. Our results indicate that the primary P2X(2)R gene transcript in pituitary cells undergoes extensive alternative splicing, with generation of six isoforms. Two of these isoforms encode functional channels when expressed in GT1 or HEK293 cells: the wild-type p2X(2)R and the spliced isoform P2X(2-2)R, which lacks a stretch of carboxyl-terminal amino acids (Val(370)-Gln(438)). Four other clones showed different alterations, including an interfered reading frame starting in the first transmembrane domain and a 27-amino acid deletion in the large extracellular loop. When expressed separately or in combination with wild-type channels, these clones were nonfunctional. In single cell Ca2+ current and cytosolic Ca2+ concentration ([Ca2+](i)) measurements, the P2X(2)R and P2X(2-2)R had similar EC50 values for ATP and time courses for activation and recovery from desensitization but differed significantly in their desensitization rates. The spliced isoform exhibited rapid and complete desensitization, whereas the wild-type channel desensitized slowly and incompletely. The mRNAs for wild-type and spliced channels were identified in enriched somatotroph, but not gonadotroph or lactotroph fractions. Expression of a functional ATP-gated channel in somatotrophs was confirmed by the ability of ATP to increase the frequency of [Ca2+], spikes in spontaneously active cells or initiate spiking in quiescent cells. When voltage-gated Ca2+ influx was blocked, ATP increased [Ca2+](i), with a similar profile and EC50 to those observed in GT1 cells heterologously expressing wild-type or spliced P2X(2)R. The ligand-selectivity profile of native channels was consistent with the presence of P2X(2)R in somatotrophs. Finally, the desensitization rate of P2X(2)R in a majority of somatotrophs was comparable to that observed in neurons coexpressing wild-type and spliced channels. These data indicate that alternative splicing of P2X(2)R and coexpression of P2X(2)R and P2X(2-2)R subunits provide effective mechanisms for controlled cationic influx in somatotrophs. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. RI Tomic, Melanija/C-3371-2016; OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 28 TC 63 Z9 63 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 1998 VL 12 IS 7 BP 901 EP 913 DI 10.1210/me.12.7.901 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZX073 UT WOS:000074476700001 PM 9658396 ER PT J AU Mancilla, EE De Luca, F Baron, J AF Mancilla, EE De Luca, F Baron, J TI Activating mutations of the Ca2+-sensing receptor SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Ca2+-sensing receptor; parathyroid hormone; autosomal dominant hypoparathyroidism; hypercalciuria ID FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM; NEONATAL SEVERE HYPERPARATHYROIDISM; BOVINE PARATHYROID CELLS; CALCIUM-SENSING RECEPTOR; BENIGN HYPERCALCEMIA; SPORADIC HYPOPARATHYROIDISM; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; HORMONE GENE AB The Ca2+-sensing receptor (CaR) is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. It is expressed in parathyroid, kidney, and other tissues. In parathyroid, activation of the CaR by extracellular Ca2+ negatively regulates the secretion of parathyroid hormone. In the the thick ascending limb of Henle's loop, receptor activation decreases renal reabsorption of Ca2+. Heterozygous inactivating mutations of the CaR cause familial benign hypocalciuric hypercalcemia while homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Conversely, activating mutations of the CaR cause autosomal dominant and sporadic hypoparathyroidism. Affected individuals have hypocalcemia which ranges from mild and asymptomatic to life-threatening. They also show a greater tendency to hypercalciuria than do other patients with hypoparathyroidism. Most, but not all, of the reported activating mutations occur in the amino-terminal, extracellular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and increased maximal signal transduction capacity (C) 1998 Academic Press. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Baron, J (reprint author), NICHD, DEB, NIH, Bldg 10,Room 10N262,10 Ctr Dr MSC 1862, Bethesda, MD 20892 USA. NR 42 TC 17 Z9 18 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 1998 VL 64 IS 3 BP 198 EP 204 DI 10.1006/mgme.1998.2716 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 116YD UT WOS:000075751900007 PM 9719629 ER PT J AU Fiala, M Zhang, L Gan, XH Sherry, B Taub, D Graves, MC Hama, S Way, D Weinand, M Witte, M Lorton, D Kuo, YM Roher, AE AF Fiala, M Zhang, L Gan, XH Sherry, B Taub, D Graves, MC Hama, S Way, D Weinand, M Witte, M Lorton, D Kuo, YM Roher, AE TI Amyloid-beta induces chemokine secretion and monocyte migration across a human blood-brain barrier model SO MOLECULAR MEDICINE LA English DT Article ID ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; APOLIPOPROTEIN-E; TNF-ALPHA; MICROGLIA; PERMEABILITY; PROTEIN; LESIONS; PLAQUES; CELLS AB Background: Aside from numerous parenchymal and vascular deposits of amyloid beta (A beta) peptide, neurofibrillary tangles, and neuronal and synaptic loss, the neuropathology of Alzheimer's disease is accompanied by a subtle and chronic inflammatory reaction that manifests itself as microglial activation. However, in Alzheimer's disease, alterations in the permeability of the blood-brain barrier and chemotaxis, in part mediated by chemokines and cytokines, may permit the recruitment and transendothelial passage of peripheral cells into the brain parenchyma. Materials and Methods: Human monocytes from different donors were tested for their capacity to differentiate into macrophages and their ability to secrete cytokines and chemokines in the presence of A beta 1-42. A paradigm of the blood-brain barrier was constructed utilizing human brain endothelial and astroglial cells with the anatomical and physiological characteristics observed in vivo. This model was used to test the ability of monocytes/macrophages to transmigrate when challenged by A beta 1-42 on the brain side of the blood-brain barrier model. Results: In cultures of peripheral monocytes, A beta 1-42 induced the secretion of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta, and IL-12, as well as CC chemokines MCP-1, MIP-1 alpha, and MIP-1 beta, and CXC chemokine IL-8 in a dose-related fashion. In the blood-brain barrier model, A beta 1-42 and monocytes on the brain side potentiated monocyte transmigration from the blood side to the brain side. A beta 1-42 stimulated differentiation of monocytes into adherent macrophages in a dose-related fashion. The magnitude of these proinflammatory effects of A beta 1-42 varied dramatically with monocytes from different donors. Conclusion: In some individuals, circulating monocytes/macrophages, when recruited by chemokines produced by activated microglia and macrophages, could add to the inflammatory destruction of the brain in Alzheimer's disease. C1 Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Picower Inst Med Res, Manhasset, NY USA. NIA, Baltimore, MD 21224 USA. Univ Arizona, Dept Surg, Tucson, AZ USA. Sun Hlth Res Inst, Haldeman Lab Alzheimer Dis Res, Sun City, AZ USA. RP Fiala, M (reprint author), Univ Calif Los Angeles, Sch Med, Dept Neurol, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM fiala@ucla.edu RI Kuo, Yu-Min/A-9050-2013 OI Kuo, Yu-Min/0000-0003-4867-2482 NR 55 TC 147 Z9 154 U1 0 U2 2 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL PY 1998 VL 4 IS 7 BP 480 EP 489 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 107XG UT WOS:000075235800005 PM 9713826 ER PT J AU van Putten, JPM Duensing, TD Cole, RL AF van Putten, JPM Duensing, TD Cole, RL TI Entry of OpaA(+) gonococci into HEp-2 cells requires concerted action of glycosaminoglycans, fibronectin and integrin receptors SO MOLECULAR MICROBIOLOGY LA English DT Article ID EXTRACELLULAR-MATRIX PROTEINS; TISSUE-PLASMINOGEN ACTIVATOR; HUMAN-PLASMA FIBRONECTIN; STAPHYLOCOCCUS-AUREUS; EPITHELIAL-CELLS; BINDING-SITES; NEISSERIA-GONORRHOEAE; ESCHERICHIA-COLI; MONOCLONAL-ANTIBODIES; HEPARAN-SULFATE AB Heparan sulphate proteoglycans are increasingly implicated as eukaryotic cell surface receptors for bacterial pathogens. Here, we report that Neisseria gonorrhoeae adheres to proteoglycan receptors on HEp-2 epithelial cells but that internalization of the bacterium by this cell type requires the serum glycoprotein fibronectin. Fibronectin was shown to bind specifically to gonococci producing the OpaA adhesin, Binding assays with fibronectin fragments located the bacterial binding site near the N-terminal end of the molecule. However, none of the tested fibronectin fragments supported gonococcal entry into the eukaryotic cells; a 120 kDa fragment carrying the cell adhesion domain with the amino acid sequence RGD even inhibited the fibronectin-mediated uptake of MS11-OpaA. This inhibition could be mimicked by an RGD-containing hexapeptide and by alpha 5 beta 1 integrin-specific antibodies, suggesting that interaction of the central region of fibronectin with integrin receptors facilitated bacterial uptake. Fibronectin was unable to promote gonococcal entry into HEp-2 cells that had been treated with the enzyme heparinase ill, which degrades the glycosaminoglycan side-chains of proteoglycan receptors. On the basis of these results, we propose a novel cellular uptake pathway for bacteria, which involves the binding of the pathogen to glycosaminoglycans that, in turn, act as co-receptors facilitating fibronectin-mediated bacterial uptake through integrin receptors. in this scenario, fibronectin would act as a molecular bridge linking the Opa-proteoglycan complex with host cell integrin receptors. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP van Putten, JPM (reprint author), NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jos_van_putten@nih.gov OI van Putten, Jos/0000-0002-4126-8172 NR 61 TC 102 Z9 103 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 1998 VL 29 IS 1 BP 369 EP 379 DI 10.1046/j.1365-2958.1998.00951.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 100UZ UT WOS:000074834900032 PM 9701828 ER PT J AU Li, ZW Vaidya, VA Alvaro, JD Iredale, PA Hsu, R Hoffman, G Fitzgerald, L Curran, PK Machida, CA Fishman, PH Duman, RS AF Li, ZW Vaidya, VA Alvaro, JD Iredale, PA Hsu, R Hoffman, G Fitzgerald, L Curran, PK Machida, CA Fishman, PH Duman, RS TI Protein kinase C-mediated down-regulation of beta(1)-adrenergic receptor gene expression in rat C6 glioma cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID BETA-ADRENERGIC-RECEPTOR; ADENYLATE-CYCLASE; MESSENGER-RNA; CYCLIC-AMP; PHORBOL ESTERS; BETA(2)-ADRENERGIC RECEPTOR; PKC ISOFORMS; PHOSPHORYLATION; DESENSITIZATION; TRANSCRIPTION AB In the current study, we investigated the mechanism by which protein kinase C (PKC) regulates the expression of beta(1)-adrenergic receptor (beta(1)AR) mRNA in rat C6 glioma cells. Exposure of the cells to 4 beta-phorbol-12-myristate-13-acetate (PMA), an activator PKC, resulted in a down-regulation of both beta(1)AR binding sites and mRNA levels in a time- and concentration-dependent manner. This effect was not observed with phorbol esters that do not activate PKC and was blocked by bisindolylmaleimide, a specific PKC inhibitor. Activation of PKC did not reduce the half-life of beta(1)AR mRNA but significantly decreased the activity of the beta(1)AR promoter, as determined by reporter analysis. A putative response element, with partial homology to a consensus cAMP response element, was identified by mutation analysis of the promoter at positions -343 to -336, relative to the translational start site. Mutation of this putative regulatory element, referred to as a beta(1)AR-PKC response element, completely blocked the PKC-mediated down-regulation of beta(1)AR promoter activity. Gel mobility shift analysis detected two specific bands when C6 cell extracts were incubated with a labeled DNA probe containing the beta(1)AR-PKC response element sequence. Formation of one of these bands was inhibited by an oligonucleotide probe containing a consensus CRE and disrupted by an antibody for cAMP response element binding protein. Based on these studies, we propose that the PKC-induced down-regulation of beta(1)AR gene transcription in C6 cells is mediated in part by a cAMP response element binding protein-dependent mechanism acting on a novel response element. C1 Yale Univ, Sch Med, Dept Psychiat, Div Mol Psychiat, New Haven, CT 06508 USA. Yale Univ, Sch Med, Dept Pharmacol, Div Mol Psychiat, New Haven, CT 06508 USA. NINDS, Cellular & Mol Neurobiol Lab, Membrane Biochem Sect, NIH, Bethesda, MD 20892 USA. Oregon Reg Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Grad Programs Neurosci & Mol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Grad Program Cell Biol, Portland, OR 97201 USA. RP Duman, RS (reprint author), Yale Univ, Sch Med, Dept Psychiat, Div Mol Psychiat, 34 Pk St, New Haven, CT 06508 USA. EM ronald.duman@yale.edu FU NIMH NIH HHS [MH45481, MH53199, 2-PO1-MH25642] NR 40 TC 16 Z9 16 U1 0 U2 0 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 JUL PY 1998 VL 54 IS 1 BP 14 EP 21 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZZ987 UT WOS:000074789400003 PM 9658185 ER PT J AU Kohlhagen, G Paull, KD Cushman, M Nagafuji, P Pommier, Y AF Kohlhagen, G Paull, KD Cushman, M Nagafuji, P Pommier, Y TI Protein-linked DNA strand breaks induced by NSC 314622, a novel noncamptothecin topoisomerase I poison SO MOLECULAR PHARMACOLOGY LA English DT Article ID ANTITUMOR AGENT; ACTINOMYCIN-D; CAMPTOTHECIN; INHIBITION; CLEAVAGE; CYTOTOXICITY; DERIVATIVES; INDUCTION; IDENTIFICATION; RESISTANT AB NSC 314622 was found to have a cytotoxicity profile comparable to the topoisomerase I (top1) inhibitors camptothecin (CPT) and saintopin in the National Cancer Institute In Vitro Anticancer Drug Discovery Screen using the COMPARE analysis. In vitro data showed that NSC 314622 induced DNA cleavage in the presence of top1 at micromolar concentrations. Cleavage specificity was different from CPT in that NSC 314622 did not cleave all sites induced by CPT whereas some sites were unique to the NSC 314622 treatment. Top1-induced DNA cleavage was also more stable than cleavage induced by CPT. NSC 314622 did not induce DNA cleavage in the presence of human topoisomerase II. High concentrations of NSC 314622 did not produce detectable DNA unwinding, which suggests that NSC 314622 is not a DNA intercalator. DNA damage analyzed in human breast carcinoma MCF7 cells by alkaline elution showed that NSC 314622 induced protein-linked DNA single-strand breaks that reversed more slowly than CPT-induced strand breaks. CEM/C2, a CPT-resistant cell line because of a top1 point mutation [Cancer Res 55:1339-1346 (1995)], was cross-resistant to NSC 314622. These results demonstrate that NSC 314622 is a novel top1-targeted drug with a unique chemical structure. C1 NCI, Div Basic Sci, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,NIH, Bethesda, MD 20892 USA. Purdue Univ, Dept Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. RP Pommier, Y (reprint author), NCI, Div Basic Sci, Mol Pharmacol Lab, NIH, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 41 TC 131 Z9 134 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUL PY 1998 VL 54 IS 1 BP 50 EP 58 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZZ987 UT WOS:000074789400007 PM 9658189 ER PT J AU Philibert, RA King, BH Winfield, S Cook, EH Lee, YH Stubblefield, B Damschroder-Williams, P Dea, C Palotie, A Tengstrom, C Martin, BM Ginns, EI AF Philibert, RA King, BH Winfield, S Cook, EH Lee, YH Stubblefield, B Damschroder-Williams, P Dea, C Palotie, A Tengstrom, C Martin, BM Ginns, EI TI Association of an X-chromosome dodecamer insertional variant allele with mental retardation SO MOLECULAR PSYCHIATRY LA English DT Article DE mental retardation; autism; X-chromosome; repetitive DNA; genetics; linkage ID INSITU HYBRIDIZATION; DNA-SEQUENCES; GENE; IDENTIFICATION; DROSOPHILA; OPA; HYDROCEPHALUS; EXPRESSION; SPECTRUM; FAMILIES AB Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<<1% in non-ill males) having an increased prevalence in non-fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation. C1 NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Helsinki, Cent Hosp, Mol Genet Lab, Dept Clin Chem, Helsinki, Finland. Lab Cytogenet, Espoo, Finland. RP Philibert, RA (reprint author), NIMH, Clin Neurosci Branch, Bldg 49,Rm B1EE16,49 Convent Dr,MSC 4405, Bethesda, MD 20892 USA. EM philiber@irp.nimh.nih.gov FU NIMH NIH HHS [K02 MH01389, R01 MH33779, R01 MH52223] NR 27 TC 35 Z9 37 U1 1 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1998 VL 3 IS 4 BP 303 EP 309 DI 10.1038/sj.mp.4000442 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BP UT WOS:000075474500007 PM 9702738 ER PT J AU Burgess, CE Lindblad, K Sidransky, E Yuan, QP Long, RT Breschel, T Ross, CA McInnis, M Lee, P Ginns, EI Lenane, M Kumra, S Jacobsen, L Rapoport, JL Schalling, M AF Burgess, CE Lindblad, K Sidransky, E Yuan, QP Long, RT Breschel, T Ross, CA McInnis, M Lee, P Ginns, EI Lenane, M Kumra, S Jacobsen, L Rapoport, JL Schalling, M TI Large CAG/CTG repeats are associated with childhood-onset schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE multi-dimensionally impaired; trinucleotide repeat expansion; neuropsychiatric disorders; repeat expansion detection; CTG18.1 ID BIPOLAR AFFECTIVE-DISORDER; EXPANDED CAG REPEATS; TRINUCLEOTIDE REPEATS; ANTICIPATION; EXPANSION; POPULATIONS; DISEASE; HISTORY; GENOME; LIGHT AB Recent studies have shown an association between trinucleotide repeat expansions (TREs) and adult-onset schizophrenia (AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. We have used the repeat expansion detection (RED) method to investigate the occurrence of repeat expansions in a group of well-characterized COS patients as well as a set of clinically related childhood-onset psychosis cases labeled 'multidimensionally impaired' (MDI). The difference observed in the CAG/CTG RED product distribution between normal (n = 44) and COS (n = 36) samples was only marginally significant (P = 0.036). However, male COS samples.(n = 20) had a significantly different RED product distribution compared to male controls (n = 25, P = 0.002) with longer RED products in COS. No such difference was seen in females (n(cont) = 10; n(COS) = 16; P = 0.236). The difference remained significant between male COS (n = 12) and male controls (n = 24) when only Caucasian samples were used (P = 0.003). Similarly, the RED product distribution in male MDI samples (n = 18) was significantly different compared to male controls (P = 0.018). Some of the detected TREs in all three populations (COS, NIDI and control) correlated with expanded alleles found at the CTG18.1 locus on chromosome 18, In conclusion, we have found an association between TREs and COS. This association is specifically significant in the male population. Thus, the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, possibly in combination with other factors. C1 Karolinska Hosp, Ctr Mol Med, Neurogenet Unit, S-17176 Stockholm, Sweden. NIMH, Clin Neurosci Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Schalling, M (reprint author), Karolinska Hosp, Ctr Mol Med, Neurogenet Unit, L8-00, S-17176 Stockholm, Sweden. RI Ross, Christopher/H-8395-2013; Schalling, Martin/F-1518-2015 OI Schalling, Martin/0000-0001-5011-2922 NR 44 TC 25 Z9 25 U1 2 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1998 VL 3 IS 4 BP 321 EP 327 DI 10.1038/sj.mp.4000405 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BP UT WOS:000075474500009 PM 9702740 ER PT J AU Malhotra, AK Goldman, D Mazzanti, C Clifton, A Breier, A Pickar, D AF Malhotra, AK Goldman, D Mazzanti, C Clifton, A Breier, A Pickar, D TI A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics SO MOLECULAR PSYCHIATRY LA English DT Article DE psychosis; schizophrenia; serotonin; polymorphism; hallucinations; gene ID GENE REGULATORY REGION; FRONTAL-CORTEX; RECEPTORS; SYMPTOMS; BINDING AB The neurotransmitter serotonin has been implicated in the pathophysiology of psychosis. The serotonin transporter (5-HTT) plays a critical role in regulation of serotonergic function. A recently identified polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) produces significant differences in 5-HTT expression and function and was found to be associated with anxiety-related traits in healthy volunteers. We investigated whether 5-HTTLPR is associated with psychosis in neuroleptic-free schizophrenic or schizoaffective patients. Fifty patients with schizophrenia or schizoaffective disorder by DSM-III-R criteria were genotyped at 5-HTTLPR and underwent double-blind Brief Psychiatric Rating Scale (BPRS) ratings while neuroleptic-free for approximately 4 weeks. Patients with the 5-HTTLPR II genotype (n = 19) had significantly higher BPRS ratings for psychosis than patients with the is (n = 25) or ss (n = 6) genotypes. Examination of individual items revealed a specific significant increase in intensity of hallucinations in patients with the 5-HTTLPR Il genotype. These data provide preliminary evidence for a role of serotonin in the pathophysiology of hallucinations and may represent the identification of an allelic variant that modifies the complex clinical presentation of schizophrenia. C1 NIMH, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Malhotra, AK (reprint author), Hillside Hosp, Unit Mol Psychiat, 75-59 263rd St, Glen Oaks, NY 11004 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 27 TC 93 Z9 95 U1 5 U2 6 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1998 VL 3 IS 4 BP 328 EP 332 DI 10.1038/sj.mp.4000412 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BP UT WOS:000075474500010 PM 9702741 ER PT J AU Baas, D Dalencon, D Fressinaud, C Vitkovic, L Sarlieve, LL AF Baas, D Dalencon, D Fressinaud, C Vitkovic, L Sarlieve, LL TI Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells express glutamine synthetase: developmental and cell type-specific regulation SO MOLECULAR PSYCHIATRY LA English DT Article DE O-2A cells; astrocytes; oligodendrocytes; culture; glutamine synthetase; mRNA; protein; activity ID FIBROBLAST GROWTH-FACTORS; CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; PRIMARY CULTURES; MESSENGER-RNA; PROLIFERATION; LOCALIZATION; GAP-43; DIFFERENTIATION; OLIGODENDROGLIA AB Glutamine synthetase (GS), the enzyme that catalyses glutamine synthesis from glutamate and ammonia, plays a central role in the detoxification of brain ammonia.(1) In the central nervous system (CNS), GS also subserves additional important functions such as regulating glutamate, GABA and amino acid metabolism.(2) Oligodendrocytes (OL) form the myelin sheath in the central nervous system (CNS) and are essential for efficient propagation of nerve impulses. In culture, OL arise from bipotential O-2A progenitor cells. These O-2A cells give rise to type-2 astrocytes in the presence of serum. GS is expressed in mature glial cells(3-7) in vivo and in vitro, but it is unknown whether GS is present in glial progenitors. In addition, a comparison of the GS expression level among the various types of glial cells has never been done in vitro. The current study investigates in vitro GS expression levels in O-2A progenitors, astrocytes and OL. We demonstrate that the GS gene is expressed in O-2A progenitors and is expressed at different levels in each cultured glial cell type. GS also is stimulated during OL developmental maturation. Thus, the GS gene is expressed in O-2A cells and is regulated in a developmental and macroglial cell type-specific manner. C1 CNRS, Ctr Neurochim, UPR 416, F-67084 Strasbourg, France. CHU Angers, Serv Neurol B, Angers, France. NIMH, Div Neurosci & Behav Sci, NIH, Rockville, MD 20857 USA. RP Baas, D (reprint author), CNRS, Ctr Neurochim, UPR 416, 5 Rue Blaise Pascal, F-67084 Strasbourg, France. EM dominique.baas@yale.edu; sarlieve@neurochem.u-strasbg.fr RI Fressinaud, Catherine/K-4393-2015 NR 29 TC 6 Z9 6 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 1998 VL 3 IS 4 BP 356 EP 361 DI 10.1038/sj.mp.4000379 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112BP UT WOS:000075474500016 PM 9702747 ER PT J AU Lehrnbecher, T Briegel, W Horwitz, AE Kenn, W Rauh, V Marx, A Kuhl, J AF Lehrnbecher, T Briegel, W Horwitz, AE Kenn, W Rauh, V Marx, A Kuhl, J TI Kasabach-Merritt syndrome in sinusoidal hemangiomatosis of the spleen SO MONATSSCHRIFT KINDERHEILKUNDE LA German DT Article DE sinusoidal hemangiomatosis; spleen; Kasabach-Merritt syndrome ID SPLENIC HEMANGIOMA AB We report on a 13-month-old girl who developed Kasabach-Merritt syndrome because of sinusoidal hemangiomatosis of the spleen. The combination of consumption coagulopathy and tumor of the spleen suggested a vascular process. Discussion: For a tumor of the spleen, sinusoidal hemangiomatosis has to be considered as differential diagnosis. Splenectomy is the treatment of choice when consumption coagulopathy occurs. C1 Univ Wurzburg, Kinderklin, D-97070 Wurzburg, Germany. RP Lehrnbecher, T (reprint author), NCI, Pediat Oncol Branch, Bldg 10,13N240, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0026-9298 J9 MONATSSCHR KINDERH JI Mon.schr. Kinderheilkd. PD JUL PY 1998 VL 146 IS 7 BP 665 EP 668 DI 10.1007/s001120050307 PG 6 WC Pediatrics SC Pediatrics GA 108HB UT WOS:000075259200004 ER PT J AU Anderson, DW Rocca, WA de Rijk, MC Grigoletto, F Melcon, MO Breteler, MMB Maraganore, DM AF Anderson, DW Rocca, WA de Rijk, MC Grigoletto, F Melcon, MO Breteler, MMB Maraganore, DM TI Case ascertainment uncertainties in prevalence surveys of Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE bias; epidemiology; parkinsonism; Parkinson's disease; prevalence ID GENDER DIFFERENCES; DISORDERS; ROTTERDAM; SYMPTOMS AB Using unpublished data from five completed prevalence surveys of Parkinson's disease (PD), we investigated case ascertainment uncertainties that potentially have a direct effect on prevalence. These uncertainties arise from the choice of diagnostic criteria, the choice of screening method, and the amount of information lost because of nonresponse. The surveys were conducted in Argentina, India, China, Italy, and the Netherlands. Our analyses consisted of simple comparisons of prevalence results, positive predictive values (a screening measure), and nonresponse percentages. We found that (a) prevalence comparisons between surveys have diminished value if the surveys used different diagnostic criteria for PD; (b) screening performance may be affected adversely if symptom questions are answered by one family member for the entire family living together rather than by each family member individually; and (c) nonresponse from refusal or unavailability does not necessarily lead to bias, but special caution may be appropriate with prevalence results pertaining to elderly women. C1 NINDS, Biometry & Field Studies Branch, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. Erasmus Univ, Sch Med, Dept Epidemiol & Biostat, NL-3000 DR Rotterdam, Netherlands. Erasmus Univ, Sch Med, Dept Neurol, NL-3000 DR Rotterdam, Netherlands. Erasmus Univ, Sch Med, Erasmus Ctr Res Aging, NL-3000 DR Rotterdam, Netherlands. Univ Padua, Inst Hyg, Padua, Italy. Reg Hosp, Dept Neurol, Junin, Buenos Aires, Argentina. RP Anderson, DW (reprint author), NINDS, Biometry & Field Studies Branch, NIH, Fed Bldg,Room 7C-16, Bethesda, MD 20892 USA. RI Breteler, Monique /J-5058-2014 FU NINDS NIH HHS [NS33978] NR 17 TC 28 Z9 28 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 1998 VL 13 IS 4 BP 626 EP 632 DI 10.1002/mds.870130403 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA ZZ394 UT WOS:000074725000002 PM 9686765 ER PT J AU Fine, EJ Hallett, M Litvan, I Tresser, N Katz, D AF Fine, EJ Hallett, M Litvan, I Tresser, N Katz, D TI Dysfunction of Ib (autogenic) spinal inhibition in patients with progressive supranuclear palsy SO MOVEMENT DISORDERS LA English DT Article DE progressive supranuclear palsy; Ib interneurons; autogenic inhibition; Ia afferent; rigidity; H reflex ID RICHARDSON-OLSZEWSKI-SYNDROME; SKELETAL-MUSCLE; STRETCH REFLEX; CRITERIA AB We compared the activity of Ib spinal interneurons in five patients with progressive supranuclear palsy (PSP) with six age-matched control subjects. Stimulation of the medial gastrocnemius nerve at motor threshold intensity activated Ib afferents that in turn inhibit H reflexes from the soleus muscle. Maximum inhibition occurred at interstimulus intervals of 6 and 8 ms for both control subjects and PSP patients and was significantly greater in the PSP patients. Increased Ib activity of PSP patients may be caused by loss of inhibition of Ib interneurons through degeneration of the medullary reticulospinal pathway. The corticospinal pathways, unopposed by the medullary reticulospinal tract, may excessively activate Ib interneurons. C1 Dept Vet Affairs Med Ctr, Neurol Serv, Buffalo, NY USA. SUNY Buffalo, Dept Neurol, Buffalo, NY 14260 USA. NINDS, NIH, Bethesda, MD 20892 USA. Hartford Hosp, Dept Pathol & Lab Med, Hartford, CT 06115 USA. RP Fine, EJ (reprint author), VA Med Ctr, Neurol Serv, 3495 Bailey Ave, Buffalo, NY 14215 USA. OI Litvan, Irene/0000-0002-3485-3445 NR 22 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 1998 VL 13 IS 4 BP 668 EP 672 DI 10.1002/mds.870130410 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA ZZ394 UT WOS:000074725000009 PM 9686772 ER PT J AU Valls-Sole, J Hallett, M Brasil-Neto, J AF Valls-Sole, J Hallett, M Brasil-Neto, J TI Modulation of vastus medialis motoneuronal excitability by sciatic nerve afferents SO MUSCLE & NERVE LA English DT Article DE reciprocal inhibition; quadriceps; muscle afferents; H reflex; cortical stimulation; presynaptic inhibition ID RECIPROCAL IA INHIBITION; PRESYNAPTIC INHIBITION; QUADRICEPS MOTONEURONES; MUSCLE AFFERENTS; HUMAN FOREARM; FLEXOR; FACILITATION; PROJECTIONS; STIMULATION; EXTENSOR AB We activated the sciatic nerve afferents by either the discharge of a magnetic coil or a needle inserted near the nerve. Both types of stimulation induced facilitation of the vastus medialis (VM) H reflex, and of the VM response to transcranial magnetic stimulation, at the joint time of arrival of conditioning and test volleys, while a subsequent inhibition was induced only in the H reflex. We conclude that sciatic nerve afferents induce reciprocal inhibition of VM motoneurons presynaptically on the la afferent terminals. (C) 1998 John Wiley & Sons, Inc. C1 Univ Barcelona, Hosp Clin, Dept Med, Unitat EMG,Serv Neurol, E-08036 Barcelona, Spain. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. UnB, IB ICC, Dept Ciencias Fisiol, Neurobiol Lab, Brasilia, DF, Brazil. RP Valls-Sole, J (reprint author), Univ Barcelona, Hosp Clin, Dept Med, Unitat EMG,Serv Neurol, Villarroel 170, E-08036 Barcelona, Spain. RI Brasil-Neto, Joaquim/A-1171-2009 NR 18 TC 3 Z9 3 U1 0 U2 0 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 JUL PY 1998 VL 21 IS 7 BP 936 EP 939 DI 10.1002/(SICI)1097-4598(199807)21:7<936::AID-MUS12>3.0.CO;2-O PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZU806 UT WOS:000074236800012 PM 9626254 ER PT J AU Samii, A Lopez-Devine, J Wasserman, EM Dalakas, MC Clark, K Grafman, J Hallett, M AF Samii, A Lopez-Devine, J Wasserman, EM Dalakas, MC Clark, K Grafman, J Hallett, M TI Normal postexercise facilitation and depression of motor evoked potentials in postpolio patients SO MUSCLE & NERVE LA English DT Article DE motor evoked potential; postexercise facilitation; postexercise depression; transcranial magnetic stimulation; postpolio; human ID TRANSCRANIAL MAGNETIC STIMULATION; FATIGUE AB We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation in healthy subjects and postpolio patients. Subjects performed repeated sets of isometric exercise until the muscle fatigued. In both groups, the mean MEP amplitude immediately after each exercise set was approximately twice that of the baseline amplitude, indicating similar postexercise facilitation, and after fatigue was approximately half that of the baseline amplitude, indicating similar postexercise depression. We conclude that the intracortical component of central fatigue is normal in postpolio patients. (C) 1998 John Wiley & Sons, Inc. C1 NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. OI Grafman, Jordan H./0000-0001-8645-4457 NR 16 TC 11 Z9 11 U1 0 U2 0 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 JUL PY 1998 VL 21 IS 7 BP 948 EP 950 DI 10.1002/(SICI)1097-4598(199807)21:7<948::AID-MUS16>3.0.CO;2-M PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZU806 UT WOS:000074236800016 PM 9626258 ER PT J AU Brooks, PJ AF Brooks, PJ TI Detection of excision nuclease in cell-free extracts from the adult mammalian brain SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE xeroderma pigmentosum; nucleotide excision repair; excision nuclease ID DNA-REPAIR; XERODERMA-PIGMENTOSUM; RAT-BRAIN; DAMAGE; ENZYME; COMPLEMENTATION; RADIATION; PROTEIN; ADDUCTS; RODENT AB The autosomal recessive disorder xeroderma pigmentosum (XP) results from defects in the nucleotide excision repair (NER) pathway for DNA repair. NER normally repairs bulky DNA lesions, such as pyrimidine dimers resulting from UV radiation. XP patients have high rates of skin cancer, and some also develop progressive neurological degeneration. To better understand the mechanism of this neurodegeneration, I used a specific assay for the multicomponent excision nuclease of the NER pathway in cell-free extracts from the adult rat brain. Excision nuclease activity was detectable in whole-cell extracts prepared from the cerebellum, whereas extracts prepared from the forebrain, which has a lower density of cell nuclei, had much less activity. Nuclear extracts from both areas were equally capable of restoring activity to extracts from two different NER-deficient cell lines, despite large differences in the ratio of neurons to nonneuronal cells in the cerebellum and forebrain. These results indicate that the NER pathway is functional in neuronal cells in the adult brain. The implications of this finding for XP and other neurodegenerative diseases is discussed. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIAAA, Mol Neurobiol Sect, Neurogenet Lab, Rockville, MD 20852 USA. RP Brooks, PJ (reprint author), NIAAA, Mol Neurobiol Sect, Neurogenet Lab, 12501 Washington Ave, Rockville, MD 20852 USA. EM pjbrooks@dicbr.niaaa.nih.gov NR 51 TC 17 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8777 J9 MUTAT RES-DNA REPAIR JI Mutat. Res.-DNA Repair PD JUL PY 1998 VL 408 IS 1 BP 37 EP 46 DI 10.1016/S0921-8777(98)00018-4 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA ZZ439 UT WOS:000074729500005 PM 9678062 ER PT J AU Mezey, E Dehejia, A Harta, G Papp, MI Polymeropoulos, MH Brownstein, MJ AF Mezey, E Dehejia, A Harta, G Papp, MI Polymeropoulos, MH Brownstein, MJ TI Alpha synuclein in neurodegenerative disorders: Murderer or accomplice? SO NATURE MEDICINE LA English DT Editorial Material ID MULTIPLE SYSTEM ATROPHY; OLIVOPONTOCEREBELLAR ATROPHY AB Several neurodegenerative disorders are characterized by intracellular protein accumulations or inclusions, such as the Lewy bodies of Parkinson's disease. Although little is know about the origin of these accumulations and their specific affect on neurons, it seems likely that as they grow they prove fatal to the cell. Here Michael Brownstein and colleagues speculate on a broad role for alpha synuclein in the development of Lewy bodies and the other protein inclusions associated with neurodegeneration. C1 NINDS, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Semmelweis Univ Med, Sch Med, Dept Neurol, H-1083 Budapest, Hungary. NIMH, NHGRI, NIH, Bethesda, MD 20892 USA. RP Mezey, E (reprint author), NINDS, NIH, 9000 Rockville Pike,Bldg 36,Room 3D06, Bethesda, MD 20892 USA. RI Brownstein, Michael/B-8609-2009 NR 18 TC 167 Z9 169 U1 0 U2 5 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 JUL PY 1998 VL 4 IS 7 BP 755 EP 757 DI 10.1038/nm0798-755 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX687 UT WOS:000074543900017 PM 9662355 ER PT J AU Kohn, DB Hershfield, MS Carbonaro, D Shigeoka, A Brooks, J Smogorzewska, EM Barsky, LW Chan, R Burotto, F Annett, G Nolta, JA Crooks, G Kapoor, N Elder, M Wara, D Bowen, T Madsen, E Snyder, FF Bastian, J Muul, L Blaese, RM Weinberg, K Parkman, R AF Kohn, DB Hershfield, MS Carbonaro, D Shigeoka, A Brooks, J Smogorzewska, EM Barsky, LW Chan, R Burotto, F Annett, G Nolta, JA Crooks, G Kapoor, N Elder, M Wara, D Bowen, T Madsen, E Snyder, FF Bastian, J Muul, L Blaese, RM Weinberg, K Parkman, R TI T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34(+) cells in ADA-deficient SCID neonates SO NATURE MEDICINE LA English DT Article ID ADENOSINE-DEAMINASE DEFICIENCY; SEVERE COMBINED IMMUNODEFICIENCY; BONE-MARROW TRANSPLANTATION; PEG-ADA; THERAPY; ENGRAFTMENT; REVERSION; PATIENT; MOLONEY; VIRUS AB Adenosine deaminase-deficient severe combined immunodeficiency was the first disease investigated for gene therapy because of a postulated production or survival advantage for gene-corrected T lymphocytes, which may overcome inefficient gene transfer. Four years after three newborns with this disease were given infusions of transduced autologous umbilical cord blood CD34(+) cells, the frequency of gene-containing T lymphocytes has risen to 1-10%, whereas the frequencies of other hematopoietic and lymphoid cells containing the gene remain at 0.01-0.1%. Cessation of polyethylene glycol-conjugated adenosine deaminase enzyme replacement in one subject led to a decline in immune function, despite the persistence of gene-containing T lymphocytes. Thus, despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect. C1 Childrens Hosp Los Angeles, Div Immunol Res Bone Marrow Transplantat, Los Angeles, CA 90027 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Univ Utah, Dept Pediat, Salt Lake City, UT 84132 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5CT, Canada. Childrens Hosp & Hlth Ctr, San Diego, CA 92123 USA. Natl Ctr Human Genome Res, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Kohn, DB (reprint author), Childrens Hosp Los Angeles, Div Immunol Res Bone Marrow Transplantat, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. RI Kohn, Donald/N-5085-2016; OI Kohn, Donald/0000-0003-1840-6087; Nolta, Jan/0000-0003-4576-8542 FU NCRR NIH HHS [3 MO1 RR0043-35S1, M01 RR000043]; NHLBI NIH HHS [1P50 HL54850, P50 HL054850]; NIDDK NIH HHS [DK20902, R01 DK020902, R01 DK053041, R01 DK053041-06] NR 22 TC 229 Z9 234 U1 0 U2 3 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 JUL PY 1998 VL 4 IS 7 BP 775 EP 780 DI 10.1038/nm0798-775 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX687 UT WOS:000074543900030 PM 9662367 ER PT J AU Tang, BW Bottinger, EP Jakowlew, SB Bagnall, KM Mariano, J Anver, MR Letterio, JJ Wakefield, LM AF Tang, BW Bottinger, EP Jakowlew, SB Bagnall, KM Mariano, J Anver, MR Letterio, JJ Wakefield, LM TI Transforming growth factor-beta 1 is a new form of tumor suppressor with true haploid insufficiency SO NATURE MEDICINE LA English DT Article ID FACTOR-BETA; DISEASE PROGRESSION; TRANSGENIC MICE; SKIN TUMORS; IN-VIVO; GENE; GROWTH-FACTOR-BETA-1; TGF-BETA-1; INHIBITION; EXPRESSION AB Components of the transforming growth factor-beta (TGF-beta) signal pathway function as classic tumor suppressors, but the role of the TGF-beta s themselves is less clear. Here we show that mice heterozygous for deletion of the TGF-beta 1 gene express only 10-30% of wild-type TGF-beta 1 protein levels. Although grossly normal, these mice have a subtly altered proliferative phenotype, with increased cell turnover in the liver and lung. Treatment of these mice with chemical carcinogens resulted in enhanced tumorigenesis when compared with wild-type littermates. However, tumors in the heterozygous mice did not lose the remaining wild-type TGF-beta 1 allele, indicating that the TCF-beta 1 ligand is a new form of tumor suppressor that shows true haploid insufficiency in its ability to protect against tumorigenesis. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Natl Canc Inst, Cell & Canc Biol Dept, Rockville, MD 20850 USA. Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Wakefield, LM (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, 41 Lib Dr MSC 5055, Bethesda, MD 20892 USA. EM wakefiel@dce41.nci.nih.gov NR 45 TC 254 Z9 263 U1 0 U2 5 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 JUL PY 1998 VL 4 IS 7 BP 802 EP 807 DI 10.1038/nm0798-802 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX687 UT WOS:000074543900034 PM 9662371 ER PT J AU Kononen, J Bubendorf, L Kallioniemi, A Barlund, M Schraml, P Leighton, S Torhorst, J Mihatsch, MJ Sauter, G Kallioniemi, OP AF Kononen, J Bubendorf, L Kallioniemi, A Barlund, M Schraml, P Leighton, S Torhorst, J Mihatsch, MJ Sauter, G Kallioniemi, OP TI Tissue microarrays for high-throughput molecular profiling of tumor specimens SO NATURE MEDICINE LA English DT Article ID HUMAN BREAST-CANCER; AMPLIFICATION; HYBRIDIZATION; EXPRESSION; CARCINOMAS; ONCOGENE; BLOCK AB Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes(1,2). These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray, Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors. C1 Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33521 Tampere, Finland. Tampere Univ Hosp, FIN-33521 Tampere, Finland. Beecher Instruments, Silver Spring, MD USA. RP Kallioniemi, OP (reprint author), Natl Human Genome Res Inst, Canc Genet Lab, NIH, 49 Convent Dr MSC 4470,Room 4A24, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 20 TC 2811 Z9 3062 U1 24 U2 147 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 JUL PY 1998 VL 4 IS 7 BP 844 EP 847 DI 10.1038/nm0798-844 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX687 UT WOS:000074543900042 PM 9662379 ER PT J AU Walker, RE Carter, CS Muul, L Natarajan, V Herpin, BR Leitman, SF Klein, HG Mullen, CA Metcalf, JA Baseler, M Falloon, J Davey, RT Kovacs, JA Polis, MA Masur, H Blaese, RM Lane, HC AF Walker, RE Carter, CS Muul, L Natarajan, V Herpin, BR Leitman, SF Klein, HG Mullen, CA Metcalf, JA Baseler, M Falloon, J Davey, RT Kovacs, JA Polis, MA Masur, H Blaese, RM Lane, HC TI Peripheral expansion of pre-existing mature T cells is an important means of CD4(+) T-cell regeneration HIV-infected adults SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BLOOD LYMPHOCYTES; GENE-THERAPY; BONE-MARROW; IN-VIVO; TRIAL AB The CD4(+) T-cell pool in HIV-infected patients is in a constant state of flux as CD4(+) T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4(+) T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA(+) T-cell population relative to the CD4/CD45RO(+) population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4(+) T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace. C1 NIAID, Immunoregulat Lab, Clin & Mol Retrovirol Sect, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. Frederick Canc Res & Dev Ctr, SAIC, Frederick, MD 21701 USA. RP Lane, HC (reprint author), NIAID, Immunoregulat Lab, Clin & Mol Retrovirol Sect, NIH, Bldg 10 Room 11S231, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 22 TC 99 Z9 101 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 JUL PY 1998 VL 4 IS 7 BP 852 EP 856 DI 10.1038/nm0798-852 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA ZX687 UT WOS:000074543900044 PM 9662381 ER PT J AU Bewley, CA Gustafson, KR Boyd, MR Covell, DG Bax, A Clore, GM Gronenborn, AM AF Bewley, CA Gustafson, KR Boyd, MR Covell, DG Bax, A Clore, GM Gronenborn, AM TI Solution structure of cyanovirin-N, a potent HIV-inactivating protein SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID DIRECT REFINEMENT; CHEMICAL-SHIFTS; NMR; IMPACT; HYDROPHOBICITY; RESTRAINTS; ALIGNMENT; PROGRAM AB The solution structure of cyanovirin-N, a potent 11,000 M-r HIV-inactivating protein that binds with high affinity and specificity to the HIV surface envelope protein gp120, has been solved by nuclear magnetic resonance spectroscopy, including extensive use of dipolar couplings which provide a priori long range structural information. Cyanovirin-N is an elongated, largely beta-sheet protein that displays internal two-fold pseudosymmetry. The two sequence repeats (residues 1-50 and 51-101) share 32% sequence identity and superimpose with a backbone atomic root-mean-square difference of 1.3 Angstrom. The two repeats, however, do not form separate domains since the overall fold is dependent on numerous contacts between them. Rather, two symmetrically related domains are formed by strand exchange between the two repeats. Analysis of surface hydrophobic clusters suggests the location of potential binding sites for protein-protein interactions. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Drug Discovery Res & Dev, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Clore, GM (reprint author), NIDDK, 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 47 TC 207 Z9 219 U1 2 U2 15 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 JUL PY 1998 VL 5 IS 7 BP 571 EP 578 DI 10.1038/828 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZW821 UT WOS:000074451700017 PM 9665171 ER PT J AU Atack, JR Rapoport, SI Schapiro, MB AF Atack, JR Rapoport, SI Schapiro, MB TI Cerebrospinal fluid production is normal in Down syndrome SO NEUROBIOLOGY OF AGING LA English DT Article DE cerebrospinal fluid; Down syndrome; protein; caudorostral gradient ID LUMBAR AB The rate of production of cerebrospinal fluid (CSF) and the caudorostral gradients of total CSF protein were measured in seven subjects with Down syndrome (DS) and compared to age-matched healthy normal volunteers. The CSF production rate in DS subjects (0.35 +/- 0.02 mL/min.) did not differ significantly from normal subjects (0.37 +/- 0.09 mL/min.). In addition, the caudorostral gradient of total protein was similar in DS and normal subjects, with more caudal fractions of lumbar CSF having higher total protein levels than more rostral fractions. These data suggest that there is no gross distrubance in CSF dynamics in DS. (C) 1998 Elsevier Science Inc. C1 Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England. NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Atack, JR (reprint author), Merck Sharp & Dohme Ltd, Neurosci Res Ctr, Terlings Pk,Eastwick Rd, Harlow CM20 2QR, Essex, England. NR 15 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL-AUG PY 1998 VL 19 IS 4 BP 307 EP 309 DI 10.1016/S0197-4580(98)00069-4 PG 3 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 115HK UT WOS:000075658000003 PM 9733162 ER PT J AU Borchelt, DR Wong, PC Becher, MW Pardo, CA Lee, MK Xu, ZS Thinakaran, G Jenkins, NA Copeland, NG Sisodia, SS Cleveland, DW Price, DL Hoffman, PN AF Borchelt, DR Wong, PC Becher, MW Pardo, CA Lee, MK Xu, ZS Thinakaran, G Jenkins, NA Copeland, NG Sisodia, SS Cleveland, DW Price, DL Hoffman, PN TI Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice SO NEUROBIOLOGY OF DISEASE LA English DT Article DE axonal transport; superoxide dismutase 1; slow component b; familial amyotrophic lateral sclerosis; mutant ID AMYOTROPHIC-LATERAL-SCLEROSIS; NERVOUS-SYSTEM; SLOW COMPONENT; MOTOR-NEURONS; PROTEINS; MUTATION; SUPEROXIDE-DISMUTASE-1; IDENTIFICATION; DEGENERATION; PRECURSOR AB Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selective degeneration of motor neurons. Transgenic mice expressing FALS mutant human (Hu) SOD1 at high levels develop a motor neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstrate that transgenic mice expressing Hu SOD1 with the G37R FALS mutation, but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neurofilament H epitopes are found adjacent to small vacuoles in axons. Using metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow component b in motor and sensory axons of the sciatic nerve. Together, these findings suggest that anterogradely transported mutant SOD1 may act locally to damage motor axons. (C) 1998 Academic Press. C1 Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Worcester Fdn Expt Biol Inc, Shrewsbury, MA 01545 USA. NCI, Mammalian Genet Lab, Frederick, MD 21701 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Neurosci, Ludwig Inst, La Jolla, CA 92093 USA. RP Borchelt, DR (reprint author), Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RI Lee, Michael/D-9491-2013 OI Lee, Michael/0000-0001-5865-9682 FU NINDS NIH HHS [NS 01719, NS 27036, NS 32724] NR 25 TC 69 Z9 70 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUL PY 1998 VL 5 IS 1 BP 27 EP 35 DI 10.1006/nbdi.1998.0178 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 107AM UT WOS:000075183700003 PM 9702785 ER PT J AU Stebbins, JW Jaffe, H Moller, JR AF Stebbins, JW Jaffe, H Moller, JR TI Characterization of myelin-associated glycoprotein (MAG) proteolysis in the human central nervous system SO NEUROCHEMICAL RESEARCH LA English DT Article DE myelin; protease; demyelination; multiple sclerosis ID MULTIPLE-SCLEROSIS LESIONS; BASIC-PROTEIN; CATHEPSIN-L; RAT-BRAIN; NEUTRAL PROTEASE; QUANTITATION; PEPTIDES AB Purified human central nervous system myelin contains an endogenous cysteine protease which degrades the 100-kDa myelin-associated glycoprotein into a slightly smaller 90-kDa derivative called dMAG, and which has been implicated in demyelinating diseases. The native proteolytic site in human MAG was determined in order to characterize this cysteine protease in humans further. This was accomplished by identifying the carboxy-terminus of purified dMAG. The results of these experiments, in conjunction with peptidolysis assays of myelin, demonstrated that the enzyme which proteolyses MAG is extracellular and has cathepsin L-like specificity. Furthermore, it was shown that this cathepsin L-like activity potentially was regulated by the endogenous extracellular inhibitor cystatin C. C1 NINDS, LNC, Protein Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. NINDS, LMCN, Demyelinating Disorders Unit, Bethesda, MD USA. RP Stebbins, JW (reprint author), 49 Convent Dr,MSC 4440, Bethesda, MD 20892 USA. EM stebbins@helix.nih.gov NR 35 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD JUL PY 1998 VL 23 IS 7 BP 1005 EP 1010 DI 10.1023/A:1021092624046 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 101KZ UT WOS:000074869300012 PM 9690744 ER PT J AU Ye, FQ Smith, AM Mattay, VS Ruttimann, UE Frank, JA Weinberger, DR McLaughlin, AC AF Ye, FQ Smith, AM Mattay, VS Ruttimann, UE Frank, JA Weinberger, DR McLaughlin, AC TI Quantitation of regional cerebral blood flow increases in prefrontal cortex during a working memory task: A steady-state arterial spin-tagging study SO NEUROIMAGE LA English DT Article ID HUMAN BRAIN; ACTIVATION; SCHIZOPHRENIA; PERFORMANCE AB Steady-state arterial spin-tagging MRI approaches were used to quantitate regional cerebral blood flow increases in prefrontal cortex during a working memory ("two-back") task in six normal subjects. Statistically significant increases in cerebral blood flow in prefrontal cortex were observed in all six subjects: the average increase in cerebral blood flow in activated prefrontal cortex regions was 22 +/- 5 cc/100 g/min (23 +/- 7%). The results demonstrate that spin-tagging approaches can be used to follow focal activation in prefrontal cortex during cognitive tasks. (C) 1998 Academic Press. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Lab Diagnost Radiol Res, OIR, NIH, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. RP Ye, FQ (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 33 TC 23 Z9 23 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL PY 1998 VL 8 IS 1 BP 44 EP 49 DI 10.1006/nimg.1998.0342 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 107AN UT WOS:000075183800004 PM 9698574 ER PT J AU Floeter, MK Valls-Sole, J Toro, C Jacobowitz, D Hallett, M AF Floeter, MK Valls-Sole, J Toro, C Jacobowitz, D Hallett, M TI Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome SO NEUROLOGY LA English DT Article ID SOLEUS H-REFLEX; GLUTAMIC-ACID DECARBOXYLASE; POST-ACTIVATION DEPRESSION; RECIPROCAL INHIBITION; PRESYNAPTIC INHIBITION; RECURRENT INHIBITION; GABAERGIC NEURONS; ANKLE EXTENSORS; BREAST-CANCER; HUMAN FOREARM AB Objective: To test inhibitory spinal circuits in patients with stiff-person syndrome (SPS). Background: Patients with SPS have fluctuating muscle stiffness and spasms, and most have antibodies against GABAergic neurons. We predicted they would also have abnormalities of spinal GABAergic circuits. Design/Methods: Physiologic methods using H-reflexes were used to test reciprocal inhibition in the forearm and thigh, vibration-induced inhibition of flexor carpi radialis and soleus H-reflexes, recurrent inhibition, and nonreciprocal (Ib) inhibition of soleus H-reflexes. Results: Vibration-induced inhibition of H-reflexes was diminished in eight of nine patients tested, but the presynaptic period of reciprocal inhibition was normal in most patients. Bath circuits are presumed to involve presynaptic inhibition and GABAergic interneurons. Presumed glycinergic circuits, including the first period of reciprocal inhibition and nonreciprocal (Ib) inhibition, showed occasional abnormalities. Recurrent inhibition was normal in all five patients tested. Conclusion: Differences between the two presumptive GABAergic circuits may indicate that not all populations of GABAergic neurons are uniformly affected in SPS. The involvement of presumptive glycinergic circuits in some patients could point to impairment of nonGABAergic neurons, unrecognized involvement of GABAergic neurons in these inhibitory circuits, or, more likely, alterations of supraspinal systems that exert descending control over spinal circuits. C1 NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. Univ Barcelona, Hosp Clin, Unitat EMG, Barcelona, Spain. RP Floeter, MK (reprint author), NINDS, EMG Sect, NIH, Bld 10 Room 5C101,10 Ctr Dr MSC-1404, Bethesda, MD 20892 USA. NR 61 TC 38 Z9 39 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 1998 VL 51 IS 1 BP 85 EP 93 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 103HL UT WOS:000075151800021 PM 9674784 ER PT J AU Metman, LV Del Dotto, P Natte, R van den Munckhof, P Chase, TN AF Metman, LV Del Dotto, P Natte, R van den Munckhof, P Chase, TN TI Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease SO NEUROLOGY LA English DT Article ID NMDA RECEPTOR BLOCKADE; METHYL-D-ASPARTATE; HUNTINGTONS-DISEASE; FLUCTUATIONS; PATHOGENESIS; ANTAGONISTS; MECHANISMS; MODULATION; INHIBITION; LIGANDS AB Objective: This study assessed the effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson's disease (PD). Background: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. Methods: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief IV levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. Results: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. Conclusions: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C104,10 Ctr Dr,MSC 1406, Bethesda, MD 20892 USA. NR 30 TC 80 Z9 81 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 1998 VL 51 IS 1 BP 203 EP 206 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 103HL UT WOS:000075151800040 ER PT J AU Calabresi, PA Fields, NS Maloni, HW Hanham, A Carlino, J Moore, J Levin, MC Dhib-Jalbut, S Tranquill, LR Austin, H McFarland, HF Racke, MK AF Calabresi, PA Fields, NS Maloni, HW Hanham, A Carlino, J Moore, J Levin, MC Dhib-Jalbut, S Tranquill, LR Austin, H McFarland, HF Racke, MK TI Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS SO NEUROLOGY LA English DT Article ID REMITTING MULTIPLE-SCLEROSIS; GROWTH-FACTOR-BETA-1; EXPRESSION AB Transforming growth factor (TGF)-beta 2 is a pleiotropic cytokine associated with remissions in multiple sclerosis (MS) and amelioration of allergic encephalomyelitis. We assessed the safety of TGF-beta 2 in an open-label trial of 11 patients with secondary progressive (SP) MS. Five patients had a reversible decline in the glomerular filtration rate. There was no change in expanded disability status scale or MRI lesions during treatment. Systemic TGF-beta 2 may be associated with reversible nephrotoxicity, and further investigation of its therapeutic potential in MS should be performed with caution. C1 Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD 20892 USA. NIDDKD, NIH, Kidney Dis Sect, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. Celtrix Pharmaceut Inc, Santa Clara, CA USA. RP McFarland, HF (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Room 5B-16,10 Ctr Dr,MSC-1400, Bethesda, MD 20892 USA. NR 10 TC 89 Z9 94 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL PY 1998 VL 51 IS 1 BP 289 EP 292 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 103HL UT WOS:000075151800062 PM 9674825 ER PT J AU Rueckert, L Grafman, J AF Rueckert, L Grafman, J TI Sustained attention deficits in patients with lesions of posterior cortex SO NEUROPSYCHOLOGIA LA English DT Article DE parietal cortex; vigilance ID CLOSED-HEAD-INJURY; UNILATERAL NEGLECT; FRONTAL LESIONS; VIGILANCE; PARIETAL; NETWORK; SYSTEM; TASK AB Patients with lesions to posterior cortex were compared to controls, matched for age and education, on tests on sustained attention. One test was a simple reaction time task requiring subjects to respond whenever they saw an 'X'. The other was a Continuous Performance Test that required subjects to respond to an 'X' but refrain from responding to other letters. The patients missed more targets than control subjects on both tests. On the Continuous Performance Test the difference between patients and controls increased with time on task, suggesting a sustained attention deficit similar to that previously observed in patients with right frontal lesions. However, whereas frontal patients showed a tendency toward greater impairment when the rate of stimulus presentation was relatively slow, the posterior patients performed significantly worse when the stimuli were presented at a faster rate. (C) 1998 Published by Elsevier Science Ltd. All rights reserved. C1 NINDS, Cognit Neurosci Sect, NIH, Chicago, IL USA. RP Rueckert, L (reprint author), NE Illinois Univ, Dept Psychol, 5500 N St Louis Ave, Chicago, IL 60625 USA. OI Grafman, Jordan H./0000-0001-8645-4457 NR 40 TC 41 Z9 41 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JUL PY 1998 VL 36 IS 7 BP 653 EP 660 DI 10.1016/S0028-3932(97)00150-4 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 106JN UT WOS:000075126300007 PM 9723936 ER PT J AU Liu, X Vaupel, DB Grant, S London, ED AF Liu, X Vaupel, DB Grant, S London, ED TI Effect of cocaine-related environmental stimuli on the spontaneous electroencephalogram in polydrug abusers SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE brain metabolism; cocaine; craving; electroencephalogram; positron emission tomography ID EVENT-RELATED DESYNCHRONIZATION; HUMANS AB Relationships between the spontaneous electroencephalogram (EEG), self-reports of cocaine craving, and cerebral glucose metabolism, determined using 2-[F-18]fluoro-2-deoxy-D-glucose and positron emission tomography, were assessed during the presentation of either neutral or cocaine-related environmental stimuli. In cocaine users but not non-drug-abusing controls, EEG power in the alpha(1) and alpha(2) frequency bands was significantly lowered during presentation of the drug-related stimuli when compared with the neutral test session. Decreases in alpha, power were negatively correlated with increases in global glucose metabolism but were not correlated with either the time course or the magnitude of craving throughout the 30-min test session. Although EEG desynchronization is related to global brain metabolism, the difference in the time courses between EEG power and craving suggests that self-reports of cue-elicited cocaine craving do not simply reflect increases in the state of cortical arousal. Published by Elsevier Science Inc. C1 NIDA, Brain Imaging Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP London, ED (reprint author), NIDA, Brain Imaging Ctr, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 22 TC 18 Z9 19 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 JUL PY 1998 VL 19 IS 1 BP 10 EP 17 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZN952 UT WOS:000073700200002 PM 9608572 ER PT J AU Cohen, RM Nordahl, TE Semple, WE Andreason, P Pickar, D AF Cohen, RM Nordahl, TE Semple, WE Andreason, P Pickar, D TI Abnormalities in the distributed network of sustained attention predict neuroleptic treatment response in schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE striatum; frontal cortex; thalamus; deoxyglucose; cerebral metabolic rates; positron emission tomography ID POSITRON EMISSION TOMOGRAPHY; GLUCOSE METABOLIC-RATE; CEREBRAL BLOOD-FLOW; PREFRONTAL SUBSTRATE; BRAIN PATTERN; DYSFUNCTION; CLOZAPINE; DISORDER; ILLNESS; SYSTEM AB The regional cerebral metabolic rates of 19 male medication-withdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless gf the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics. Published by Elsevier Science Inc. C1 NIMH, Cerebral Metab Lab, Sect Clin Brain Imaging, NIH, Bethesda, MD 20892 USA. NIMH, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, RM (reprint author), NIMH, Cerebral Metab Lab, Sect Clin Brain Imaging, NIH, Bldg 36,Room 1A05,36 Convent Dr,MSC 4030, Bethesda, MD 20892 USA. RI Nordahl, Thomas/J-7643-2013 OI Nordahl, Thomas/0000-0002-8627-0356 NR 44 TC 28 Z9 29 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUL PY 1998 VL 19 IS 1 BP 36 EP 47 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZN952 UT WOS:000073700200005 PM 9608575 ER PT J AU Little, JT Johnson, DN Minichiello, M Weingartner, H Sunderland, T AF Little, JT Johnson, DN Minichiello, M Weingartner, H Sunderland, T TI Combined nicotinic and muscarinic blockade in elderly normal volunteers: Cognitive, behavioral, and physiologic responses SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE scopolamine; mecamylamine; cognitive; geriatrics; muscarinic antagonist; nicotinic antagonist ID ALZHEIMERS-DISEASE; CONTROLLED TRIAL; CEREBRAL-CORTEX; BINDING-SITES; CHOLINERGIC RECEPTORS; DOUBLE-BLIND; DEMENTIA; MEMORY; BRAIN; SCOPOLAMINE AB Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received foul separate drug challenges (scopolamine (0.4 mg IV), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone. Published by Elsevier Science Inc. C1 NIMH, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. NIAAA, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Colgate Univ, Dept Psychol, Hamilton, NY 13346 USA. RP Little, JT (reprint author), NIMH, Geriatr Psychiat Branch, 10-3N228 MSC 1275, Bethesda, MD 20892 USA. NR 64 TC 46 Z9 47 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 JUL PY 1998 VL 19 IS 1 BP 60 EP 69 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZN952 UT WOS:000073700200007 PM 9608577 ER PT J AU Palkovits, M Young, WS Kovacs, K Toth, ZS Makara, GB AF Palkovits, M Young, WS Kovacs, K Toth, ZS Makara, GB TI Alterations in corticotropin-releasing hormone gene expression of central amygdaloid neurons following long-term paraventricular lesions and adrenalectomy SO NEUROSCIENCE LA English DT Article DE CRH mRNA; amygdala; paraventricular nucleus; adrenalectomy; Phaseolus vulgaris; leucoagglutinin; in situ hybridization ID FACTOR-LIKE IMMUNOREACTIVITY; MESSENGER RIBONUCLEIC-ACID; CENTRAL NUCLEUS; FACTOR RECEPTORS; MEDIAN-EMINENCE; IMMUNOHISTOCHEMICAL LOCALIZATION; DIFFERENTIAL REGULATION; HORSERADISH-PEROXIDASE; AFFERENT CONNECTIONS; BRAIN SITES AB Corticotropin-releasing hormone messenger RNA expression in the amygdala of rats after adrenalectomy and bilateral lesions of the hypothalamic paraventricular nucleus was examined by in situ hybridization histochemistry. Corticotropin-releasing hormone messenger RNA-containing cells are abundant in the intermediate subdivision of the central amygdaloid nucleus. Some corticotropin-releasing hormone-labeled cells are scattered in other subdivisions of the central nucleus and throughout the anterior amygdaloid area. Five days after bilateral adrenalectomy, the number of corticotropin-releasing hormone messenger RNA-containing cells was reduced both in the central nucleus and the anterior area of the amygdala. This reduction was prevented by corticosterone replacement and contrasts sharply with the known rise of corticotropin-releasing hormone messenger RNA in the paraventricular nucleus after adrenalectomy. Corticotropin-releasing hormone messenger RNA expression in the amygdala was up-regulated in rats with six-week bilateral lesions of the paraventricular nucleus. This elevation in corticotropin-releasing hormone messenger RNA was not influenced by adrenalectomy or corticosterone, and it did not correlate with plasma levels of adrenocorticotrophic hormone or corticosterone. The possible direct innervation of the amygdala by the paraventricular nucleus is supported by the demonstration of labeled axons from the paraventricular nucleus to the amygdala after injection of an anterograde tracer, Phaseolus vulgaris leucoagglutinin, into the paraventricular nucleus. Labeled fibers take two courses: through the lateral hypothalamus-ventral amygdalofugal path and through the stria terminalis. Data presented here suggest that the paraventricular nucleus-amygdala connection is likely to be inhibitory to corticotropin-releasing hormone neurons in the central amygdala. These neurons may participate in behavioral responses to stress effected through brainstem autonomic centers rather than directly through the hypothalamo-pituitary-adrenal axis. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 Semmelweis Univ Med, Sch Med, Neuromorphol Lab, H-1450 Budapest, Hungary. NIMH, Genet Sect, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. RP Palkovits, M (reprint author), Semmelweis Univ Med, Sch Med, Neuromorphol Lab, H-1450 Budapest, Hungary. RI Young, W Scott/A-9333-2009; Palkovits, Miklos/F-2707-2013; Makara, Gabor/H-8397-2013 OI Young, W Scott/0000-0001-6614-5112; Makara, Gabor/0000-0001-9220-0373 NR 53 TC 31 Z9 31 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL PY 1998 VL 85 IS 1 BP 135 EP 147 DI 10.1016/S0306-4522(97)00621-0 PG 13 WC Neurosciences SC Neurosciences & Neurology GA ZH341 UT WOS:000073098300012 PM 9607709 ER PT J AU Zhang, Q Schafer, M Elde, R Stein, C AF Zhang, Q Schafer, M Elde, R Stein, C TI Effects of neurotoxins and hindpaw inflammation on opioid receptor immunoreactivities in dorsal root ganglia SO NEUROSCIENCE LA English DT Article DE opioid receptor; capsaicin; 6-hydroxydopamine; inflammation; dorsal root ganglia ID GENE-RELATED PEPTIDE; NEONATAL CAPSAICIN TREATMENT; PRIMARY AFFERENT NEURONS; PRIMARY SENSORY NEURONS; SUBSTANCE-P; UNILATERAL INFLAMMATION; PERIPHERAL-NERVE; SPINAL-CORD; RAT; EXPRESSION AB Three types of opioid receptors mediate peripheral opioid antinociception in inflammation. Recently, antisera that recognize unique epitopes of the cloned mu-, delta-, and kappa-opioid receptors have been developed. Using these antisera we examined the regulation of opioid receptors in rat dorsal root ganglia after hindpaw inflammation and the influence of neurotoxins for primary afferent neurons and sympathetic neurons thereon. Peripheral tissue inflammation was produced by injection of complete Freund's adjuvant into the right hindpaw. Capsaicin was injected subcutaneously once a day for three days using a total dose of 150 mg/kg. 6-hydroxydopamine was injected intraperitoneally 75 mg/kg/day for three days. Freund's adjuvant induced a marked increase in the percentage of mu-, but a decrease in delta and kappa-opioid receptor-positive neurons. Capsaicin significantly decreased mu-, delta-and kappa opioid receptor immunoreactivity in both Freund's adjuvant treated and non-treated rats. No significant changes on the mu-, delta-and kappa-opioid receptor immunoreactivities were observed after 6-hydroxydopamine treatment in either Freund's adjuvant-treated or non-treated rats. Our studies indicate: (1) Peripheral inflammation can differentially regulate the expression of the three opioid receptors in dorsal root ganglia neurons with an up-regulation of mu-and down-regulation of delta-and kappa-opioid receptors. 2) A significant portion of mu-, delta-and kappa-opioid receptors are located on capsaicin-sensitive neurons in dorsal root ganglia of both non-inflamed and inflamed hindlimbs. 3) The expression of opioid receptors in dorsal root ganglia of either inflamed or non-inflamed hindlimbs is not influenced by sympathetic postganglionic neurons. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 Johns Hopkins Hosp, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. NIDA, Addict Res Ctr, Behav Pharmacol & Genet Sect, NIH, Baltimore, MD 21224 USA. Univ Minnesota, Dept Cell Biol & Neuroanat, Minneapolis, MN 55455 USA. RP Stein, C (reprint author), Johns Hopkins Hosp, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21287 USA. OI Stein, Christoph/0000-0001-5240-6836 FU NINDS NIH HHS [R01NS32466] NR 48 TC 70 Z9 73 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL PY 1998 VL 85 IS 1 BP 281 EP 291 DI 10.1016/S0306-4522(97)00647-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZH341 UT WOS:000073098300022 PM 9607719 ER PT J AU Fitoussi, N Sotnik-Barkai, I Tornatore, C Herzberg, U Yadid, G AF Fitoussi, N Sotnik-Barkai, I Tornatore, C Herzberg, U Yadid, G TI Dopamine turnover and metabolism in the striatum of parkinsonian rats grafted with genetically-modified human astrocytes SO NEUROSCIENCE LA English DT Article DE astrocytes; catechol metabolites; extracellular fluid; genetic engineering; microdialysis; Parkinson's disease AB The potential of a novel therapeutic approach for treating Parkinson's disease, which involves the transplantation of a transfected human astrocyte cell line SVG-TH, that stably expresses the rate-limiting enzyme for dopamine production, tyrosine hydroxylase, was examined. SVG-TH and untransfected parent cells were grafted into the diseased striatum of rats in which Parkinson's disease had been induced by the administration of 6-hydroxydapamine. The in situ production and spillover of 3,4-dihydroxyphenylalanine (the precursor of dopamine), dopamine and their metabolites in the striatal extracellular fluid of the grafted rats was determined in conscious animals using the microdialysis technique and a high pressure liquid chromatography apparatus. Alleviation of symptoms of Parkinson's disease (abnormal movements) was evaluated by rotation tests. Upon transplantation of the SVG-TH cells into the striatum of the parkinsonian rats, the levels of dopamine in extracellular fluid of the striatum reached those of the normal rats, and correlated well with the improvement (74%) in their rotating behaviour (behavioural deficit). The levels of the two main dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, were low in the lesioned rats, even after SVG-TH transplantation. An alternative route of metabolism of dopamine may occur in the transplanted striatum, since the dopamine metabolite, 3-O-methoxy-4-hydroxy-phenylethylamine, appeared, which indicates activity of catechol-O-methyl transferase. Upon blockade of L-aromatic-amino acid decarboxylase, 3,4-dihydroxyphenylalanine accumulated in extracellular fluid of the 6-hydroxydopamine-lesioned and SVG-TH-grafted rats, which indicated that these cells produced active tyrosine hydroxylase in vivo. These findings indicate the potential of treating Parkinson's disease by the intrabrain grafting of human astrocyte cells transfected with the rate limiting enzyme for dopamine production. (C) 1998 IBRO. Published by Elsevier Science Ltd. C1 Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. NINDS, Mol Therapeut Sect, NIH, Bethesda, MD 20892 USA. NINDS, Monoaminerg Mechanisms Sect, NIH, Bethesda, MD 20892 USA. RP Yadid, G (reprint author), Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. NR 0 TC 30 Z9 32 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL PY 1998 VL 85 IS 2 BP 405 EP 414 DI 10.1016/S0306-4522(97)00635-0 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZN622 UT WOS:000073664400009 PM 9622240 ER PT J AU Kaler, SG Schwartz, JP AF Kaler, SG Schwartz, JP TI Expression of the Menkes disease homolog in rodent neuroglial cells SO NEUROSCIENCE RESEARCH COMMUNICATIONS LA English DT Article DE copper ATPase; Menkes disease; astrocytes; gene expression; blood-brain barrier ID CANDIDATE GENE; MACULAR MOUSE; MUTATIONS; ASTROCYTES; LOCALIZATION; CEREBELLUM; STRIATUM; ENCODES; CORTEX; ATPASE AB We surveyed qualitative expression of the Menkes disease homolog in a variety of brain regions, and cultured neurons and glia from rat and mouse. Cultured astrocytes from adult rat cerebral cortex, corpus striatum and cerebellum all expressed the gene, as did cerebellar granule cell neurons isolated from whole cerebellum. Pulse-chase experiments with radiolabeled copper demonstrated normal copper handling by cultured adult astrocytes. We also assessed expression of the Menkes homolog in astrocytes from various earlier developmental stages (embryonic day 20, postnatal days 3 and 8), and detected expression on D3 and D8 but not in E20 astrocytes. Our data provide evidence that this copper transport gene is expressed in specific glial cells and neurons, findings that may be pertinent to treatment considerations in human patients with Menkes disease. C1 NINDS, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Washington, DC USA. RP Kaler, SG (reprint author), NINDS, Clin Neurosci Branch, NIH, Bldg 10,Rm 4D-20,MSC 1424,10 Ctr Dr, Bethesda, MD 20892 USA. EM sgk@box-s.nih.gov NR 19 TC 8 Z9 8 U1 0 U2 0 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 JUL-AUG PY 1998 VL 23 IS 1 BP 61 EP 66 DI 10.1002/(SICI)1520-6769(199807/08)23:1<61::AID-NRC7>3.0.CO;2-J PG 6 WC Neurosciences SC Neurosciences & Neurology GA 111GB UT WOS:000075428000007 ER PT J AU Gatley, SJ Ding, YS Brady, D Gifford, AN Dewey, SL Carroll, FI Fowler, JS Volkow, ND AF Gatley, SJ Ding, YS Brady, D Gifford, AN Dewey, SL Carroll, FI Fowler, JS Volkow, ND TI In vitro and ex vivo autoradiographic studies of nicotinic acetylcholine receptors using [F-18]fluoronorchloroepibatidine in rodent and human brain SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE epibatidine; nicotinic receptor; thalamus; fluorine-18; phosphor imaging ID H-3 CYTISINE BINDING; RAT-BRAIN; CHOLINERGIC RECEPTORS; MOUSE-BRAIN; REGIONAL DISTRIBUTION; ALPHA-BUNGAROTOXIN; EPIBATIDINE; SITES; MEMBRANES; THALAMUS AB A fluorine-18-labeled analog of the potent nicotinic agonist epibatidine is a candidate radioligand for positron emission tomographic (PET) studies of nicotinic acetylcholine receptors (nAcChR). Following intravenous administration of [F-18]exo-2-(2'-fluoro-5'-pyridinyl)-7-azabicylo[2.2.1]heptane (NFEP), high uptake in thalamus was visualized in sections of mouse and rat brain by autoradiography using a phosphor imaging, device. Binding of [[F-18]NFEP to rat thalamic homogenate was consistent with a single class of binding site with a Kd value of 71 FM. In vitro autoradiography of thaw-mounted sections of human thalamus revealed a heterogeneous pattern of binding; Bmax values for ventrolateral nucleus, insular cortex and dorsomedial nucleus, and internal capsule were 20, 8, and 3 pmol/cc of tissue, respectively. However, similar Kd values close to 50 pM were calculated for all regions. These studies support the suitability of [F-18]NFEP as a radioligand for PET studies of nAcChR in the living human brain. NUCL MED BIOL 25;5: 449-454 1998. (C) 1998 Elsevier Science Inc. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. NIA, Neurosci Lab, Bethesda, MD 20892 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11786 USA. RP Gatley, SJ (reprint author), Brookhaven Natl Lab, Dept Med, 490 Bell Ave, Upton, NY 11973 USA. FU NINDS NIH HHS [NS15380] NR 48 TC 20 Z9 21 U1 2 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 JUL PY 1998 VL 25 IS 5 BP 449 EP 454 DI 10.1016/S0969-8051(98)00007-9 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ZV536 UT WOS:000074314800002 PM 9720662 ER PT J AU Bialkowski, K Kasprzak, KS AF Bialkowski, K Kasprzak, KS TI A novel assay of 8-oxo-2 '-deoxyguanosine 5 '-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) activity in cultured cells and its use for evaluation of cadmium(II) inhibition of this activity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-SYNTHESIS; MUTAGENIC SUBSTRATE; ESCHERICHIA-COLI; MUTT PROTEIN; CLONING; CDNA; ELIMINATION; REPLICATION; HYDROLYZES; NUCLEOTIDE AB 8-Oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is a product of oxidative modification of dGTP, that can be misincorporated into DNA, causing AT-->CG mutations. Cells are protected against 8-oxo-dGTP by 8-oxo-dGTP 5'-pyrophosphohydrolases (8-oxo-dGTPases) that convert it to 8-oxo-dGMP. Thus, inhibition of 8-oxo-dGTPases may lead to cancer. To elucidate the involvement of 8-oxo-dGTPases in carcinogenesis, an assay of the 8-oxo-dGTPase activity is required. This paper presents such an assay developed for Chinese hamster ovary (CHO) cells that can be applied to any biological material. It includes: (i) a convenient method for preparing 8-oxo-2'-deoxyguanosine 5'-phosphates; (ii) an HPLC/UV quantification of 8-oxo-dGTP hydrolysis products and (iii) separation of 8-oxo-dGTPase activity from interfering 8-oxo-dGTP phosphatase(s), The 8-oxo-dQTPase activity of CHO cells depends on magnesium, has a pH optimum of 8.5, K-m for 8-oxo-dGTP of 9.3 mu M, and is inhibited by 8-oxo-dGDP, the product of interfering 8-oxo-dGTP phosphatases. The latter must be removed from the assayed samples by ultrafiltration through 30 kDa cut-off membranes. The method was used to test the inhibition by cadmium ions of the activity of 8-oxo-dGTPase in CHO cells. The cells cultured with 0.3-3 mu M cadmium(II) acetate for up to 24 h had their 8-oxo-dGTPase activity suppressed in a Cd(II) concentration-dependent manner, down to 70% of the control value. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Univ Sch Med Sci, Dept Clin Biochem, PL-85092 Bydgoszcz, Poland. RP Bialkowski, K (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Bldg 538,Room 205E, Frederick, MD 21702 USA. RI Bialkowski, Karol/E-2328-2014 NR 28 TC 61 Z9 65 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 1998 VL 26 IS 13 BP 3194 EP 3201 DI 10.1093/nar/26.13.3194 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX893 UT WOS:000074566000017 PM 9628918 ER PT J AU Sparks, SM AF Sparks, SM TI Untitled SO NURSING OUTLOOK LA English DT Letter C1 Natl Lib Med, Div Extramural Programs, Bethesda, MD 20894 USA. RP Sparks, SM (reprint author), Natl Lib Med, Div Extramural Programs, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD JUL-AUG PY 1998 VL 46 IS 4 BP 186 EP 186 DI 10.1016/S0029-6554(98)90075-6 PG 1 WC Nursing SC Nursing GA 113AJ UT WOS:000075526900013 PM 9739536 ER PT J AU Grady, C Anderson, R Chase, GA AF Grady, C Anderson, R Chase, GA TI Fatigue in HIV-infected men receiving investigational interleukin-2 SO NURSING RESEARCH LA English DT Article DE fatigue; symptoms; HIV therapy AB Background: Although fatigue is an almost universal clinical complaint of people with human immunodeficiency virus (HIV) infection, little has been done to study systematically the etiology, frequency severity, response to, or management of HIV-related fatigue. In addition, HIV-related treatments may contribute to fatigue. Objectives: To describe the extent and severity of perceived fatigue in a cohort of HIV-infected men (N = 50) who, as participants in a randomized clinical trial, were randomized to receive or not to receive investigational interleukin-2 (IL-2). Method: A modified Piper Fatigue Scale was used to measure fatigue at baseline, at the end of 5 days of IL-2 therapy, 1 week later at home, and 1 month later for three consecutive cycles of IL-2 therapy. Results: Against a variable background of baseline fatigue in all subjects, those receiving IL-2 reported a significant increase in their level of fatigue after receiving IL-2. Fatigue levels remained elevated 1 week later but returned to baseline by 1 month. Fatigue was related to the dose of IL-2 but not to the reported amount or quality of sleep. Conclusions: Against a background of fatigue related to HIV infection and its multiple manifestations and treatments, therapy with IL-2 dramatically increases the experience of fatigue. Although this increase is transient and tends to return to baseline by 1 month, during that month the patient's life function and quality may be severely affected. C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Natl Inst Nursing Res, Clin Therapeut Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Biostat & Biomath, Washington, DC 20007 USA. RP Grady, C (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM christine_grady@nih.gov NR 32 TC 20 Z9 20 U1 0 U2 0 PU AMER J NURSING CO PI NEW YORK PA 555 W 57TH ST, NEW YORK, NY 10019-2961 USA SN 0029-6562 J9 NURS RES JI Nurs. Res. PD JUL-AUG PY 1998 VL 47 IS 4 BP 227 EP 234 DI 10.1097/00006199-199807000-00008 PG 8 WC Nursing SC Nursing GA 100VV UT WOS:000074836800007 PM 9683118 ER PT J AU Cooperstock, MS Bakewell, J Herman, A Schramm, WF AF Cooperstock, MS Bakewell, J Herman, A Schramm, WF TI Association of sociodemographic variables with risk for very preterm birth in twins SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CERTIFICATES AB Objective: To assess the influence of maternal race, age, marital status, and education on risk for earlier and later preterm births in twin pregnancies. Methods: We analyzed 8109 white and 1906 black liveborn twin pregnancies in the Missouri Linked Sibship files for the years 1978-1990, using contingency tables and multiple logistic regression. Results: Black twin gestations had 1.61-fold (95% confidence interval [CI] 1.46, 1.76) greater risk than whites for preterm birth before 34 weeks' gestation. However, there was no race difference after 33 weeks. Among whites, teen age, unmarried status, and education fewer than 12 years were independently associated with risk for delivery before 34 weeks in multivariate analysis (odds ratios [OR] 1.28-1.51, each P less than or equal to .001). These associations were diminished or absent for preterm births after 33 weeks' gestation. White unmarried teen mothers with fewer than 12 years of education had 1.83-fold (95% CI 1.39, 2.40) greater risk for preterm birth before 34 weeks' gestation compared with white married women more than 19 years of age with at least 12 years of education. In blacks, this difference was 1.47-fold (95% CI 1.13, 1.92). In both races, these differences were absent after 33 weeks' gestation. Conclusion: Traditional sociodemographic risk factors were present for twin preterm birth, but mainly before 34 weeks' gestation. This, together with previous data from Missouri Linked Sibship files, indicates that dominant pathogenic mechanisms of early preterm birth in twin gestations are likely to be different from those causing later preterm twin birth. Therefore, gestational age should be accounted for in future studies seeking to identify predictive factors or biomechanisms for twin preterm birth. (C) 1998 by The American College of Obstetricians and Gynecologists. C1 Univ Missouri, Sch Med, Dept Child Hlth, Columbia, MO USA. Missouri Dept Hlth, Bur Hlth Data Anal, Jefferson City, MO USA. NICHHD, Epidemiol Branch, Bethesda, MD USA. RP Cooperstock, MS (reprint author), Univ Hosp, Dept Child Hlth, Columbia, MO 65212 USA. NR 11 TC 13 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 1998 VL 92 IS 1 BP 53 EP 56 DI 10.1016/S0029-7844(98)00142-2 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ZV533 UT WOS:000074314300011 PM 9649092 ER PT J AU Biggar, RJ AF Biggar, RJ TI Epidemiology and pathogenesis of AIDS-related lymphomas - The Aboulafia article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Biggar, RJ (reprint author), NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI HUNTINGTON PA 17 PROSPECT ST, HUNTINGTON, NY 11743 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD JUL PY 1998 VL 12 IS 7 BP 1087 EP 1088 PG 2 WC Oncology SC Oncology GA 102BZ UT WOS:000074904500024 ER PT J AU Horti, J Figg, WD Weinberger, B Kohler, D Sartor, O AF Horti, J Figg, WD Weinberger, B Kohler, D Sartor, O TI A phase II study of bromocriptine in patients with androgen-independent prostate cancer SO ONCOLOGY REPORTS LA English DT Article DE prolactin; hormone-refractory ID PROLACTIN AB Prolactin is an important physiological regulator of prostate development and growth in preclinical models. In prostate cancer there is strong evidence that prolactin exerts a trophic effect independent of testosterone. In addition, patients with prostate cancer that have an elevated prolactin level correlated with a poorer prognosis. Based on these data, we evaluated the clinical effect of prolactin suppression using bromocriptine in patients with androgen-independent prostate cancer. We conducted an open-label phase II trial of bromocriptine in patients with progressive metastatic prostate cancer. Basal and thyrotropin releasing hormone (TRH)-stimulated prolactin levels were utilized as biological endpoints for determining the dose of bromocriptine. All patients continued to receive complete androgen blockade. Thirteen patients were enrolled (median age 69.5 years). There were no complete or partial responses associated with bromocriptine in 11 of the evaluable patients. The mean duration of bromocriptine treatment was 8.2 weeks (2-14 weeks). One patient had a clinically insignificant decrease in prostate-specific antigen (PSA) and another patient had a 19.9% decrease in PSA with progression of a soft tissue mass. The vast majority of patients (10 of 11) had suppression of prolactin with a bromocriptine dose of 2.5 mg three times a day. One patient required a dose adjustment due to inadequate suppression, with a final maintenance dose of bromocriptine 12.5 mg per day resulting in complete suppression. No serious treatment-related toxicities were observed. The most common complications noted were nausea, headaches, dizziness, and fatigue. Our data showed that 2.5 mg three times per day of bromocriptine suppressed prolactin in 90% of the patients. Furthermore, this dose appears to be well tolerated. C1 NCI, Med Branch, Div Clin Sci, 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 18 TC 13 Z9 14 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL-AUG PY 1998 VL 5 IS 4 BP 893 EP 896 PG 4 WC Oncology SC Oncology GA ZU208 UT WOS:000074173100022 PM 9625840 ER PT J AU Fogt, F Zhuang, ZP Linehan, WM Merino, MJ AF Fogt, F Zhuang, ZP Linehan, WM Merino, MJ TI Collecting duct carcinomas of the kidney: A comparative loss of heterozygosity study with clear cell renal cell carcinoma SO ONCOLOGY REPORTS LA English DT Article DE collecting duct carcinoma; von Hippel Lindau gene; loss of heterozygosity ID BLADDER-CANCER; MICROSATELLITE ALTERATIONS; SUPPRESSOR LOCI; TUMORS; P16; DELETION; GENE; CHROMOSOME-9; 9P21 AB Origin of collecting duct carcinomas (CDC) of the kidney is not entirely known, although it is thought that they originate from the distal collecting duct system, whereas clear cell renal cell carcinoma (cRCC) may originate from the proximal tubular epithelium. In cRCC, the von Hippel Lindau gene (vHL) is damaged in almost 100% of cases; the frequency of vHL deletions in CDC is not known. Loss of heterozygosity (LOH) of CDC and cRCC of VHL (3p), p16 (9p), p53 (17p) and the retinoblastoma (RB) gene (13q) was studied to evaluate possible genetic differences between the two. LOH of the vHL was seen in 77.7% of cRCC and in 55% of CDC. P16 was lost in 33% of cRCC and in 50% of CDC. LOH in p53 was observed in 0/8 cases of cRCC compared to 18.7% in CDC. LOH in 13q was seen in 25% of both CDC and cRCC. The high LOH rate of the vHL gene in CDC has not been observed previously. The findings indicate that CDC and cRCC share certain genetic alterations, including frequent deletion of the vHL gene. CDC is not clearly related to cRCC but may be of heterogeneous origin. C1 Univ Penn, Presbyterian Med Ctr, Dept Pathol, Philadelphia, PA 19104 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Fogt, F (reprint author), Univ Penn, Presbyterian Med Ctr, Dept Pathol, 39th & Market St, Philadelphia, PA 19104 USA. NR 27 TC 14 Z9 14 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL-AUG PY 1998 VL 5 IS 4 BP 923 EP 926 PG 4 WC Oncology SC Oncology GA ZU208 UT WOS:000074173100029 PM 9625847 ER PT J AU Welles, SL Dosik, H Joseph, E Levine, PH AF Welles, SL Dosik, H Joseph, E Levine, PH TI Undiagnosed adult T-cell leukemia/lymphoma in central Brooklyn, NY SO ONCOLOGY REPORTS LA English DT Article DE adult T-cell leukemia/lymphoma; human T-cell lymphotropic virus type-I ID VIRUS TYPE-I; LEUKEMIA-LYMPHOMA; HTLV-I; UNITED-STATES; RETROVIRUS; PARTICLES; JAMAICA AB We present a case, identified by surveillance for adult T-cell leukemia/lymphoma (ATL), who had initial symptoms not specifically related to ATL, and who would not have been identified as having ATL otherwise. A 51-year-old Trinidadian black woman was hospitalized for abdominal pain, nausea, and vomiting. Hematology and clinical chemistry revealed leukocytosis (19,600/mm(3)), an elevated lymphocyte percent (63%), and hypercalcemia (19.4 mg/dl). The patient was serologically confirmed with HTLV-I-associated ATL. Lymphoma was diagnosed at autopsy. This case is representative of ATL, which along with HTLV-I infection, may be emerging public health problems in urban communities of the northeast and southeast United States. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. New York Methodist Hosp, Dept Med, Brooklyn, NY 11215 USA. Interfaith Med Ctr, Dept Med, Brooklyn, NY 11238 USA. NCI, Viral Epidemiol Branch, Rockville, MD USA. RP Welles, SL (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. FU NCI NIH HHS [N01-CP9-5612-00] NR 19 TC 2 Z9 2 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL-AUG PY 1998 VL 5 IS 4 BP 935 EP 937 PG 3 WC Oncology SC Oncology GA ZU208 UT WOS:000074173100032 PM 9625850 ER PT J AU Murata, M Nakagawa, M Takahashi, S AF Murata, M Nakagawa, M Takahashi, S TI Molecular variant of the human paraoxonase/arylesterase gene is associated with central retinal vein occlusion in the Japanese population SO OPHTHALMOLOGICA LA English DT Article DE paraoxonase polymorphism; central retinal vein occlusion; atherosclerosis ID PARAOXONASE ARYLESTERASE; POLYMORPHISM; SERUM AB Central retinal vein occlusion (CRVO) is a complex trait caused by a number of local and systemic factors. Among the latter, atherosclerosis has been attributed a major pathogenic role. Recently, the paraoxonase/arylesterase (PONA) enzyme has been implicated in the pathogenesis of atherosclerosis. There is a 10- to 40-fold variability in the activity of this enzyme among individuals. This variability is due to the presence of an A/G polymorphism in the coding region of the gene. The A and G alleles code for glutamine (A genotype) and arginine (B genotype), respectively. We determined the PONA genotypes and alleles in 42 patients with CRVO and in 45 control subjects of the Japanese population. The distribution of AA, AB and BE genotypes were 9.6, 45.2 and 45.2%, respectively, in the patients and 26.7, 53.3 and 20.0% in the control subjects, respectively (p < 0.05). The A allele frequency was 0.32 in patients and 0.53 in controls (p < 0.01). In conclusion, molecular variants of the PONA gene are involved in the predisposition to CRVO. Further studies are needed to characterize the molecular mechanism by which the PONA enzyme is involved in atherosclerosis. C1 Yamagata Univ, Sch Med, Dept Ophthalmol, Yamagata 99023, Japan. RP Murata, M (reprint author), NEI, LOT, NIH, 10-10B09,10 Ctr Dr MSC 1850, Bethesda, MD 20892 USA. NR 10 TC 6 Z9 6 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-3755 J9 OPHTHALMOLOGICA JI Ophthalmologica PD JUL-AUG PY 1998 VL 212 IS 4 BP 257 EP 259 DI 10.1159/000027303 PG 3 WC Ophthalmology SC Ophthalmology GA ZW633 UT WOS:000074431200008 PM 9672215 ER PT J AU Gaasterland, DE Ederer, F Sullivan, K VanVeldhuisen, PC Vela, MA Weiss, H AF Gaasterland, DE Ederer, F Sullivan, K VanVeldhuisen, PC Vela, MA Weiss, H CA AGIS Investigators TI The Advanced Glaucoma Intervention Study (AGIS): 4. Comparison of treatment outcomes within race - Seven-year results SO OPHTHALMOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; ARGON-LASER TRABECULOPLASTY; LONG-TERM EFFICACY; 10-YEAR FOLLOW-UP; FILTRATION SURGERY; POSTOPERATIVE CORTICOSTEROIDS; RACIAL-DIFFERENCES; TRABECULECTOMY; PREVALENCE; CATARACT AB Objective: The purpose of this report is to present separately for black and white patients with advanced glaucoma 7-year results of two alternative surgical intervention sequences. Design: A randomized controlled trial. Participants: A total of 332 black patients (451 eyes), 249 white patients (325 eyes), and 10 patients of other races (13 eyes) participated. Potential follow-up ranged from 4 to 7 years. Intervention: Eyes were randomly assigned to either an argon laser trabeculoplasty (ALT)-trabeculectomy-trabeculectomy (ATT) sequence or a trabeculectomy-ALT-trabeculectomy (TAT) sequence, The second and third interventions were offered after failure of the first and second interventions, respectively. Main Outcome Measures: Average percent of eyes with decrease of visual field (APDVF), average percent of eyes with decrease of visual acuity (APDVA), and average percent of eyes with decrease of vision (APDV) are the outcome measures. Decrease of visual field (DVF) is an increase from baseline of at least 4 points on a glaucoma visual field defect scale ranging from 0 to 20, decrease of visual acuity (DVA) is a decrease from baseline of at least 15 letters (3 lines), and decrease of Vision (DV) is the occurrence of either DVF or DVA, The averages are of percent decreases observed at 6-month intervals from the first B-month visit to the end of the specified observation period. Results: In both black and white patients throughout 7-year follow-up, the mean decrease in intraocular pressure was greater in eyes assigned to TAT, and the cumulative probability of failure of the first intervention was greater in eyes assigned to ATT, In black patients, APDVF, APDVA, and APDV are less for the ATT sequence than for the TAT sequence throughout the 7 years. In white patients, APDVF also favors the ATT sequence but only for the first year, after which it favors the TAT sequence through the seventh year; APDVA also favors the ATT sequence, but the ATT-TAT difference progressively diminishes over 7 years; and APDV favors ATT over TAT initially, but after 4 years, the advantage switches to and remains with TAT, Conclusions: These data support use of the ATT sequence for all black patients. For white patients without life-threatening health problems, the data support use of the TAT sequence. C1 Univ Ophthalm Consultants Washington, Washington, DC 20016 USA. Emory Univ, Atlanta, GA 30322 USA. Georgetown Univ, Washington, DC USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Ohio State Univ, Columbus, OH 43210 USA. Piedmont Hosp, Atlanta, GA USA. Sinai Hosp, Southfield, MI USA. Univ Illinois, Chicago, IL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Virginia, Charlottesville, VA USA. Washington Hosp Ctr, Chevy Chase, MD USA. Wills Eye Hosp, Philadelphia, PA USA. Yale Univ, New Haven, CT 06520 USA. NEI, Bethesda, MD 20892 USA. RP Gaasterland, DE (reprint author), Univ Ophthalm Consultants Washington, 4910 Massachusetts Ave NW,Suite 210, Washington, DC 20016 USA. NR 57 TC 127 Z9 128 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 1998 VL 105 IS 7 BP 1146 EP 1164 PG 19 WC Ophthalmology SC Ophthalmology GA ZY929 UT WOS:000074677100014 ER PT J AU Hiller, R Podgor, MJ Sperduto, RD Nowroozi, L Wilson, PWF D'Agostino, RB Colton, T AF Hiller, R Podgor, MJ Sperduto, RD Nowroozi, L Wilson, PWF D'Agostino, RB Colton, T CA Framingham Eye Studies Grp TI A longitudinal study of body mass index and lens opacities - The Framingham studies SO OPHTHALMOLOGY LA English DT Article ID HEALTH OUTCOMES; RISK-FACTORS; CATARACT; VARIABILITY; WEIGHT; MOUSE AB Objective: The purpose of the study was to determine whether body mass index (BMI) is an independent risk factor for the development of nuclear, cortical, or posterior subcapsular lens opacities. Design: A cohort study. Participants and Methods: Eye examinations were conducted on surviving members of the Framingham Heart Study Cohort from 1973 to 1975 (Framingham Eye Study I) and again from 1986 to 1989 (Framingham Eye Study II). Data from the Framingham Heart Study, including weight measurements collected biennially from 1948, were used to examine associations between BMI (mean BMI across examinations, slope of BMI over time, and fluctuations in BMI) and the development of lens opacities. This analysis included 714 individuals, aged 52-80 years, who were free of lens opacities at the first eye examination. Main Outcome Measures: Development of nuclear, cortical, and posterior subcapsular lens opacities. Results: A total of 444 persons developed lens opacities during the approximately 13 years between eye examinations. In logistic regression analyses that controlled for age, sex, education, diabetes, and smoking, the risk of developing cortical opacity increased with higher BMI at the time of the first eye examination (P = 0.002), Risk of cortical opacities also increased, at a borderline level of significance, with higher average BMI (P = 0.09) across examinations and increasing BMI levels over time (P = 0.10). There was a strong association between increasing BMI over time and the development of posterior subcapsular lens opacities (P = 0.002). No associations were found for nuclear lens opacities. Conclusions: Although the mechanism explaining the association is unclear, these findings suggest that BMI, a potentially modifiable characteristic, is associated with the development of cortical and posterior subcapsular lens opacities. C1 NEI, Div Biometry & Epidemiol, Bethesda, MD 20892 USA. NHLBI, Framingham, MA USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Dept Epidemiol & Biostat, Boston, MA 02215 USA. RP Hiller, R (reprint author), NEI, Div Biometry & Epidemiol, Bldg 31,Room 6A52,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. NR 22 TC 53 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 1998 VL 105 IS 7 BP 1244 EP 1250 DI 10.1016/S0161-6420(98)97029-4 PG 7 WC Ophthalmology SC Ophthalmology GA ZY929 UT WOS:000074677100030 PM 9663229 ER PT J AU Vrabec, TR Baldassano, VF Whitcup, SM AF Vrabec, TR Baldassano, VF Whitcup, SM TI Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Meeting of the Retina-Society CY SEP 09, 1997 CL VANCOUVER, CANADA SP Retina Soc ID SUSTAINED-RELEASE; VIRUS RETINITIS; GANCICLOVIR; RESISTANCE; FOSCARNET; INFECTION; TRIAL; AIDS AB Objective: To determine whether maintenance therapy can be discontinued safely in patients with quiescent cytomegalovirus retinitis (CMVR) and increased CD4+ counts after treatment with highly active antiretroviral therapy (HAART). Design: A prospective observational case series. Participants: Eight human immunodeficiency virus (HIV)-positive patients with quiescent CMVR who were taking HAART and had CD4+ counts above 100 cells/mu l elected to discontinue anti-CMV maintenance treatment. Intervention: Biweekly-to-monthly indirect ophthalmoscopy and fundus photographs, monthly-to-quarterly CD4+ counts, and quarterly HIV viral loads were ordered, Main Outcome Measures: Twelve previously affected eyes were examined for evidence of recurrent retinitis, which was defined as any retinal whitening, border opacification, or expansion of areas of retinal pigment epithelial (RPE) atrophy greater than 750 mu m. Four previously unaffected fellow eyes were observed for new CMVR. Results: There was no reactivation or progression of retinitis in any patient during the mean follow-up interval of 11.4 months (range, 3-16 months). No previously unaffected eye developed CMVR, CD4+ remained elevated in all patients (range, 70-725; mean, 255). The HIV viral load ranged from undetectable to 139,000 copies. Conclusion: Discontinuation of maintenance therapy may be considered in patients with HAART-induced elevated CD4+ counts above 100 cells/mu l, prolonged relapse-free intervals during the reconstitution period before CD4+ counts rise above 100 cells/mu l, and completely quiescent retinitis characterized by RPE scarring only. Reduced risks of drug toxicity and drug-resistant organisms are potential benefits. Close observation for evidence of recurrent retinitis is indicated. C1 Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Hosp, Retina Serv, Philadelphia, PA 19107 USA. Temple Univ, Dept Ophthalmol, Philadelphia, PA 19122 USA. NEI, Bethesda, MD 20892 USA. RP Vrabec, TR (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Hosp, Retina Serv, 9th & Walnut St, Philadelphia, PA 19107 USA. NR 24 TC 98 Z9 102 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 1998 VL 105 IS 7 BP 1259 EP 1264 DI 10.1016/S0161-6420(98)97031-2 PG 6 WC Ophthalmology SC Ophthalmology GA ZY929 UT WOS:000074677100032 PM 9663231 ER PT J AU Horton, WE Lethbridge-Cejku, M Hochberg, MC Balakir, R Precht, P Plato, CC Tobin, JD Meek, L Doege, K AF Horton, WE Lethbridge-Cejku, M Hochberg, MC Balakir, R Precht, P Plato, CC Tobin, JD Meek, L Doege, K TI An association between an aggrecan polymorphic allele and bilateral hand osteoarthritis in elderly white men: data from the Baltimore Longitudinal Study of Aging (BLSA) SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE osteoarthritis; genetics; polymorphism; proteoglycan ID KNEE; GENE; MUTATION; COL2A1; WOMEN AB Objective: The aggrecan proteoglycan is a major component of articular cartilage and supports the biomechanical function of this tissue. A variable number tandem repeat (VNTR) polymorphism has been discovered recently in a region of the human aggrecan gene that codes for the chondroitin sulfate attachment sites. We examined whether alleles of this polymorphism displayed a non-random association with bilateral hand or knee osteoarthritis (OA) in men from the Baltimore Longitudinal Study of Aging (BLSA). Design: DNA was obtained from 93 Caucasian men, aged 60 and above, who had bilateral hand and standing knee radiographs read for changes of OA. The DNA was analyzed by polymerase chain reaction (PCR) and/or Southern blotting for the presence of the VNTR alleles. Results: Bilateral hand OA and knee OA were present in 46 and 30% of the men respectively. The following distribution of alleles was observed: allele 33 (0.5%), 29 (2.2%), 28 (31.7%), 27 (43.0%), 26 (16.7%), 25 (3.2%), 22 (2.2%) and 19 (0.5%). This distribution was similar to that detected in a random population of individuals from a separate study. In multiple logistic regression analysis, adjusting for age and body mass index, the presence of allele 27 was associated with bilateral hand OA with an odds ratio (OR) = 3.23 (95% confidence intervals (CI): 1.24-8.41). No other alleles showed an association with bilateral hand OA and the association between allele 27 and bilateral knee OA was not statistically significant (OR = 1.14; 95% CI: 0.45-2.88). Conclusions: These data demonstrate the first association between a human aggrecan gene polymorphic allele and hand OA. This finding supports the concept that genetic factors may play a role in the development and/or progression of some forms of age-onset OA. C1 Shriners Hosp Children, Portland, OR 97201 USA. NIA, Biol Chem Lab, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Med, Div Clin Immunol & Rheumatol, Baltimore, MD 21201 USA. VA Maryland Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. VA Maryland Hlth Care Syst, Geriatr Serv, Baltimore, MD USA. NIA, Appl Physiol Sect, Lab Clin Physiol, Gerontol Res Ctr,NIH, Bethesda, MD 20892 USA. RP Shriners Hosp Children, 3101 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. EM FAXKJD@SHCC.ORG NR 28 TC 52 Z9 54 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUL PY 1998 VL 6 IS 4 BP 245 EP 251 DI 10.1053/joca.1998.0117 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 101QU UT WOS:000074880300002 PM 9876393 ER PT J AU Rogan, WJ AF Rogan, WJ CA Treatment Lead Exposed Children Trial Group TI The treatment of lead-exposed children (TLC) trial: design and recruitment for a study of the effect of oral chelation on growth and development in toddlers SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID CINCINNATI LEAD; INTELLIGENCE; COHORT; AGE AB Exposure to lead impairs cognitive development in young children, but the benefits of lowering blood lead pharmacologically are not clear. This report describes the design, recruitment, enrolment and baseline results of the Treatment of Lead-Exposed Children (TLC) trial, a randomised, multicentre, placebo-controlled, double-blind clinical trial of the effects of treating lead-exposed children with succimer, a drug that enhances urinary excretion of lead, on cognitive, behavioural and physical development. TLC clinical sites were in Baltimore, Cincinnati and Columbus, Newark and Philadelphia. Children were eligible for TLC if they were between 12 and 33 months of age, had a confirmed blood lead concentration between 20 and 44 mu g/dL and lived in a residence suitable for lead dust reduction. Randomised children received up to three 26-day courses of succimer or placebo, and were then followed for 3 years. The study can detect a three-point difference in full-scale IQ at 3-year follow-up. Statistical power for the other end points is more difficult to estimate. A total of 1854 children were evaluated and 780 children were randomised between August 1994 and January 1997. The mean age of randomised children was 24 months and mean blood lead level 26 mu g/dL. Three-quarters were African-American. Most children had poor, single mothers who had completed 12 or fewer years of school and who lived in older, poorly maintained residences. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21205 USA. Kennedy Krieger Inst, Baltimore, MD USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. Childrens Hosp Columbus, Cincinnati, OH USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Newark, NJ 07103 USA. Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Philadelphia, PA 19104 USA. CDC, Nutr Biochem Branch, Atlanta, GA 30333 USA. Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 27 TC 30 Z9 30 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 1998 VL 12 IS 3 BP 313 EP 333 PG 21 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 105QP UT WOS:000075085400008 ER PT J AU Klebanoff, MA Zemel, BS Buka, S Zierler, S AF Klebanoff, MA Zemel, BS Buka, S Zierler, S TI Long-term follow-up of participants in the Collaborative Perinatal Project: Tracking the next generation SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID STRATEGIES AB This report describes the methods used in conducting a long-term follow-up study and the factors associated with the successful location of subjects. In 1987-91, we selected, from among the women who were born in 1959-66 as members of the Philadelphia and Providence cohorts of the Collaborative Perinatal Project (CPP), 391 who were preterm at birth, 413 who were small-for-gestational age (SGA) and 978 who were term and appropriately grown; 1314 were from Philadelphia and 468 from Providence. Tracing was accomplished using original CPP records, telephone directories, voter registration and driver's licence records, birth certificate files and credit bureaux. A total of 61% of the women were located, 55% at Philadelphia and 77% at Providence. After adjustment, the odds ratio for ease of location, compared with women who were term and appropriately grown, was 0.85 [95% CI 0.66-1.11] for women who were preterm and 1.02 [0.78-1.34] for women who were SGA. In Philadelphia, African-American women were more likely than white women to be located, but in Providence, African-American women were less likely than white women to be located. Women whose own mothers were older at the time of their birth were more likely to be located, as were those who had more siblings followed in the CPP. Compared with women who did not complete their original CPP examinations at ages 4 and 7 years, those whose original CPP follow-up was more complete were more likely to be located. These findings demonstrate that long-term follow up in a US urban setting can be accomplished, and that successful location was not associated with birth status. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Univ Penn, Krogman Growth Ctr, Philadelphia, PA 19104 USA. Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. Brown Univ, Ctr Child Study, Providence, RI 02912 USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, 6100 Bldg Room 7B03, Bethesda, MD 20892 USA. RI Zemel, Babette/D-1117-2009; Buka, Stephen/H-7335-2014 OI Buka, Stephen/0000-0002-8578-9308 FU NICHD NIH HHS [N01-HD-7-2909] NR 16 TC 17 Z9 17 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 1998 VL 12 IS 3 BP 334 EP 346 DI 10.1046/j.1365-3016.1998.00125.x PG 13 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 105QP UT WOS:000075085400009 PM 9690267 ER PT J AU Zhang, J Harville, E AF Zhang, J Harville, E TI Birthweight-for-gestational-age patterns by race, sex and parity in the United States population: the 5th percentile SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Zhang, J (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 1 TC 6 Z9 6 U1 0 U2 2 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 1998 VL 12 IS 3 BP 352 EP 354 DI 10.1046/j.1365-3016.1998.00113.x PG 3 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 105QP UT WOS:000075085400011 PM 9690269 ER PT J AU Ceha, HM Clement, MJ Polak, MM Offerhaus, GJA Slebos, RJC AF Ceha, HM Clement, MJ Polak, MM Offerhaus, GJA Slebos, RJC TI Mutational analysis of the p16-binding domain of cyclin-dependent kinase 4 in tumors in the head region of the pancreas SO PANCREAS LA English DT Article DE pancreatic neoplasms; CDK4; p16 tumor suppressor gene; cyclin-dependent kinase 4; K-ras oncogene ID FAMILIAL MELANOMA; SUPPRESSOR GENE; CANCER; ADENOCARCINOMA; CARCINOMAS; KINDREDS; CDK4 AB Alterations in genes involved in cell cycle regulation are common in many tumor types. In pancreatic adenocarcinomas, inactivating mutations in the CDKN2 gene, encoding the cyclin-dependent kinase inhibitor p16, are frequently observed. CDKN2 mutations have also been identified in the germline of 50% of patients with hereditary melanoma. Interestingly, such patients also have an increased risk for pancreatic cancers. In melanoma-prone kindreds with CDKN2 wild-type status, a mutation in one of the targets of p16, cyclin-dependent kinase 4 (CDK4) was reported, which abolishes p16 inhibition. To test the possible involvement of CDK4 mutations in pancreatic carcinoma, we analyzed sequence alterations in the p16-binding domain of CDK4 in DNA isolated from 32 tumors in the head region of the pancreas. Alterations in the CDK4 region between codon I and codon 56 were not observed in any of the tumors. Our results do not support disruption of the p16 pathway through CDK4 mutation as an oncogenic mechanism in pancreatic head tumorigenesis. C1 Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Dept Radiotherapy, NL-1105 AZ Amsterdam, Netherlands. RP Slebos, RJC (reprint author), NIEHS, Mol Carcinogenesis Lab, Mail Drop C2-01,POB 12233, Res Triangle Pk, NC 27709 USA. NR 14 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD JUL PY 1998 VL 17 IS 1 BP 85 EP 88 DI 10.1097/00006676-199807000-00011 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA ZW557 UT WOS:000074422900011 PM 9667525 ER PT J AU Simamora, P Dannenfelser, RM Tabibi, SE Yalkowsky, SH AF Simamora, P Dannenfelser, RM Tabibi, SE Yalkowsky, SH TI Emulsion formulations for intravenous administration of paclitaxel SO PDA JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY LA English DT Article ID TAXOL; INVITRO; AGENT; ACID C1 Univ Arizona, Coll Pharm, Dept Pharm Practice, Tucson, AZ 85721 USA. MOVA Pharmaceut Co, Dept Prod Dev, Caguas, PR USA. Novartis Pharmaceut Corp, E Hanover, NJ USA. NCI, NIH, Pharmaceut Resources Branch, Bethesda, MD 20892 USA. RP Yalkowsky, SH (reprint author), Univ Arizona, Coll Pharm, Dept Pharm Practice, Tucson, AZ 85721 USA. FU NCI NIH HHS [N01-CM-27757] NR 24 TC 19 Z9 19 U1 0 U2 2 PU PARENTERAL DRUG ASSOC INC PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 620, BETHESDA, MD 20814 USA SN 1076-397X J9 PDA J PHARM SCI TECH JI PDA J. Pharm. Sci. Technol. PD JUL-AUG PY 1998 VL 52 IS 4 BP 170 EP 172 PG 3 WC Engineering, Biomedical; Pharmacology & Pharmacy SC Engineering; Pharmacology & Pharmacy GA 116WZ UT WOS:000075749200006 PM 9752712 ER PT J AU Stratakis, CA Mastorakos, G Mitsiades, NS Mitsiades, CS Chrousos, GP AF Stratakis, CA Mastorakos, G Mitsiades, NS Mitsiades, CS Chrousos, GP TI Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia SO PEDIATRIC DERMATOLOGY LA English DT Article ID DISORDERS; RECOVERY AB Cushing disease (CD) is a common cause of endogenous hypercortisolism in childhood. Its skin manifestations include striae, facial acne, hirsutism, acanthosis nigricans, fungal infections, hyperpigmentation and easy bruisability. We followed 36 children and adolescents with CD (14 boys and 22 girls), to define the natural history of skin disease in endogenous hypercortisolism. Physical examination and 24 hour urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17-OHS) excretion values were obtained preoperatively and quarterly for 18 months. Preoperatively our patients exhibited purple subcutaneous striae (77.7%), steroid-induced acne (58.3%), hirsutism (63.7% of the 22 girls), acanthosis nigricans (27.7%), ecchymoses (27.7%), hyperpigmentation (16.6%), and fungal infections (11.1%). The levels of UFG and 17-OHS preoperatively were 351.84 +/- 243.85 mu g/m(2)/day (mean +/- SD) and 17.92 +/- 7.86 mg/g creatinine/day, respectively. No correlation was found between these levels and the severity of the lesions. All patients were cured. Symptoms decreased dramatically within the 3 postoperative months and progressively disappeared within the first year of the follow-up period with the exception of light-colored striae; they were present in 5.6% of the patients at 18 months postoperatively. No acanthosis nigricans or hyperpigmentation were observed at 3 months postoperatively. Hirsutism was not present at 9 months postoperatively. We conclude that in children with CD the skin is affected at multiple sites; however, the severity of the manifestations does not correlate with the biochemical indices of the disease. With the exception of striae, cutaneous effects of endogenous hypercortisolism completely heal within the first year after surgical cure of the disease. C1 NICHHD, Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch,NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Sect Pediat Endocrinol, Dev Endocrinol Branch,NIH, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 30 TC 21 Z9 21 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD JUL-AUG PY 1998 VL 15 IS 4 BP 253 EP 258 DI 10.1046/j.1525-1470.1998.1998015253.x PG 6 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 109XT UT WOS:000075350200001 PM 9720685 ER PT J AU Fanaroff, AA Korones, SB Wright, LL Verter, J Poland, RL Bauer, CR Tyson, JE Philips, JB Edwards, W Lucey, JF Catz, CS Shankaran, S Oh, W AF Fanaroff, AA Korones, SB Wright, LL Verter, J Poland, RL Bauer, CR Tyson, JE Philips, JB Edwards, W Lucey, JF Catz, CS Shankaran, S Oh, W CA Natl Inst Child Hlth Human Dev Neonatal Res TI Incidence, presenting features risk factors and significance of late onset septicemia in very low birth weight infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE sepsis; nosocomial infection; very low birth weight infants; prematurity; gamma-globulin; immunoglobulin; National Institute of Child Health and Human Development Neonatal Research Network ID NEGATIVE STAPHYLOCOCCAL BACTEREMIA; DEVELOPMENT NEONATAL NETWORK; INTRAVENOUS IMMUNE GLOBULIN; NOSOCOMIAL INFECTIONS; UNITED-STATES; SEPSIS; OUTCOMES; PREVENTION AB Background. Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. Methods. Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. Results. Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 us. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). Conclusions. Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value. C1 Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Tennessee, Memphis, TN USA. NICHHD, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Wayne State Univ, Detroit, MI USA. Univ Miami, Miami, FL 33152 USA. Univ Texas, Dallas, TX 75230 USA. Univ Alabama, Birmingham, AL USA. Dartmouth Hitchcock Med Ctr, Hanover, NH USA. Univ Vermont, Burlington, VT USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. RP Fanaroff, AA (reprint author), Rainbow Babies & Childrens Hosp, 11100 Euclid Rd,Rm RBC 3020, Cleveland, OH 44106 USA. EM aaf2@po.cwru.edu FU NICHD NIH HHS [U01 HD19897, U10 HD21415, U10 HD21364] NR 19 TC 229 Z9 238 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 1998 VL 17 IS 7 BP 593 EP 598 DI 10.1097/00006454-199807000-00004 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 101JY UT WOS:000074866900003 PM 9686724 ER PT J AU Mueller, BU Sleasman, J Nelson, RP Smith, S Deutsch, PJ Ju, W Steinberg, SM Balis, FM Jarosinski, PF Brouwers, P Mistry, G Winchell, G Zwerski, S Sei, SZ Wood, LV ZEichner, S Pizzo, PA AF Mueller, BU Sleasman, J Nelson, RP Smith, S Deutsch, PJ Ju, W Steinberg, SM Balis, FM Jarosinski, PF Brouwers, P Mistry, G Winchell, G Zwerski, S Sei, SZ Wood, LV ZEichner, S Pizzo, PA TI A phase I/II study of the protease inhibitor indinavir in children with HIV infection SO PEDIATRICS LA English DT Article DE protease inhibitor; child HIV-1; CD4 cells; HIV RNA; pharmacokinetics ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 RNA; ENCEPHALOPATHY; ZIDOVUDINE; PLASMA AB Background. Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Methods. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m(2), 350 mg/m(2), and 500 mg/m(2) per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and greater than or equal to 12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm(3), and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine. C1 NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Univ Florida, Gainesville, FL USA. Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. Merck Res Labs, Rahway, NJ USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Pharm, Bethesda, MD 20892 USA. RP Mueller, BU (reprint author), Childrens Hosp, Dept Med, Hunnewell 302,HU-215,300 Longwood Ave, Boston, MA 02115 USA. NR 18 TC 49 Z9 49 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 1998 VL 102 IS 1 BP 101 EP 109 DI 10.1542/peds.102.1.101 PG 9 WC Pediatrics SC Pediatrics GA 100CF UT WOS:000074795800017 PM 9651421 ER PT J AU Ghirardelli, TG Egeth, HE AF Ghirardelli, TG Egeth, HE TI Goal-directed and stimulus-driven attention in cross-dimensional texture segregation SO PERCEPTION & PSYCHOPHYSICS LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Psychonomic-Society CY NOV 12, 1995 CL LOS ANGELES, CALIFORNIA SP Psychon Soc ID VISUAL-SEARCH; PERCEPTUAL SELECTIVITY; CONJUNCTION SEARCH; CONTROL SETTINGS; CAPTURE; COLOR; ORIENTATION; CONTINGENT; PRECEDENCE; DOMINANCE AB Goal-directed and stimulus-driven control of attention was examined in a visual texture segregation task. Recent published reports have debated the existence and efficiency of goal-directed guidance of attention. Some of this research has focused on the apparent stimulus-driven attentional priority given to salient distracters, even when they are known to be irrelevant to the task. In the present study, subjects searched a texture array for targets defined along one dimension. These displays also included distracters created by variation in an irrelevant dimension. Targets were of three different overall shapes. On each trial, distracters could be the same shape as the target or one of the other two shapes. In two experiments subjects were informed of the overall shape of the target prior to stimulus presentation. In these experiments, distracters that did not match the overall shape of the target caused less interference than distracters that matched the target's shape. In the third experiment, subjects were not informed of the overall shape of the target. In this experiment all distracters caused roughly equal interference. The results of these experiments demonstrate that if subjects are given information about the overall shape of the target, they are able to use this information to reduce interference from distractors that do not match the overall target shape. While acknowledging some stimulus-driven interference, this illustrates a previously unexplored source of goal-directed guidance that can reduce interfering effects of even salient distractors and argues against purely stimulus-driven control of attention. C1 Johns Hopkins Univ, Baltimore, MD USA. RP Ghirardelli, TG (reprint author), NIAAA, NIH, 10 Ctr Dr,Room 6S240,MSC 1610, Bethesda, MD 20892 USA. EM ghirardelli@nih.gov FU NIMH NIH HHS [5 T32 MH18125, R01 MH57388] NR 49 TC 8 Z9 8 U1 1 U2 4 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0031-5117 J9 PERCEPT PSYCHOPHYS JI Percept. Psychophys. PD JUL PY 1998 VL 60 IS 5 BP 826 EP 838 DI 10.3758/BF03206066 PG 13 WC Psychology; Psychology, Experimental SC Psychology GA ZZ725 UT WOS:000074760900008 PM 9682607 ER PT J AU Schweri, MM de Costa, BR Rice, KC AF Schweri, MM de Costa, BR Rice, KC TI Fourphit, an acylating phencyclidine derivative, attenuates cocaine-induced hyperactivity in rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE cocaine; antagonist; methylphenidate; stimulant; phencyclidine; dopamine transporter; Fourphit (4-isothiocyanato-1-[1-phenylcyclohexyl]piperidine); rats; striatum; male; female ID DOPAMINE UPTAKE; AUDIOGENIC-SEIZURES; RECEPTOR ACYLATOR; BINDING-SITE; METAPHIT; MICE; BRAIN; METHYLPHENIDATE; TRANSPORTER; ACTIVATION AB Fourphit (4-isothiocyanato-1-[1-phenylcyclohexyl]piperidine), an acylating phencyclidine derivative that irreversibly inhibits stimulant binding to the dopamine transporter in vitro (Schweri et al., J. Pharmacol. Exp. Ther. 261:936-942, 1992), was tested in rats for its ability to block the increased locomotor activity caused by cocaine. Administration of Fourphit (20 mg/kg, IV) significantly reduced the hyperactivity caused by challenge with either 15 or 40 mg/kg (-)cocaine.HCl (LP) 24 h later. It also increased the amount of thigmotaxis and decreased the rearing frequency of rats given the higher dose of cocaine. Only negligible effects on behavior were found upon acute administration of the compound by itself, or in response to a saline challenge 24 h later. Activity during the dark cycle immediately following Fourphit administration, however, was moderately depressed. Contrary to the results predicted from its activity in vitro, Fourphit did not inhibit the ex vivo binding of [H-3]methylphenidate to stimulant receptors in the striatal tissue of treated rats. These results show that Fourphit can antagonize some behavioral actions of cocaine, but these effects are not likely due to covalent modification of the site on the dopamine transporter recognized by cocaine. (C) 1998 Elsevier Science Inc. C1 Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Schweri, MM (reprint author), Mercer Univ, Sch Med, Div Basic Med Sci, 1550 Coll St, Macon, GA 31207 USA. FU NIDA NIH HHS [DA06305]; NINDS NIH HHS [NS28584] NR 26 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUL PY 1998 VL 60 IS 3 BP 615 EP 623 DI 10.1016/S0091-3057(98)00040-9 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA ZX923 UT WOS:000074569000003 PM 9678644 ER PT J AU Bilski, P Martinez, LJ Koker, EB Chignell, CF AF Bilski, P Martinez, LJ Koker, EB Chignell, CF TI Influence of solvent polarity and proticity on the photochemical properties of norfloxacin SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID INDUCED CUTANEOUS PHOTOTOXICITY; QUINOLONE ANTIBACTERIAL AGENTS; OXYGEN; MICE; PHOTOSENSITIZATION AB The fluoroquinolone antibacterial norfloxacin (NF) is a moderate photosensitizer of singlet molecular oxygen (O-1(2)), We have studied photosensitization by NF as a function of medium polarity and proticity in solvent mixtures, We have used 1,4-dioxane and propylene carbonate mixtures to keep proticity constant while modulating polarity, and water/D2O and ethylene carbonate mixtures to alter proticity without large changes in polarity. The absorption spectrum of NF was little affected by solvent changes, as compared to the fluorescence spectrum that exhibited as much as a 50 nm blue-shift, e.g. 1,4-dioxane versus D2O, The quantum yield of NF fluorescence saturated at an almost 10 times higher value (similar to 0.14) when proticity was increased by added water, up to 0.2 mol fraction, to ethylene carbonate. Less pronounced, the increasing polarity in 1,4-dioxane/propylene carbonate mixtures affected the fluorescence yield much less. Norfloxacin produces O-1(2) and is able to quench O-1(2). The rate constant for O-1(2) quenching is 4.5 x 10(7) M-1 s(-1) in propylene carbonate but decreases ca four times in D2O. The quantum yield of O-1(2) photogeneration was also up to five times higher in solvents that were both protic and polar than vice versa, Our data show that NF is more photochemically active in an environment that is both protic and polar, This suggests the involvement of polar excited state(s) and possible proton/hydrogen transfer during photoexcitation. Similar processes may initiate the phototoxic response reported in some patients treated with the fluoroquinolone drugs. The phototoxicity of NF and other fluoroquinolone antibiotics may strongly depend on their localization in hydrophilic or hydrophobic cell/tissue regions. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Elizabeth City State Univ, Elizabeth City, NC USA. RP Bilski, P (reprint author), NIEHS, Lab Pharmacol & Chem, Mail Drop F0-06, Res Triangle Pk, NC 27709 USA. NR 22 TC 42 Z9 42 U1 2 U2 7 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL PY 1998 VL 68 IS 1 BP 20 EP 24 DI 10.1111/j.1751-1097.1998.tb03247.x PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 102PE UT WOS:000074932400004 PM 9679447 ER PT J AU Wertheimer, E Taylor, SI Tennenbaum, T AF Wertheimer, E Taylor, SI Tennenbaum, T TI Insulin receptor regulation of cell surface integrins: A possible mechanism contributing to the development of diabetic complications SO PROCEEDINGS OF THE ASSOCIATION OF AMERICAN PHYSICIANS LA English DT Article DE cellular growth; basement membranes; skin fibroblasts ID GROWTH-FACTOR-I; EXTRACELLULAR-MATRIX; SIGNAL-TRANSDUCTION; ADHESION; PHOSPHORYLATION; MICROANGIOPATHY; TUMORIGENESIS; ROLES; GENE AB Insulin plays a central role in regulating cellular growth in addition re its classic effects to regulate fuel metabolism. In a previous study, we have identified a patient who was homozygous for a deletion of the insulin receptor gene. In our current investigation, we used cultured skin fibroblasts fi om this patient as a model system in which to investigate the mechanisms whereby insulin regulates cellular growth in vitro. After cell division, skin fibroblasts from normal individuals migrate on the tissue culture plate and appear to be distributed randomly over the surface of the plate. In contrast, the patient's cells grew in clumps. Furthermore, the patient's fibroblasts exhibited a marked increase in the expression of several integrin subunits, especially the alpha 5- and beta 1-subunits that comprise the fibronectin receptor. Because the cellular growth pattern was restored to normal when cells were cultivated in the presence of blocking antibodies directed against either alpha 5- or beta 1-integrin subunits, we infer that increased expression of alpha 5 beta 1-integrin may be the cause of the observed abnormality in the growth of the patient's cells in vitro. Furthermore, insulin stimulation led to downregulation of the levels of the a5- and pl-integrin subunits in normal human fibroblasts but not in the patient's cells that lacked insulin receptors. Taken together, these data suggest that insulin's ability to regulate the expression of cell surface integrins may contribute to the mechanisms whereby insulin regulates cell growth. In light of the important role of integrins in mediating interactions between cells and the basement membrane, we suggest that dysregulation of integrin expression might contribute to the abnormalities in the structure of the basement membranes associated with the chronic microvascular complications of diabetes. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. Bar Ilan Univ, Dept Life Sci, Ramat Gan, Israel. RP Taylor, SI (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 9S-213,10 Ctr Dr,MSC 1829, Bethesda, MD 20892 USA. NR 24 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1081-650X J9 P ASSOC AM PHYSICIAN JI Proc. Assoc. Am. Phys. PD JUL-AUG PY 1998 VL 110 IS 4 BP 333 EP 339 PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 101KB UT WOS:000074867200007 PM 9686681 ER PT J AU Doris, PA Bagrov, AY AF Doris, PA Bagrov, AY TI Endogenous sodium pump inhibitors and blood pressure regulation: An update on recent progress SO PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Review ID MILAN HYPERTENSIVE RATS; OUABAIN-LIKE COMPOUND; BOVINE ADRENOCORTICAL-CELLS; DIGITALIS-LIKE SUBSTANCE; CL COTRANSPORT SYSTEM; CHRONIC-RENAL-FAILURE; NA+-K+-ATPASE; HUMAN PLASMA; MARINOBUFAGENIN-LIKE; NATRIURETIC FACTORS AB Rapid progress has occurred recently in understanding the origin, chemistry, synthesis, control, and actions of endogenous materials that may be ligands for the cardiac glycoside binding site on the mammalian sodium pump (Na,K-ATPase), The present paper reviews this progress and examines in detail the evidence supporting ouabain-like and bufodienolide-like compounds as functioning in endogenous control of sodium pump activity, renal sodium excretion, blood pressure, and cardiovascular contractility. Other novel compounds identified in this search as potentially influencing natriuresis and blood pressure are also discussed. C1 Univ Texas, Inst Mol Med, Hlth Sci Ctr, Houston, TX 77025 USA. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. RP Doris, PA (reprint author), Univ Texas, Inst Mol Med, Hlth Sci Ctr, 2121 W Holcombe Blvd, Houston, TX 77025 USA. EM pdoris@imm2.imm.uth.tmc.edu FU NIDDK NIH HHS [DK45538] NR 138 TC 39 Z9 45 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0037-9727 J9 P SOC EXP BIOL MED JI Proc. Soc. Exp. Biol. Med. PD JUL PY 1998 VL 218 IS 3 BP 156 EP 167 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZU828 UT WOS:000074239500002 PM 9648933 ER PT J AU Barry, CE Lee, RE Mdluli, K Sampson, AE Schroeder, BG Slayden, RA Yuan, Y AF Barry, CE Lee, RE Mdluli, K Sampson, AE Schroeder, BG Slayden, RA Yuan, Y TI Mycolic acids: Structure, biosynthesis and physiological functions SO PROGRESS IN LIPID RESEARCH LA English DT Review ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MOLECULAR-SPECIES COMPOSITION; MYCOBACTERIAL CELL-WALL; MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION; SLOWLY GROWING MYCOBACTERIA; NUCLEAR MAGNETIC-RESONANCE; THIN-LAYER CHROMATOGRAPHY; CYCLOPROPANE FATTY-ACIDS; VAR BOVIS BCG; SP-NOV C1 NIAID, TB Res Stn, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Barry, CE (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM clifton_barry@nih.gov RI Barry, III, Clifton/H-3839-2012; Lee, Richard/J-4997-2013; Slayden, Richard/O-8626-2016 OI Lee, Richard/0000-0002-2397-0443; Slayden, Richard/0000-0001-6857-7277 FU Intramural NIH HHS [Z01 AI000783-11] NR 286 TC 334 Z9 342 U1 6 U2 49 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7827 J9 PROG LIPID RES JI Prog. Lipid. Res. PD JUL-AUG PY 1998 VL 37 IS 2-3 BP 143 EP 179 DI 10.1016/S0163-7827(98)00008-3 PG 37 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 108TL UT WOS:000075281500003 PM 9829124 ER PT J AU Rick, SW Erickson, JW Burt, SK AF Rick, SW Erickson, JW Burt, SK TI Reaction path and free energy calculations of the transition between alternate conformations of HIV-1 protease SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE conformational change; free energy calculations; HIV protease; molecular dynamics simulations; protein structure ID MOLECULAR-DYNAMICS; 3-DIMENSIONAL STRUCTURE; ASPARTYL PROTEASE; CRYSTAL-STRUCTURE; FORCE-FIELDS; INHIBITOR; RESOLUTION; SIMULATION; SOLVATION; PROTEINS AB Two different structures of ligand-free HIV protease have been determined by X-ray crystallography. These structures differ in the position of two 12 residue, beta-hairpin regions (or "flaps") which cap the active site, The movements of the flaps must be involved in the binding of substrates since, in either conformation, the flaps block the binding site. One of these structures is similar to structures of the ligand-bound enzyme; however, the importance of both structures to enzyme function is unclear, This transformation takes place on a time scale too long for conventional molecular dynamics simulations, so the process was studied by first identifying a reaction path between the two structures and then calculating the free energy along this path using umbrella sampling, For the ligand-free enzyme, it is found that the two structures are nearly equally stable, with the ligand-bound-type structure being less stable, consistent with X-ray crystallography data, The more stable open structure does not have a lower potential energy, but is stabilized by entropy, The transition occurs through a collapse and reformation of the beta-sheet structure of the conformationally flexible, glycine-rich flap ends. Additionally, some problems in studying conformational changes in proteins through the use of a single reaction path are addressed, Proteins 32:7-16, 1998, (C) 1998 Wiley-Liss, Inc. C1 NCI, Frederick Biomed Supercomp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP NCI, Frederick Biomed Supercomp Ctr, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 44 TC 59 Z9 59 U1 0 U2 7 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 JUL 1 PY 1998 VL 32 IS 1 BP 7 EP 16 DI 10.1002/(SICI)1097-0134(19980701)32:1<7::AID-PROT3>3.0.CO;2-K PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZZ094 UT WOS:000074695100003 PM 9672038 ER PT J AU Altschul, SF AF Altschul, SF TI Generalized affine gap costs for protein sequence alignment SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE structural alignment; multiple alignment; pattern recognition; statistical significance; BRCA1 ID ACID SUBSTITUTION MATRICES; HIDDEN MARKOV-MODELS; MULTIPLE ALIGNMENT; STATISTICAL DISTRIBUTION; EVOLUTIONARY DISTANCES; MOLECULAR SEQUENCES; ALGORITHM; SIMILARITIES; STRATEGY; MOTIFS AB Based on the observation that a single mutational event can delete or insert multiple residues, affine gap costs for sequence alignment charge a penalty for the existence of a gap, and a further length-dependent penalty. From structural or multiple alignments of distantly related proteins, it has been observed that conserved residues frequently fall into ungapped blocks separated by relatively nonconserved regions. To take advantage of this structure, a simple generalization of affine gap costs is proposed that allows nonconserved regions to be effectively ignored. The distribution of scores from local alignments using these generalized gap costs is shown empirically to follow an extreme value distribution. Examples are presented for which generalized affine gap costs yield superior alignments from the standpoints both of statistical significance and of alignment accuracy. Guidelines for selecting generalized affine gap costs are discussed, as is their possible application to multiple alignment. Proteins 32:88-96, 1998. (C) 1998 Wiley-Liss, Inc.dagger. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM altschul@ncbi.nlm.nih.gov NR 68 TC 47 Z9 48 U1 2 U2 10 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 JUL 1 PY 1998 VL 32 IS 1 BP 88 EP 96 DI 10.1002/(SICI)1097-0134(19980701)32:1<88::AID-PROT10>3.0.CO;2-J PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZZ094 UT WOS:000074695100010 PM 9672045 ER PT J AU Li, AJ Nussinov, R AF Li, AJ Nussinov, R TI A set of van der Waals and Coulombic radii of protein atoms for molecular and solvent-accessible surface calculation, packing evaluation, and docking SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE van der Waals radius; Coulombic radius; docking; molecular surface; solvent-accessible surface; protein-protein interface; protein-water boundary ID NUCLEIC-ACIDS; HYDROGEN-BOND; FORCE-FIELD; COMPLEMENTARITY; ENERGY; VOLUME; SIMULATIONS; INTERFACES; ALGORITHM; DYNAMICS AB We analyze the contact distance distributions between nonbonded atoms in known protein structures. A complete set of van der Waals (VDW) radii for 24 protein atom types and for crystal-bound water is derived from the contact distance distributions of these atoms with a selected group of apolar atoms. In addition, a set of Coulombic radii for polar atoms is derived from their contacts with water, The contact distance distributions and the two sets of radii are derived in a systematic and self-consistent manner using an iterative procedure. The Coulombic radii for polar atoms are, on average, 0.18 Angstrom smaller than their VDW radii, The VDW radius of water is 1.7 Angstrom, which is 0.3 Angstrom larger than its Coulombic radius. We show that both the VDW and the Coulombic radii of polar atoms are needed in calculating the molecular and solvent-accessible surfaces of proteins. The VDW radii are needed to generate the apolar portions of the surface and the Coulombic radii for the polar portions. The fact that polar atoms have two apparent sizes implies that a hydrophobic cavity has to be larger than a polar cavity in order to accommodate the same number of water molecules, Most surface area calculations have used only one radius for each polar atom. As a result, unreal cavities, grooves, or pockets may be generated if the Coulombic radii of polar atoms are used. On the other hand, if the VDW radii of polar atoms are used, the details of the polar regions of the surface may be lost. The accuracy of the molecular and the solvent-accessible surfaces of proteins can be improved if the radii of polar atoms are allowed to change depending on the nature of their contacting neighbors, The surface of a protein at a protein-protein interface differs from that in solution in that it has to be generated using at least two kinds of probes, one representing a typical apolar atom and the other a typical polar atom. This observation has important implications for docking, which relies on surface complementarity at the interface, Proteins 32:111-127, 1998, (C) 1998 Wiley-Liss,Inc. C1 NCI, Lab Expt & Computat Biol, IRSP, SAIC,FCRDC, Frederick, MD 21701 USA. Tel Aviv Univ, Sch Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Lab Expt & Computat Biol, IRSP, SAIC,FCRDC, Bldg 469,Room 151, Frederick, MD 21701 USA. EM ruthn@ncifcrf.gov FU NCI NIH HHS [1-CO-74102] NR 45 TC 113 Z9 113 U1 1 U2 24 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 JUL 1 PY 1998 VL 32 IS 1 BP 111 EP 127 DI 10.1002/(SICI)1097-0134(19980701)32:1<111::AID-PROT12>3.0.CO;2-H PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZZ094 UT WOS:000074695100012 PM 9672047 ER PT J AU Rocha, BA Odom, LA Barron, BA Ator, R Wild, SA Forster, MJ AF Rocha, BA Odom, LA Barron, BA Ator, R Wild, SA Forster, MJ TI Differential responsiveness to cocaine in C57BL/6J and DBA/2J mice SO PSYCHOPHARMACOLOGY LA English DT Article DE inbred mice; C57BL/6J; DBA/2J; locomotor activity; IV self-administration; cocaine dose-response; cocaine brain levels ID INBRED MOUSE STRAINS; LOCOMOTOR-ACTIVITY; SELF-SELECTION; DRUG-ABUSE; SENSITIZATION; AMPHETAMINE; VULNERABILITY; STIMULATION; ACQUISITION; SENSITIVITY AB The present study compared cocaine-induced hyperlocomotion and cocaine IV self-administration in DBA/2J and C57BL/6J mice. In the locomotor activity experiment, these strains were tested for hyperlocomotion after IP cocaine injection (0-60.0 mg/kg), using a Digiscan Animal Activity Monitoring System. In the cocaine IV self-administration experiment, they were compared for their ability to acquire and maintain cocaine self-administration in operant chambers with levers as the manipulanda. Animals were first trained to respond for food as a reinforcer (condensed milk solution); they were then submitted to surgical IV insertion of an indwelling catheter, and required to respond for IV cocaine (0.25-4.0 mg/kg per injection) as a reinforcer. DBA/2J mice showed significantly higher maximal cocaine-induced hyperlocomotion, more rapid acquisition of cocaine self-administration, and significantly lower rates of cocaine self-administration. Cocaine concentration in the brains of DBA/2J and C57BL/6J mice failed to differ following IP injection, suggesting that distribution factors were not involved in the differential responses to cocaine. Although not conclusive, this pattern of effects may suggest that cocaine has greater reinforcing efficacy in DBA/2J mice, confirming genetic make-up as a determinant factor in cocaine taking behavior. C1 UNTHSCFW, Dept Integrat Physiol, Ft Worth, TX 76107 USA. UNTHSCFW, Dept Pharmacol, Ft Worth, TX 76107 USA. RP Rocha, BA (reprint author), NIDA, Behav Neurosci Branch, NIH, Div Intramural Res, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [DA 10457, DA 4173] NR 50 TC 43 Z9 43 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 1998 VL 138 IS 1 BP 82 EP 88 DI 10.1007/s002130050648 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA ZZ521 UT WOS:000074737700011 PM 9694530 ER PT J AU Parascandola, M AF Parascandola, M TI Epidemiology: Second-rate science? SO PUBLIC HEALTH REPORTS LA English DT Article ID PHILOSOPHY AB In recent years epidemiology has come under increasing criticism in regulatory and public arenas for being "unscientific." The tobacco industry has taken advantage of this, insisting for decades that evidence linking cigarettes and lung cancer falls short of proof. Moreover, many epidemiologists remain unduly skeptical and self-conscious about the status of their own causal claims. This situation persists in part because of a widespread belief that only the laboratory can provide evidence sufficient for scientific proof. Adherents of this view erroneously believe that there is no element of uncertainty or inductive inference in the "direct observation" of the laboratory researcher and that epidemiology provides mere "circumstantial" evidence. The historical roots of this attitude can be traced to philosopher John Stuart Mill and physiologist Claude Bernard and their influence on modern experimental thinking. The author uses the debate over cigarettes and lung cancer to examine ideas of proof in medical science and public health, concluding that inductive inference from a limited sample to a larger population is an element in all empirical science. RP Parascandola, M (reprint author), NIH, NIH Histor Off, Bldg 31,Rm 2B09, Bethesda, MD 20892 USA. EM mparas@erols.com NR 29 TC 13 Z9 14 U1 0 U2 1 PU US GOVERNMENT PRINTING OFFICE PI WASHINGTON PA SUPT OF DOCUMENTS, WASHINGTON, DC 20402-9325 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JUL-AUG PY 1998 VL 113 IS 4 BP 312 EP 320 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZZ717 UT WOS:000074760000023 PM 9672568 ER PT J AU Morrison, HI Villeneuve, PJ Lubin, JH Schaubel, DE AF Morrison, HI Villeneuve, PJ Lubin, JH Schaubel, DE TI Radon-progeny exposure and lung cancer risk in a cohort of Newfoundland fluorspar miners SO RADIATION RESEARCH LA English DT Article ID UNDERGROUND MINERS AB Although radon is a well-established lung carcinogen, there are uncertainties concerning the exposure-response relationship, whether exposures in early life are particularly hazardous, and how smoking affects the risks associated with radon exposure. A cohort study of the mortality experience of 1,743 underground fluorspar miners and 321 surface workers from 1950 to 1984 reported previously has been extended to include 6 additional years of follow-up (1985-1990). A statistically significant relationship was noted between radon-progeny exposure and risk of lung cancer mortality. Our analysis found no effect for age at first exposure. Attained age was strongly predictive of excess relative risk (ERR) per working level month (WLM) of radon exposure, falling from 0.025 for those aged less than 50 years to 0.002 for those 70 years or older. An inverse exposure-rate effect was also observed, wherein for equal total exposure, a high exposure rate (and short duration) is less harmful than a low exposure rate (and long duration). The ERR/WLM increased from 0.0019 for exposures of less than 10 years to 0.0076 for exposures of 20 or more years. The analysis of time-since-exposure windows revealed a greater ERR/WLM for exposures received in more recent periods, similar to the result for time since last exposure. Excess relative risks per WLM were higher for current smokers than for nonsmokers (never and former smokers). Analyses were consistent with a multiplicative relationship between radon-progeny exposure and current smoking and the risk of lung cancer. The assessment of radon exposure and lung cancer risk should incorporate the effects of exposure rate, time since exposure, smoking status and attained age. (C) 1998 by Radiation Research Society. C1 Hlth Canada, Canc Bur, Lab Ctr Dis Control, Ottawa, ON K1A 0L2, Canada. Univ Toronto, Dept Prevent Med & Biostat, Toronto, ON, Canada. NCI, Biostat Branch, Bethesda, MD 20892 USA. RP Morrison, HI (reprint author), Hlth Canada, Canc Bur, Lab Ctr Dis Control, Tunneys Pasture, Ottawa, ON K1A 0L2, Canada. NR 12 TC 28 Z9 29 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 1998 VL 150 IS 1 BP 58 EP 65 DI 10.2307/3579646 PG 8 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA ZV652 UT WOS:000074327300010 PM 9650603 ER PT J AU Gilbert, ES Griffith, WC Boecker, BB Dagle, GE Guilmette, RA Hahn, FF Muggenburg, BA Park, JF Watson, CR AF Gilbert, ES Griffith, WC Boecker, BB Dagle, GE Guilmette, RA Hahn, FF Muggenburg, BA Park, JF Watson, CR TI Statistical modeling of carcinogenic risks in dogs that inhaled (PuO2)-Pu-238 SO RADIATION RESEARCH LA English DT Article ID INDUCTION; RADON; LUNG; RATS AB Combined analyses of data on 260 life-span beagle dogs that inhaled (PuO2)-Pu-238 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets. (C) 1998 by Radiation Research Society. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Lovelace Resp Res Inst, Albuquerque, NM 87185 USA. Washington State Univ, US Transuranium & Uranium Registries, Richland, WA 99352 USA. Pacific NW Natl Lab, Richland, WA 99352 USA. Univ Washington, Dept Environm Hlth, Consortium Risk Evaluat Stakeholder Participat, Seattle, WA 98105 USA. RP Gilbert, ES (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI WSU, USTUR/I-1056-2013 NR 30 TC 13 Z9 13 U1 0 U2 2 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 1998 VL 150 IS 1 BP 66 EP 82 DI 10.2307/3579647 PG 17 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA ZV652 UT WOS:000074327300011 PM 9650604 ER PT J AU Doppman, JL Skarulis, MC Chang, R Alexander, HR Bartlett, D Libutti, SK Marx, SJ Spiegel, AM AF Doppman, JL Skarulis, MC Chang, R Alexander, HR Bartlett, D Libutti, SK Marx, SJ Spiegel, AM TI Hypocalcemic stimulation and nonselective venous sampling for localizing parathyroid adenomas: Work in progress SO RADIOLOGY LA English DT Article DE angiography; iopamidol; parathyroid, neoplasms; parathyroid, vascular studies ID SELECTIVE INTRAARTERIAL INJECTION; ZOLLINGER-ELLISON SYNDROME; CONTRAST-MEDIA; CALCIUM; LOCALIZATION; INSULINOMAS; GASTRINOMAS; SECRETIN AB PURPOSE: To evaluate whether the release of parathyroid hormone (PTH) from parathyroid tumors during selective parathyroid arteriography can help localize the tumors. MATERIALS AND METHODS: In 20 patients (six men, 14 women; age range, 24-72 years) with parathyroid tumors undergoing parathyroid arteriography after failed surgery, serial measurements of PTH were obtained during selective arteriography with nonionic contrast material. PTH levels were measured in the superior vena cava (SVC) before and at varying times from 20 to 120 seconds after arteriography. RESULTS: a 1.4-fold increase in the PTH level of the postarteriographic SVC samples enabled correct prediction of the site of adenoma in 13 of the 20 patients (65%). Of nine patients with positive arteriograms, eight had positive results of postarteriographic sampling. Of 11 patients with negative arteriograms, five had positive results of postarteriographic sampling. CONCLUSION: Sampling the SVC for PTH gradients after selective parathyroid arteriography correctly indicated the site of the adenoma in 13 of 20 patients (65%). C1 NIDDKD, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Oncol Branch, Div Canc Treatment, NIH, Bethesda, MD 20892 USA. RP Doppman, JL (reprint author), NIDDKD, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, NIH, Bldg 10,Rm 1C660, Bethesda, MD 20892 USA. NR 14 TC 6 Z9 6 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 1998 VL 208 IS 1 BP 145 EP 151 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ZV355 UT WOS:000074296300024 PM 9646806 ER PT J AU Chapin, RE Sloane, RA Haseman, JK AF Chapin, RE Sloane, RA Haseman, JK TI Reproductive endpoints in general toxicity studies: Are they predictive? SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE reproductive endpoints; toxicity studies; sperm motility; vaginal cytology ID CONTINUOUS BREEDING REPRODUCTION; NATIONAL TOXICOLOGY PROGRAM; ORGAN WEIGHT DATA; VAGINAL CYTOLOGY; CARCINOGENICITY; DESIGNS; SPERM; MICE AB The ability to use necropsy and in-life vaginal cytology data from 90-d general toxicity studies to predict the outcome of more definitive reproductive toxicity tests was evaluated using data from 18 compounds tested by the National Toxicology Program, Sperm motility and vaginal cytology evaluations (SMVCE) were performed at the end of 90-d toxicity studies. When these same compounds were tested in the definitive Reproductive Assessment by Continuous Breeding (RACB) design, 13 of the 18 compounds were classified the same way by both tests. The different conclusions for five compounds can be explained by differences in dose used or in endpoints evaluated. We conclude that reproductive-system necropsy data from general toxicity studies can provide a valuable preliminary indication of the likely reproductive toxicity of the compound under study, (C) 1998 Elsevier Science Inc. C1 NIEHS, RTP, Reprod Toxicol Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chapin, RE (reprint author), NIEHS, RTP, Reprod Toxicol Grp, POB 12233,B3-05, Res Triangle Pk, NC 27709 USA. OI Chapin, Robert/0000-0002-5997-1261 NR 12 TC 16 Z9 18 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD JUL-AUG PY 1998 VL 12 IS 4 BP 489 EP 494 DI 10.1016/S0890-6238(98)00026-4 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 104EN UT WOS:000075001900009 PM 9717700 ER PT J AU Wilson, PW AF Wilson, PW TI Why treat dyslipidemia? SO SAUDI MEDICAL JOURNAL LA English DT Review DE cholesterol; coronary artery disease ID CORONARY HEART-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; ARTERY DISEASE; MYOCARDIAL-INFARCTION; LOWERING CHOLESTEROL; HDL CHOLESTEROL; HYPERLIPIDEMIA; PREVENTION; RISK; MEN AB Considerable observational clinical trial data have been collected concerning abnormal lipid levels and coronary disease incidence over the past 20 years. Middle-aged men with elevated cholesterol levels have been studied the most. Affected individuals tend to experience greatly increased risk for atherosclerosis and myocardial infarction. Bile acid resins, nicotinic acid, fibrates, and statin therapies have all been associated with a decreased vascular disease incidence. In general, each percentage lowering in blood cholesterol level has been associated with a 2% lowering in coronary heart disease incidence over a 5-year follow-up interval. Complementary data from atherosclerosis regression trials have shown that-persons taking lipid lowering medication typically exhibit less progression of atherosclerotic lesions in coronary and carotid arteries. Less data is available concerning the efficacy of lipid lowering in women and the elderly, but observational data suggest some benefit might be expected. Most clinical trials have emphasized the importance of lipid intervention using medications, but dietary trials have also demonstrated efficacy, and current dietary recommendations call for middle-aged persons to consume less than 30% of their calories as fat. While the impact of dyslipidemia on coronary heart disease has been emphasized, it is also important to recognize that control of lipids may have long-term impact on other diseases, such as diabetes mellitus, carotid stenosis, and pancreatitis. C1 National Heart Lung & Blood Institute, Framingham Heart Study, Framingham, MA 01701 USA. RP Wilson, PW (reprint author), National Heart Lung & Blood Institute, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701 USA. NR 46 TC 0 Z9 0 U1 0 U2 1 PU SAUDI MED J PI RIYADH PA ARMED FORCES HOSPITAL, PO BOX 7897,, RIYADH 11159, SAUDI ARABIA SN 0379-5284 J9 SAUDI MED J JI Saudi Med. J. PD JUL-AUG PY 1998 VL 19 IS 4 BP 376 EP 381 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 117AR UT WOS:000075758000005 PM 27704101 ER PT J AU Baltimore, D Heilman, C AF Baltimore, D Heilman, C TI HIV vaccines: Prospects and challenges SO SCIENTIFIC AMERICAN LA English DT Article C1 NIH, AIDS Vaccine Res Comm, Bethesda, MD 20892 USA. CALTECH, Pasadena, CA 91125 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. RP Baltimore, D (reprint author), NIH, AIDS Vaccine Res Comm, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD JUL PY 1998 VL 279 IS 1 BP 98 EP 103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW260 UT WOS:000074391600038 PM 9648305 ER PT J AU Cheson, BD AF Cheson, BD TI Chronic lymphocytic leukemia in the purine analog era: New insights and challenges SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NCI, Med Sect, Clin Invest Branch, Bethesda, MD 20892 USA. RP Cheson, BD (reprint author), 11028 Waycroft Way, N Bethesda, MD 20852 USA. NR 0 TC 1 Z9 1 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 1998 VL 35 IS 3 SU 3 BP 1 EP 2 PG 2 WC Hematology SC Hematology GA 100CT UT WOS:000074797300001 ER PT J AU Arbuck, SG Takimoto, CH AF Arbuck, SG Takimoto, CH TI An overview of topoisomerase I - Targeting agents SO SEMINARS IN HEMATOLOGY LA English DT Review ID CELL LUNG-CANCER; EVERY 3 WEEKS; 24-HOUR CONTINUOUS-INFUSION; COLONY-STIMULATING FACTOR; METASTATIC COLORECTAL-CANCER; EPITHELIAL OVARIAN-CANCER; ACTIVE METABOLITE SN-38; DNA CLEAVABLE COMPLEXES; ADVANCED SOLID TUMORS; EARLY CLINICAL-TRIALS C1 NCI, Investigat Drug Branch, Div Canc Treatment Diag & Ctr, Bethesda, MD 20892 USA. Bethesda Naval Hosp, Div Clin Sci, NCI, Bethesda, MD USA. RP Arbuck, SG (reprint author), NCI, Investigat Drug Branch, Div Canc Treatment Diag & Ctr, 6130 Execut Blvd,EPN 715, Bethesda, MD 20892 USA. NR 127 TC 31 Z9 33 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 1998 VL 35 IS 3 SU 4 BP 3 EP 12 PG 10 WC Hematology SC Hematology GA 128NA UT WOS:000076411800002 PM 9779876 ER PT J AU Cheson, BD AF Cheson, BD TI Therapy for previously untreated chronic lymphocytic leukemia: A reevaluation SO SEMINARS IN HEMATOLOGY LA English DT Article ID PREVIOUSLY TREATED PATIENTS; PHASE-II TRIAL; CELL MALIGNANCIES; FLUDARABINE; 2-CHLORODEOXYADENOSINE; CLADRIBINE; PENTOSTATIN; CANCER; AGENT; EXPERIENCE C1 NCI, Med Sect, Clin Invest Branch, Bethesda, MD 20892 USA. RP Cheson, BD (reprint author), 11028 Waycroft Way, N Bethesda, MD 20852 USA. NR 35 TC 15 Z9 15 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 1998 VL 35 IS 3 SU 3 BP 14 EP 21 PG 8 WC Hematology SC Hematology GA 100CT UT WOS:000074797300003 PM 9685175 ER PT J AU Pappalardo, PA Bonner, R Krizman, DB Emmert-Buck, MR Liotta, LA AF Pappalardo, PA Bonner, R Krizman, DB Emmert-Buck, MR Liotta, LA TI Microdissection, microchip arrays, and molecular analysis of tumor cells (primary and metastases) SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID DENSITY OLIGONUCLEOTIDE ARRAYS; POLYMERASE CHAIN-REACTION; GENE-EXPRESSION PATTERNS; CLONAL ANALYSIS; PROBE ARRAYS; MICROARRAY; HYBRIDIZATION; CARCINOMA; LIBRARY; CANCER C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Pappalardo, PA (reprint author), NCI, Pathol Lab, NIH, 9000 Rockville Pike,Bldg 10,Room 2C-500, Bethesda, MD 20892 USA. RI Bonner, Robert/C-6783-2015 NR 32 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 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 1998 VL 8 IS 3 BP 217 EP 223 DI 10.1016/S1053-4296(98)80047-7 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA ZZ789 UT WOS:000074767300009 PM 9634498 ER PT J AU Massing, MW Rywik, SL Jasinski, B Manolio, TA Williams, OD Tyroler, HA AF Massing, MW Rywik, SL Jasinski, B Manolio, TA Williams, OD Tyroler, HA TI Opposing national stroke mortality trends in Poland and for African Americans and whites in the United States, 1968 to 1994 SO STROKE LA English DT Article DE cardiovascular diseases; cerebrovascular disorders; epidemiology; mortality ID CORONARY HEART-DISEASE; MIDDLE-AGED MEN; RISK-FACTORS; PHYSICAL-ACTIVITY; DIABETES-MELLITUS; CEREBROVASCULAR-DISEASE; CARDIOVASCULAR-DISEASE; SOCIAL INEQUALITIES; BLOOD-PRESSURE; POPULATION AB Background and Purpose-The United States (US) has experienced declines in stroke mortality in contrast to the increases reported for Poland. As part of the Poland and US Agreement on Cardiovascular and Cardiopulmonary Research, stroke mortality trends in Polish and US subpopulations were compared in the context of cross-population differences in competing causes of death and determinants of stroke. Methods-Age-adjusted annual stroke, cardiovascular disease (CVD), non-CVD, and all-cause mortality rates were determined for men and women aged 35 to 64 and 65 to 74 years from 1968 to 1994 for African Americans and US whites and in Poland. Mean annual percent changes of mortality rates were estimated during 1968 to 1980 and 1981 to 1994 with the use of piecewise log-linear regression. Results-US stroke mortality rates declined 3.7% to 4.8% annually during 1968 to 1980 and 2.0% to 3.1% during 1981 to 1994, with similar declines in each ethnic, gender, and age group. Polish rates increased 3.3% to 5.5% annually for all age-gender groups in Poland during 1968 to 1980. Polish men aged 35 to 64 experienced increasing rates during 1981 to 1994 (1.6% annually), while Polish women and older men experienced slight declines or little change. Only Polish men aged 35 to 64 years exhibited increases in stroke, CVD, and non-CVD mortality rates during both time intervals. Conclusions-Poland and the US experienced opposing stroke mortality rate trends between 1968 and 1994. These national and ethnic trends occurring in just one generation suggest major effects of lifestyle, socioenvironmental, and/or medical care determinants. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. Natl Inst Cardiol, Dept Cardiovasc Epidemiol & Prevent Cardiovasc Di, Warsaw, Poland. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. RP Massing, MW (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Suite 306,137 E Franklin St, Chapel Hill, NC 27514 USA. EM mark_massing@unc.edu FU NHLBI NIH HHS [N01-HV-1-2243, N01-HV-1-08112, N01-HV-59224] NR 85 TC 9 Z9 9 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 1998 VL 29 IS 7 BP 1366 EP 1372 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA ZX128 UT WOS:000074482200015 PM 9660388 ER PT J AU DeGraba, TJ Siren, AL Penix, L McCarron, RM Hargraves, R Sood, S Pettigrew, KD Hallenbeck, JM AF DeGraba, TJ Siren, AL Penix, L McCarron, RM Hargraves, R Sood, S Pettigrew, KD Hallenbeck, JM TI Increased endothelial expression of intercellular adhesion molecule-1 in symptomatic versus asymptomatic human carotid atherosclerotic plaque SO STROKE LA English DT Article DE atherosclerosis; carotid endarterectomy; endothelium; intercellular adhesion molecule-1; inflammation ID TUMOR-NECROSIS-FACTOR; SURFACE EXPRESSION; CELLS; STRESS; BRAIN; INFLAMMATION; PROCOAGULANT; HEMORRHAGE; ULCERATION; STROKE AB Background and Purpose-The mechanisms that cause carotid atherosclerotic plaque to become symptomatic remain unclear. Evidence suggests that mediators of inflammation are not only instrumental in the formation of plaque but may also be involved in the rapid progression of atheromatous lesions leading to plaque fissuring, endothelial injury, and intraluminal thrombosis. Our goal is to determine whether intercellular adhesion molecule-1 (ICAM-1), a known component of the inflammatory pathway, is preferentially expressed on symptomatic versus asymptomatic carotid plaques. Methods-Carotid plaques from symptomatic (n=25) and asymptomatic (n=17) patients undergoing carotid endarterectomy with lesions involving >60% stenosis were snap-frozen at the time of surgery. Immunofluorescence studies were performed to measure the percentage of luminal endothelial surface that expressed ICAM-1. The relationships of stroke risk factors, white blood cell count, percent stenosis, and soluble ICAM-1 (sICAM-1) plasma levels to endothelial ICAM-1 expression were investigated. Results-An increased expression of ICAM-1 was found in the high-grade regions of symptomatic (29.5%+/-2.4%, mean+/-SEM) versus asymptomatic (15.7%+/-2.7%, mean+/-SEM) plaques (P=0,002) and in the high-grade versus the low-grade region of symptomatic plaques (29,5+/-2.4, mean+/-SEM, versus 8.9+/-1.6; P<0.001). Plasma sICAM-1 levels were not predictive of symptomatic disease, and no significant correlation between risk factor exposure and endothelial ICAM-1 expression was found. Conclusions-An elevation in ICAM-1 expression in symptomatic versus asymptomatic plaque suggests that mediators of inflammation are involved in the conversion of carotid plaque to a symptomatic state. The data also suggest a differential expression of ICAM-1, with a greater expression found in the high-grade region than in the low-grade region of the plaque specimen. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Natl Naval Med Ctr, Dept Neurosurg, Bethesda, MD USA. NIMH, NIH, Bethesda, MD 20892 USA. RP DeGraba, TJ (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr MSC 4128,Bldg 36 Room 4A03, Bethesda, MD 20892 USA. EM tjd@helix.nih.gov OI Siren, Anna-Leena/0000-0002-2217-0081 NR 36 TC 84 Z9 89 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 1998 VL 29 IS 7 BP 1405 EP 1410 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA ZX128 UT WOS:000074482200023 PM 9660396 ER PT J AU Doudet, DJ Chan, GLY Holden, JE McGeer, EG Aigner, TA Wyatt, RJ Ruth, TJ AF Doudet, DJ Chan, GLY Holden, JE McGeer, EG Aigner, TA Wyatt, RJ Ruth, TJ TI 6-[F-18]fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys SO SYNAPSE LA English DT Article DE FDOPA; PET; dopamine; MPTP; parkinsonism ID POSITRON EMISSION TOMOGRAPHY; TREATED MONKEYS; F-18 FLUORODOPA; RHESUS-MONKEYS; DISEASE; SYSTEM; BRAIN; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; METABOLISM; RECOVERY AB This report describes a method to assess, in vivo, the turnover of dopamine (DA) and describes its application to the evaluation of DA function in normal monkeys and monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced lesions of the DA nigro-striatal pathway. Using positron emission tomography with the tracer of presynaptic DA function, 6-[F-18]fluoro-L-DOPA (FDOPA), and an extension of the graphical method of analysis, we measured the striatal FDOPA uptake rate constant, K-i, and the rate of reversibility of FDOPA trapping k(loss) in normal and MPTP-treated monkeys, either neurologically normal or displaying a parkinsonian symptomatology. An index of effective DA turnover was defined as the ratio of k(loss)/K-i. Compared to normal controls, K-i was decreased and k(loss) was increased in the MPTP-lesioned monkeys. The index of DA turnover was significantly increased in the monkeys displaying a parkinsonian symptomatology as compared to the controls and the neurologically normal MPTP-treated monkeys. The DA turnover index was also significantly increased in the neurologically normal MPTP-lesioned animals compared to normals. This suggests that an increase in DA turnover develops early in the disease process and may be one of the compensatory mechanisms partly responsible for the delay in the development of the clinical manifestations in Parkinson's disease. (C) 1998 Wiley-Liss, Inc. C1 Univ British Columbia, Dept Med, Div Neurol, Vancouver, BC V6T 2B5, Canada. Univ British Columbia, Ctr Neurodegenerat Disorders, Vancouver, BC V6T 2B5, Canada. Univ British Columbia, Kinsmen Lab Neurol Res, Vancouver, BC V6T 2B5, Canada. Univ British Columbia, TRIUMF, Vancouver, BC V6T 2B5, Canada. Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Doudet, DJ (reprint author), Univ British Columbia, Dept Med, Div Neurol, Rm M36,Purdy Pavil,2221 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 30 TC 55 Z9 56 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 1998 VL 29 IS 3 BP 225 EP 232 DI 10.1002/(SICI)1098-2396(199807)29:3<225::AID-SYN4>3.0.CO;2-8 PG 8 WC Neurosciences SC Neurosciences & Neurology GA ZQ927 UT WOS:000073917000004 PM 9635892 ER PT J AU Highfield, DA Grant, S AF Highfield, DA Grant, S TI Ng-nitro-L-arginine, an NOS inhibitor, reduces tolerance to morphine in the rat locus coeruleus SO SYNAPSE LA English DT Article DE brain slice; nitric oxide; single-cell; extracellular; noradrenaline ID OXIDE SYNTHASE INHIBITORS; DEPENDENT PROTEIN-KINASE; DOSE-RESPONSE CURVES; OPIOID WITHDRAWAL; BRAIN-SLICES; PRECIPITATED WITHDRAWAL; POTASSIUM CONDUCTANCE; PELLET IMPLANTATION; PHYSICAL-DEPENDENCE; OPIATE WITHDRAWAL AB Ng-nitro-L-arginine (L-NArg), a potent nitric oxide synthase inhibitor, has been implicated as a potential mechanism for attenuating the development of tolerance to opioid drugs and for suppressing opioid withdrawal. Neurons in the locus coeruleus (LC) express opioid receptors and these neurons exhibit both tolerance to chronic administration of opioids and antagonist-precipitated withdrawal hyperactivity. This study tested the hypothesis that L-NArg would attenuate the development of opioid tolerance in LC neurons. Challenge doses of morphine were administered while recording single-cell extracellular activity in brain slices from rats who had been concurrently treated for 5 days with morphine (75 mg morphine sulfate base pellets) and L-NArg (10 mg/kg, ip, bid). The average ED50 for morphine of cells from rats who received L-NArg injections and morphine pellets was similar to that in cells from rats who had been implanted with sham pellets (14.5-18 nM). In contrast, the average ED50 Of cells from morphine pelleted animals who received saline injections was substantially higher (34.5 nM). These results demonstrate that L-NArg attenuates the development of tolerance to morphine in LC neurons. (C) 1998 Wiley-Liss, Inc. C1 NIDA, Brain Imaging Sect, Intramural Res Program, Baltimore, MD 21224 USA. Univ Maryland, Sch Med, Dept Neurobiol & Anat, Baltimore, MD 21201 USA. RP Grant, S (reprint author), NIDA, Brain Imaging Sect, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 49 TC 18 Z9 19 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 1998 VL 29 IS 3 BP 233 EP 239 PG 7 WC Neurosciences SC Neurosciences & Neurology GA ZQ927 UT WOS:000073917000005 PM 9635893 ER PT J AU DeLa Cadena, RA Majluf-Cruz, A Stadnicki, A Tropea, M Reda, D Agosti, JM Colman, RW Suffredini, AF AF DeLa Cadena, RA Majluf-Cruz, A Stadnicki, A Tropea, M Reda, D Agosti, JM Colman, RW Suffredini, AF TI Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR : Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans SO THROMBOSIS AND HAEMOSTASIS LA English DT Article ID HUMAN INFLAMMATORY RESPONSES; SEPTIC SHOCK; INTRAVENOUS ENDOTOXIN; MONOCLONAL-ANTIBODIES; LETHAL BACTEREMIA; PATHOGENESIS; CHIMPANZEES; INHIBITION AB The effects of inhibition of tumor necrosis factor (TNF) on cell and protease activation were evaluated in 18 normal volunteers given endotoxin (4 ng/kg, iv) after an infusion of low (10 mg/m(2) iv, n = 6) or high dose (60 mg/m(2) iv. n = 6) recombinant human dimeric TNF receptor protein ((TNFR:Fc) or its vehicle (placebo n = 6). Activation of the coagulation system occurred by 2 h in the TNFR:Fe vehicle-placebo group manifested by decreased prekallikrein functional levels and increased levels of prothrombin F1+2 fragments (p <0.0001). High or low dose TNFR:Fe delayed the fall in prekallikrein functional levels by 1 h and 1 h. respectively (p <0.0002), but did not inhibit the increase in circulating levels of prothrombin F1+2 fragments. In contrast, endothelium activation, characterized by increased levels of tissue plasminogen activator, plasminogen activator inhibitor-1. and von Willebrand Factor antigen was blunted by both low and high dose TNFR:Fc ip <0.001), While the endotoxin-associated decrease in platelet number Has not altered. platelet-derived beta-thromboglobulin peak levels were blunted and delayed by TNFR:Fe (p <0.02). Increased levels of neutrophil elastase were attenuated by low and high dose TNFR:Fc (p <0.001). These results suggest that although TNF is functionally linked to the activation of endothelium, neutrophils, coagulation. and fibrinolysis. alternative pathways are present in vivo that result in activation of the kallikrein-kinin system after endotoxin-induced TNF release. These alternative pathways may limit some of the anti-inflammatory effects of TNFR:Fc. C1 Temple Univ, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Temple Univ, Sch Med, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19104 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. Immunex Corp, Seattle, WA USA. RP DeLa Cadena, RA (reprint author), Temple Univ, Sch Med, Dept Pathol & Lab Med, Rm 403,OMS,3400 N Broad St, Philadelphia, PA 19104 USA. EM cadena@astro.ocis.temple.edu FU NHLBI NIH HHS [HL-02681, HL 56914-01] NR 29 TC 34 Z9 34 U1 0 U2 0 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 45, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 1998 VL 80 IS 1 BP 114 EP 118 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA ZZ969 UT WOS:000074787600020 PM 9684796 ER PT J AU Sakkinen, PA Cushman, M Psaty, BM Kuller, LH Bajaj, SP Sabharwal, AK Boineau, R Macy, E Tracy, RP AF Sakkinen, PA Cushman, M Psaty, BM Kuller, LH Bajaj, SP Sabharwal, AK Boineau, R Macy, E Tracy, RP TI Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort SO THROMBOSIS AND HAEMOSTASIS LA English DT Article ID LINKED IMMUNOSORBENT-ASSAY; CARDIOVASCULAR HEALTH; HUMAN-PLASMA; RISK-FACTORS; T-PA; INHIBITOR; DISEASE; ATHEROSCLEROSIS; COAGULATION; DEFICIENCY AB The majority of fatal acute myocardial infarctions occur in the elderly, Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin. Protein C, Protein S, and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women greater than or equal to 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong ape-associated trends, although Protein C was lower in older women (p less than or equal to 0.001). and TFPI was higher in older men (p less than or equal to 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen, plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment FI-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend less than or equal to 0.01; and carotid wall thickness, p trend less than or equal to 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen: the fibrinolytic marker plasmin-antiplasmin complex: LDL-cholesterol: and carotid wall thickness (R-2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age. and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage. (250) C1 Univ Vermont, Dept Pathol & Biochem, Colchester, VT 05446 USA. Univ Vermont, Dept Med, Colchester, VT 05446 USA. Univ Vermont, Dept Pathol, Colchester, VT 05446 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. St Louis Univ, Dept Med, St Louis, MO 63103 USA. St Louis Univ, Dept Biochem, St Louis, MO 63103 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. RP Tracy, RP (reprint author), Univ Vermont, Dept Pathol & Biochem, Aquatec Bldg,T205,55A S Pk Dr, Colchester, VT 05446 USA. FU NHLBI NIH HHS [T32HL07594, N01-HC-85079, N01-HC-85086] NR 47 TC 42 Z9 45 U1 0 U2 1 PU F K SCHATTAUER VERLAG GMBH PI STUTTGART PA P O BOX 10 45 45, LENZHALDE 3, D-70040 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 1998 VL 80 IS 1 BP 134 EP 139 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA ZZ969 UT WOS:000074787600023 PM 9684799 ER PT J AU Eastin, WC Haseman, JK Mahler, JF Bucher, JR AF Eastin, WC Haseman, JK Mahler, JF Bucher, JR TI The National Toxicology Program evaluation of genetically altered mice as predictive models for identifying carcinogens SO TOXICOLOGIC PATHOLOGY LA English DT Article DE Tg.AC mice; p53; carcinogenicity; toxicity; bioassay; National Toxicology Program; mutagenicity AB National Institute of Environmental Health Sciences researchers are exploring the utility of genetically altered mice to study mechanisms of carcinogenesis. Two of these mouse models, the Tg.AC (carrier of an activated mouse H-ras oncogene) and the p53(+/-) (heterozygous for the wild-type tumor suppressor gene Trp53), have genetic alterations that appear to hasten their expression of chemically induced tumors. These 2 models have been proposed as a basis for new strategies for identifying chemical carcinogens and for assessing risk. The National Toxicology Program (NTP) is conducting a series of studies with these 2 genetically altered strains to further examine their strengths and weaknesses for identification of documented rodent and human carcinogens. In this first evaluation. candidates for study were drawn from the NTP historical database of 2-yr rodent carcinogenicity studies and the open literature (primarily for drugs). Results with this first set of 11 chemicals tested in genetically altered mice, compared with previous findings in the traditional 2-yr rodent assays and literature on human tumor findings, appear to support the premise advanced by Tennant et al that these models have the potential to serve as more rapid and less expensive test systems to identify carcinogens. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Eastin, WC (reprint author), NIEHS, Mail Drop E1-02,POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 54 Z9 55 U1 1 U2 1 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 461 EP 473 PG 13 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900001 PM 9715504 ER PT J AU Nylander-French, LA French, JE AF Nylander-French, LA French, JE TI Tripropylene glycol diacrylate but not ethyl acrylate induces skin tumors in a twenty-week short-term tumorigenesis study in Tg.AC (v-ha-ras) mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE exposure; dermal; monofunctional acrylates; multifunctional acrylates; transgenic mouse; toxicity; carcinogenicity; oncogene AB The toxicity of the esters of acrylic acid are poorly understood even though significant human exposure occurs. To conduct rapid comparative short-term bioassays, we used the Tg.AC (v-Ha-ras) transgenic mouse model to determine the toxicity and potential carcinogenicity of tripropylene glycol diacrylate (TPGDA) alone and in a reference formulated ultraviolet radiation curable lacquer (Lacquer A), which is used in the ultraviolet radiation curable surface coatings. For comparison, ethyl acrylate (EA) was used as a reference acrylate. Insertion of the zeta -globin promoted v-Ha-ras transgene into the FVB mouse genome (Tg.AC) introduced a defined genetic lesion, which is critical but insufficient by itself to induce benign or malignant tumors in the skin unless activated. Activation and expression of the transgenic ras oncoprotein in this mouse line induces a dose-related increase in papillomas (skin reporter phenotype) within weeks. Based on dose-related increases in skin hyperplasia following dermal exposure to EA, TPGDA, or Lacquer A (applied equimolar for TPGDA concentration), the dosing regimen was selected. Starting at 12 wk of age, the agents were administered topically (200 mul of acetone vehicle) 3 times/wk for 20 wk to the shaved dorsal skin of female Tg.AC mice (n = 10/group). TPGDA and reference Lacquer A (equimolar for TPGDA) at 5 or 10 mu moles/mouse but not EA (60, 300, or 600 mu moles/mouse) or TPGDA or Lacquer A at 1 mu mole/mouse induced a dose-related increase in papillomas between 6 and 12 wk of treatment that reached a maximum number of papillomas per mouse between 19 and 20 wk of treatment. These results indicate that TPGDA is significantly more potent than EA for inducing the skin reporter phenotype and may be predicted to be carcinogenic in long-term cancer bioassays at the site of contact. C1 Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. RP Nylander-French, LA (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, POB 12233, Res Triangle Pk, NC 27709 USA. NR 35 TC 10 Z9 10 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 476 EP 483 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900003 PM 9715506 ER PT J AU Mahler, JF Flagler, ND Malarkey, DE Mann, PC Haseman, JK Eastin, W AF Mahler, JF Flagler, ND Malarkey, DE Mann, PC Haseman, JK Eastin, W TI Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE mice; genetically altered; hazard identification; neoplasms; carcinogenicity AB Recently, the use of selected genetically altered mouse models in the detection of carcinogens after shea-term chemical exposures has been evaluated. Studies of several chemicals conducted by the National Toxicology Program in Tg.AC transgenic and heterozygous p53-deficient mice have been completed recently and represent a major contribution to this effort, as well as the largest accumulation to date of toxicologic pathology data in these 2 lines of mice. The purpose of this report is to describe the proliferative target organ effects observed in this set of studies, as well as to present the tumor profile in the control groups of this data set. These findings provide a comprehensive toxicologic assessment of these 2 genetically altered mouse strains, which are of emerging importance in toxicologic pathology. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Mahler, JF (reprint author), NIEHS, Mail Drop B3-06,POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 51 Z9 52 U1 0 U2 2 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 501 EP 511 PG 11 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900006 PM 9715509 ER PT J AU Asano, S Trempus, CS Spalding, JW Tennant, RW Battalora, MS AF Asano, S Trempus, CS Spalding, JW Tennant, RW Battalora, MS TI Morphological characterization of spindle cell tumors induced in transgenic Tg.AC mouse skin SO TOXICOLOGIC PATHOLOGY LA English DT Article DE squamous cell carcinoma; fibrosarcoma; malignant fibrous histiocytoma; keratin; desmosome; v-Ha-ras; carcinogenesis AB Transgenic Tg.AC mice carry a v-Ha-ras coding region flanked by a zeta -globin promoter and an SV40 polyadenylation signal sequence. These mice respond to carcinogens by developing epidermal papillomas. In some cases, malignancies develop at the sites of these papillomas. Various patterns of squamous cell differentiation were observed in these malignancies. One malignancy that developed at the site of the papillomas was composed of bundles of spindle cells. This lesion is difficult to distinguish from fibrosarcomas by light microscopy. We characterized 16 of these malignancies (tentatively classified as spindle cell tumors) to determine if they were of epithelial or mesenchymal origin. Papillomas were induced in Tg.AC mice by full thickness wounding, 12-O-tetradecanoyl-13-phorbol acetate treatment, or ultraviolet radiation. With time, some papillomas became broad-based, downwardly invading lesions. These lesions were examined by light microscopy with immunohistochemical analysis for cytokeratins and by electron microscopy. Immunohistochemical examination with a polyclonal anti-cytokeratin antibody demonstrated various degrees of keratin staining in all tumors examined. Attenuated desmosomes were also observed in these lesions by electron microscopy. These results indicate an epithelial origin for these malignancies; therefore, they should be classified as spindle cell carcinomas. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Battalora, MS (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 39 TC 9 Z9 9 U1 1 U2 1 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 512 EP 519 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900007 PM 9715510 ER PT J AU Humble, MC Szczesniak, CJ Luetteke, NC Spalding, JW Cannon, RE Hansen, LA Lee, DC Tennant, RW AF Humble, MC Szczesniak, CJ Luetteke, NC Spalding, JW Cannon, RE Hansen, LA Lee, DC Tennant, RW TI TGF alpha is dispensable for skin tumorigenesis in Tg.AC mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE transgenic mice; v-Ha-ras; TPA; wounding; epidermal growth factor receptor (EGFR); oncogene AB Alterations in growth factor signaling pathways frequently accompany the development and maintenance of epithelial neoplasia. Transforming growth factor alpha (TGF alpha) and its epidermal growth factor receptor have been thought to play an especially important role in epithelial neoplasia. In this study, mice were derived genetically deficient (null) in functional TGF alpha expression and carrying the Tg.AC/v-Ha-ras transgene. The goals were to determine if (a) papillomagenesis was dependent on TGF alpha and (b) progression to malignancy was dependent on TGF alpha expression. Groups of male and female mice heterozygous or homozygous for the TGF alpha null allele and hemizygous for the Tg.AC transgene were treated twice weekly for 10 or 15 wk with doses of 12-O-tetradecanoylphorbol-13-acetate (TPA) known to produce papillomas in Tg.AC mice. Papillomas were readily induced in both male and female TGF alpha null mice. Malignant progression of papillomas was observed in all TGF alpha null treatment groups. Additionally, we examined the response of TGF alpha null mice to full thickness dorsal wounds, a stimulus known to promote papillomagenesis in Tg.AC mice. As in the TPA study, papillomas were induced in both male and female TGF alpha null mice. These studies indicate that TGF alpha is not required for the induction and maintenance of papillomas nor is it essential for the malignant conversion of papillomas in Tg.AC mice. C1 Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27514 USA. RP Tennant, RW (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, POB 12233,MD F1-05, Res Triangle Pk, NC 27709 USA. FU NCI NIH HHS [CA43793]; NIEHS NIH HHS [T32 ES07126] NR 44 TC 8 Z9 8 U1 0 U2 0 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 562 EP 569 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900013 PM 9715516 ER PT J AU Enomoto, A Sandgren, EP Maronpot, RR AF Enomoto, A Sandgren, EP Maronpot, RR TI Altered differentiation of hepatocytes in a transgenic mouse model of hepatocarcinogenesis SO TOXICOLOGIC PATHOLOGY LA English DT Article AB Transgenic mice carrying the SV40 T antigen (TAg) gene, which develop hepatocellular and biliary cell tumors by 4 mo of age, show ductular structures in the neonatal liver. Coexpression of c-myc with TAg increases the extent and persistence of ductular lesions and also accelerates tumor development. To analyze possible links between altered gene expression and cell differentiation and to determine the relationship between the ductular structures and tumor development in these mice, ductular cells in single (TAg) and bitransgenic (TAg x c-myc) mice were characterized for biliary and hepatocellular differentiation, transgene expression, and proliferation activity. The results show that the ductular cells in these transgenic mice have characteristics of biliary cells, including basement membrane formation, positive laminin staining, and bile duct-specific lectin (Dolichos biflorus agglutinin and peanut agglutinin) binding, and characteristics of hepatocytes, including albumin expression and ultrastructural features such as round nuclei with 1 or 2 nucleoli and well-developed cytoplasmic organelles. However, differences in transgene expression and cell proliferation between the ductular cells and nonductular hepatocytes were not apparent. Thus, the ductular cells could not be defined as tumor progenitor cells in these mouse livers. However, this model suggests that manipulation of gene expression can alter differentiation of hepatic parenchymal cells. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Enomoto, A (reprint author), Inst Environm Toxicol, Pathol Lab, 4321 Uchimoriya, Mitsukaido, Ibaraki 3030043, Japan. NR 33 TC 5 Z9 5 U1 0 U2 0 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 570 EP 578 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900014 PM 9715517 ER PT J AU Maronpot, RR AF Maronpot, RR TI The potential of genetically altered mice as animal models for carcinogen identification - Commentary SO TOXICOLOGIC PATHOLOGY LA English DT Editorial Material C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Maronpot, RR (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. NR 21 TC 3 Z9 3 U1 0 U2 0 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JUL-AUG PY 1998 VL 26 IS 4 BP 579 EP 581 PG 3 WC Pathology; Toxicology SC Pathology; Toxicology GA V2647 UT WOS:000165536900015 PM 9715518 ER PT J AU Mathews, JM Etheridge, AS Matthews, HB AF Mathews, JM Etheridge, AS Matthews, HB TI Dose-dependent metabolism of benzene in hamsters, rats, and mice SO TOXICOLOGICAL SCIENCES LA English DT Article ID VOLATILE ORGANIC-COMPOUNDS; B6C3F1 MICE; LIVER-MICROSOMES; EXPOSURE; IDENTIFICATION; HYDROQUINONE; DISPOSITION; PHENOL AB The disposition of oral doses of [C-14]benzene was investigated using a range of doses that included lower levels (0.02 and 0.1 mg/kg) than have been studied previously in rat, mouse, and in hamster, a species which has not been previously examined for its capacity to metabolize benzene. Saturation of metabolism of benzene was apparent as the dose increased, and a considerable percentage of the highest doses (100 mg/kg) was exhaled unchanged. Most of the remainder of the radioactivity was excreted as metabolites in urine, and significant metabolite-specific changes occurred as a function of dose and species. Phenyl sulfate was the predominant metabolite in rat urine at all dose levels (64-73% of urinary radioactivity), followed by prephenylmercapturic acid (10-11%). Phenyl sulfate (24-32%) and hydroquinone glucuronide (27-29%) were the predominant metabolites formed by mice. Mice produced considerably more muconic acid (15%), which is derived from the toxic metabolite muconaldehyde, than did rats (7%) at a dose of 0.1 mg/kg. Unlike both rats and mice, hydroquinone glucuronide (24-29%) and muconic acid (19-31%) were the primary urinary metabolites formed by hamsters. Two metabolites not previously detected in the urine of rats or mice after single doses, 1,2,4-trihydroxybenzene and catechol sulfate, were found in hamster urine. These data indicate that hamsters metabolize benzene to more highly oxidized, toxic products than do rats or mice. (C) 1998 Society of Toxicology. C1 Res Triangle Inst, Ctr Bioorgan Chem, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Mathews, JM (reprint author), Res Triangle Inst, Ctr Bioorgan Chem, POB 12194, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES-15329] NR 36 TC 17 Z9 17 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 1998 VL 44 IS 1 BP 14 EP 21 DI 10.1006/toxs.1998.2474 PG 8 WC Toxicology SC Toxicology GA 113AL UT WOS:000075527100002 PM 9720136 ER PT J AU Parham, FM Portier, CJ AF Parham, FM Portier, CJ TI Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls - II: Rates of metabolism SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article ID CHLORINATED BIPHENYLS; HEPATIC MICROSOMES; EXCRETION; HEXACHLOROBIPHENYL; CONGENERS; ISOMERS; MOUSE AB Physiologically based pharmacokinetic (PBPK) models are useful in describing the distribution, metabolism, and fate of xenobiotics across multiple species. The eventual goal of the present research is to create PBPK models for all 209 polychlorinated biphenyls (PCBs). Key parameters in any PBPK model are the metabolic rates. Data on metabolic rates of PCBs were derived from in vitro experiments and from fitting of PBPK models to in vivo data. The rate of metabolism was assumed to be a linear function of PCB concentration. Structural descriptors suggested by the literature were used in a stepwise regression to find an expression for the metabolic rate of PCBs as a function of five structural descriptors related to the degree and pattern of chlorine substitution. R-2 for the fit of the model to the data is 0.9606. (C) 1998 Academic Press. C1 NIEHS, OAO, Res Triangle Pk, NC 27709 USA. RP Parham, FM (reprint author), NIEHS, OAO, POB 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 23 TC 24 Z9 25 U1 3 U2 8 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 JUL PY 1998 VL 151 IS 1 BP 110 EP 116 DI 10.1006/taap.1998.8441 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 110JD UT WOS:000075376900013 PM 9705893 ER PT J AU Stroncek, DF Jaszcz, W Herr, GP Clay, ME McCullough, J AF Stroncek, DF Jaszcz, W Herr, GP Clay, ME McCullough, J TI Expression of neutrophil antigens after 10 days of granulocyte-colony-stimulating factor SO TRANSFUSION LA English DT Article ID STEM-CELL TRANSPLANTATION; HEALTHY-VOLUNTEERS; PROGENITOR CELLS; BLOOD; ANTIBODIES; RECEPTOR; DONORS; NB1 AB BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is becoming the standard agent for mobilizing granulocytes. Most granulocyte donors are given a single dose of G-CSF, but in some cases they are given G-CSF for several days, and multiple granulocyte concentrates are collected.The administration of a single dose of G-CSF induces several changes in the expression of neutrophil antigens, but the effects of multiple daily doses of G-CSF are not known. STUDY DESIGN AND METHODS: Seven healthy people received 5 mu g per kg of G-CSF for 10 days.Their expression of several neutrophil antigens before, during, and after the administration of G-CSF was analyzed through the use of flow cytometry. RESULTS: The expression of L-selectin (CD62L), Fc gamma receptor (Fc gamma R) III (Fc gamma RIII, CD16), and the leukocyte function antigen (CD11a) decreased throughout the course of G-CSF administration, while the expression of Fc gamma RI (Fc gamma RI, CD64) and lipopolysaccharide-binding protein receptor (CD14) increased. The expression of Fc gamma R II (Fc gamma RII, CD32) also increased, but not until the fourth day of G-CSF administration.The expression of amino peptidase N (CD13), C3bi receptor (CD11b), and the neutrophil beta(2) integrin unit (CD18) did not change during the administration of G-CSF, but that of both CD13 and CD18 increased 3 days after the last dose. The expression of neutrophil-specific antigen NB1 initially increased, returned to pre-G-CSF levels after 4 days, and then increased again after 10 days of G-CSF administration. CONCLUSION: Changes in the expression of several neutrophil antigens occurred throughout a 10-day course of G-CSF. Most of the changes occurred after one dose, but additional changes occurred later in the 10-day course and after its completion. These changes may affect the function of G-CSF-mobilized granulocytes. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Lab Serv Sect, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Amer Red Cross, Blood Serv, N Cent Reg, St Paul, MN USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Lab Serv Sect, 10 Ctr Dr MSC 1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. NR 22 TC 39 Z9 39 U1 0 U2 1 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 1998 VL 38 IS 7 BP 663 EP 668 DI 10.1046/j.1537-2995.1998.38798346635.x PG 6 WC Hematology SC Hematology GA 102ZN UT WOS:000074956300008 PM 9683105 ER PT J AU Rechler, MM Clemmons, DR AF Rechler, MM Clemmons, DR TI Regulatory actions of insulin-like growth factor-binding proteins SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID FACTOR IGF BINDING; FACTOR (IGF)-BINDING PROTEIN-3; BREAST-CANCER CELLS; FACTOR-I; TUMOR HYPOGLYCEMIA; TRANSGENIC MICE; FIBROBLASTS; PROTEOLYSIS; POTENTIATION; INHIBITION AB The six insulin-like growth factor-binding proteins (IGFBPs) are important regulators of insulin-like growth factor (IGF) action, Circulating high molecular weight complexes that contain IGF and IGFBP-3 restrict IGF bioavailability, and excess IGFBPs inhibit IGF action by forming biologically inactive complexes. IGFs can be released front these complexes by proteolysis. Potentiation of IGF activity might occur under specific circumstances, and involves the slow dissociation of IGFs from IGFBP complexes localized in the pericellular space, whose affinity has been reduced by dephosphorylation or association with the cell surface or extracellular matrix. Several IGFBPs or IGFBP fragments also have activities that do not involve IGFs or IGF receptors. The mechanisms by which IGFBPs regulate IGF action and exert their independent actions will be examined. C1 NIDDK, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. RP Rechler, MM (reprint author), NIDDK, Growth & Dev Sect, Mol & Cellular Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 64 TC 87 Z9 92 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD JUL PY 1998 VL 9 IS 5 BP 176 EP 183 DI 10.1016/S1043-2760(98)00047-2 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZZ578 UT WOS:000074744200002 PM 18406262 ER PT J AU Rubin, EM Mockrin, S AF Rubin, EM Mockrin, S TI Giving genomics a heart SO TRENDS IN GENETICS LA English DT Editorial Material C1 Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Genome Sci, Berkeley, CA 94720 USA. NIH, Bethesda, MD 20892 USA. RP Rubin, EM (reprint author), Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Genome Sci, Bldg 74,1 Cyclotron Rd, Berkeley, CA 94720 USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 1998 VL 14 IS 7 BP 260 EP 261 DI 10.1016/S0168-9525(98)01505-4 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA ZZ556 UT WOS:000074742000004 PM 9676525 ER PT J AU Simone, NL Bonner, RF Gillespie, JW Emmert-Buck, MR Liotta, LA AF Simone, NL Bonner, RF Gillespie, JW Emmert-Buck, MR Liotta, LA TI Laser-capture microdissection: opening the microscopic frontier to molecular analysis SO TRENDS IN GENETICS LA English DT Article ID TISSUE AB As the list of expressed human genes expands, a major scientific challenge is to understand tbe molecular events that drive normal tissue morphogenesis and the evolution of pathological lesions in actual tissue. Laser capture microdissection (LCM) has been developed ro provide a reliable method to procure pure populations of cells from specific microscopic regions of tissue sections, in one step tenner direct visualization. The cells of interest are transferred to a polymer film that is activated by laser pulses. The exact morphology of the procured cells (with intact DNA, RNA and proteins) is retained and held on the transfer film. With the advent of LCM, cDNA libraries can be developed from pure cells obtained directly from stained tissue, and microhybridization arrays of thousands of genes can now be used to examine gene expression in microdissected human tissue biopsies. The fluctuation of expressed genes or alterations in the cellular DNA that correlate with a particular disease stage can ultimately be compared within or between individual patients. Such a fingerprint of gene-expression patterns call provide crucial clues for etiology and might, ultimately, contribute to diagnostic decisions and therapies tailored to the individual patient. Molecules found to be associated with a defined pathological lesion might serve as imaging or therapeutic targets. C1 NCI, Pathol Lab, Bethesda, MD 20895 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Simone, NL (reprint author), NCI, Pathol Lab, Bethesda, MD 20895 USA. RI Bonner, Robert/C-6783-2015 NR 12 TC 326 Z9 347 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 1998 VL 14 IS 7 BP 272 EP 276 DI 10.1016/S0168-9525(98)01489-9 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA ZZ556 UT WOS:000074742000008 PM 9676529 ER PT J AU Wen, H Bennett, E Wiesler, DG AF Wen, H Bennett, E Wiesler, DG TI Shielding of piezoelectric ultrasonic probes in Hall effect imaging SO ULTRASONIC IMAGING LA English DT Article DE Hall effect; Hall effect imaging; piezoelectric; shielding; ultrasound probe AB This paper addresses significant sources of electromagnetic noise in Hall effect imaging. Hall effect imaging employs large electrical pulses for signal generation and high sensitivity ultrasonic probes for signal reception. Coherent noise arises through various coupling mechanisms between the excitation pulse and the probe. In this paper, the coupling mechanisms are experimentally isolated and theoretically analyzed. Several methods of shielding the probe from electromagnetic interference are devised and tested. These methods are able to reduce the noise to levels below the random thermal noise, thereby improving the signal-to-noise ratio in HEI by two orders of magnitude. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Wen, H (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10,Room B1D-161, Bethesda, MD 20892 USA. RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Intramural NIH HHS [Z01 HL004606-11, ZIA HL004606-13] NR 12 TC 3 Z9 3 U1 1 U2 8 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0161-7346 J9 ULTRASONIC IMAGING JI Ultrason. Imaging PD JUL PY 1998 VL 20 IS 3 BP 206 EP 220 PG 15 WC Acoustics; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 158GQ UT WOS:000078108000005 PM 9921620 ER PT J AU Enomoto, A Sandgren, EP Maronpot, RR AF Enomoto, A Sandgren, EP Maronpot, RR TI Interactive effects of c-myc and transforming growth factor alpha transgenes on liver tumor development in simian virus 40 T antigen transgenic mice SO VETERINARY PATHOLOGY LA English DT Article DE c-myc; liver; neoplasia; SV40 T antigen; transforming growth factor alpha; transgenic mice ID HEPATOCELLULAR-CARCINOMA; RAT-LIVER; INCREASED EXPRESSION; SV40-T ANTIGEN; CELL-CYCLE; TGF-ALPHA; CARCINOGENESIS; OVEREXPRESSION; APOPTOSIS; P53 AB To analyze the effects of c-myc and transforming growth factor alpha (TGF alpha) on hepatocarcinogenesis induced by simian virus 40 T antigen (TAg), livers from single and bitransgenic mice, 3 to 11 mice per line, were examined morphologically 1 to 8 weeks after birth. Mice carrying c-myc or TGF alpha alone exhibited centrilobular hypertrophy and increased apoptosis (c-myc mice only) of hepatocytes after 3 or 4 weeks of age, but no detectable changes in cell proliferation or proliferative lesions were observed in either line during the 8 weeks. Mice carrying TAg alone exhibited increased cell proliferation, apoptosis, and dysplasia of hepatocytes with notably high mitotic and apoptotic indices as major changes before development of putative preneoplastic lesions after 4 weeks of age and neoplastic lesions after 6 weeks. In bitransgenic mice coexpressing c-myc or TGF alpha with TAg, nonproliferative lesions and mitotic and apoptotic indices were similar to those in mice carrying TAg alone. In TAg X c-myc bitransgenic mice, however, both preneoplastic and neoplastic lesions developed sooner and grew more rapidly than those in TAg mice, whereas in TAg x TGF alpha bitransgenic mice, rapid tumor growth was the principle observation. Because of the effects of transgene coexpression, livers from TAg x c-myc and TAg x TGF alpha mice had multiple tumors as early as 3 and 6 weeks of age, respectively. The results indicate cooperative functions of c-myc and TGF alpha with TAg during development and/or growth of liver tumors in vivo. C1 Inst Environm Toxicol, Pathol Lab, Mitsukaido, Ibaraki 303, Japan. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. RP Enomoto, A (reprint author), Inst Environm Toxicol, Pathol Lab, 4321 Uchimoriya Machi, Mitsukaido, Ibaraki 303, Japan. NR 42 TC 5 Z9 5 U1 0 U2 0 PU AMER COLL VET PATHOLOGIST PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD JUL PY 1998 VL 35 IS 4 BP 283 EP 291 PG 9 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 167FN UT WOS:000078622000007 PM 9684972 ER PT J AU Shimoda, A Sugata, F Chen, HS Miller, RH Purcell, RH AF Shimoda, A Sugata, F Chen, HS Miller, RH Purcell, RH TI Evidence for a bidirectional promoter complex within the X gene of woodchuck hepatitis virus SO VIRUS RESEARCH LA English DT Article DE woodchuck hepatitis virus; promoter; luciferase; gene expression; X gene ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYMERASE CHAIN-REACTION; EPSTEIN-BARR VIRUS; NUCLEAR FACTOR-I; B-VIRUS; ANTISENSE RNA; FIREFLY LUCIFERASE; MAMMALIAN-CELLS; BINDING-PROTEIN; MESSENGER-RNA AB The genetic organization of hepadnaviruses is unusual in that all cis-acting regulatory sequences are located within genes. Thus, in the mammalian hepadnavirus genome, the presurface, surface, and X transcript promoters reside within the polymerase gene while the pregenome transcript promoter is located within the X gene. In this study we have identified two additional promoters within the woodchuck hepatitis virus (WHV)X gene that stimulate production of transcripts in vitro. First, we cloned regions of the WHV X gene into a promoterless expression vector (pGL2) to examine their ability to promote expression of firefly luciferase and mapped a previously unidentified promoter to positions 1475-1625 of the WHV8 genome. Deletion analysis revealed that the essential domain of this promoter, termed the ORF5/Delta X transcript promoter, mapped to nucleotides 1525-1625. Analysis revealed that this transcript initiated at nucleotide 1572 in both human (HuH-7) and woodchuck (WLC-3) hepatoma cell lines. Consistent with this finding, DNA footprinting analysis revealed protection of nucleotides 1567-1578 on the positive strand of the WHV8 genome. The function of this transcript in vivo is unclear, however, it may be used to produce a truncated form of the X protein that initiates at an AUG codon at position 1743-1745 on the WHV8 genome. Next, a second promoter was identified at positions 1625-1975 that was responsible for production of an antisense transcript. The activity of this promoter was comparable to that of the previously characterized surface transcript promoter of WHV in the absence of an enhancer. The antisense transcript promoter resides immediately upstream of open reading frame (ORF) 6, a previously identified ORF on the strand opposite of the known WHV protein-encoding sequences, that is thought to represent a vestigial gene. Analysis indicates that the antisense transcript had C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Miller, RH (reprint author), NIAID, Targeted Intervent Branch, Basic Sci Program, Div Aids,NIH, Bethesda, MD 20892 USA. NR 69 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUL PY 1998 VL 56 IS 1 BP 25 EP 39 DI 10.1016/S0168-1702(98)00050-1 PG 15 WC Virology SC Virology GA 123ZJ UT WOS:000076155400003 PM 9784063 ER PT J AU Oleksiewicz, MB Wolfinbarger, JB Bloom, ME AF Oleksiewicz, MB Wolfinbarger, JB Bloom, ME TI A comparison between permissive and restricted infections with Aleutian mink disease parvovirus (ADV): characterization of the viral protein composition at nuclear sites of virus replication SO VIRUS RESEARCH LA English DT Article DE Aleutian mink disease parvovirus; parvovirus; confocal microscopy ID MINUTE VIRUS; DNA-REPLICATION; ADULT MINK; TRANSFORMED-CELLS; MURINE CELLS; MACROPHAGES; MICE; ANTIBODY; NS2; IDENTIFICATION AB We used three-color fluorescent labeling and confocal microscopy to compare the permissive and the antibody-mediated, restricted replication of Aleutian mink disease parvovirus (ADV). In both permissive (CRFK cells) and restricted (K562 cells) situations, both ADV non-structural proteins (NS1 and NS2) concentrated at focal sites in the nucleus, which also contained viral DNA. Bromodeoxyuridine labeling demonstrated that these sites also supported active ADV single-strand DNA synthesis, indicating that they were replication compartments. ADV capsid proteins were located in intranuclear shells surrounding the replication compartments. At later time points, NS2 was readily detected in the cytoplasm of permissively infected CRFK cells, whereas the cytoplasmic presence of NS2 was much less pronounced in the K562 cells. These results showed that both permissive and restricted ADV replication are associated with a tight nuclear subcompartmentalization of viral products. Furthermore, differences between the permissive and restricted virus-cell interactions were noted, suggesting that there may be a morphological basis for examining the outcome of ADV infection. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM mbloom@nih.gov NR 48 TC 7 Z9 8 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUL PY 1998 VL 56 IS 1 BP 41 EP 51 DI 10.1016/S0168-1702(98)00053-7 PG 11 WC Virology SC Virology GA 123ZJ UT WOS:000076155400004 PM 9784064 ER PT J AU Perrett, DI Oram, MW AF Perrett, DI Oram, MW TI Visual recognition based on temporal cortex cells: Viewer-centred processing of pattern configuration SO ZEITSCHRIFT FUR NATURFORSCHUNG C-A JOURNAL OF BIOSCIENCES LA English DT Article; Proceedings Paper CT Workshop on Natural Organisms, Artificial Organisms, and Their Brains CY MAR 08-12, 1998 CL UNIV BIELEFELD, BIELEFELD, GERMANY HO UNIV BIELEFELD DE visual recognition; temporal cortex cells; pattern configuration ID OBJECT RECOGNITION; INFEROTEMPORAL CORTEX; FACE RECOGNITION; MACAQUE MONKEY; POLYSENSORY AREA; SINGLE NEURONS; SHAPE REPRESENTATION; RECEPTIVE-FIELD; ALERT MACAQUE; TERM-MEMORY AB A model of recognition is described based on cell properties in the ventral cortical stream of visual processing in the primate brain. At a critical intermediate stage in this system, 'Elaborate' feature sensitive cells respond selectively to visual features in a way that depends on size (+/-1 octave), orientation (+/-45 degrees) but does not depend on position within central vision (+/-5 degrees). These features are simple conjunctions of 2-D elements (e.g. a horizontal dark area above a dark smoothly convex area). They can arise either as elements of an object's surface pattern or as a 3-D component bounded by an object's external contour. By requiring a combination of several such features without regard to their position within the central region of the visual image, 'Pattern' sensitive cells at higher levels can exhibit selectivity for complex configurations that typify objects seen under particular viewing conditions. Given that input features to such Pattern sensitive cells are specified in approximate size and orientation, initial cellular 'representations' of the visual appearance of object type (or object example) are also selective for orientation and size. At this level, sensitivity to object view (+/-60 degrees) arises because visual features disappear as objects are rotated in perspective. Processing is thus viewer-centred and the neurones only respond to objects seen from particular viewing conditions or 'object instances'. Combined sensitivity to multiple features (conjunctions of elements) independent of their position, establishes selectivity for the configurations of object parts (from one view) because rearranged configurations of the same parts yield images lacking some of the 2-D visual features present in the normal configuration. Different neural populations appear to be selectively tuned to particular components of the same biological object (e.g. face, eyes, hands, legs), perhaps because the independent articulation of these components gives rise to correlated activity in different sets of input visual features. Generalisation over viewing conditions for a given object can be established by hierarchically pooling outputs of view-condition specific cells with pooling operations dependent on the continuity in experience across viewing conditions. Different object parts are seen together and different views are seen in succession when the observer walks around the object. The view specific coding that characterises the selectivity of cells in the temporal lobe can be seen as a natural consequence of selective experience of objects from particular vantage points. View specific coding for the face and body also has great utility in understanding complex social signals, a property that may not be feasible with object-centred processing. C1 NIMH, NIH, Bethesda, MD 20892 USA. Univ St Andrews, Psychol Lab, St Andrews KY16 9JU, Fife, Scotland. RP Perrett, DI (reprint author), NIMH, NIH, Bldg 49,Room 1B80,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mike@ln.nimh.nih.gov RI Oram, Michael/A-2558-2010 NR 108 TC 24 Z9 24 U1 1 U2 1 PU VERLAG Z NATURFORSCH PI TUBINGEN PA POSTFACH 2645, W-7400 TUBINGEN, GERMANY SN 0939-5075 J9 Z NATURFORSCH C JI Z.Naturforsch.(C) PD JUL-AUG PY 1998 VL 53 IS 7-8 BP 518 EP 541 PG 24 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 117RE UT WOS:000075794900007 PM 9755511 ER PT J AU Molloy, AM Mills, JL Kirke, PN Ramsbottom, D McPartlin, JM Burke, H Conley, M Whitehead, AS Weir, DG Scott, JM AF Molloy, AM Mills, JL Kirke, PN Ramsbottom, D McPartlin, JM Burke, H Conley, M Whitehead, AS Weir, DG Scott, JM TI Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE neural tube defects; red cell folates; plasma folate; homocysteine; vitamin B12; 5,10-methylenetetrahydrofolate reductase ID NEURAL-TUBE DEFECTS; METHYLENE TETRAHYDROFOLATE REDUCTASE; GENETIC RISK FACTOR; METHYLENETETRAHYDROFOLATE REDUCTASE; SPINA-BIFIDA; MILD HYPERHOMOCYSTEINEMIA; MICROBIOLOGICAL ASSAY; HOMOCYSTEINE LEVELS; MICROTITRE PLATES; COMMON MUTATION AB Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 mu g/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 mu g/L had eight times higher risk of NTD than subjects with levels over 400 mu g/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs. Am. J. Med. Genet. 78:155-159, 1998. (C) 1998 Wiley-Liss, Inc. C1 Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. Trinity Coll, Dept Clin Med, Dublin, Ireland. NICHHD, Bethesda, MD 20892 USA. Trinity Coll, Dept Genet, Dublin, Ireland. Trinity Coll, Inst Biotechnol, Dublin, Ireland. Hlth Res Board, Dublin, Ireland. RP Molloy, AM (reprint author), Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. NR 25 TC 61 Z9 65 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 30 PY 1998 VL 78 IS 2 BP 155 EP 159 DI 10.1002/(SICI)1096-8628(19980630)78:2<155::AID-AJMG11>3.0.CO;2-M PG 5 WC Genetics & Heredity SC Genetics & Heredity GA ZX392 UT WOS:000074511200011 PM 9674907 ER PT J AU Heidary, G Hampton, LL Schanen, NC Rivkin, MJ Darras, BT Battey, J Francke, U AF Heidary, G Hampton, LL Schanen, NC Rivkin, MJ Darras, BT Battey, J Francke, U TI Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE autism; candidate gene exclusion; mutation search; single-strand conformation; analysis; X chromosome ID MENTAL-RETARDATION; TRANSLOCATION; MUTATIONS AB The gene for the gastrin-releasing peptide receptor (GRPR) has been mapped to a candidate region for Rett syndrome (RTT) on the short arm of the X chromosome. The recent report of a translocation that disrupted the gene in an individual with mental retardation and autistic behavior prompted us to examine GRPR as a possible locus for RTT, Genomic polymerase chain reaction amplification of exons followed by single-strand conformation analysis screening in 25 unrelated RTT-affected individuals and by direct sequencing in 12 others has failed to detect any mutation. No gross structural rearrangements were found by Southern analysis of DNA from six unrelated RTT-affected individuals. A high-frequency biallelic polymorphism caused by two single nucleotide substitutions in exon 2 was discovered. The allele frequencies were identical in the RTT population as compared to 100 normal control X chromosomes. This polymorphism will enable future evaluation of the GRPR locus as a candidate for other X-linked mental retardation or neurobehavioral syndromes. Am. J, Med. Genet. 78:173-175, 1998. (C) 1998 Wiley-Liss, Inc. C1 Stanford Univ, Med Ctr, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. Natl Inst Deafness & Other Commun Disorders, Mol Biol Lab, Rockville, MD USA. Boston Childrens Hosp, Dept Neurol, Boston, MA USA. RP Francke, U (reprint author), Stanford Univ, Med Ctr, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. OI Heidary, Gena/0000-0002-3557-0420 NR 15 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 30 PY 1998 VL 78 IS 2 BP 173 EP 175 DI 10.1002/(SICI)1096-8628(19980630)78:2<173::AID-AJMG15>3.0.CO;2-K PG 3 WC Genetics & Heredity SC Genetics & Heredity GA ZX392 UT WOS:000074511200015 PM 9674911 ER PT J AU Baker, AS Ciocci, MJ Metcalf, WW Kim, J Babbitt, PC Wanner, BL Martin, BM Dunaway-Mariano, D AF Baker, AS Ciocci, MJ Metcalf, WW Kim, J Babbitt, PC Wanner, BL Martin, BM Dunaway-Mariano, D TI Insights into the mechanism of catalysis by the P-C bond-cleaving enzyme phosphonoacetaldehyde hydrolase derived from gene sequence analysis and mutagenesis SO BIOCHEMISTRY LA English DT Article ID CARBON-PHOSPHORUS BOND; L-2-HALO ACID DEHALOGENASE; ESCHERICHIA-COLI; ACTIVE-SITE; PHOSPHOENOLPYRUVATE PHOSPHOMUTASE; PHOSPHOGLYCOLATE PHOSPHATASE; ACETOACETATE DECARBOXYLASE; SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE-SEQUENCE; AMINO GROUP AB Phosphonoacetaldehyde hydrolase (phosphonatase) catalyzes the hydrolysis of phosphonoacetaldehyde to acetaldehyde and inorganic phosphate. In this study, the genes encoding phosphonatase in Bacillus cereus and in Salmonella typhimurium were cloned for high-level expression in Escherichia coli. The kinetic properties of the purified, recombinant phosphonatases were determined. The Schiff base mechanism known to operate in the B. cereus enzyme was verified for the S. typhimurium enzyme by phosphonoacetaldehyde-sodium borohydride-induced inactivation and by site-directed mutagenesis of the catalytic lysine 53. The protein sequence inferred from the B. cereus phosphonatase gene was determined, and this sequence was used along with that from the S. typhimurium phosphonatase gene sequence to search the primary sequence databases for possible structural homologues. We found that phosphonatase belongs to a novel family of hydrolases which appear to use a highly conserved active site aspartate residue in covalent catalysis. On the basis of this finding and the known stereochemical course of phosphonatase-catalyzed hydrolysis at phosphorus (retention), we propose a mechanism which involves Schiff base formation with lysine 53 followed by phosphoryl transfer to aspartate (at position 11 in the S. typhimurium enzyme and position 12 in the B. cereus phosphonatase) and last hydrolysis at the imine C(1) and acyl phosphate phosphorus. C1 Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. NIMH, NIH, Clin Neurosci Branch, IRP, Bethesda, MD 20892 USA. RP Martin, BM (reprint author), Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. FU NIGMS NIH HHS [GM-35392, GM-36360] NR 64 TC 63 Z9 65 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 30 PY 1998 VL 37 IS 26 BP 9305 EP 9315 DI 10.1021/bi972677d PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZY085 UT WOS:000074585100011 PM 9649311 ER PT J AU Topka, H Massaquoi, SG Benda, N Hallett, M AF Topka, H Massaquoi, SG Benda, N Hallett, M TI Motor skill learning in patients with cerebellar degeneration SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE trajectory formation; motor learning; motor adaptation; cerebellum ID ARM MOVEMENTS; ADAPTATION AB To explore the role of the cerebellum in learning a complex motor task, we studied nineteen patients with cerebellar degeneration and sixteen healthy subjects who attempted to improve their performance in generating a trajectory connecting five via points on a data tablet. Multijoint arm movements were performed at a constant total movement time, and spatial error was measured. Subjects performed 100 trials at a movement time of 3.5 s (slow movements), and another 100 trials at maximum speed (fast movements). With slow movements, patients and normal subjects reduced the error over trials to the same extent, but in patients, the rate of improvement was slightly slower. With fast movements, patients showed less improvement than normal subjects. When tested 24 h later, patients demonstrated significant retention of acquired skill and tended to improve more rapidly when performing both slow and fast movements than during the first session. We conclude that patients with cerebellar degeneration can exhibit almost normal performance in skill learning with slow movements, but with fast movements, their performance improves to a lesser extent. The problem may be difficulty in the refinement of motor execution, which is more of a requirement for fast movements than for slow ones. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Tubingen, Dept Neurol, D-72076 Tubingen, Germany. Univ Tubingen, Dept Med Biometry, D-72076 Tubingen, Germany. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. NR 23 TC 15 Z9 16 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JUN 30 PY 1998 VL 158 IS 2 BP 164 EP 172 DI 10.1016/S0022-510X(98)00115-4 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 105QC UT WOS:000075084300007 PM 9702687 ER PT J AU Verbeke, G Lesaffre, E Brant, LJ AF Verbeke, G Lesaffre, E Brant, LJ TI The detection of residual serial correlation in linear mixed models SO STATISTICS IN MEDICINE LA English DT Article ID LONGITUDINAL DATA; ERRORS AB Diggle (1988) described how the empirical semi-variogram of ordinary least squares residuals can be used to suggest an appropriate serial correlation structure in stationary linear mixed models. In this paper, this approach is extended to non-stationary models which include random effects other than intercepts, and will be applied to prostate cancer data, taken from the Baltimore Longitudinal Study of Aging. A simulation study demonstrates the effectiveness of this extended variogram for improving the covariance structure of the linear mixed model used to describe the prostate data. (C) 1998 John Wiley & Sons, Ltd. C1 Catholic Univ Louvain, Univ Ziekenhuis St Rafael, Biostat Ctr Clin Trials, B-3000 Louvain, Belgium. NIA, Gerontol Res Ctr, Longitudinal Studies Branch, Baltimore, MD 21224 USA. RP Verbeke, G (reprint author), Catholic Univ Louvain, Univ Ziekenhuis St Rafael, Biostat Ctr Clin Trials, Kapucijnenvoer 35, B-3000 Louvain, Belgium. RI Verbeke, Geert/I-5587-2015 NR 21 TC 20 Z9 20 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 30 PY 1998 VL 17 IS 12 BP 1391 EP 1402 DI 10.1002/(SICI)1097-0258(19980630)17:12<1391::AID-SIM851>3.0.CO;2-4 PG 12 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 ZX823 UT WOS:000074559000006 PM 9682327 ER PT J AU Nagababu, E Rifkind, JM AF Nagababu, E Rifkind, JM TI Formation of fluorescent heme degradation products during the oxidation of hemoglobin by hydrogen peroxide SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID RED-BLOOD-CELLS; LIPID-PEROXIDATION; FENTON REACTION; CROSS-LINKING; IRON; DENATURATION; ERYTHROCYTES; SUPEROXIDE; MYOGLOBIN; REAGENT AB Hemoglobin and methemoglobin oxidized by hydrogen peroxide generate ferrylhemoglobin and oxoferrylhemoglobin, respectively. Two fluorescent compounds were found to be produced during the reaction of oxyhemoglobin, but not methemoglobin, with H2O2. These two compounds had excitation wavelengths of 321 nm and 460 nm, respectively, with emission wavelengths of 465 nm and 525 nm, respectively. The formation of the same fluorescent products during the reaction of H2O2 with ferroprotoporphyrin-IX and ferriprotoporphyrin-IX demonstrate that these compounds originate from the heme moiety. The release of heme iron during the formation of these fluorescent compounds indicates that they are associated with heme degradation. The time course for the formation of fluorescent products show that the extent of heme degradation is dependent on H2O2 concentration. The results of this investigation indicate that the heme moiety of Fe(II) hemoglobin undergoes degradation in presence of H2O2. The ability to detect this process by fluorescence provides a sensitive marker in order to asses hemoglobin and RBC oxidative stress under pathological conditions. (C) 1998 Academic Press. C1 NIA, NIH, Cellular & Mol Biol Lab, Sect Mol Dynam, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, NIH, Cellular & Mol Biol Lab, Sect Mol Dynam, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 103 Z9 103 U1 1 U2 7 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 29 PY 1998 VL 247 IS 3 BP 592 EP 596 DI 10.1006/bbrc.1998.8846 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZY101 UT WOS:000074586700011 PM 9647738 ER PT J AU Yoshiji, H Buck, TB Harris, SR Ritter, LM Lindsay, CK Thorgeirsson, UP AF Yoshiji, H Buck, TB Harris, SR Ritter, LM Lindsay, CK Thorgeirsson, UP TI Stimulatory effect of endogenous tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpression on type IV collagen and laminin gene expression in rat mammary carcinoma cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID EXTRACELLULAR-MATRIX; BASEMENT-MEMBRANE; TUMORS AB We recently reported enhanced tumor growth and stimulation of vascular endothelial growth factor (VEGF) expression in rat mammary carcinoma cells transfected with a human tissue inhibitor of metalloproteinases-1 (hTIMP-1) cDNA (1). In the present study, we examined if the composition of the stroma was altered in the tumors with the highest hTIMP-1 production. Immunohistological examination revealed increased amounts of the basement membrane (BM) components, type IV collagen and laminin, in the hTIMP-1 overexpressing tumors compared to that of the control. In vitro studies also revealed upregulation of type IV collagen and laminin gene expression associated with the hTIMP-1 overexpression. Endogenous RNA levels of rat TIMP-1 and the rat matrix metalloproteinases (MMPs), MMP-2, MMP-3, and MMP-9, were not affected by the hTIMP-1 transfection, suggesting that the increase in BM deposition was not a result of decreased collagenolytic activity. This is the first report to show an association between overexpression of TIMP-1 and increased tumor BM matrix production through stimulation of type IV collagen and laminin gene expression. (C) 1998 Academic Press. C1 NCI, Tumor Biol & Carcinogenesis Sect, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, UP (reprint author), NCI, Tumor Biol & Carcinogenesis Sect, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. NR 30 TC 18 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 29 PY 1998 VL 247 IS 3 BP 605 EP 609 DI 10.1006/bbrc.1998.8805 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZY101 UT WOS:000074586700013 PM 9647740 ER PT J AU Tober, KL Cannon, RE Spalding, JW Oberyszyn, TM Parrett, ML Rackoff, AI Oberyszyn, AS Tennant, RW Robertson, FM AF Tober, KL Cannon, RE Spalding, JW Oberyszyn, TM Parrett, ML Rackoff, AI Oberyszyn, AS Tennant, RW Robertson, FM TI Comparative expression of novel vascular endothelial growth factor vascular permeability factor transcripts in skin, papillomas, and carcinomas of v-Ha-ras Tg.AC transgenic mice and FVB/N mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID MOUSE SKIN; TUMOR ANGIOGENESIS; FACTOR FAMILY; FACTOR GENE; CARCINOGENESIS; IDENTIFICATION; INDUCTION; FORMS; VEGF; HYPERPLASIA AB One of the most frequently detected changes in human solid tumors is the mutation of the ras oncogene, which has been associated with production of angiogenic growth factors such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Using the v-Ha-ras Tg.AC transgenic mice and the background FVB/N strain of inbred mice, the pattern of expression of specific VEGF/VPF transcripts was characterized in major organs and in skin, papillomas, and carcinomas during multi-stage skin carcinogenesis. Three VEGF/VPF transcripts were found to be constitutively expressed in skin as well as the major organs in both mouse strains, which corresponded in size and sequence to previously reported murine VEGF(120) with a bp size of 331, VEGF(164) with a bp size of 333, and VEGF(188) with a bp size of 407. A previously unreported fourth murine transcript was also detected in skin and major tissues from both mouse strains which corresponded to rat VEGF(144), with a bp size of 404. In addition, a unique 425 bp VEGF transcript which corresponded to human VEGF(206) was present in highly vascularized tissues including heart, lung, liver, kidney, brain, as well in papillomas and carcinomas isolated from v-Ha-ras Tg.AC mice. In contrast, VEGF(205) was present only in carcinomas derived from FVB/N mice. An antibody generated from a peptide sequence designed to detect each of the five VEGF/VPF peptides defined by RT-PCR analysis confirmed the existence of these five peptides and confirmed that the murine VEGF(205) peptide was selectively expressed in papillomas and carcinomas derived from v-Ha-ras Tg.AC mice. These results demonstrate that there is significant alternative splicing of the murine VEGF/VPF gene during multi-stage carcinogenesis, which results in four commonly expressed VEGF transcripts. In addition, these studies identified a fifth VEGF transcript and peptide at the later stages of tumor promotion and in progression which appears to be linked to the presence of v-Ha-ras. (C) 1998 Academic Press. C1 Ohio State Univ, Coll Med & Publ Hlth, Ctr Comprehens Canc, Dept Med Microbiol & Immunol, Columbus, OH 43210 USA. NIEHS, Lab Mol & Environm Carcinogenesis, Res Triangle Pk, NC 27709 USA. RP Robertson, FM (reprint author), Ohio State Univ, Coll Med & Publ Hlth, Ctr Comprehens Canc, Dept Med Microbiol & Immunol, Columbus, OH 43210 USA. EM robertson.48@osu.edu RI Oberyszyn, Tatiana/E-3774-2011 FU NCI NIH HHS [CA-51443, CA-76567] NR 34 TC 31 Z9 32 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 29 PY 1998 VL 247 IS 3 BP 644 EP 653 DI 10.1006/bbrc.1998.8787 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZY101 UT WOS:000074586700020 PM 9647747 ER PT J AU Steinhoff, MC Moulton, L Clemens, J AF Steinhoff, MC Moulton, L Clemens, J TI Effectiveness of pneumococcal vaccine SO LANCET LA English DT Letter ID EFFICACY C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Steinhoff, MC (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. OI Moulton, Lawrence/0000-0001-7041-7387 NR 5 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 27 PY 1998 VL 351 IS 9120 BP 1961 EP 1962 DI 10.1016/S0140-6736(05)78648-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZW951 UT WOS:000074464700055 PM 9654290 ER PT J AU Tarasova, NI Stauber, RH Michejda, CJ AF Tarasova, NI Stauber, RH Michejda, CJ TI Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LYMPHOCYTE CHEMOATTRACTANT; RETROVIRAL VECTORS; HIV-1 ENTRY; INFECTION; SDF-1; 7-TRANSMEMBRANE; INTERNALIZATION; LESTR/FUSIN; CLONING; BLOCKS AB A chimeric protein consisting of CXC-chemokine receptor 4 (CXCR4) and the green fluorescent protein (GFP) was used for studying receptor localization and trafficking in real time in stably transduced HeLa, U-937, GEM, and NIH/3T3 cells. CXCR4-GFP was fully active as a co-receptor in mediating human immunodeficiency virus (HIV) entry. Both CXCR4 and CXCR4-GFP were found to undergo significant spontaneous endocytosis, Only 51.5 +/- 7.8% of receptor molecules were found on the plasma membrane in CD4-positive cells, 43.9 +/- 8.5% were found in CD4-negative HeLa cells, 75.6 +/- 9.7% were found in U-937 cells, 72.5 +/- 7.9 were found in CEM cells, and almost none were found in in NIH/3T3 cells. Stromal cell-derived factor-1 alpha induced rapid endocytosis of cell surface receptor molecules. A significant part of CXCR4 was targeted to lysosomes upon binding of the ligands, and recycling of internalized CXCR4 was not efficient. Only about 30% of receptor molecules recycled back to the cell surface in HeLa cells, 5% recycled in U937, and 10% recycled in CEM cells, suggesting that the protective effect of chemokines against HIV infection can be attributed not only to competition for binding but also to depletion of the co-receptor molecules from the cell surface. Envelope glycoprotein gp120 of syncytia-inducing/lymphocyte tropic HIV-1 strains induced rapid internalization of CXCR4 in both CD4-negative and CD4-positive cells, suggesting that gp120 is a high affinity ligand of CXCR4. C1 NCI, Mol Aspects Drug Design Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Inst Virol, D-91054 Erlangen, Germany. RP Tarasova, NI (reprint author), NCI, Mol Aspects Drug Design Sect, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. OI Stauber, Roland/0000-0002-1341-4523 NR 26 TC 132 Z9 133 U1 1 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 JUN 26 PY 1998 VL 273 IS 26 BP 15883 EP 15886 DI 10.1074/jbc.273.26.15883 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW685 UT WOS:000074436600002 PM 9632631 ER PT J AU Sainz, E Akeson, M Mantey, SA Jensen, RT Battey, JF AF Sainz, E Akeson, M Mantey, SA Jensen, RT Battey, JF TI Four amino acid residues are critical for high affinity binding of neuromedin B to the neuromedin B receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GASTRIN-RELEASING PEPTIDE; BOMBESIN-LIKE PEPTIDES; LUNG-CARCINOMA CELLS; SWISS 3T3 CELLS; STIMULATES GROWTH; MOLECULAR-CLONING; SUBSTANCE-P; NONPEPTIDE; DNA; ANTAGONISTS AB Three mammalian bombesin receptor subtypes have been characterized: the gastrin-releasing peptide receptor (GRP-R), the neuromedin B receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3). In a previous report we identified four amino acids that are critical for high affinity binding of bombesin and gastrin-releasing peptide (GRP) to the GRP-R. These four amino acids are conserved in all species variants of the GRP-R and NMB-R which bind bombesin with high affinity, but they are diverged in BRS-3, the bombesin receptor subtype that binds bombesin with much lower affinity. Substituting these four divergent amino acids in BRS-3 for the conserved amino acids in either GRP-R or NMB-R increased the affinity of the mutated BRS-3 (4 Delta BRS-3) for bombesin compared with wild-type BRS-3 We hypothesized that the same four amino acids might be critical for high affinity NMB binding to the NMB-R. hr this study we confirm this hypothesis by showing that the affinity of NMB is increased in a mutant BRS-3 receptor (4 Delta BRS-3) that contains these four substitutions resulting in an affinity that is close to the affinity of wild-type NMB-R for NMB. In contrast, these four amino acid substitutions in BRS-3 did not result in the formation of a high affinity binding site for the recently described non-peptide NMB-R antagonist PD168368. C1 NINCD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Battey, JF (reprint author), 5 Res Ct,Rm 2B28, Rockville, MD 20850 USA. EM jbattey@pop.nidcd.nih.gov NR 32 TC 27 Z9 27 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 JUN 26 PY 1998 VL 273 IS 26 BP 15927 EP 15932 DI 10.1074/jbc.273.26.15927 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW685 UT WOS:000074436600010 PM 9632639 ER PT J AU Chatterjee-Kishore, M Kishore, R Hicklin, DJ Marincola, FM Ferrone, S AF Chatterjee-Kishore, M Kishore, R Hicklin, DJ Marincola, FM Ferrone, S TI Different requirements for signal transducer and activator of transcription 1 alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HLA CLASS-I; PEPTIDASE ACTIVITIES; T-CELLS; GAMMA; PROTEASOMES; IRF-1; TAP1; IFN; ELEMENTS; LMP2 AB The components of the antigen processing machinery, low molecular mass polypeptide (LMP) 2 and transporter associated with antigen processing (TAP) 1, are encoded by closely linked genes within the major histocompatibility complex class II subregion. Although the two genes share a bi-directional promoter, LMP2 and TAP1 have differential cellular expression. TAP1 is expressed constitutively. However, LMP2 expression requires induction by interferon-gamma in most cells. The regulatory elements within the LMP2/TAP1 promoter and the transcription factors that bind these elements have been defined, However, how these transactivators regulate differential TAP1 and LMP2 gene transcription is not known. We have addressed this question by analyzing three human melanoma cell lines with distinct phenotypes of LMP2 and TAP1 expression.Whereas binding of either interferon regulatory factor 1 or Stat1 to the overlapping interferon consensus sequence-2/GAS is sufficient for regulating transcription of the TAP1 gene, binding of both factors is required for LMP2 gene transcription. This conclusion is supported by restoration of LMP2 gene transcription following transfection of wild type Stat1 alpha or interferon regulatory factor 1 cDNA into cells lacking these transcription factors. The flexibility in the regulation of the TAP1 gene may reflect its role in maintaining immune surveillance. Furthermore, lack of LMP2 gene transcription in quiescent human cells suggests that LMP2 expression reflects a state of cell activation. C1 New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Ferrone, S (reprint author), New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. FU NCI NIH HHS [CA 67108] NR 34 TC 74 Z9 75 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 JUN 26 PY 1998 VL 273 IS 26 BP 16177 EP 16183 DI 10.1074/jbc.273.26.16177 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW685 UT WOS:000074436600044 PM 9632673 ER PT J AU Chen, ZG Blandl, T Prorok, M Warder, SE Li, LP Zhu, Y Pedersen, LG Ni, F Castellino, FJ AF Chen, ZG Blandl, T Prorok, M Warder, SE Li, LP Zhu, Y Pedersen, LG Ni, F Castellino, FJ TI Conformational changes in conantokin-G induced upon binding of calcium and magnesium as revealed by NMR structural analysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METHYL-D-ASPARTATE; GAMMA-CARBOXYGLUTAMATE; H-1-NMR SPECTRA; SPECTROSCOPY; PEPTIDES; PROTEINS; COSY; ASSIGNMENT; RESOLUTION; CONSTANTS AB The apo- and metal-bound solution conformations of synthetic conantokin-G (con-G, G(1)E gamma gamma L(5)Q gamma NQ gamma(10)- LIR gamma (KSN)-S-15-CONH2, gamma = gamma-carboxyglutamic acid), an antagonist of N-methyl-D-aspartate receptor-derived neuronal ion channels, have been examined by one- and two-dimensional H-1 NMR at neutral pH. A complete structure for the Mg2+-loaded peptide was defined by use of distance geometry calculations and was found to exist as an cc-helix that spans the entire peptide. The a-helical nature of Mg2+/con-G was also supported by the small values (<5.5 Hz) of the (3)J(HN alpha) coupling constants measured for amino acid residues 3-5, 8, 9, and 11-16, and the small values (<4 ppb/K) of the temperature coefficients observed for the alpha NH protons of residues 5-17. This conformation contrasted with that obtained for apo-con-G, which was nearly structureless in solution. Docking of Mg2+ into con-G was accomplished by use of the genetic algorithm/molecular dynamics simulation method, employing the NMR-derived Mg2+-loaded structure for initial coordinates in the midpoint calculations. For the 3 Mg2+/con-G model, it was found that binding of one Mg2+ ion is stabilized by oxygen atoms from three gamma-carboxylates of Gla(3), Gla(4), and Gla(7); another Mg2+ is coordinated by two oxygen atoms, one from each of the gamma-carboxylates of Gla(7); and a third metal ion through three donor oxygen atoms of gamma-carboxylates from Gla(10) and Gla(14). As shown from direct metal binding measurements to mutant con-G) peptides, these latter two Gla residues probably stabilized the tightest binding Mg2+ ion. Circular dichroism studies of these same peptide variants demonstrated that all Gla residues contribute to the adoption of the Mg2+-dependent alpha-helical conformation in con-G. The data obtained in this investigation provide a molecular basis for the large conformational alteration observed in apo-con-G as a result of divalent cation binding and allow assessment of the roles of individual Gla residues in defining certain of the structure-function properties of con-G. C1 Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. Natl Res Council Canada, Biotechnol Res Inst, Biomol NMR Lab, Montreal, PQ H4P 2R2, Canada. Natl Res Council Canada, Biotechnol Res Inst, Montreal Joint Ctr Struct Biol, Montreal, PQ H4P 2R2, Canada. NIEHS, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Castellino, FJ (reprint author), Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 NR 35 TC 71 Z9 74 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 JUN 26 PY 1998 VL 273 IS 26 BP 16248 EP 16258 DI 10.1074/jbc.273.40.26248 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW685 UT WOS:000074436600055 PM 9632684 ER PT J AU Ammanamanchi, S Kim, SJ Sun, LZ Brattain, MG AF Ammanamanchi, S Kim, SJ Sun, LZ Brattain, MG TI Induction of transforming growth factor-beta receptor type II expression in estrogen receptor-positive breast cancer cells through SP1 activation by 5-aza-2 '-deoxycytidine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLON-CARCINOMA CELLS; TGF-BETA; MICROSATELLITE INSTABILITY; DNA METHYLATION; PROTEIN-KINASE; GENE; MECHANISM; BINDING; TRANSCRIPTION; INHIBITION AB Previous studies suggest that estrogen receptor-positive (ER+) breast cancer cells acquire resistance to transforming growth factor-beta (`TGF-beta) because of reduced expression levels of TGF-beta receptor type II (RII). We now report that treatment of ER+ breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-2'-dC) leads to accumulation of RII transcript and protein in three different cell lines. RII induction restored TGF-beta response in MCF-7L breast cancer cells as indicated by the enhanced activity of a TGF-beta responsive promoter-reporter construct (p3TP-Lux). A transiently transfected RII promoter-reporter element (RII-chloramphenicol acetyltransferase) showed an increase in activity in the 5-aza-2'-dC-treated MCF-7L cells compared with untreated cells, suggesting the activation of a transactivator of RII transcription. Using electrophoretic mobility shift assays, the enhanced binding: of proteins from 5-aza-2'-dC-treated MCF-7L nuclear extracts to radiolabeled Sp1 oligonucleotides was demonstrated. An RII promoter-chloramphenicol acetyltransferase construct containing a mutation in the Sp1 site was not expressed in the 5-aza-2'-dC-treated MCF-7L cells, further demonstrating that induction of Sp1 activity by 5-aza-2'-dC in the MCF-7L cells was critical to RII expression. Northern analysis indicated that 5-aza-2'-dC treatment did not affect the Sp1 transcript levels. Western blot analysis revealed an increase of Sp1 protein in the 5-aza-2'-dC-treated MCF-7L cells, but there was no change in the c-Jun levels. Studies after cyclohexamide treatment suggested an increase in the Sp1 protein stability from the 5-aza-2'-dC-treated MCF-7L extracts compared with untreated control extracts. These results indicate that the transcriptional repression of RII in the ER+ breast cancer cells is caused by suboptimal activity of Sp1, whereas treatment with 5-aza-2'-dC stabilizes the protein thus increasing steady-state Sp1 levels and thereby leads to enhanced RII transcription and subsequent restoration of TGF-beta sensitivity. C1 Med Coll Ohio, Dept Biochem & Mol Biol, Toledo, OH 43614 USA. NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. Univ Kentucky, Coll Med, Dept Pharmacol, Lexington, KY 40536 USA. RP Brattain, MG (reprint author), Univ Texas, Hlth Sci Ctr, Dept Surg, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NCI NIH HHS [CA 38173, CA 54807, CA 72001] NR 39 TC 57 Z9 59 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 JUN 26 PY 1998 VL 273 IS 26 BP 16527 EP 16534 DI 10.1074/jbc.273.26.16527 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW685 UT WOS:000074436600093 PM 9632722 ER PT J AU Erard, M Barker, DG Amalric, F Jeang, KT Gatignol, A AF Erard, M Barker, DG Amalric, F Jeang, KT Gatignol, A TI An Arg/Lys-rich core peptide mimics TRBP binding to the HIV-1 TAR RNA upper-stem/loop SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE TAR; TRBP; double-stranded RNA-binding domain; protein-RNA interaction; molecular modelling ID IMMUNODEFICIENCY-VIRUS TYPE-1; DOUBLE-STRANDED-RNA; CIRCULAR-DICHROISM; PROTEIN-KINASE; DROSOPHILA STAUFEN; CRYSTAL-STRUCTURE; ARGININE BINDING; RECOGNITION; COMPLEX; DOMAIN AB TRBP is a cellular protein that binds to the HIV-1 leader RNA, TAR. Circular dichroism experiments have shown that a 24 amino acid peptide (TR1), located within a dsRNA binding domain (dsRBD) of TRBP, binds TAR with a 3:1 stoichiometry, eliciting a conformational change involving base unstacking. The binding characteristics of synthetic structural variants of TAR indicate that guanine residues play a key role in the TR1-RNA interaction and that binding sites exist in the upper-stem/loop and lower stem region of TAR. Deletion analysis of TR1 has led to the identification of a 15 amino acid subpeptide (TR13) which is necessary and sufficient to bind to the high affinity upper-stem/loop binding site of TAR. Alanine scanning of TR13 has revealed that mutations in either Lys or Arg residues result in altered TAR-binding, and molecular modelling/docking experiments have shown that the two Arg residues of TR13 can interact with two appropriately spaced guanine residues in the upper-stem/loop of TAR. The TR13 lysine residues appear to be essential for maintaining structural integrity and the correct positioning of the Arg side-chains. We propose that TRBP binds TAR by means of a "2-G hook" motif and that the binding specificity of this particular member of the family of double-stranded RNA-binding proteins lies within the highly conserved dsRBD core motif. Finally, our results also suggest that TRBP may function in vivo by modifying the tertiary structure of TAR RNA. (C) 1998 Academic Press. C1 CNRS, Lab Biol Mol Eucaryote, F-31062 Toulouse, France. INRA, CNRS, Lab Biol Mol Relat Plantes Microorganismes, F-31326 Castanet Tolosan, France. NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Inst Cochin Genet Mol, INSERM, U332, F-75014 Paris, France. RP Erard, M (reprint author), CNRS, Inst Pharmacol & Biol Struct, 205 Route Narbonne, F-31077 Toulouse 4, France. RI Jeang, Kuan-Teh/A-2424-2008 NR 62 TC 31 Z9 32 U1 0 U2 3 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 26 PY 1998 VL 279 IS 5 BP 1085 EP 1099 DI 10.1006/jmbi.1998.1831 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZY738 UT WOS:000074654400006 PM 9642086 ER PT J AU Conway, JF Cheng, N Zlotnick, A Stahl, SJ Wingfield, PT Belnap, DM Kanngiesser, U Noah, M Steven, AC AF Conway, JF Cheng, N Zlotnick, A Stahl, SJ Wingfield, PT Belnap, DM Kanngiesser, U Noah, M Steven, AC TI Hepatitis B virus capsid: Localization of the putative immunodominant loop (Residues 78 to 83) on the capsid surface, and implications for the distinction between c and e-antigens SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE hepatitis B virus core antigen; virus capsid structure; cryo-electron microscopy; immunodominant epitope; three-dimensional image reconstruction ID HERPES-SIMPLEX VIRUS; X-RAY CRYSTALLOGRAPHY; CORE ANTIGEN; 3-DIMENSIONAL STRUCTURE; NEUTRALIZING ANTIBODY; ELECTRON-MICROSCOPY; ESCHERICHIA-COLI; CRYOELECTRON MICROSCOPY; MONOCLONAL-ANTIBODIES; SIMIAN VIRUS-40 AB Hepatitis B virus capsid protein comprises a 149 residue "assembly" domain that polymerizes into icosahedral particles, and a 34 residue RNA-binding "protamine" domain. Recently, the capsid structure has been studied to resolutions below 10 Angstrom by cryo-electron microscopy, revealing much of its alpha-helical substructure and that it appears to have a novel fold for a capsid protein; however, the resolution is still too low for chain-tracing by conventional criteria. Aiming to establish a fiducial marker to aid in the process of chain-tracing, we have used cryomicroscopy to pinpoint the binding site of a monoclonal antibody that recognizes the peptide from residues 78 to 83. This epitope resides on the outer rim of the 30 Angstrom long spikes that protrude from the capsid shell. These spikes are four-helix bundles formed by the pairing of helix-turn-helix motifs from two subunits; by means of a tilting experiment, we have determined that this bundle is right-handed. Variants of the same protein present two clinically important and non-crossreactive antigens: core antigen (HBcAg), which appears early in infection as assembled capsids; and the sentinel e-antigen (HBeAg), a non-particulate form. Knowledge of the binding site of our anti-HBcAg antibody bears on the molecular basis of the distinction between the two antigens, which appears to reflect conformational differences between the assembled and unassembled states of the capsid protein dimer, in addition to epitope masking in capsids. C1 NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. Behring Diagnost GmBH, Marburg, Germany. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 NR 56 TC 69 Z9 72 U1 1 U2 5 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 JUN 26 PY 1998 VL 279 IS 5 BP 1111 EP 1121 DI 10.1006/jmbi.1998.1845 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZY738 UT WOS:000074654400008 PM 9642088 ER PT J AU Coop, A Janetka, JW Lewis, JW Rice, KC AF Coop, A Janetka, JW Lewis, JW Rice, KC TI L-selectride as a general reagent for the O-demethylation and N-decarbomethoxylation of opium alkaloids and derivatives SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID METHYL PHENYL ETHERS; MORPHINE; STAUROSPORINE; NALTREXONE; HYDRIDE AB L-Selectride was shown to be an efficient and general O-demethylating agent for the opium alkaloids and their derivatives and also an efficient reagent for the cleavage of methyl carbamates, thus offering a convenient method for the N-demethylation of opioids. Further, it was shown that by choice of reaction conditions it is possible to achieve both N-decarbomethoxylation and O-demethylation in one pot, or only render N-decarbomethoxylation in high yield without accompanying O-demethylation. C1 NIDDKD, Med Chem Lab, Bethesda, MD 20892 USA. Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. RI Janetka, James/A-8216-2011 OI Janetka, James/0000-0002-9888-5411 NR 33 TC 39 Z9 39 U1 0 U2 11 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 JUN 26 PY 1998 VL 63 IS 13 BP 4392 EP 4396 DI 10.1021/jo9801972 PG 5 WC Chemistry, Organic SC Chemistry GA ZY295 UT WOS:000074605800034 ER PT J AU Bassan, M Zamostiano, R Giladi, E Davidson, A Wollman, Y Pitman, J Hauser, J Brenneman, DE Gozes, I AF Bassan, M Zamostiano, R Giladi, E Davidson, A Wollman, Y Pitman, J Hauser, J Brenneman, DE Gozes, I TI The identification of secreted heat shock 60-like protein from rat glial cells and a human neuroblastoma cell line SO NEUROSCIENCE LETTERS LA English DT Article DE heat shock-like 60 protein; vasoactive intestinal peptide; stress proteins; astrocytes; neuroblastoma ID VASOACTIVE-INTESTINAL-PEPTIDE AB The intracellular stress-induced proteins provide protection against toxic insults. Here, a 60 000-Da heat shock 60 (hsp60)-like protein was detected, with five different antibodies, in conditioned media derived from rat cortical astrocytes and a human neuroblastoma cell line. Extracellular neuroblastoma hsp80-like immunoreactivity was increased 3-fold in the presence of the neuropeptide vasoactive intestinal peptide (VIP) and was augmented 2-fold after temperature elevation. Intracellular hsp60 immunoreactivity was reduced 2-3-fold in the presence of VIP; this reduction was attenuated in the presence of brefeldin A, an inhibitor of protein secretion. In contrast, the activity of lactate dehydrogenase (LDH), an intracellular marker, did not change in the presence of VIP. Essentially no extracellular LDH activity was detected, indicating no cellular damage. A novel aspect for stress proteins having extracellular protective roles is suggested. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-64239 Tel Aviv, Israel. Tel Aviv Med Ctr, Dept Nephrol, IL-64239 Tel Aviv, Israel. NICHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Gozes, I (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-64239 Tel Aviv, Israel. NR 16 TC 35 Z9 36 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 26 PY 1998 VL 250 IS 1 BP 37 EP 40 DI 10.1016/S0304-3940(98)00428-5 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 103JT UT WOS:000075154300010 PM 9696060 ER PT J AU Herman, EH Zhang, J Hasinoff, BB Tran, KT Chadwick, DP Clark, JR Ferrans, VJ AF Herman, EH Zhang, J Hasinoff, BB Tran, KT Chadwick, DP Clark, JR Ferrans, VJ TI Comparison of the chronic toxicity of piroxantrone, losoxantrone and doxorubicin in spontaneously hypertensive rats SO TOXICOLOGY LA English DT Article DE piroxantrone; losoxantrone; doxorubicin; cardiotoxicity; nephrotoxicity; reactive oxygen species; electronmicroscopy; iron complexes ID SOUTHWEST-ONCOLOGY-GROUP; METASTATIC BREAST-CANCER; PHASE-II TRIAL; ANTHRAPYRAZOLE; ICRF-187; AGENTS; CARDIOTOXICITY; ANTHRACYCLINE; INHIBITION; COMPLEXES AB Comparisons were made of the toxic effects produced in the heart, kidney and small intestine of spontaneously hypertensive rats (SHR) by the administration of 12 consecutive weekly doses of doxorubicin (I mg/kg), and high, intermediate and low doses of piroxantrone (3, 1.5 and 0.75 mg/kg) and losoxantrone (1, 0.5 and 0.25 mg/kg). Animals receiving saline were used as controls. The toxicities of the three drugs were evaluated by clinical chemistry and hematological determinations, light microscopy and transmission electron microscopy. The severity of the histologic alterations in heart, kidney and small intestine was assessed semiquantitatively. Biochemical and molecular modeling studies were made to evaluate the formation of complexes of Fe(III) with piroxantrone and losoxantrone. The cardiac (myofibrillar loss and dilatation of the sarcoplasmic reticulum) and renal (glomerular vacuolization, tubular damage and laboratory evidence of a nephrotic syndrome) lesions induced by all three agents had similar features. However, the cardiac lesions induced by losoxantrone and doxorubicin were significantly more severe (Billingham scores) than those produced by piroxantrone. The renal lesions induced by piroxantrone and losoxantrone were less severe than those produced by doxorubicin. Similarly losoxantrone and piroxantrone-induced intestinal alterations (denudation of epithelial layer and inflammatory cellular infiltration) were less severe than those occurring after treatment with doxorubicin. Both losoxantrone and piroxantrone were shown to form Fe(III): drug complexes that may cause oxidative damage to various tissues. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 US FDA, Div Appl Pharmacol Res, Laurel, MD 20708 USA. Univ Manitoba, Fac Pharm, Winnipeg, MB R3T 2N2, Canada. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Herman, EH (reprint author), US FDA, Div Appl Pharmacol Res, HFD-910,8301 Muirkirk Rd, Laurel, MD 20708 USA. NR 36 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 26 PY 1998 VL 128 IS 1 BP 35 EP 52 DI 10.1016/S0300-483X(98)00049-3 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 106RP UT WOS:000075164500005 PM 9704904 ER PT J AU Dreifus, FE Rosman, NP Cloyd, JC Pellock, JM Kuzniecky, RI Lo, WD Matsuo, F Sharp, GB Conry, JA Bergen, DC Bell, WE AF Dreifus, FE Rosman, NP Cloyd, JC Pellock, JM Kuzniecky, RI Lo, WD Matsuo, F Sharp, GB Conry, JA Bergen, DC Bell, WE TI A comparison of rectal diazepam gel and placebo for acute repetitive seizures SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ADULT EPILEPTIC PATIENTS; N-DESMETHYLDIAZEPAM; HOME USE; CHILDREN; INFANTS; BIOAVAILABILITY; CONVULSIONS; LORAZEPAM; EEG AB Background Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. Methods We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at doses ranging from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses - one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. Results Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. Conclusions Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures. (N Engl J Med 1998;338:1869-75.) (C) 1998, Massachusetts Medical Society. C1 Univ Virginia, Dept Neurol, Charlottesville, VA USA. New England Med Ctr, Div Pediat Neurol, Boston, MA 02111 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Neurol, Richmond, VA 23298 USA. Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. Childrens Hosp, Dept Pediat, Columbus, OH 43205 USA. Univ Utah, Dept Neurol, Salt Lake City, UT 84112 USA. Arkansas Childrens Hosp, Dept Neurol, Little Rock, AR 72202 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. NIH, Bethesda, MD 20892 USA. RP Rosman, NP (reprint author), Floating Hosp Children, NEMC 330, Div Pediat Neurol, 750 Washington St, Boston, MA 02111 USA. NR 43 TC 133 Z9 134 U1 0 U2 1 PU MASS MEDICAL SOC PI BOSTON PA 10 SHATTUCK, BOSTON, MA 02115 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 25 PY 1998 VL 338 IS 26 BP 1869 EP 1875 DI 10.1056/NEJM199806253382602 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZV898 UT WOS:000074352800002 PM 9637805 ER PT J AU Matsuo, T Thiele, CJ AF Matsuo, T Thiele, CJ TI p27(Kip1): a key mediator of retinoic acid induced growth arrest in the SMS-KCNR human neuroblastoma cell line SO ONCOGENE LA English DT Article DE neuroblastoma; retinoids; cell cycle; p27(Kip1); N-myc; G1 cyclin; cdk ID DEPENDENT KINASE INHIBITOR; HUMAN NEURO-BLASTOMA; POTENTIAL MEDIATOR; CDK2 ACTIVITY; CYCLIN-E; DIFFERENTIATION; EXPRESSION; INDUCTION; G(1); ACTIVATION AB Retinoic acid (RA) treatment of SMS-KCNR neuroblastoma (NB) cells leads to G1 growth arrest and neuronal differentiation. To investigate the molecular mechanisms by which RA alters cell growth, we analysed the expression and activity of components of the cell cycle machinery after culture in RA. Within 2 days of RA treatment and prior to the arrest of NE cells in the G1 phase of the cell cycle, there is a complete downregulation of G1 cyclin/Cdk activities. Protein levels for the G1 cyclin/Cdks were essentially unchanged during this time although there was a decrease in the steady-state levels of p67(N-Myc) and hyperphosphorylated Rb proteins. The Cdk inhibitors, p21(Cipl) and p27(Kip1) were constitutively expressed in KCNR while p15(INK4B) and p16(INK4A) were not detected. RA induced an increase in the expression of p27(Kip1) but not p21(Cip1). Furthermore, coincident with the decrease in kinase activity there was an increase in G1 cyclin/Cdk bound p27(Kip1). These results indicate that changes in the level of p27(Kip1) and its binding to G1 cyclin/Cdks may play a key role in RA induced growth arrest of NB cells. C1 NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, 10 Ctr Dr,MSC-1928, Bethesda, MD 20892 USA. NR 44 TC 72 Z9 74 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 25 PY 1998 VL 16 IS 25 BP 3337 EP 3343 DI 10.1038/sj.onc.1201830 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV810 UT WOS:000074343600016 PM 9681834 ER PT J AU Ioannidis, JPA AF Ioannidis, JPA TI Time lag bias in publishing clinical trials - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. RP Ioannidis, JPA (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Ioannidis, John/G-9836-2011 NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 24 PY 1998 VL 279 IS 24 BP 1952 EP 1953 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZU945 UT WOS:000074252100025 ER PT J AU Kim, PJ Sakaguchi, K Sakamoto, H Saxinger, C Day, R McPhie, P Rubin, JS Bottaro, DP AF Kim, PJ Sakaguchi, K Sakamoto, H Saxinger, C Day, R McPhie, P Rubin, JS Bottaro, DP TI Colocalization of heparin and receptor binding sites on keratinocyte growth factor SO BIOCHEMISTRY LA English DT Article ID INFLAMMATORY BOWEL-DISEASE; FIBROBLAST GROWTH; AFFINITY; SPECIFICITY; EXPRESSION; MOLECULES; SULFATE; DOMAINS; CELLS; IDENTIFICATION AB Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. FGFs are also known as heparin-binding growth factors because they bind to heparin and their physical and biological properties are modulated by heparin. Consistent with a role as a paracrine effector, KGF is produced by cells of mesenchymal origin but is active primarily, if not exclusively, on epithelial cells. KGF is involved in a variety of physiological processes, including proliferation, differentiation, wound healing, and cytoprotection. To identify regions in KGF that contribute to heparin and tyrosine kinase receptor interactions, nine peptides spanning defined motifs in the predicted structure of KGF were synthesized, and their heparin and receptor binding properties were analyzed. Peptides at the amino and carboxyl termini bound heparin, and one peptide showed relative binding comparable to that of KGF, Competitive binding studies showed that this peptide along with two other overlapping peptides specifically displaced KGF bound to the KGF receptor. These three peptides were also selectively recognized by a neutralizing monoclonal antibody against KGF, though only in the presence of heparin, Together, these data suggest that the sites for heparin and receptor binding both reside in the amino and carboxyl termini of KGF, which are spatially juxtaposed in the predicted three-dimensional structure of this molecule. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Tumor Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37,Room 1E24,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; Sakamoto, Hiroshi/A-3181-2011 OI Bottaro, Donald/0000-0002-5057-5334; NR 50 TC 12 Z9 14 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 23 PY 1998 VL 37 IS 25 BP 8853 EP 8862 DI 10.1021/bi9801917 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW925 UT WOS:000074462100006 PM 9636026 ER PT J AU Lee, AY Zhang, S Kongsaeree, P Clardy, J Ganem, B Erickson, JW Xie, D AF Lee, AY Zhang, S Kongsaeree, P Clardy, J Ganem, B Erickson, JW Xie, D TI Thermodynamics of a transition state analogue inhibitor binding to Escherichia coli chorismate mutase: Probing the charge state of an active site residue and its role in inhibitor binding and catalysis SO BIOCHEMISTRY LA English DT Article ID DIRECTED MUTAGENESIS; PROTEIN; ENERGETICS; MECHANISM AB Electrostatic interactions play important roles in the catalysis of chorismate to prephenate by chorismate mutase. Mutation of Gln88 to glutamate in the monofunctional chorismate mutase from Escherichia coli results in an enzyme with a pH profile of activity significantly different from that of the wild type protein. To investigate whether the mutation alters the substrate binding process or the catalysis, we have directly determined the thermodynamic parameters of a transition state analogue inhibitor binding to the wild-type chorismate mutase and its Q88E mutant using isothermal titration calorimetry. The results demonstrate that solvent reorganization and hydrophobic interactions contribute the predominant free energy to inhibitor binding. The charge state of Glu88 in the Q88E mutant was experimentally determined and was shown to be protonated at pH 4.5 and ionized at pH 7.8, consistent with earlier hypotheses. Most surprisingly, inhibitor binding energetics do not exhibit significant pH dependency for both enzymes. Our findings indicate that the charge state of Glu88 has a small impact on inhibitor binding but plays an important role in the catalytic process. C1 NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Cornell Univ, Baker Lab, Dept Chem, Ithaca, NY 14853 USA. RP Xie, D (reprint author), NCI, Struct Biochem Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Bldg 322,Rm 27C, Frederick, MD 21702 USA. EM xie@ncifcrf.gov FU NCI NIH HHS [N01 CO-56000, CA 24487]; NIGMS NIH HHS [GM 24054] NR 27 TC 7 Z9 7 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 23 PY 1998 VL 37 IS 25 BP 9052 EP 9057 DI 10.1021/bi980217u PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW925 UT WOS:000074462100030 PM 9636050 ER PT J AU Page, JE Zajc, B Oh-Hara, T Lakshman, MK Sayer, JM Jerina, DM Dipple, A AF Page, JE Zajc, B Oh-Hara, T Lakshman, MK Sayer, JM Jerina, DM Dipple, A TI Sequence context profoundly influences the mutagenic potency of trans-opened benzo[a]pyrene 7,8-diol 9,10-epoxide-purine nucleoside adducts in site-specific mutation studies SO BIOCHEMISTRY LA English DT Article ID INDUCED FRAMESHIFT MUTAGENESIS; SINGLE-STRANDED VECTOR; DIOL-EPOXIDE; 11,12-DIHYDRODIOL 13,14-EPOXIDE; CYCLOBUTANE DIMER; ESCHERICHIA-COLI; DNA; CARCINOGEN; ADENINE; DEOXYADENOSINE AB The postoligomerization method was used to prepare oligonucleotide 16-mers that contained dAdo or dGuo adducts, derived from trans opening of each enantiomer of the two diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxides, in two sequence contexts. These 16 oligonucleotides, along with the four corresponding oligonucleotides containing unsubstituted purines, were ligated into single-stranded DNA from bacteriophage M13mp7L2 and transfected into Escherichia coli SMH77. The mutagenic effects of replication past these adducts were then evaluated. The various adduct isomers induced point mutations at different frequencies and with different distributions of mutation types, as was anticipated. However, sequence context had the most substantial effects on mutation frequency. A high frequency of deletions of a single guanine was found in a concert where the dGuo adduct was at the 3'-end of a run of five guanines, whereas no single base deletion was found in the other context studied, 5'-C (G) under bar A-3', Mutation frequencies in constructs containing dAdo adducts were much higher in a 5'-T (A) under bar G-3' context (37-58%, depending on the individual isomer) than in a 5'-G (A) under bar T-3' context (5-20%), and for a given adduct, mutation frequency was up to 10-fold higher in the former sequence than in the latter, These findings indicate that sequence context effects need more thorough evaluation if the goal of understanding the mechanism through which DNA adducts lead to mutation is to be achieved. C1 NCI, Chem Carcinogenesis Lab, Adv Biosci Labs, Basic Res Program,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dipple, A (reprint author), NCI, Chem Carcinogenesis Lab, Adv Biosci Labs, Basic Res Program,Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 55 TC 89 Z9 89 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 23 PY 1998 VL 37 IS 25 BP 9127 EP 9137 DI 10.1021/bi980273v PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW925 UT WOS:000074462100039 PM 9636059 ER PT J AU Chirgadze, DY Hepple, J Byrd, RA Sowdhamini, R Blundell, TL Gherardi, E AF Chirgadze, DY Hepple, J Byrd, RA Sowdhamini, R Blundell, TL Gherardi, E TI Insights into the structure of hepatocyte growth factor scatter factor (HGF/SF) and implications for receptor activation SO FEBS LETTERS LA English DT Article DE hepatocyte growth factor scatter factor; protein domain; NMR; X-ray analysis; receptor activation ID C-MET RECEPTOR; MOLECULAR-CLONING; PLASMINOGEN; DOMAIN; IDENTIFICATION; PURIFICATION; DELETION; PROTEIN; BINDING; CHAIN AB The modular structure of HGF/SF offers a reductionist or 'divide and rule' approach to the analysis of structure and function. Domain deletion experiments have established that the N domain, kringle 1 and kringle 2 are essential for HGF/SF activity and that truncated variants containing the N domain and kringle 1 (NK1) or kringles 1 and 2 (NK2) can exhibit partial agonistic or antagonistic activity depending on target cells. Comparative modelling has been used to predict the 3D structures of the six domains of HGF/SF, More recently, NMR methods have shown that the N domain has a novel fold, the charge distribution of which suggests a heparin binding site. Crystals of NK1 indicate the relationship of this domain to the kringle 1, offering further insights into the mechanism of domain interactions and receptor activation. (C) 1998 Federation of European Biochemical Societies. C1 Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. MRC Ctr, Growth Factors Grp, Dept Oncol, Cambridge CB2 2QH, England. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol NMR Sect, Frederick, MD 21702 USA. RP Blundell, TL (reprint author), Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA, England. EM tom@cryst.bioc.cam.ac.uk RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Wellcome Trust NR 25 TC 24 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 23 PY 1998 VL 430 IS 1-2 SI SI BP 126 EP 129 DI 10.1016/S0014-5793(98)00558-4 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZZ833 UT WOS:000074771700024 PM 9678607 ER PT J AU Pritsker, M Jones, P Blumenthal, R Shai, YC AF Pritsker, M Jones, P Blumenthal, R Shai, YC TI A synthetic all D-amino acid peptide corresponding to the N-terminal sequence of HIV-1 gp41 recognizes the wild-type fusion peptide in the membrane and inhibits HIV-1 envelope glycoprotein-mediated cell fusion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PHOSPHOLIPID-MEMBRANES; INFLUENZA HEMAGGLUTININ; TRANSMEMBRANE PROTEIN; ENERGY-TRANSFER; DOMAIN; ORIENTATION; BILAYERS; ANALOGS; IDENTIFICATION AB Recent studies demonstrated that a synthetic fusion peptide of HIV-1 self-associates in phospholipid membranes and inhibits HIV-1 envelope glycoprotein-mediated cell fusion, presumably by interacting with the N-terminal domain of gp41 and forming inactive heteroaggregates [Kliger, Y., Aharoni, A., Rapaport, D,, Jones, P., Blumenthal, R, & Shai, Y. (1997) J. Biol. Chem, 272, 13496-13505]. Here, we show that a synthetic all D-amino acid peptide corresponding to the N-terminal sequence of HIV-1 gp41 (D-WT) of HIV-1 associates with its enantiomeric wild-type fusion (WT) peptide in the membrane and inhibits cell fusion mediated by the HIV-1 envelope glycoprotein, D-WT does not inhibit cell fusion mediated by the HIV-2 envelope glycoprotein. WT and D-WT are equally potent in inducing membrane fusion, D-WT peptide but not WT peptide is resistant to proteolytic digestion. Structural analysis showed that the CD spectra of D-WT in trifluoroethanol/water is a mirror image of that of WT, and attenuated total reflectance-fourier transform infrared spectroscopy revealed similar structures and orientation for the two enantiomers in the membrane. The results reveal that the chirality of the synthetic peptide corresponding to the HIV-1 gp41 N-terminal sequence does not play a role in liposome fusion and that the peptides' chirality is not necessarily required for peptide-peptide interaction within the membrane environment. Furthermore, studies along these lines may provide criteria to design protease-resistant therapeutic agents against HIV and other viruses. C1 Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. NCI, Sect Membrane Struct & Funct, NIH, Frederick, MD 21702 USA. RP Shai, YC (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. EM bmshai@weizmann.weizmann.ac.il NR 57 TC 44 Z9 46 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7287 EP 7292 DI 10.1073/pnas.95.13.7287 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400011 PM 9636141 ER PT J AU Yeager, M Wilson-Kubalek, EM Weiner, SG Brown, PO Rein, A AF Yeager, M Wilson-Kubalek, EM Weiner, SG Brown, PO Rein, A TI Supramolecular organization of immature and mature murine leukemia virus revealed by electron cryo-microscopy: Implications for retroviral assembly mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE image processing; retroviruses; virus assembly ID ROUS-SARCOMA VIRUS; IMMUNODEFICIENCY-VIRUS; 3-DIMENSIONAL STRUCTURE; NUCLEOCAPSID PROTEIN; CRYSTAL-STRUCTURE; CRYOELECTRON MICROSCOPY; ANGSTROM RESOLUTION; PARTICLE FORMATION; MEMBRANE-BINDING; MATRIX PROTEIN AB We have used electron cryo-microscopy and image analysis to examine the native structure of immature, protease-deficient (PR-) and mature, wild-type (WT) Moloney murine leukemia virus (MuLV). Maturational cleavage of the Gag polyprotein by the viral protease is associated with striking morphological changes. The PR- MuLV particles exhibit a rounded central core, which has a characteristic track-like shell on its surface, whereas the WT MuLV cores display a polygonal surface with loss of the track-like feature. The pleomorphic shape and inability to refine unique orientation angles suggest that neither the PR- nor the WT MuLV adheres to strict icosahedral symmetry. Nevertheless, the PR- MuLV particles do exhibit paracrystalline order with a spacing between Gag molecules of approximate to 45 Angstrom and a length of approximate to 200 Angstrom. Because of the pleomorphic shape and paracrystalline packing of the Gag-RNA complexes, we raise the possibility that assembly of MuLV is driven by protein-RNA, as well as protein-protein, interactions. The maturation process involves a dramatic reorganization of the packing arrangements within the ribonucleoprotein core with disordering and loosening of the individual protein components. C1 Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. NCI, Lab Mol Virol & Carcinogenesis, Adv Biosci Labs, Basic Res Program,Frederick Canc Res Facil, Frederick, MD 21702 USA. Stanford Univ, Med Ctr, Howard Hughes Med Inst, Dept Biochem, Stanford, CA 94305 USA. RP Yeager, M (reprint author), Scripps Res Inst, Dept Cell Biol, MB28,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NHLBI NIH HHS [R01 HL048908, R01HL48908]; NIAID NIH HHS [R01AI31535] NR 68 TC 131 Z9 131 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7299 EP 7304 DI 10.1073/pnas.95.13.7299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400013 PM 9636143 ER PT J AU Furumura, M Sakai, C Potterf, SB Vieira, WD Barsh, GS Hearing, VJ AF Furumura, M Sakai, C Potterf, SB Vieira, WD Barsh, GS Hearing, VJ TI Characterization of genes modulated during pheomelanogenesis using differential display SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE agouti; melanogenesis; pheomelanin; pigmentation; gene expression ID MELANOCYTE-STIMULATING-HORMONE; MOUSE AGOUTI GENE; HUMAN HOMOLOG; TYROSINASE GENE; RED HAIR; PROTEIN; EXPRESSION; RECEPTOR; YELLOW; PIGMENTATION AB Molecular and biochemical mechanisms that modulate the production of eumelanin or pheomelanin pigments involve the opposing effects of two intercellular signaling molecules, alpha-melanocyte stimulating hormone (MSH) and agouti signal protein (ASP). ASP is an antagonist of MSH signaling through the melanocyte-specific MSH receptor, although its mechanism(s) of action is controversial. We previously have reported significant down-regulation of all known melanogenic genes during the eumelanin to pheomelanin switch in murine hair follicle melanocytes and in cultured melanocytes treated with recombinant ASP. To identify factors that might be involved in the switch to pheomelanogenesis, we screened ASP-treated melanocytes by using differential display and identified three up-regulated genes: a DNA replication control protein, a basic helix-loop-helix transcription factor, and a novel gene. We have simultaneously identified six down-regulated genes in ASP-treated melanocytes; two of those encode tyrosinase and TRP2, melanogenic genes known to be down-regulated during pheomelanogenesis, which provide good internal controls for this approach. These results suggest that there are complex mechanisms involved in the switch to pheomelanin production, and that these modulated genes might be involved in the pleiotropic changes seen in yellow mice, including the change in coat color. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Pediat, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,room 1B25, Bethesda, MD 20892 USA. NR 43 TC 55 Z9 56 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7374 EP 7378 DI 10.1073/pnas.95.13.7374 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400026 PM 9636156 ER PT J AU Xiang, BS Weiler, S Nirenberg, M Ferretti, JA AF Xiang, BS Weiler, S Nirenberg, M Ferretti, JA TI Structural basis of an embryonically lethal single Ala -> Thr mutation in the vnd/NK-2 homeodomain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nuclear magnetic resonance; structure; folding; DNA binding ID CENTRAL-NERVOUS-SYSTEM; NK-2 HOMEOBOX GENE; CRYSTAL-STRUCTURE; DROSOPHILA-MELANOGASTER; DNA INTERACTIONS; COMPLEX; PROTEINS; SPECTROSCOPY; EXPRESSION; RESOLUTION AB The structural and DNA binding behavior is described for an analog of the vnd/NK-2 homeodomain, which contains a single amino acid residue alanine to threonine replacement in position 35 of the homeodomain. Multidimensional nuclear magnetic resonance, circular dichroism, and electrophoretic gel retardation assays were carried out on recombinant 80-aa residue proteins that encompass the wildtype and mutant homeodomains. The mutant A35T vnd/NK-2 homeodomain is unable to adopt a folded conformation free in solution at temperatures down to -5 degrees C in contrast to the behavior of the corresponding wild-type vnd/NK-2 homeodomain, which is folded into a functional three-dimensional structure below 25 degrees C. The A35T vnd/NK-2 binds specifically to the vnd/NK-2 target DNA sequence, but with an affinity that is 50-fold lower than that of the wild-type homeodomain, Although the three-dimensional structure of the mutant A35T vnd/NK-2 in the DNA bound state shows characteristic helix-turn-helix behavior similar to that of the wild-type homeodomain, a notable structural deviation in the mutant A35T analog is observed for the amide proton of leucine-40. The wild-type homeodomain forms an unusual i,i-5 hydrogen bond with the backbone amide oxygen of residue 35. In the A35T mutant this amide proton resonance is shifted upfield by 1.27 ppm relative to the resonance frequency for the wild-type analog, thereby indicating a significant alteration of this i,i-5 hydrogen bond. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Ferretti, JA (reprint author), NHLBI, Biophys Chem Lab, NIH, 3 Ctr Dr,Bldg 3,Room 412,MSC-0380, Bethesda, MD 20892 USA. NR 39 TC 14 Z9 14 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7412 EP 7416 DI 10.1073/pnas.95.13.7412 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400033 PM 9636163 ER PT J AU Altschuler, DL Ribeiro-Neto, F AF Altschuler, DL Ribeiro-Neto, F TI Mitogenic and oncogenic properties of the small G protein rap1b SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GTP-BINDING PROTEIN; CYCLIC-AMP; SWISS 3T3-CELLS; DEPENDENT ACTIVATION; AMINO-ACIDS; RAS; TRANSFORMATION; IDENTIFICATION; SIGNAL; RELATIVES AB It has been widely reported that the small GTP-binding protein Rap1 has an anti-Ras and antimitogenic activity, Thus, it is generally accepted that a normal physiological role of Rap1 proteins is to antagonize Ras mitogenic signals, presumably by forming nonproductive complexes with proteins that are typically effecters or modulators of Ras, Rap1 is activated by signals that raise intracellular levels of cAMP, a molecule that has long been known to exert both inhibitory and stimulatory effects on cell growth,We have now tested the intriguing hypothesis that Rap1 could have mitogenic effects in systems in which cAMP stimulates cell proliferation. The result of experiments addressing this possibility revealed that Rap1 has full oncogenic potential. Expression of Rap1 in these cells results in a decreased doubling time, an increased saturation density, and an unusual anchorage-dependent morphological transformation. Most significantly, however, Rap1-expressing cells formed tumors when injected into nude mice. Thus, we propose that the view that holds Rap1 as an antimitogenic protein should be restricted and conclude that Rap1 is a conditional oncoprotein. C1 Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Altschuler, DL (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. FU NCI NIH HHS [R29 CA071649, R29 CA71649] NR 31 TC 109 Z9 110 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7475 EP 7479 DI 10.1073/pnas.95.13.7475 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400044 PM 9636174 ER PT J AU Fondon, JW Mele, GM Brezinschek, RI Cummings, D Pande, A Wren, J O'Brien, KM Kupfer, KC Wei, MH Lerman, M Minna, JD Garner, HR AF Fondon, JW Mele, GM Brezinschek, RI Cummings, D Pande, A Wren, J O'Brien, KM Kupfer, KC Wei, MH Lerman, M Minna, JD Garner, HR TI Computerized polymorphic marker identification: Experimental validation and a predicted human polymorphism catalog SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN GENOME; TETRANUCLEOTIDE REPEAT; PROTEIN SEQUENCES; DNA-SEQUENCE; LINKAGE MAP; TRINUCLEOTIDE; LOCUS; IMPLEMENTATION; CONSTRUCTION; ALGORITHM AB A computational system for the prediction of polymorphic loci directly and efficiently from human genomic sequence was developed and verified. A suite of programs, collectively called POMPOUS (polymorphic marker prediction of ubiquitous simple sequences) detects tandem repeats ranging from dinucleotides up to 250 mers, scores them according to predicted level of polymorphism, and designs appropriate flanking primers for PCR amplification. This approach was validated on an approximately 750-kilobase region of human chromosome 3p213, involved in lung and breast carcinoma homozygous deletions. Target DNA from 36 paired B lymphoblastoid and lung cancer lines was amplified and allelotyped for 33 loci predicted by POMPOUS to be variable in repeat size,We found that among those 36 predominately Caucasian individuals 22 of the 33 (67%) predicted loci were polymorphic with an average heterozygosity of 0.42, Allele loss in this region was found in 27/36 (75%) of the tumor lines using these markers. POMPOUS provides the genetic researcher with an additional tool for the rapid and efficient identification of polymorphic markers, and through a World Wide Web site, investigators can use POMPOUS to identify polymorphic markers for their research. A catalog of 13,261 potential polymorphic markers and associated primer sets has been created from the analysis of 141,779,504 base pairs of human genomic sequence in GenBank. This data is available on our Web site (pompous.swmed.edu) and will be updated periodically as GenBank is expanded and algorithm accuracy is improved. C1 Univ Texas, SW Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Ctr Biomed Invent, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75235 USA. NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Garner, HR (reprint author), Univ Texas, SW Med Ctr, McDermott Ctr Human Growth & Dev, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. EM garner@swmed.edu RI Wren, Jonathan/E-5611-2011 OI Wren, Jonathan/0000-0003-2776-3545 FU NCI NIH HHS [CA 71618, P50 CA070907, P50 CA70907, R01 CA071618] NR 39 TC 51 Z9 52 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7514 EP 7519 DI 10.1073/pnas.95.13.7514 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400051 PM 9636181 ER PT J AU Greten, TF Slansky, JE Kubota, R Soldan, SS Jaffee, EM Leist, TP Pardoll, DM Jacobson, S Schneck, JP AF Greten, TF Slansky, JE Kubota, R Soldan, SS Jaffee, EM Leist, TP Pardoll, DM Jacobson, S Schneck, JP TI Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19-specific CD8(+) T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID I-ASSOCIATED MYELOPATHY; VIRUS TYPE-I; TROPICAL SPASTIC PARAPARESIS; CYTOTOXIC LYMPHOCYTES-T; CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD LESIONS; NEUROLOGICAL DISEASE; PROVIRAL DNA; RECEPTOR; TAX AB Human T lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropic spastic paraparesis is a demyelinating inflammatory neurologic disease associated with HTLV-1 infection. HTLV-1 Tax11-19-specific cytotoxic T cells have been isolated from HLA-A2-positive patients. We have used a peptide-loaded soluble HLA-A2-Ig complex to directly visualize HTLV-1 Tax11-19-specific T cells from peripheral blood and cerebrospinal fluid without in vitro stimulation. Five of six HTLV-1-associated myelopathy/tropic spastic paraparesis patients carried a significant number (up to 13.87%) of CD8(+) lymphocytes specific for the HTLV-1 Tax11-19 peptide in their peripheral blood, which were not found in healthy controls. Simultaneous comparison of peripheral blood and cerebrospinal fluid from one patient revealed 2.5-fold more Tax11-19-specific T cells in the cerebrospinal fluid (23.7% vs. 9.4% in peripheral blood lymphocyte). Tax11-19-specific T cells were seen consistently over a 9-yr time course in one patient as far as 19 yrs after the onset of clinical symptoms, Further analysis of HTLV-1 Tax11-19-specific CD8(+) T lymphocytes in HAM/TSP patients showed different expression patterns of activation markers, intracellular TNF-alpha and gamma-interferon depending on the severity of the disease. Thus, visualization of antigen-specific T cells demonstrates that HTLV-1 Tax11-19-specific CD8(+) T cells are activated, persist during the chronic phase of the disease, and accumulate in cerebrospinal fluid, showing their pivotal role in the pathogenesis of this neurologic disease. C1 Johns Hopkins Univ, Sch Med, Dept Pathol & Oncol, Baltimore, MD 21205 USA. NINDS, Viral Neuroimmunol Sect, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol & Oncol, 720 Rutland Ave,Ross 364, Baltimore, MD 21205 USA. RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 NR 40 TC 166 Z9 168 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7568 EP 7573 DI 10.1073/pnas.95.13.7568 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400060 PM 9636190 ER PT J AU Eissa, NT Yuan, JW Haggerty, CM Choo, EK Palmer, CD Moss, J AF Eissa, NT Yuan, JW Haggerty, CM Choo, EK Palmer, CD Moss, J TI Cloning and characterization of human inducible nitric oxide synthase splice variants: A domain, encoded by exons 8 and 9, is critical for dimerization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MESSENGER-RNA; STRUCTURAL DIVERSITY; MOLECULAR-CLONING; ELECTRON-TRANSFER; NADPH-DIAPHORASE; CALMODULIN; REVEALS; GENE; TETRAHYDROBIOPTERIN; MACROPHAGES AB The inducible nitric oxide synthase (iNOS) contains an amino-terminal oxygenase domain, a carboxyterminal reductase domain, and an intervening calmodulin-binding region. For the synthesis of nitric oxide (NO), iNOS is active as a homodimer. The human iNOS mRNA is subject to alternative splicing, including deletion of exons 8 and 9 that encode amino acids 242-335 of the oxygenase domain. In this study, iNOS(8-9-) and full-length iNOS (iNOS(FL)) were cloned from bronchial epithelial cells. Expression of iNOS(8-9-) in 293 cell line resulted in generation of iNOS(8-9-) mRNA and protein but did not lead to NO production. In contrast to iNOS(FL), iNOS(8-9-) did not form dimers, Similar to iNOS(FL), iNOS(8-9-) exhibited NADPH-diaphorase activity and contained tightly bound calmodulin, indicating that the reductase and calmodulin-binding domains were functional. To identify sequences in exons 8 and 9 that are critical for dimerization, iNOS(FL) was used to construct 12 mutants, each with deletion of eight residues in the region encoded by exons 8 and 9, In addition, two "control" iNOS deletion mutants were synthesized, lacking either residues 45-52 of the oxygenase domain or residues 1131-1138 of the reductase domain. Whereas both control deletion mutants generated NO and formed dimers, none of the 12 other mutants formed dimers or generated NO. The region encoded by exons 8 and 9 is critical for iNOS dimer formation and NO production but not for reductase activity, This region could be a potential target for therapeutic interventions aimed at inhibiting iNOS dimerization and hence NO synthesis. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Eissa, NT (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, MSC 1590,Room 6D03,Bldg 10, Bethesda, MD 20892 USA. OI Choo, Esther/0000-0001-8847-5745 NR 30 TC 64 Z9 64 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 1998 VL 95 IS 13 BP 7625 EP 7630 DI 10.1073/pnas.95.13.7625 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400070 PM 9636200 ER PT J AU Sora, I Wichems, C Takahashi, N Li, XF Zeng, ZZ Revay, R Lesch, KP Murphy, DL Uhl, GR AF Sora, I Wichems, C Takahashi, N Li, XF Zeng, ZZ Revay, R Lesch, KP Murphy, DL Uhl, GR TI Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NONHUMAN-PRIMATES; UPTAKE INHIBITORS; DRUGS; BINDING; RATS; BEHAVIOR; MONKEYS; HUMANS; SITES AB Cocaine and methylphenidate block uptake by neuronal plasma membrane transporters for dopamine, serotonin, and norepinephrine. Cocaine also blocks voltage-gated sodium channels, a property not shared by methylphenidate. Several lines of evidence have suggested that cocaine blockade of the dopamine transporter (DAT), perhaps with additional contributions from serotonin transporter (5-HTT) recognition, was key to its rewarding actions. We now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences. Each strain displays cocaine-conditioned place preference in this major mouse model for assessing drug reward, while methylphenidate-conditioned place preference is also maintained in DAT knockout mice. These results have substantial implications for understanding cocaine actions and for strategies to produce anticocaine medications. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Psychiat, D-97080 Wurzburg, Germany. RP Uhl, GR (reprint author), Box 5180, Baltimore, MD 21224 USA. RI Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 34 TC 317 Z9 325 U1 1 U2 13 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 JUN 23 PY 1998 VL 95 IS 13 BP 7699 EP 7704 DI 10.1073/pnas.95.13.7699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZW683 UT WOS:000074436400083 PM 9636213 ER PT J AU Vannucci, SJ Koehler-Stec, EM Li, K Reynolds, TH Clark, R Simpson, IA AF Vannucci, SJ Koehler-Stec, EM Li, K Reynolds, TH Clark, R Simpson, IA TI GLUT4 glucose transporter expression in rodent brain: effect of diabetes SO BRAIN RESEARCH LA English DT Article DE glucose; insulin; db/db mouse; cerebellum; granule cell; exercise ID GROWTH FACTOR-I; RAT-BRAIN; GENE-EXPRESSION; AUTORADIOGRAPHIC LOCALIZATION; INSULIN; RECEPTORS; REGIONS; AREAS AB This study describes the regional and cellular expression of the insulin-sensitive glucose transporter, GLUT4, in rodent brain. A combination of in situ hybridization, immunohistochemistry and inmunoblot techniques was employed to localize GLUT4 mRNA and protein to the granule cells of the olfactory bulb, dentate gyrus of the hippocampus and the cerebellum, with the greatest level of expression being in the cerebellum. Estimates of the concentration of GLUT4 in cerebellar membranes indicate that this transporter isoform is present in significant amounts, relative to the other isoforms, GLUT1 and GLUT3, Cerebellar GLUT4 expression was increased in the genetically diabetic, hyperinsulinemic, db/db mouse relative to the non-diabetic control, and even higher levels were observed in db/db female than db/db male mice. Levels of expression of GLUT4 protein in cerebellum appear to respond to the level of circulating insulin, and are reduced in the hypoinsulinemic streptozotocin-diabetic rat. Exercise training also results in reduced insulin levels and comparably reduced levels of GLUT4 in the cerebellum. These studies demonstrate a chronic insulin-sensitive regulation of GLUT4 in rodent brain and raise the possibility of acute modulations of glucose uptake in these GLUT4 expressing cells. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDDK, EDMNS, DB, NIH, Bethesda, MD 20892 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Pediat & Mol & Cellular Physiol, Hershey, PA 17033 USA. RP Simpson, IA (reprint author), NIDDK, EDMNS, DB, NIH, Bldg 10,Rm 5N102,10 Ctr Dr MSC 1420, Bethesda, MD 20892 USA. EM ians@bdg10.niddk.nih.gov NR 32 TC 89 Z9 90 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 22 PY 1998 VL 797 IS 1 BP 1 EP 11 DI 10.1016/S0006-8993(98)00103-6 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 101MM UT WOS:000074872800001 PM 9630471 ER PT J AU Baca, SM Lipska, BK Egan, MF Bachus, SE Ferguson, JN Hyde, TM AF Baca, SM Lipska, BK Egan, MF Bachus, SE Ferguson, JN Hyde, TM TI Effects of prefrontal cortical lesions on neuropeptide and dopamine receptor gene expression in the striatum-accumbens complex SO BRAIN RESEARCH LA English DT Article DE mPFC lesions; in situ hybridization histochemistry; basal ganglia; D2; D1; enkephalin; GAD65; substance P ID IBOTENIC ACID LESIONS; INSITU HYBRIDIZATION HISTOCHEMISTRY; HALOPERIDOL-INDUCED CATALEPSY; RAT CAUDATE-PUTAMEN; NUCLEUS-ACCUMBENS; MESSENGER-RNA; D2 RECEPTORS; TOPOGRAPHICAL ORGANIZATION; STRIATOPALLIDAL NEURONS; TYROSINE-HYDROXYLASE AB In the rat, neurochemical, behavioral, and anatomical investigations suggest that medial prefrontal cortical input modulates the activity of the basal ganglia. To understand how prefrontal dysfunction might alter striatal-accumbens function, in situ hybridization histochemistry with S-35-labeled oligonucleotide probes was used to assess changes in striaral-accumbens gene expression following bilateral excitotoxic ibotenic acid (IA) lesions of the rat medial prefrontal cortex. Quantitative densitometry was used to measure changes in mRNA levels for preproenkephalin A (ENK), D1 dopamine receptor, protachykinin (SubP), glutamic acid decarboxylase (GAD65), and D2 dopamine receptor. No differences were found between sham and lesion groups for ENK, D1, SubP, or GAD65 mRNA levels in the striatum or nucleus accumbens (NAC). D2 receptor mRNA levels were, however, significantly higher in the dorsomedial striatum and in the core area of the NAC of the lesioned rats. Although the functional significance of increased D2 mRNA is unclear, these findings demonstrate that glutamate mPFC projections modulate gene expression in relatively regionally-localized subcortical neuronal populations. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, St Elizabeths Hosp, Clin Brain Disorders Branch, Intramural Res Program,Neurosci Ctr, Washington, DC 20032 USA. RP NIMH, St Elizabeths Hosp, Clin Brain Disorders Branch, Intramural Res Program,Neurosci Ctr, Washington, DC 20032 USA. EM hydet@dirpc.nimh.nih.gov RI Lipska, Barbara/E-4569-2017 NR 81 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JUN 22 PY 1998 VL 797 IS 1 BP 55 EP 64 DI 10.1016/S0006-8993(98)00343-6 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 101MM UT WOS:000074872800007 PM 9630515 ER PT J AU Nonaka, S Chuang, DM AF Nonaka, S Chuang, DM TI Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats SO NEUROREPORT LA English DT Article DE cerebral ischemia; glutamate; lithium; neuroprotection ID GRANULE CELLS; HIPPOCAMPUS; ASPARTATE; GLUTAMATE; STRIATUM; SURVIVAL; LESIONS; BRAIN AB WE have recently shown that long-term, but not acute, treatment with lithium robustly protects cultured CNS neurons against excitotoxicity mediated by NMDA receptors. Since NMDA receptor over-excitation has been strongly implicated in the ischemic brain injury, we examined the effects of chronic lithium treatment on neurological deficit and brain infarct induced by occlusion of the left middle cerebral artery in rats. Subcutaneous injection of LiCl for 16 days significantly improved neurological deficits, including abnormal posture and hemiplegia, measured 24h after artery occlusion. Importantly, the size of ischemic infarct was reduced by 56% after lithium pretreatment. These results raise the possibility that lithium may be useful for reducing focal ischemia-induced brain damage and neurological abnormalities. (C) 1998 Rapid Science Ltd. C1 NIMH, Sect Mol Endocrinol, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Nonaka, S (reprint author), NIMH, Sect Mol Endocrinol, Biol Psychiat Branch, NIH, 10 Ctr Dr MSC 1272, Bethesda, MD 20892 USA. NR 23 TC 204 Z9 213 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 22 PY 1998 VL 9 IS 9 BP 2081 EP 2084 DI 10.1097/00001756-199806220-00031 PG 4 WC Neurosciences SC Neurosciences & Neurology GA ZX497 UT WOS:000074522100032 PM 9674597 ER PT J AU Goedert, JJ Cote, TR Virgo, P Scoppa, SM Kingma, DW Gail, MH Jaffe, ES Biggar, RJ AF Goedert, JJ Cote, TR Virgo, P Scoppa, SM Kingma, DW Gail, MH Jaffe, ES Biggar, RJ CA AIDS-Canc Match Study Grp TI Spectrum of AIDS-associated malignant disorders SO LANCET LA English DT Article ID EPSTEIN-BARR-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; TESTICULAR CANCER; HODGKINS-DISEASE; LYMPHOMAS; INFECTION; TUMOR; RISK AB Background To clarify which types of cancer result from AIDS, we compared the cancer experiences of people with AIDS with those of the general population by matching population-based cancer and AIDS registries in the USA and Puerto Rico. Methods We used a probabilistic matching algorithm to compare names, birth dates, and, where available, social-security numbers of 98 336 people with AIDS and 1 125 098 people with cancer aged less than 70 years. We defined AIDS-related cancers as those with both significantly raised incidence post-AIDS and increasing prevalence from 5 years pre-AIDS to 2 years post-AIDS. Findings Among people with AIDS, we found 7028 cases of Kaposi's sarcoma (KS), 1793 of non-Hodgkin lymphoma (NHL), and 712 other cases of histologically defined cancer. Incidence rates among people with AIDS were increased 310-fold for KS, 113-fold for NHL, and l.9-fold (95% CI 1.5-2.3) for other cancers. Of 38 malignant disorders other than KS and NHL, only angiosarcoma (36.7-fold), Hodgkin's disease (7.6-fold), multiple myeloma (4.5-fold), brain cancer (3.5-fold), and seminoma (2.9-fold) were raised and increasing significantly (p<0.02) from the pre-AIDS to the post-AIDS period. Interpretation Interpretation is complicated by screening and shared risk factors, such as sexual behaviour and cigarette smoking. However, our data indicate that AIDS leads to a significantly increased risk of Hodgkin's disease, multiple myeloma, brain cancer, and seminoma. Immunological failure to control herpes or other viral infections may contribute to these malignant diseases. C1 NCI, Viral Epidemiol Branch, Rockville, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Comp Sci Corp, Rockville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. NCI, Biostat Branch, Rockville, MD USA. RP Goedert, JJ (reprint author), 6130 Execut Blvd,Suite 434, Rockville, MD 20852 USA. FU NCI NIH HHS [N01-CP-40514, N01-CP-40521, YO1-CP-0003-01] NR 37 TC 469 Z9 481 U1 0 U2 5 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 20 PY 1998 VL 351 IS 9119 BP 1833 EP 1839 DI 10.1016/S0140-6736(97)09028-4 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZV842 UT WOS:000074347100009 PM 9652666 ER PT J AU Lee, SR Kwon, KS Kim, SR Rhee, SG AF Lee, SR Kwon, KS Kim, SR Rhee, SG TI Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THIOREDOXIN REDUCTASE; ENDOPLASMIC-RETICULUM; CRYSTAL-STRUCTURE; CATALYTIC ROLE; HUMAN-PLACENTA; PURIFICATION; PHOSPHORYLATION; SEQUENCE; H2O2; DEPHOSPHORYLATION AB Stimulation of various cells with growth factors results in a transient increase in the intracellular concentration of H2O2 that is required for growth factor-induced protein tyrosine phosphorylation. The effect of H2O2 produced in response to epidermal growth factor (EGF) on the activity of protein-tyrosine phosphatase PB (PTP1B) was investigated in A431 human epidermoid carcinoma cells. H2O2 inactivated recombinant PTP1B in vitro by oxidizing its catalytic site cysteine, most likely to sulfenic acid. The oxidized enzyme was reactivated more effectively by thioredoxin than by glutaredoxin or glutathione at their physiological concentrations. Oxidation by H2O2 prevented modification of the catalytic cysteine of PTP1B by iodoacetic acid, suggesting that it should be possible to monitor the oxidation state of PTP1B in cells by measuring the incorporation of radioactivity into the enzyme after lysis of the cells in the presence of radiolabeled iodoacetic acid. The amount of such radioactivity associated with PTP1B immunoprecipitated from A431 cells that lead been stimulated with EGF for 10 min was 27% less than that associated with PTP1B from unstimulated cells. The amount of iodoacetic acid-derived radioactivity associated with PTP1B reached a minimum PO min after stimulation of cells with EGF and returned to base line values by 40 min, suggesting that the oxidation of PTP1B is reversible in cells. These results indicate that the activation of a receptor tyrosine kinase by binding of the corresponding growth factor may not be sufficient to increase the steady state level of protein tyrosine phosphorylation in cells and that concurrent inhibition of protein-tyrosine phosphatases by N2O2 might also be required. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 3,Rm 122, Bethesda, MD 20892 USA. EM sgrhee@helix.nih.gov NR 54 TC 662 Z9 681 U1 2 U2 25 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 JUN 19 PY 1998 VL 273 IS 25 BP 15366 EP 15372 DI 10.1074/jbc.273.25.15366 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200012 PM 9624118 ER PT J AU Zeitlmann, L Knorr, T Knoll, M Romeo, C Sirim, P Kolanus, W AF Zeitlmann, L Knorr, T Knoll, M Romeo, C Sirim, P Kolanus, W TI T cell activation induced by novel gain-of-function mutants of Syk and ZAP-70 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE KINASE; RECEPTOR ZETA-CHAIN; DOMAIN-CONTAINING PROTEINS; TANDEM SH2 DOMAINS; ANTIGEN RECEPTOR; SIGNAL-TRANSDUCTION; EXPRESSION SYSTEM; BINDING; PHOSPHORYLATION; TCR AB The Syk family tyrosine kinases play a crucial role in antigen receptor-mediated signal transduction, but their regulation and cellular targets remain incompletely defined. Following receptor engagement, phosphorylation of tyrosine residues within ZAP-70 and Syk is thought to control both kinase activity and recruitment of modulatory factors. We report here the characterization of novel mutants of ZAP-70 and Syk, in which conserved C-terminal tyrosine residues have been replaced by phenylalanines (ZAP YF-C, Syk YF-C), Both mutant kinases display a prominent gain-of-function phenotype in Jurkat T cells, as demonstrated by lymphokine promoter activation, tyrosine phosphorylation of potential targets in vivo, and elevated intracellular calcium mobilization. While the presence of p56-Lck was required for ZAP YF-C-induced signaling, Syk YF-C showed enhanced functional activity in Lck-deficient JCaM1 Jurkat cells. Our results implicate the C terminus of Syk family kinases as an important regulatory region modulating T cell activation. C1 Univ Munich, Mol Biol Lab, Genzentrum, D-81377 Munich, Germany. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Kolanus, W (reprint author), Univ Munich, Mol Biol Lab, Genzentrum, Feodor Lynen Str 25, D-81377 Munich, Germany. EM kolanus@lmb.uni-muenchen.de NR 48 TC 33 Z9 33 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 JUN 19 PY 1998 VL 273 IS 25 BP 15445 EP 15452 DI 10.1074/jbc.273.25.15445 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200023 PM 9624129 ER PT J AU Hesselgesser, J Ng, HP Liang, M Zheng, W May, K Bauman, JG Monahan, S Islam, I Wei, GP Ghannam, A Taub, DD Rosser, M Snider, RM Morrissey, MM Perez, HD Horuk, R AF Hesselgesser, J Ng, HP Liang, M Zheng, W May, K Bauman, JG Monahan, S Islam, I Wei, GP Ghannam, A Taub, DD Rosser, M Snider, RM Morrissey, MM Perez, HD Horuk, R TI Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONPEPTIDE ANTAGONIST; GENERATION COMPOUNDS; EXPRESSION; RANTES; POTENT; ENCEPHALOMYELITIS; INTERLEUKIN-8; CHEMOTAXIS; CYTOKINES; PROTEINS AB The CC chemokines macrophage inflammatory pro tein-1 alpha (MIP-1 alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis, Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had K-i values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitrite), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1 alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1 alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 mu M. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1 alpha, RANTES, and CCR1. C1 Berlex BioSci, Dept Immunol, Richmond, CA 94806 USA. Berlex BioSci, Dept Pharmaceut Discovery, Richmond, CA 94806 USA. NIA, Natl Inst Hlth, Immunol Lab, Baltimore, MD 21224 USA. RP Horuk, R (reprint author), Berlex BioSci, Dept Immunol, 15049 San Pablo Ave, Richmond, CA 94806 USA. OI Zheng, Wei/0000-0003-1034-0757 NR 29 TC 114 Z9 115 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 JUN 19 PY 1998 VL 273 IS 25 BP 15687 EP 15692 DI 10.1074/jbc.273.25.15687 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200058 PM 9624164 ER PT J AU Hodge, DR Dunn, KJ Pei, GK Chakrabarty, MK Heidecker, G Lautenberger, JA Samuel, KP AF Hodge, DR Dunn, KJ Pei, GK Chakrabarty, MK Heidecker, G Lautenberger, JA Samuel, KP TI Binding of c-Raf1 kinase to a conserved acidic sequence within the carboxyl-terminal region of the HIV-1 Nef protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; GLUTATHIONE-S-TRANSFERASE; CD4 DOWN-REGULATION; HUMAN T-CELLS; SERINE PHOSPHORYLATION; PHYSICAL INTERACTION; PLASMA-MEMBRANE; GENE-PRODUCT; IN-VITRO; RAS-GTP AB Nef is a membrane-associated cytoplasmic phosphoprotein that is well conserved among the different human (HIV-1 and HIV-8) and simian immunodeficiency viruses and has important roles in down-regulating the CD4 receptor and modulating T-cell signaling pathways. The ability to modulate T-cell signaling pathways suggests that Nef may physically interact with T-cell signaling proteins. In order to identify Nef binding proteins and map their site(s) of interaction, we targeted a highly conserved acidic sequence at the carboxyl-terminal region of Nef sharing striking similarity with an acidic sequence at the c-Raf1-binding site within the Ras effector region. Here, we used deletion and site-specific mutagenesis to generate mutant Nef proteins fused to bacterial glutathione S-transferase in in vitro precipitation assays and immunoblot analysis to map the specific interaction between the HIV-1(LAI) Nef and c-Raf1 to a conserved acidic sequence motif containing the core sequence Asp-Asp-X-X-X-Glu (position 174-179). Significantly, we demonstrate that substitution of the nonpolar glycine residue for either or both of the conserved negatively charged aspartic acid residues at positions 174 and 175 in the full-length recombinant Nef protein background completely abrogated binding of c-Raf1 in vitro. In addition, lysates from a permanent CEM T-cell line constitutively expressing the native HIV-1 Nef protein was used to coimmunoprecipitate a stable Nef c-Raf1 complex, suggesting that molecular interactions between Nef and c-Raf1, an important downstream transducer of cell signaling through the c-Raf1-MAP kinase pathway, occur in vivo. This interaction may account for the Nef-induced perturbations of T-cell signaling and activation pathways in vitro and in vivo. C1 Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Frederick, MD 21702 USA. Natl Human Genome Res Lab, Lab Genet Dis Res, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Gen Divers, Frederick, MD 21702 USA. Frederick Canc Res & Dev Ctr, SAIC, Frederick, MD 21702 USA. Morgan State Univ, Dept Biol, Baltimore, MD 21239 USA. RP Samuel, KP (reprint author), Morgan State Univ, Dept Biol, Spencer Hall,Rm 110,1700 Cold Spring Ln, Baltimore, MD 21251 USA. EM ksamuel@moac.morgan.edu FU NCRR NIH HHS [2P20RR011606-02] NR 58 TC 31 Z9 31 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 JUN 19 PY 1998 VL 273 IS 25 BP 15727 EP 15733 DI 10.1074/jbc.273.25.15727 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200064 PM 9624170 ER PT J AU Boge, M Wyss, S Bonifacino, JS Thali, M AF Boge, M Wyss, S Bonifacino, JS Thali, M TI Membrane-proximal tyrosine-based signal mediates internalization of the HIV-1 envelope glycoprotein via interaction with the AP-2 clathrin adaptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CYTOPLASMIC DOMAIN; SORTING SIGNALS; PROTEIN; GP41; TAIL; ENDOCYTOSIS; ASSOCIATION; MECHANISM; MATRIX AB The envelope glycoprotein (Env) of human immunodeficiency virus, type 1 (HIV-1) undergoes rapid internalization after its transport to the cell surface. Env internalization is dependent upon information contained within the cytosolic domain of the protein, Here, we report that the cytosolic domain of Env binds specifically to the medium chain, mu 2, of the clathrin-associated protein complex AP-2, as well as to the complete AP-2 complex. The Env cytosolic domain contains two highly conserved tyrosine-based motifs ((YSPL)-S-712 and (YHRL)-H-768), both of which are capable of binding to mu 2 when presented as short peptides, However, only the membrane-proximal motif (YSPL)-S-712 binds to mu 2 and is required for internalization in the context of the whole cytosolic domain of Env, A glycine residue (Gly(711)) adjacent to the (YSPL)-S-712 motif is also important for binding to mu 2/AP-2 and internalization. These observations suggest that the accessibility of the membrane-proximal GY(712)SPL to mu 2/AP-2 determines its function as a signal for recruitment of HIV-1 Env into clathrin-coated pits and its ensuing internalization. C1 CHU Vaudois, Inst Microbiol, CH-1011 Lausanne, Switzerland. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Thali, M (reprint author), CHU Vaudois, Inst Microbiol, CH-1011 Lausanne, Switzerland. NR 31 TC 130 Z9 130 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 JUN 19 PY 1998 VL 273 IS 25 BP 15773 EP 15778 DI 10.1074/jbc.273.25.15773 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200070 PM 9624176 ER PT J AU Factor, VM Kiss, A Woitach, JT Wirth, PJ Thorgeirsson, SS AF Factor, VM Kiss, A Woitach, JT Wirth, PJ Thorgeirsson, SS TI Disruption of redox homeostasis in the transforming growth factor-alpha c-myc transgenic mouse model of accelerated hepatocarcinogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARTERY ENDOTHELIAL-CELLS; REACTIVE-OXYGEN; HYDROGEN-PEROXIDE; THIOREDOXIN REDUCTASE; MITOCHONDRIAL-DNA; FACTOR-BETA; SUPEROXIDE-DISMUTASE; LIPID-PEROXIDATION; HUMAN-FIBROBLASTS; OXIDATIVE DAMAGE AB In previous studies we have demonstrated that transforming growth factor (TGF)-alpha/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that mag be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors, By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2',7'-dichlorofluorescin diacetate, was significantly elevated in TGF-alpha/c-myc transgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in Lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However; hepatic tumors which developed in TGF-alpha/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathiolae peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-alpha and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-alpha/c-myc mouse model. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, NIH, 37 Convent Dr,MSC4255,Bldg 37,Rm 3C28, Bethesda, MD 20892 USA. NR 81 TC 90 Z9 91 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 JUN 19 PY 1998 VL 273 IS 25 BP 15846 EP 15853 DI 10.1074/jbc.273.25.15846 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200079 PM 9624185 ER PT J AU Hong, JX Lee, FJS Patton, WA Lin, CY Moss, J Vaughan, M AF Hong, JX Lee, FJS Patton, WA Lin, CY Moss, J Vaughan, M TI Phospholipid- and GTP-dependent activation of cholera toxin and phospholipase D by human ADP-ribosylation factor-like protein 1 (HARL1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE-BINDING PROTEINS; ARF-FAMILY; SELECTIVE AMPLIFICATION; CLONING; PURIFICATION; EXPRESSION; MEMBER; BRAIN; GENE; RIBOSYLTRANSFERASE AB AY)P-ribosylation factors (ARFs), 20-kDa guanine nucleotide-binding proteins named for their ability to activate cholera toxin (CT) ADP-ribosyltransferase activity, have a critical role in vesicular transport slid activate a phospholipase D (PLD) isoform. Although ARF-like (ARL) proteins are very similar in sequence to ARFs, they were initially believed not to activate CT or PLD. mRNA for human ATL1. (hARL1), which is 57% identical in amino acid sequence to hARF1, is present in all tissues, with the highest amounts in kidney and pancreas and barely detectable amounts in brain. Relative amounts of hARL1 protein were similar to mRNA levels. Purified hARL1 (rARL1) synthesized in Escherichia coli had less activity toward PLD than did rARF1, although PLD activation by both proteins was guanosine guanosine 5'-(gamma-thio)triphosphate (GTP gamma S)-dependent. ARL1 stimulation of CT-catalyzed ADP-ribosylation was considerably less than that by rARF1 and was phospholipid dependent. GTP gamma S-binding by rARL1 was also phospholipid- and detergent-dependent, and in assays containing phosphatidylserine, was greater than that by rARF1. In vitro, the activities of rARL1 and rARF1 are similar. Rather than being a member of a separate subfamily, hARL1, which activates PLD and CT in a phospholipid-dependent manner, appears to be part of a continuum of ARF family proteins. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Natl Taiwan Univ, Sch Med, Inst Mol Med, Taipei 100, Taiwan. RP Lee, FJS (reprint author), 7 Chung Shan S Rd, Taipei, Taiwan. OI LEE, FANG-JEN/0000-0002-2167-2426 NR 31 TC 29 Z9 30 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 19 PY 1998 VL 273 IS 25 BP 15872 EP 15876 DI 10.1074/jbc.273.25.15872 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV238 UT WOS:000074284200083 PM 9624189 ER PT J AU Vernick, KD McCutchan, TF AF Vernick, KD McCutchan, TF TI A novel class of supercoil-independent nuclease hypersensitive site is comprised of alternative DNA structures that flank eukaryotic genes SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE nucleic acid conformation; deoxyribonuclease; nuclease hypersensitivity; genome organization; transcription termination ID ALCOHOL-DEHYDROGENASE; DROSOPHILA-MELANOGASTER; TRANSCRIPTION TERMINATION; KINETOPLAST DNA; MESSENGER-RNA; GENOMIC DNA; SEQUENCES; PROTEIN; INTEGRATION; RECOGNITION AB The cell makes a fundamental distinction between genes and non-gene sequences, which mechanistically underlies the process of gene regulation. Here, we describe the properties of a novel class of genetic sites that reproducibly flank and delineate the coding regions of the eukaryotic genes tested. Defined in vitro reaction conditions that include altered solvation and elevated temperature rendered the sites hypersensitive to nuclease cleavage. Consequently, the complete coding regions of the Drosophila genes tested were quantitatively excised from genomic DNA or genomic clones by this treatment. Identical reaction products were generated from linear or supercoiled DNA substrates. Chemical modification and fine-structure analysis of several cleavage sites flanking Drosophila genes showed that the cleavage sites were stable nucleic acid structures that contained specific arrangements of paired and unpaired nucleotides. The locations and properties of the cleavage sites did not correspond to previously known nuclease hypersensitive sites nor to known alternative DNA structures. Thus, they appear to represent a new class of genetic site. Ln a deletion analysis, the minimal sequence information necessary to direct in vitro nuclease cleavage 3' to the Drosophila GART gene colocalized with the signal required for termination of transcription in vitro. The data suggest that a novel class of DNA site with distinct structural properties encodes biological information by marking the boundaries of at least some gene expression units in organisms as diverse as Plasmodium and Drosophila. (C) 1998 Academic Press Limited. C1 NYU, Sch Med, Dept Med & Mol Parasitol, New York, NY 10010 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Vernick, KD (reprint author), NYU, Sch Med, Dept Med & Mol Parasitol, 341 E 25th St, New York, NY 10010 USA. NR 51 TC 5 Z9 5 U1 1 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 19 PY 1998 VL 279 IS 4 BP 737 EP 751 DI 10.1006/jmbi.1998.1806 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX265 UT WOS:000074496900006 PM 9642057 ER PT J AU Biswas, I Yamamoto, A Hsieh, P AF Biswas, I Yamamoto, A Hsieh, P TI Branch migration through DNA sequence heterology SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE recombination; Holliday junction; branch migration; mismatches ID MEDIATED STRAND EXCHANGE; HOMOLOGOUS RECOMBINATION; HOLLIDAY JUNCTION; ESCHERICHIA-COLI; BASE MISMATCHES; RUVAB PROTEINS; RECA; INSERTIONS; KINETICS; REPAIR AB Branch migration of a DNA Holliday junction is a key step in genetic recombination. Previously, it was shown that a single base-pair heterology between two otherwise identical DNA sequences is a substantial barrier to passage of a Holliday junction during spontaneous branch migration. Here, we exploit this inhibitory effect of sequence heterology to estimate the step size of branch migration. We also devise a simulation of branch migration through mismatched base-pairs to arrive at the underlying molecular basis for the block to branch migration imposed by sequence heterology. Based on the observation that two adjacent sequence heterologies exert their effects on branch migration more or less independently, we conclude that the step size of branch migration is quite small, of the order of one or two base-pairs per migratory step. Comparison of branch migration experiments through a single base-pair heterology with simulations of a random walk through sequence heterology suggests that the inhibition of branch migration is largely attributable to a thermodynamic barrier arising from the formation of unpaired or mispaired bases in heteroduplex DNAs. (C) 1998 Academic Press Limited. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Hsieh, P (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. NR 35 TC 38 Z9 38 U1 0 U2 4 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 19 PY 1998 VL 279 IS 4 BP 795 EP 806 DI 10.1006/jmbi.1998.1769 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX265 UT WOS:000074496900010 PM 9642061 ER PT J AU Krylov, D Barchi, J Vinson, C AF Krylov, D Barchi, J Vinson, C TI Inter-helical interactions in the leucine zipper coiled coil dimer: pH and salt dependence of coupling energy between charged amino acids SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE coiled coil; coupling energy; electrostatic interactions; leucine zipper; thermodynamic cycle ID SURFACE ELECTROSTATIC INTERACTIONS; TRANSCRIPTION FACTOR; CRYSTAL-STRUCTURE; BASIC REGION; DNA-BINDING; ION-PAIRS; STABILITY; PROTEINS; DIMERIZATION; SPECIFICITY AB We have investigated the physical nature of the observed coupling energy (Delta Delta Delta G(int)) between the charged side-chains of the three inter-helical g <----> (i, i' + 5) pairs (E <----> R, E <----> K, and E <----> E) in the leucine zipper coiled coil dimer. Circular dichorism (CD) spectroscopy measured the thermal stability of eight proteins derived from the basic region leucine zipper domain of chicken VBP, the mammalian TEF at seven pHs and three KCl concentrations. Data from these proteins were used to construct double mutant alanine thermodynamic cycles and determine coupling energies (Delta Delta Delta G(int)) for the three g <----> e' pairs. The attractive E <----> R coupling energy of -0.6 kcal mol(-1) at low salt decreases to -0.2 kcal mol(-1) at high salt. The E <----> K coupling energy of -0.5 kcal mol(-1) at low salt decreases to -0.1 kcal mol(-1) at high salt. The repulsive E <----> E coupling energy of +0.8 kcal mol(-1) at low salt drops to +0.4 at high salt. Reducing the pH to 2.2 halved the attractive coupling energy for the E <----> R and E <----> K pairs while abolishing the repulsion of the E <----> E pair. C-13 NMR of a protein selectively labeled with [C-13(delta)] glutamate that contained three E <----> R and one R <----> E pair identified four glutamates shifted upfield. We suggest that this is due to electronic perturbation of glutamates in inter-helical E <----> R interactions. Taken together, these data indicate that the E <----> R coupling energy of -0.5 kcal mol(-1) at pH 7.4 and 150 mM KCl has an electrostatic component. (C) 1998 Academic Press Limited. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 4D06, Bethesda, MD 20892 USA. NR 45 TC 96 Z9 97 U1 0 U2 10 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 19 PY 1998 VL 279 IS 4 BP 959 EP 972 DI 10.1006/jmbi.1998.1762 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX265 UT WOS:000074496900024 PM 9642074 ER PT J AU Varmus, H Nathanson, N AF Varmus, H Nathanson, N TI Science and the control of AIDS SO SCIENCE LA English DT Editorial Material C1 NIH, Off AIDS Res, Bethesda, MD 20892 USA. RP Varmus, H (reprint author), NIH, Off AIDS Res, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 19 PY 1998 VL 280 IS 5371 BP 1815 EP 1815 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZV618 UT WOS:000074323800001 PM 9669926 ER PT J AU Smith, MW Dean, M Carrington, M Winkler, C O'Brien, SJ AF Smith, MW Dean, M Carrington, M Winkler, C O'Brien, SJ TI Progression to AIDS - Response SO SCIENCE LA English DT Letter C1 NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21702 USA. RP Smith, MW (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21702 USA. RI Smith, Michael/B-5341-2012 NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 19 PY 1998 VL 280 IS 5371 BP 1820 EP 1820 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZV618 UT WOS:000074323800009 ER PT J AU Celentano, DD Dilorio, C Hartwell, T Kelly, J Magana, R Maibach, E O'Leary, A Pequegnat, W Rotheram-Borus, MJ Schilling, R AF Celentano, DD Dilorio, C Hartwell, T Kelly, J Magana, R Maibach, E O'Leary, A Pequegnat, W Rotheram-Borus, MJ Schilling, R CA NIMH Multisite HIV Prevention Trial Grp TI The NIMH multisite HIV prevention trial: Reducing HIV sexual risk behavior SO SCIENCE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSMISSION; AIDS; MEN AB The efficacy of a behavioral intervention to reduce human immunodeficiency virus (HIV) risk behaviors was tested in a randomized, controlled trial with three high-risk populations at 37 clinics from seven sites across the United States. Compared with the 1855 individuals in the control condition, the 1851 participants assigned to a small-group, seven-session HIV risk reduction program reported fewer unprotected sexual acts, had higher levels of condom use, and were more likely to use condoms consistently over a 12-month follow-up period. On the basis of clinical record review, no difference in overall sexually transmitted disease (STD) reinfection rate was found between intervention and control condition participants. However, among men recruited from STD clinics, those assigned to the intervention condition had a gonorrhea incidence rate one-half that of those; in the control condition. Intervention condition participants also reported fewer STD symptoms over the 12-month follow-up period. Study outcomes suggest that behavioral interventions can reduce HIV-related sexual risk behavior among low-income women and men served in public health settings. Studies that test strategies for reducing sexual risk behavior over longer periods of time are needed, especially with populations that remain most vulnerable to HIV infection. C1 NIMH, NIH, Rockville, MD 20857 USA. RP Celentano, DD (reprint author), NIMH, NIH, Parklawn Bldg,Room 18-101,5600 Fishers Lane, Rockville, MD 20857 USA. RI Potter, Jennifer/C-6720-2008; OI Potter, Jennifer/0000-0002-7250-4422; Maibach, Edward/0000-0003-3409-9187 NR 17 TC 211 Z9 211 U1 1 U2 5 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 JUN 19 PY 1998 VL 280 IS 5371 BP 1889 EP 1894 DI 10.1126/science.280.5371.1889 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZV618 UT WOS:000074323800047 ER PT J AU Sternberg, EM AF Sternberg, EM TI The powerful placebo. From ancient priest to modern physician SO SCIENCE LA English DT Book Review C1 NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bldg 10,Room 2D-46,10 Ctr Dr MSC 1284, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 19 PY 1998 VL 280 IS 5371 BP 1901 EP 1902 DI 10.1126/science.280.5371.1901 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZV618 UT WOS:000074323800049 ER PT J AU Schwan, TG Hinnebusch, BJ AF Schwan, TG Hinnebusch, BJ TI Bloodstream- versus tick-associated variants of a relapsing fever bacterium SO SCIENCE LA English DT Article ID VARIABLE MAJOR PROTEINS; OUTER SURFACE PROTEIN; BORRELIA-HERMSII; ANTIGENIC VARIATION; BURGDORFERI; GENES; OSPC; CULTIVATION; SEQUENCE; EPITOPE AB The relapsing fever spirochete, Borrelia hermsii, alternates infections between a mammal and a tick vector. Whether the spirochete changes;phenotypically in the different hosts was examined by allowing the tick vector Ornithodoros hermsi to feed on mice infected with serotype 7 or serotype 8 of B. hermsii. Upon infection of ticks, the spirochetal serotype-specific variable major proteins (Vmps) 7 and 8 became undetectable and were replaced by Vmp33. This switch from a bloodstream- to tick-associated phenotype could be induced in culture by a decrease in temperature. After tick-bite transmission back to mice, the process was reversed and the spirochetes resumed expression of the same Vmp present in the previous infectious blood meal. C1 NIAID, Microbial Struct & Funct Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Schwan, TG (reprint author), NIAID, Microbial Struct & Funct Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM tom_schwan@nih.gov NR 34 TC 101 Z9 103 U1 1 U2 2 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 JUN 19 PY 1998 VL 280 IS 5371 BP 1938 EP 1940 DI 10.1126/science.280.5371.1938 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZV618 UT WOS:000074323800064 PM 9632392 ER PT J AU Menzo, S Sampaolesi, R Vicenzi, E Santagostino, E Liuzzi, G Chirianni, A Piazza, M Cohen, OJ Bagnarelli, P Clementi, M AF Menzo, S Sampaolesi, R Vicenzi, E Santagostino, E Liuzzi, G Chirianni, A Piazza, M Cohen, OJ Bagnarelli, P Clementi, M TI Rare mutations in a domain crucial for V3-loop structure prevail in replicating HIV from long-term non-progressors SO AIDS LA English DT Article DE V3 loop; selective pressure; variants; recombinant viruses; HIV-1 coreceptors; viral entry ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL-LINE; POLYMERASE CHAIN-REACTION; CHEMOKINE RECEPTOR GENE; REVERSE-TRANSCRIPTION; IN-VIVO; V3 LOOP; RETROVIRAL RECOMBINATION; NUCLEOTIDE SUBSTITUTIONS; DISEASE PROGRESSION AB Objective: To evaluate the role of the selective forces exerted by the host on the HIV-1 structures involved in viral entry. Design and methods: The V3 region of the env gene was analysed in cell-free HIV-1 RNA from 17 infected subjects: 11 long-term non-progressors (LTNP) and six symptomless, typical progressor patients. To evaluate the potential biological significance of one of the rare variants detected in the LTNP, it was reproduced by recombinant PCR into a HIV-1 molecular clone. Results: The intrapatient divergence of the V3-loop sequences averaged 8.62% in LTNP and 5.29% in progressors, although LTNP displayed lower divergence from the clade B consensus than progressors (16.65 and 19.76% respectively). The analysis of non-synonymous and synonymous substitutions indicated that selective pressure was exerted in this region in both LTNP and progressors. Individual peculiarities (unique and rare V3-loop variants) emerged, however, in most sequences from LTNP, and variants bearing mutations in a domain crucial for the V3-loop structure were more prevalent in LTNP (P = 0.0012). The pNL4-3-derived mutant reproducing a V3-loop variant detected in a LTNP was efficiently expressed upon transfection, but the mutant virus was nearly completely unable to infect CD4+ cell lines, activated primary peripheral blood lymphocytes, or monocyte-derived macrophages, suggesting that a defect impaired the entry phase of the replication cycle. Conclusions: The results indicate that host factors impose selective constraints on the evolution of the HIV-1 structures involved in viral entry. In LTNP, these factors are likely to force the virus into attenuated variants. (C) 1998 Lippincott-Raven Publishers. C1 Univ Ancona, Ist Microbiol, I-60100 Ancona, Italy. Univ Milan, San Raffaele Sci Inst, A Bianchi Bonomi Hemophilia & Thrombosis Ctr, Milan, Italy. Univ Naples Federico II, Ist Malattie Infett, Naples, Italy. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Trieste, Dipartimento Sci Biomed, Trieste, Italy. RP Menzo, S (reprint author), Univ Ancona, Ist Microbiol, Via P Ranieri, I-60100 Ancona, Italy. RI Clementi, Massimo/F-6646-2013; OI Menzo, Stefano/0000-0002-4425-3750; Clementi, Massimo/0000-0002-7461-5898; Vicenzi, Elisa/0000-0003-0051-3968 NR 77 TC 20 Z9 21 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 18 PY 1998 VL 12 IS 9 BP 985 EP 997 DI 10.1097/00002030-199809000-00004 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 102HN UT WOS:000074918500005 PM 9662194 ER PT J AU Maurizi, MR AF Maurizi, MR TI Proteasome assembly: Biting the hand ... SO CURRENT BIOLOGY LA English DT Article ID 20S PROTEASOME AB Proteasome assembly is regulated to ensure the enzyme is inactive until its active sites are compartmentalized within an interior aqueous chamber. In yeast, this depends on a dedicated chaperone that is trapped within the nascent proteasome, and degraded on maturation of the proteolytic subunits. (C) Current Biology Ltd. C1 NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, Bldg 37,Room 1B09, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 18 PY 1998 VL 8 IS 13 BP R453 EP R456 DI 10.1016/S0960-9822(98)70291-X PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZW435 UT WOS:000074410700009 PM 9651672 ER PT J AU Howard, OMZ Oppenheim, JJ Hollingshead, MG Covey, JM Bigelow, J McCormack, JJ Buckheit, RW Clanton, DJ Turpin, JA Rice, WG AF Howard, OMZ Oppenheim, JJ Hollingshead, MG Covey, JM Bigelow, J McCormack, JJ Buckheit, RW Clanton, DJ Turpin, JA Rice, WG TI Inhibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: A candidate for chemotherapeutic and microbicidal application SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INFECTION; BINDING; ENTRY; AIDS; CCR5; LESTR/FUSIN; COFACTOR; LIGAND; SDF-1; CELLS AB Select chemokine receptors act as coreceptors for HIV-1 entry into human cells and represent targets for antiviral therapy. In this report we describe a distamycin analogue, 2,2'-[4,4'-[[aminocarbonyl]amino]bis[N,4'-di[pryrrole-2-carboxamide-1,1'-dimethyl]]-6,8-naphthalenedisulfonic acid] hexasodium salt (NSC 651016), that selectively inhibited chemokine binding to CCR5, CCR3, CCRl,and CXCR4, but not to CXCR2 or CCR2b, and blocked chemokine-induced calcium flux. Inhibition was not due to nonspecific charge interactions at the cell surface, but was based on a specific competition for the ligand receptor interaction sites since the inhibitory effect was specific for some but not all chemoattractant receptors. NSC 651016 inhibited in vitro replication of a wide range of HIV-1 isolates, as well as HIV-2 and SIV, and exhibited in vivo anti-HIV-1 activity in a murine model. In contrast, a distamycin analogue with similar structure and charge and the monomeric form of NSC 651016 demonstrated no inhibitory effects. These data demonstrate that molecules which interfere with HIV-1 entry into cells by targeting specific chemokine coreceptors can provide a viable approach to anti-HIV-1 therapy. NSC 651016 represents an attractive candidate for the chemotherapeutic treatment of HIV-1 infection and as a microbicide to prevent the sexual transmisssion of HIV-1. Moreover, NSC 651016 can serve as a template for medicinal chemical modifications leading to more effective antivirals. C1 NCI, Lab Antiviral Drug Mechanisms, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, AntiAIDS Virus Drug Screening Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Univ Vermont, Dept Pharmacol, Burlington, VT 05405 USA. Univ Vermont, Vermont Reg Canc Ctr, Burlington, VT 05405 USA. Frederick Res Ctr, So Res Inst, Frederick, MD 21702 USA. RP Rice, WG (reprint author), NCI, Lab Antiviral Drug Mechanisms, Frederick Canc Res & Dev Ctr, SAIC Frederick, Bldg 431 T-B,POB B, Frederick, MD 21702 USA. EM rice@dtpax2.ncifcrf.gov RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 NR 41 TC 77 Z9 81 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2184 EP 2193 DI 10.1021/jm9801253 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600003 PM 9632350 ER PT J AU Jacobson, KA Kim, YC Wildman, SS Mohanram, A Harden, TK Boyer, JL King, BF Burnstock, G AF Jacobson, KA Kim, YC Wildman, SS Mohanram, A Harden, TK Boyer, JL King, BF Burnstock, G TI A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X(1) receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GATED ION CHANNELS; PHOSPHOLIPASE-C; PPADS; PURINOCEPTORS; RESPONSES; P-2X-PURINOCEPTORS; AGONISTS; OOCYTES; FAMILY AB Analogues of the P2 receptor antagonists pyridoxal-5'-phosphate and the 6-azophenyl-2',4'-disulfonate derivative (PPADS), in which the phosphate group was cyclized by esterification to a CH2OH group at the 4-position, were synthesized. The cyclic pyridoxine-alpha(4,5)-monophosphate, compound 2 (MRS 2219), was found to be a selective potentiator of ATP-evoked responses at rat P2X(1) receptors with an EC50 value of 5.9 +/- 1.8 mu M, while the corresponding 6-azophenyl-2',5'-disulfonate derivative, compound 3 (MRS 2220), was a selective antagonist. The potency of compound 3 at the recombinant P2X(1) receptor (IC50 10.2 +/- 2.6 mu M) was lower than PPADS (IC50 98.5 +/- 5.5 nM) or iso-PPADS (IC50 42.5 +/- 17.5 nM), although unlike PPADS its effect was reversible with washout and surmountable. Compound 3 showed weak antagonistic activity at the rat P2X(3) receptor (IC50 58.3 +/- 0.1 mu M), while at recombinant rat P2X(2) and P2X(4) receptors no enhancing or antagonistic properties were evident. Compounds 2 and 3 were found to be inactive as either agonists or antagonists at the phospholipase C-coupled P2Y(1) receptor of turkey erythrocytes, at recombinant human P2Y(2) and P2Y(4) receptors, and at recombinant rat P2Y(6) receptors. Similarly, compounds 2 and 3 did not have measurable affinity at adenosine Al, A(2A), Or A(3) receptors. The lack of an aldehyde group in these derivatives indicates that Schiffs base formation with the P2X1 receptor is not necessarily required for recognition of pyridoxal phosphate derivatives. Thus, compounds 2 and 3 are relatively selective pharmacological probes of P2X(1) receptors, filling a long-standing need ill the P2 receptor field, and are also important lead compounds for future studies. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Royal Free Hosp, Sch Med, Autonom Neurosci Inst, London NW3 2PF, England. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [HL34322, HL54889]; NIGMS NIH HHS [GM38213] NR 40 TC 44 Z9 44 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2201 EP 2206 DI 10.1021/jm980183o PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600005 PM 9632352 ER PT J AU Fan, Y Weinstein, JN Kohn, KW Shi, LM Pommier, Y AF Fan, Y Weinstein, JN Kohn, KW Shi, LM Pommier, Y TI Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID WATER-SOLUBLE DERIVATIVES; ANTITUMOR-ACTIVITY; EUKARYOTIC TOPOISOMERASE; BIOLOGICAL-ACTIVITY; BASE STACKING; ANALOGS; INHIBITION; SEQUENCE; SITE; RING AB The present studies provide a three-dimensional model for the postulated ternary cleavable complex of topoisomerase I(top1), DNA, and camptothecin(CPT). Molecular simulations were done using the AMBER force field. The results suggest that a ternary cleavable complex might be stabilized by several hydrogen bonds in the binding site. In this proposed "drug-stacking" model, CPT is pseudointercalated in the top1-linked DNA cleavage site and interacts with the protein near its catalytic tyrosine through hydrogen bonding and stacking. The structural model is consistent with the following experimental observations: (i) the N3 position of the 5' terminal purine of the cleaved DNA strand is readily alkylated by 7-chloromethyl 10,11-methylenedioxy CPT; (ii) CPT generally tolerates substituents at positions 7, 9, and 10 but is inactivated by additions at position 12; (iii) 10,11-methylenedioxy (MDO) CPT is much more potent than 10,11-dimethoxy (DMO) CPT; (iv) the lactone portion of CPT is essential for top1 inhibitory activity; (v) 20S derivatives of CPT are much more potent than the 20R analogues; (vi) a catalytic tyrosine hydroxyl in top1 covalently links to the 3' terminal base, T, of the cleaved DNA strand; and (vii) top1 mutation Asn722Ser leads to CPT resistance. A total of 18 camptothecin derivatives with different DNA cleavage potencies were docked into the hypothetical cleavable complex binding site to test and refine the model. These studies provide insight into a possible mechanism of top1 inhibition by CPT derivatives and suggest rational approaches for the design of new CPT derivatives. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Weinstein, JN (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. NR 57 TC 159 Z9 165 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2216 EP 2226 DI 10.1021/jm9605445 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600007 PM 9632354 ER PT J AU Sadler, BR Cho, SJ Ishaq, KS Chae, K Korach, KS AF Sadler, BR Cho, SJ Ishaq, KS Chae, K Korach, KS TI Three-dimensional quantitative structure-activity relationship study of nonsteroidal estrogen receptor ligands using the comparative molecular field analysis cross-validated r(2)-guided region selection approach SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DIETHYLSTILBESTROL METABOLITES; ESTRADIOL DERIVATIVES; BINDING ORIENTATION; BIOLOGICAL-ACTIVITY; ANALOGS; STEREOCHEMISTRY; STEROIDS; AFFINITY; PROBES AB A newly developed comparative molecular field analysis (CoMFA) technique, the cross-validated r(2)-guided region selection (CoMFA/q(2)-GRS) method, has been used to build a quantitative structure-activity relationship (3D-QSAR) f'or nonsteroidal estrogen receptor (ER) ligands. Ligands included in this study belong to a series of diethylstilbestrol (DES) and indenestrol analogues whose affinities for the mouse ER (mER) have been determined in our laboratory. The final model utilized 30 compounds and yielded a q(2)GRs (cross-validated r(2), guided region selection) of 0.796, as compared to a q(2) of 0.120 for conventional CoMFA, with a standard error of prediction of 0.594 at 3 principal components. This model was used to visualize steric and electrostatic features of the ligands that correspond with ER binding affinity. Results obtained from the CoMFA steric and electrostatic plots of this model have also been compared to information from the ER binding affinities of substituted estradiol analogues. This is in an effort to determine structural features of compounds in the CoMFA analysis that may correspond to those of the estradiol analogues and to further clarify the mode of binding of nonsteroidal ER ligands. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. NIEHS, Lab Reprod & Dev Biol, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Lab Mol Modeling, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. RP Ishaq, KS (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 32 TC 56 Z9 58 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2261 EP 2267 DI 10.1021/jm9705521 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600012 PM 9632359 ER PT J AU Beutler, JA Hamel, E Vlietinck, AJ Haemers, A Rajan, P Roitman, JN Cardellina, JH Boyd, MR AF Beutler, JA Hamel, E Vlietinck, AJ Haemers, A Rajan, P Roitman, JN Cardellina, JH Boyd, MR TI Structure-activity requirements for flavone cytotoxicity and binding to tubulin SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIMITOTIC AGENTS; GUTIERREZIA-MICROCEPHALA; ANTICANCER AGENTS; ANTITUMOR AGENTS; CELL-LINES; POLYMERIZATION; CONSTITUENTS; PLANTS; DOLASTATIN-10; VINBLASTINE AB A series of 79 flavones related to centaureidin (3,6,4'-trimethoxy-5,7,3'-trihydroxyflavone 1) was screened for cytotoxicity in the NCI in vitro 60-cell line human tumor screen. The resulting cytotoxicity profiles of these flavones were compared for degree of similarity to the profile of 1. Selected compounds were further evaluated with in vitro assays of tubulin polymerization and [H-3]colchicine binding to tubulin. Maximum potencies for tubulin interaction and production of differential cytotoxicity profiles characteristic of 1 were observed only with compounds containing hydroxyl substituents at C-3' and C-5 and methoxyl groups at C-3 and C-4'. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. Univ Antwerp, B-2610 Antwerp, Belgium. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 54 TC 89 Z9 94 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2333 EP 2338 DI 10.1021/jm970842h PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600019 PM 9632366 ER PT J AU Yu, QS Greig, NH Holloway, HW Brossi, A AF Yu, QS Greig, NH Holloway, HW Brossi, A TI Syntheses and anticholinesterase activities of (3aS)-N-1,N-8-bisnorphenserine, (3aS)-N-1,N-8-bisnorphysostigmine, their antipodal isomers, and other potential metabolites of phenserine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE; CARBAMATE ANALOGS; PHYSOSTIGMINE; BUTYRYLCHOLINESTERASE; (-)-ESEROLINE; INHIBITION; ACETYLCHOLINESTERASE; (-)-PHYSOSTIGMINE; CHOLINESTERASES AB Hydrolysis of the carbamate side chains in phenserine [(-)1] and physostigmine [(-)2] yields the metabolite (-)-eseroline (3), and the red dye rubreserine (4) on air oxidation of the former compound. Both compounds lacked anticholinesterase activity in concentrations up to 30 mM, which would be unachievable in vivo. A second group of potential metabolites of 1 and 2 are the N-1,N-8-bisnorcarbamates (-)9 and (-)10, prepared from (3aS)-N-8-benzylnoresermethole (-)12 by the carbinolamine route. These entirely novel compounds proved to be highly potent inhibitors of acetylcholinesterase [(-)9] and of acetyl- and butyrylcholinesterase (AChE and BChE) [(-)10], respectively. To elucidate further the structure/anticholinesterase activity relationship of the described compounds, the antipodal isomers (3aR)-N-1,N-8-bisnorcarbamates (+)9 and (+)10 were likewise synthesized from (3aR)-N-8-benzylnoresermethole (+)12 and assessed. The compounds possessed moderate but less potent anticholinesterase activity, with the same selectivity as their 3aS enantiomers. Finally, the anticholinesterase activities of intermediates N-1,N-8-bisnorbenzylcarbamates (-)18, (-)19, (+)18, and (+)19, also novel compounds, were additionally measured. The 3aS enantiomers proved to be potent and selective inhibitors of BChE, particularly (-)19, whereas the antipodal isomers lacked activity. C1 NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr 4E02, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr 4E02, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 35 TC 19 Z9 20 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2371 EP 2379 DI 10.1021/jm9800494 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600023 PM 9632370 ER PT J AU Zhang, CM Izenwasser, S Katz, JL Terry, PD Trudell, ML AF Zhang, CM Izenwasser, S Katz, JL Terry, PD Trudell, ML TI Synthesis and dopamine transporter affinity of the four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACID METHYL-ESTERS; LIGAND-BINDING; UPTAKE INHIBITORS; COCAINE RECEPTOR; ANALOGS; SITES; POTENT; COMFA; QSAR AB All four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (K-i) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found, to be 100-3000;fold less potent (K-i = 5-96 mu M) than cocaine and 2 beta-(methoxycarbonyl)-3 beta-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3 alpha-phenyl isomers (6c, 6d) were more potent than the 3 beta-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2. I]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2 beta-(methoxycarbonyl)-3-phenyltropanes. C1 Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. NIDA, Div Intramural Res, Baltimore, MD 21224 USA. RP Trudell, ML (reprint author), Univ New Orleans, Dept Chem, New Orleans, LA 70148 USA. EM MLTCM@UNO.EDU RI Izenwasser, Sari/G-9193-2012; OI Katz, Jonathan/0000-0002-1068-1159 FU NCI NIH HHS [R29 CA08055] NR 36 TC 20 Z9 20 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 18 PY 1998 VL 41 IS 13 BP 2430 EP 2435 DI 10.1021/jm9705061 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZV713 UT WOS:000074333600028 PM 9632375 ER PT J AU Tindall, KR Glaab, WE Umar, A Risinger, JI Koi, M Barrett, JC Kunkel, TA AF Tindall, KR Glaab, WE Umar, A Risinger, JI Koi, M Barrett, JC Kunkel, TA TI Complementation of mismatch repair gene defects by chromosome transfer SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 5th International Conference on Mechanisms of Antimutagenesis and Anticarcinogenesis (5th ICMAA) CY DEC 02-06, 1996 CL OKAYAMA, JAPAN DE mismatch repair; complementation; chromosome transfer; hMSH2; hMSH3; hMLH1 ID CANCER CELL-LINES; MICROSATELLITE INSTABILITY; TUMOR-CELLS; DNA-REPLICATION; GENOME INSTABILITY; ENDOMETRIAL CANCER; COLON-CANCER; DEFICIENCY; HETERODIMER; EXTRACTS AB The study of the multiple functions of mismatch repair genes in humans is being facilitated by the use of human tumor cell lines carrying defined MMR gene mutations. Such cell Lines have elevated spontaneous mutation rates and may accumulate mutations in other genes, some of which could be causally related to the phenotypes of these cells. One approach to establish a cause-effect relationship between a MMR gene defect and a phenotype is to determine if that phenotype is reversed when a normal chromosome carrying a wild-type MMR gene is introduced by microcell fusion. This approach has the advantage of presenting the gene in its natural chromosomal environment with normal regulatory controls and at a reasonable dosage. The approach also limits candidate genes to only those encoded by the introduced chromosome and not elsewhere in the genome. Here we review studies demonstrating that hMSH2, hMSH3, hMSH6 and hMLH1 gene defects can each be complemented by transferring human chromosome 2, 5, 2 or 3, respectively. These transfers restore MMR activity, sensitivity to killings by MNNG, stability to microsatellite sequences and low spontaneous HPRT gene mutation rates. (C) 1998 Elsevier Science B,V. All rights reserved. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Curriculum Toxicol, Chapel Hill, NC 27599 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, E3-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Koi, Minoru/C-3489-2012; Koi, Minoru/G-9197-2014 NR 41 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 18 PY 1998 VL 402 IS 1-2 BP 15 EP 22 DI 10.1016/S0027-5107(97)00277-7 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 106TJ UT WOS:000075166300003 PM 9675233 ER PT J AU Schaaper, RM Dunn, RL AF Schaaper, RM Dunn, RL TI Effect of Escherichia coli dnaE antimutator mutants on mutagenesis by the base analog N-4-aminocytidine SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 5th International Conference on Mechanisms of Antimutagenesis and Anticarcinogenesis (5th ICMAA) CY DEC 02-06, 1996 CL OKAYAMA, JAPAN DE N-4-aminocytidine; E-coli DNA polymerase III; base-analog mutagenesis; dnaE antimutator allele; DNA mismatch repair; UvrABC nucleotide excision repair ID SPONTANEOUS MUTATION; REPLICATION; POLYMERASE; FIDELITY; SPECIFICITY; INCREASES; ALLELES; REPAIR; MOTIF AB Previous studies in our laboratory have identified a set of mutations in the Escherichia coli dnaE gene that confer increased accuracy of DNA replication (antimutators). The dnaE gene encodes the polymerase subunit of DNA polymerase III holoenzyme that replicates the E. coli chromosome. Here, we have investigated their effect on mutagenesis by the base analog N-4-aminocytidine (4AC). For three different mutational markers, rifampicin resistance, nalidixic acid resistance and lad forward mutagenesis, the dnaE911 allele reduced 4AC-induced mutagenesis by approximately 2.5-fold, while the dnaE915 allele reduced it by 2.5-, 3.5- and 6.5-fold, respectively. We also investigated the dependence of 4AC mutagenesis on mutations in the MutHLS mismatch repair system and the UvrABC nucleotide excision repair system. The results show that mutagenesis by 4AC is unaffected by defects in either system. The combined results point to the critical role of the DNA polymerase in preventing mutations by base analogs. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Schaaper, RM (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 24 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 18 PY 1998 VL 402 IS 1-2 BP 23 EP 28 DI 10.1016/S0027-5107(97)00278-9 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 106TJ UT WOS:000075166300004 PM 9675236 ER PT J AU Kozmin, SG Schaaper, RM Shcherbakova, PV Kulikov, VN Noskov, VN Guetsova, ML Alenin, VV Rogozin, IB Makarova, KS Pavlov, YI AF Kozmin, SG Schaaper, RM Shcherbakova, PV Kulikov, VN Noskov, VN Guetsova, ML Alenin, VV Rogozin, IB Makarova, KS Pavlov, YI TI Multiple antimutagenesis mechanisms affect mutagenic activity and specificity of the base analog 6-N-hydroxylaminopurine in bacteria and yeast SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 5th International Conference on Mechanisms of Antimutagenesis and Anticarcinogenesis (5th ICMAA) CY DEC 02-06, 1996 CL OKAYAMA, JAPAN DE nucleic acid base analog; 6-N-hydroxylaminopurine; DNA replication fidelity; purine biosynthesis; antimutagenesis; mutagenic specificity ID DNA-POLYMERASE-EPSILON; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; MUTATIONAL SPECTRA; REPLICATION; SEQUENCES; GENE; ALIGNMENT; ADENINE; STRANDS AB Base analog 6-N-hydroxylaminopurine is a potent mutagen in variety of prokaryotic and eukaryotic organisms. In the review, we discuss recent results of the studies of HAP mutagenic activity, genetic control and specificity in bacteria and yeast with the emphasis to the mechanisms protecting living cells from mutagenic and toxic effects of this base analog. (C) 1998 Elsevier Science B.V. All rights reserved. C1 St Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. NIEHS, Res Triangle Pk, NC 27709 USA. Osaka Univ, Microbial Dis Res Inst, Dept Biochem & Mol Biol, Suita, Osaka 565, Japan. Russian Acad Sci, Inst Cytol & Genet, Siberian Branch, Novosibirsk 630090, Russia. CNR, Ist Tecnol Biomed Avanzate, I-20131 Milan, Italy. RP Pavlov, YI (reprint author), St Petersburg State Univ, Dept Genet & Breeding, Universitetskaya Emb 7-9, St Petersburg 199034, Russia. RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 NR 40 TC 31 Z9 32 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 18 PY 1998 VL 402 IS 1-2 BP 41 EP 50 DI 10.1016/S0027-5107(97)00280-7 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 106TJ UT WOS:000075166300006 PM 9675240 ER PT J AU Boone, CW Steele, VE Gaylor, D Kelloff, GJ AF Boone, CW Steele, VE Gaylor, D Kelloff, GJ TI Use of Druckrey analysis to quantitatively evaluate the chemopreventive efficacy of N-difluoromethylornithine (DFMO), a prototype proliferation inhibitor SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT 5th International Conference on Mechanisms of Antimutagenesis and Anticarcinogenesis (5th ICMAA) CY DEC 02-06, 1996 CL OKAYAMA, JAPAN DE cancer chemoprevention; TG.AC transgenic mouse; skin paint carcinogenesis; N-difluormethylornithine ID CARCINOGENESIS AB Druckrey analysis of the results of skin painting TG.AC transgenic mice with three different doses of benzo[a]pyrene was used to obtain quantitative estimates of the in vivo cancer chemopreventive efficacy of N-difluoromethylornithine. The percent decrease in mean rate of subvisible tumor development during the tumor latent period produced by 2000 ppm and 4000 ppm DFMO in the diet was 39% and 50%, respectively. Druckrey analysis was also successfully applied to transformations of published data on human cigarette smokers. The time before onset of lung cancer in 2% of smokers was prolonged 17 weeks for every cigarette per day not smoked. The Druckrey model, of substantiated validity because of the results in human smokers, provides a rapid quantitative screening method applicable to large numbers of candidate chemopreventive agents. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NCI, DCPC, Chemoprevent Branch, Bethesda, MD 20894 USA. Natl Ctr Toxicol Res, Little Rock, AR 72202 USA. RP Boone, CW (reprint author), NCI, DCPC, Chemoprevent Branch, Bethesda, MD 20894 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 18 PY 1998 VL 402 IS 1-2 BP 173 EP 177 DI 10.1016/S0027-5107(97)00295-9 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 106TJ UT WOS:000075166300021 PM 9675271 ER PT J AU Givol, I Givol, D Hughes, SH AF Givol, I Givol, D Hughes, SH TI Overexpression of p21(waf1/cip1) arrests the growth of chicken embryo fibroblasts that overexpress E2F1 SO ONCOGENE LA English DT Article DE retrovirus; growth suppressor; cell cycle; E2F; waf1/cip1 ID RETINOBLASTOMA SUSCEPTIBILITY GENE; CYCLIN-DEPENDENT KINASES; S-PHASE ENTRY; TRANSCRIPTION FACTOR; CELL-CYCLE; TRANS-ACTIVATION; BINDING PROTEIN; DNA-SYNTHESIS; EXPRESSION; APOPTOSIS AB P21(waf1/cip1) is a potent inhibitor of cell cycle progression and can inhibit the growth of both normal cells and cells transformed by a number of oncogenes. However, the ability of p21(waf1/cip1) to inhibit the growth of cells that overexpress the transcriptional transactivator E2F1 is controversial: it has been reported both that E2F1 can and cannot overcome the block in the cell cycle induced by p21(waf1/cip1). To avoid the complications that arise when such experiments are done with permanent cell lines, we tested the effects of overexpressing p21(waf1/cip1) and E2F1 in primary chicken embryo fibroblasts. In this system very high levels of E2F1 overexpression cause considerable apoptosis; however, the surviving cells still overexpress E2F1. These cells are transformed and their growth is blocked by overexpression of p21(waf1/cip1). C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Hughes, SH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NR 53 TC 10 Z9 10 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 18 PY 1998 VL 16 IS 24 BP 3115 EP 3122 DI 10.1038/sj.onc.1201849 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV030 UT WOS:000074261300004 PM 9671390 ER PT J AU Marston, NJ Ludwig, RL Vousden, KH AF Marston, NJ Ludwig, RL Vousden, KH TI Activation of p53 DNA binding activity by point mutation SO ONCOGENE LA English DT Article DE p53; DNA binding; cell cycle arrest; apoptosis ID HUMAN CANCER-CELLS; WILD-TYPE P53; MONOCLONAL-ANTIBODIES; TRANSCRIPTIONAL ACTIVATION; IMMUNOCHEMICAL ANALYSIS; MUTANT P53; PROTEIN; ARREST; TRANSFORMATION; APOPTOSIS AB The p53 tumor suppressor protein can adopt both latent, non-DNA binding and active, DNA binding forms, and p53 activity is thought to be regulated in cells, at least in part, through a conformational shift which leads to sequence specific DNA binding. In vitro, this allosteric regulation of DNA binding by p53 has been shown to be mediated through the C-terminus of the protein. We show here that although deletion of the C-terminal 16 amino acids of p53 did not activate DNA binding, deletion of a further eight amino acids resulted in constitutive activation of DNA binding activity. Simultaneous mutation of the three lysine residues within these eight amino acids also resulted in constitutive DNA binding activity, although this was reduced when only two of these lysines were altered, The deletion or point mutants of p53 showing constitutive DNA binding activity did not display clear evidence of DNA binding site specificity, although some binding site preference was seen with the point mutants. Each of the constitutively active p53 mutants retained transcriptional activity and induced both cell cycle arrest and apoptosis in transiently transfected cells at rates comparable with the wild type protein. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, W 7th St, Frederick, MD 21702 USA. NR 50 TC 10 Z9 10 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 18 PY 1998 VL 16 IS 24 BP 3123 EP 3131 DI 10.1038/sj.onc.1201856 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV030 UT WOS:000074261300005 PM 9671391 ER PT J AU White, A Lamb, PW Barrett, JC AF White, A Lamb, PW Barrett, JC TI Frequent downregulation of the KAI1(CD82) metastasis suppressor protein in human cancer cell lines SO ONCOGENE LA English DT Article DE KAI1 (CD82); metastasis suppressor gene; prostate cancer; transmembrane four superfamily ID LEUKEMIA-VIRUS TYPE-1; ANTIPROLIFERATIVE ANTIBODY; MONOCLONAL-ANTIBODY; SYNCYTIUM FORMATION; PROSTATE-CANCER; C33 ANTIGEN; T-CELLS; EXPRESSION; SURFACE; MOTILITY AB KAI1 is a metastasis suppressor gene on human chromosome 11p11.2 that encodes a glycoprotein of the transmembrane four superfamily, Reduced KAI1 expression associates with malignant progression of human prostatic, lung and pancreatic cancers, but the role of KAI1 protein in the malignant progression of other human cancers remains to be elucidated. We analysed KAI1 protein in normal and cancer cells of the prostate, ovary, bladder, endometrium, lung and melanocytes by Western blot to determine if KAI1 may be involved in multiple cancers. We also investigated the relationship of KAI1 expression and two other transmembrane four superfamily proteins, CD81 and CD9, in the cells. We found that KAI1 protein was downregulated in 31/42 of the cancer cell lines analysed. Alternatively, some ovarian, bladder and endometrial cells had distinct, heterogeneous KAI1 protein band patterns in Western blots that were due primarily to N-linked glycosylation. Most of the cancer cells expressed two other transmembrane four superfamily proteins, CD81 and CD9, Downregulation of KAI1 protein may be an indicator of metastatic potential in cancers of urogenital, gynecological, and pulmonary origin and in melanomas, KAI1 may also have post-translational modifications specific to tissue type or malignant progression. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Barrett, JC (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 56 Z9 65 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 18 PY 1998 VL 16 IS 24 BP 3143 EP 3149 DI 10.1038/sj.onc.1201852 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV030 UT WOS:000074261300007 PM 9671393 ER PT J AU Sekido, Y Ahmadian, M Wistuba, II Latif, F Bader, S Wei, MH Duh, FM Gazdar, AF Lerman, MI Minna, JD AF Sekido, Y Ahmadian, M Wistuba, II Latif, F Bader, S Wei, MH Duh, FM Gazdar, AF Lerman, MI Minna, JD TI Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene SO ONCOGENE LA English DT Article DE breast cancer; chromosome 3; homozygous deletion; somatic mutation; breakpoint cloning; lung cancer ID CELL LUNG-CANCER; CHROMOSOME 3P; HUMAN SEMAPHORIN; LINE U2020; FHIT GENE; CARCINOMAS; HETEROZYGOSITY; IDENTIFICATION; 3P14.2 AB Chromosome 3p abnormalities and allele loss are frequent in lung and breast cancers, and several lung cancer cell lines exhibit homozygous deletions of 3p indicating potential sites of tumor suppressor genes at regions 3p21.3, 3p14.2 and 3p12. We have identified and characterized a nem 3p21.3 homozygous deletion in a breast cancer cell line and the primary tumor that overlaps those previously described in small cell lung cancer (SCLC), This homozygous deletion is approximately 220 kb in length and represents a somatically acquired change in the primary breast cancer. Cloning and sequencing of the breakpoint demonstrated that this resulted from an interstitial deletion and precisely pinpoints this deletion within the three SCLC homozygous deletions previously reported. This deletion significantly narrows the minimum common deleted region to 120 kb and is distinct from the previously reported region that suppresses tumor formation of the murine A9 fibrosarcoma cells, These findings suggest that a common homozygous deletion region on 3p21.3 is important in both lung and breast cancers. It is likely that this very well characterized region either contains one tumor suppressor gene common to both tumor types or two closely linked tumor suppressor genes specific for each tumor. C1 Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA. NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Biol Carcinogenesis & Dev Program, SAIC Frederick, Frederick, MD 21702 USA. RP Minna, JD (reprint author), Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. RI Sekido, Yoshitaka/P-9756-2015 FU NCI NIH HHS [R01 CA71618] NR 35 TC 114 Z9 125 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 18 PY 1998 VL 16 IS 24 BP 3151 EP 3157 DI 10.1038/sj.onc.1201858 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV030 UT WOS:000074261300008 PM 9671394 ER PT J AU Burchert, A Attar, EC McCloskey, P Fridell, YWC Liu, ET AF Burchert, A Attar, EC McCloskey, P Fridell, YWC Liu, ET TI Determinants for transformation induced by the Axl receptor tyrosine kinase SO ONCOGENE LA English DT Article DE receptor tyrosine kinase; retroviruses, mutations; transformations; Axl ID GROWTH-FACTOR RECEPTOR; LONG TERMINAL REPEAT; ALTERED AUTOPHOSPHORYLATION SITES; MURINE LEUKEMIA-VIRUS; POINT MUTATION; PROTO-ONCOGENE; SIGNAL TRANSDUCTION; INSULIN-RECEPTOR; CELLS; GENE AB The Axl receptor tyrosine kinase is a transforming oncogene in NIH3T3 cells, In order to define structural requirements of the Axl receptor necessary for transformation me passaged recombinant retroviruses carrying the axl cDNA in NIH3T3 cells, generating randomly mutated axl variants. Using this strategy, we have isolated three axl viral strains (1B1, SV8, and FFa4) that show augmented 3T3 cell transforming capacity associated with elevated p140(Axl). Upon sequencing, the 1B1 and SV8 proviruses possessed only silent mutations, making p140(Axl) overexpression the most likely explanation for their increased transformation activity. However, the characterization of FFa4 revealed a deletion of sequences encoding the carboxy-terminal 45 amino acids leading to the generation of a chimeric transcript comprised of a truncated Axl receptor with a segment of the 3' UTR region. Mutational analysis revealed that the transforming activity of FFa4 was specific to the formation of the chimeric receptor rather than to the carboxyl-terminal truncation, Intriguingly, none of the viral strains were able to transform the murine cell lines. NR-6 and 32D despite equivalent expression of surface p140(Axl) protein. Further analysis showed that Axl's transforming potential is dependent on the host cell type, the presence of a putative pp190 as a facilitator for transformation, and the level of p140(Axl) expression, Taken together, these results underscore the complexity of Axl biology which is dependent on receptor stoichiometry and the cellular background. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA. RP Liu, ET (reprint author), NCI, Div Clin Sci, NIH, 31-3A11,31 Ctr Dr,MSC 2440, Bethesda, MD 20892 USA. RI Liu, Edison/C-4141-2008 FU NCI NIH HHS [CA58223-04, R01-CA49240] NR 53 TC 32 Z9 32 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 18 PY 1998 VL 16 IS 24 BP 3177 EP 3187 DI 10.1038/sj.onc.1201865 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZV030 UT WOS:000074261300011 PM 9671397 ER PT J AU Rosenberg, PS Biggar, RJ AF Rosenberg, PS Biggar, RJ TI Trends in HIV incidence among young adults in the United States SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INJECTING DRUG-USERS; INCUBATION PERIOD; HOMOSEXUAL MEN; AIDS EPIDEMIC; INFECTION; MORTALITY; AGE AB Context.-Behaviors that result in potential exposure to human immunodeficiency virus (HIV) usually begin in adolescence or young adulthood, but trends in HIV incidence in young people remain unclear. Objective.-To estimate trends in HIV incidence in teenagers and young adults. Design and Setting.-Back-calculation of past HIV incidence in persons born between 1960 and 1974 using US national acquired immunodeficiency syndrome (AIDS) incidence data and estimates of the distribution of times between HIV infection and AIDS. Main Outcome Measures.-Incidence and prevalence of HIV in 1988 and 1993 in persons aged 20 and 25 years, respectively, in each of those years. Results.-As of January 1993, about 22 000 men and 11 000 women aged 18 to 22 years were living with HIV infection in the United States. Homosexual contact was the leading route of infection among young men. Heterosexual contact was the leading route of infection among young women. The HIV incidence attributed to homosexual contact or injection drug use decreased among persons aged 20 and 25 years between 1988 and 1993, but HIV incidence attributed to heterosexual contact was stable or increasing. Notably, in men aged 20 and 25 years, HIV prevalence declined by about 50% in white men but was relatively stable in black and Hispanic men. In contrast, HIV prevalence in women aged 20 and 25 years rose by 36% and 45%, respectively, because of increasing heterosexual transmission. Overall, HIV prevalence in persons aged 20 and 25 years declined by only 14% between 1988 and 1993. Conclusions.-In young persons, HIV incidence in homosexual men and injection drug users was slowing by 1993; this favorable trend was offset by increasing heterosexual transmission, especially in minorities. C1 NCI, Biostat Branch, Bethesda, MD 20892 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Rosenberg, PS (reprint author), NCI, Biostat Branch, 6130 Execut Blvd,EPN-403, Bethesda, MD 20892 USA. FU NIAID NIH HHS [U01-AI-35039, U01-AI-35040, U01-AI-35041] NR 25 TC 100 Z9 101 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 17 PY 1998 VL 279 IS 23 BP 1894 EP 1899 DI 10.1001/jama.279.23.1894 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA ZT653 UT WOS:000074109700037 PM 9634261 ER PT J AU Takayama, S Adamson, RH Dalgard, DW Cano, M Sieber, SM Thorgeirsson, UP Arnold, LL Eklund, S Cohen, SM AF Takayama, S Adamson, RH Dalgard, DW Cano, M Sieber, SM Thorgeirsson, UP Arnold, LL Eklund, S Cohen, SM TI Re: Long-term feeding of sodium saccharin to nonhuman primates: Implications for urinary tract cancer - Responses SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID SALTS C1 NIH, Div Basic Sci, NCI, Bethesda, MD 20892 USA. Covance Labs Inc, Vienna, VA USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. Univ Nebraska, Med Ctr, Eppley Inst, Omaha, NE USA. RP Thorgeirsson, UP (reprint author), NIH, Div Basic Sci, NCI, Bldg 37,Rm 2D-02, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 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 JUN 17 PY 1998 VL 90 IS 12 BP 934 EP 935 PG 2 WC Oncology SC Oncology GA ZV649 UT WOS:000074327000014 ER PT J AU Harty, LC Hayes, RB Caporaso, NE Shields, PG Winn, DM AF Harty, LC Hayes, RB Caporaso, NE Shields, PG Winn, DM TI Re: Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID HEPATIC ALCOHOL; LIVER-DISEASE; ALDEHYDE C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIDR, Div Intramural Res, Bethesda, MD 20892 USA. RP Harty, LC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza N,Suite 439,MSC 7372, Bethesda, MD 20892 USA. NR 7 TC 3 Z9 3 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 JUN 17 PY 1998 VL 90 IS 12 BP 938 EP 939 PG 2 WC Oncology SC Oncology GA ZV649 UT WOS:000074327000018 ER PT J AU Rodriguez-Bigas, MA Srivastava, S AF Rodriguez-Bigas, MA Srivastava, S TI Re: A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: Meeting highlights and Bethesda guidelines - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID INSTABILITY C1 NCI, Early Detect Branch, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Buffalo, NY USA. RP Srivastava, S (reprint author), NCI, Early Detect Branch, Div Canc Prevent, NIH, Execut Plaza N,Room 330F, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 17 PY 1998 VL 90 IS 12 BP 940 EP 940 PG 1 WC Oncology SC Oncology GA ZV649 UT WOS:000074327000020 ER PT J AU Wu, YQ Sutton, VR Nickerson, E Lupski, JR Potocki, L Korenberg, JR Greenberg, F Tassabehji, M Shaffer, LG AF Wu, YQ Sutton, VR Nickerson, E Lupski, JR Potocki, L Korenberg, JR Greenberg, F Tassabehji, M Shaffer, LG TI Delineation of the common critical region in williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE elastin; supravalvular aortic stenosis; microdeletion; Williams syndrome; chromosome 7; LIM-kinase ID SUPRAVALVULAR AORTIC-STENOSIS; AUTOSOMAL-DOMINANT INHERITANCE; ELASTIN GENE; BEUREN SYNDROME; DELETION; HEMIZYGOSITY; 7Q11.23; LOCUS; TRANSLOCATION; CHROMOSOME-7 AB Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D751870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS, One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus. (C) 1998 Wiley-Liss, Inc. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Texas Childrens Hosp, Houston, TX 77030 USA. Cedars Sinai Med Ctr, Div Med Genet, Los Angeles, CA 90048 USA. NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. St Marys Hosp, Dept Med Genet, Manchester M13 0JH, Lancs, England. RP Shaffer, LG (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza,Room 15E, Houston, TX 77030 USA. FU NICHD NIH HHS [P01 HD 33113, R03 HD 35112] NR 40 TC 69 Z9 70 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 16 PY 1998 VL 78 IS 1 BP 82 EP 89 DI 10.1002/(SICI)1096-8628(19980616)78:1<82::AID-AJMG17>3.0.CO;2-K PG 8 WC Genetics & Heredity SC Genetics & Heredity GA ZR673 UT WOS:000074002300017 PM 9637430 ER PT J AU Guschin, D Chandler, S Wolffe, AP AF Guschin, D Chandler, S Wolffe, AP TI Asymmetric linker histone association directs the asymmetric rearrangement of core histone interactions in a positioned nucleosome containing a thyroid hormone response element SO BIOCHEMISTRY LA English DT Article ID PRIMARY ORGANIZATION; GLOBULAR DOMAIN; BINDING-SITE; RNA GENE; DNA; CHROMATIN; PARTICLE; ARRANGEMENT; ACTIVATION; RESOLUTION AB We describe histone-DNA cross-linking in a positioned nucleosome containing a thyroid hormone response element (TRE) from the Xenopus laevis thyroid hormone receptor beta A gene (TR beta A). Histones H3 and H4 are cross-linked to DNA in the nucleosome core within 30 base pairs to either side of the dyad axis. Histone H2A cross-links to DNA in the core at the dyad axis, and histones H2A and H2B have extensive interactions with DNA 40-80 bp away from the dyad axis. Linker histone H5 and the globular domain of Xenopus H1 degrees associate asymmetrically with DNA at one edge of the TR beta A nucleosome. Nevertheless, the asymmetric association of H5 leads to a significant rearrangement of core histone-DNA contacts at the dyad axis of the nucleosome. In the presence of linker histone, cross-linkings of H4 within 15 bp to one side of the dyad axis, of histone H2A at the dyad axis, and of H2A and H2B 40-80 bp to one side of the dyad axis are all reduced. This reduction in cross-linking occurs preferentially on the side of the nucleosome to which H5 is bound. Our results indicate that core histone contacts within mononucleosomes are conformationally dynamic and that linker histone incorporation at the edge of the nucleosome can influence core histone-DNA interactions in an asymmetric way including contacts at the dyad axis. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. NR 56 TC 24 Z9 24 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 16 PY 1998 VL 37 IS 24 BP 8629 EP 8636 DI 10.1021/bi9805846 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV930 UT WOS:000074356000003 PM 9628724 ER PT J AU Perez-Mediavilla, LA Chew, C Campochiaro, PA Nickells, RW Notario, V Zack, DJ Becerra, SP AF Perez-Mediavilla, LA Chew, C Campochiaro, PA Nickells, RW Notario, V Zack, DJ Becerra, SP TI Sequence and expression analysis of bovine pigment epithelium-derived factor SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE expression; sequence; translation; serpin; PEDF; retinal pigment epithelium ID PROTEIN-C INHIBITOR; MOLECULAR-CLONING; HEPARIN-BINDING; CELLS; GENE; IDENTIFICATION; EPC-1; STATE; EYES AB PEDF, a member of the serpin superfamily of proteins related through their highly conserved folded conformation, has neurotrophic properties, including promotion of neurite-outgrowth and neuronal survival. Previously, we have purified and characterized PEDF protein from extracellular matrixes of bovine eyes. Here, we show the cDNA sequence and expression analysis of bovine PEDF. Northern analysis of RNA from bovine retinal pigment epithelium (RPE) and neural retina using a human PEDF cDNA fragment reveals expression of the PEDF gene only for RPE. Sequence analysis of a cDNA clone isolated from bovine RPE predicts a polypeptide of 416 amino acid residues that shares 88.6% and 85% amino acid identity with human and mouse PEDF, respectively, It has an N-terminal signal peptide, a consensus glycosylation site and homology with serpins including the conserved residues required for maintaining the serpin tertiary structure. Cell-free expression of the bovine PEDF cDNA by in vitro transcription and translation yields a precursor polypeptide of 45,000-Mr that immunoprecipitates with an antibody to human PEDF. Expression analysis in stably transfected baby hamster kidney cells shows that the recombinant bovine protein is secreted to the culture media as a mature 50,000-Mr protein, which induces neurite-outgrowth on retinoblastoma cells, like the naturally-occurring PEDF protein. Thus, the bovine PEDF cDNA isolated here codes for a functional soluble secreted PEDF glycoprotein. (C) 1998 Elsevier Science B,V. All rights reserved. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. Georgetown Univ, Med Ctr, Dept Radiat Med, Washington, DC 20007 USA. RP Becerra, SP (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Perez-Mediavilla, Alberto/A-5246-2011; OI Zack, Don/0000-0002-7966-1973 NR 28 TC 26 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JUN 16 PY 1998 VL 1398 IS 2 BP 203 EP 214 DI 10.1016/S0167-4781(98)00055-4 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ZX396 UT WOS:000074511600010 PM 9689919 ER PT J AU Langford, CA Klippel, JH Balow, JE James, SP Sneller, MC AF Langford, CA Klippel, JH Balow, JE James, SP Sneller, MC TI Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease part 1: Rheumatologic and renal diseases SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT Clinical Staff Conference CY MAR 26, 1997 CL NIH, BETHESDA, MARYLAND SP NIH HO NIH ID SYSTEMIC LUPUS-ERYTHEMATOSUS; INTERSTITIAL LUNG-DISEASE; TERM FOLLOW-UP; CHANGE NEPHROTIC SYNDROME; CONTROLLED TRIAL; INTRAVENOUS CYCLOPHOSPHAMIDE; PULSE CYCLOPHOSPHAMIDE; POLYMYOSITIS DERMATOMYOSITIS; MEMBRANOUS GLOMERULOPATHY; THERAPY AB When cytotoxic agents were initially introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may sti II cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. Part 1 examines the manner in which these agents have been used to treat rheumatologic and renal diseases. C1 NIH, Bethesda, MD 20892 USA. RP Langford, CA (reprint author), NIH, Bldg 10,Room 11B-13, Bethesda, MD 20892 USA. NR 70 TC 31 Z9 32 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 15 PY 1998 VL 128 IS 12 BP 1021 EP 1028 PN 1 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA ZU474 UT WOS:000074201300009 PM 9625665 ER PT J AU Carpenter, C Feinberg, M Aubry, W Averitt, D Coffin, J Cooper, D Follansbee, S Hamburg, P Harrington, M Hidalgo, J Jaffe, H Landers, D Masur, H Pizzo, P Richman, D Saag, M Schooley, R Stone, V Thompson, M Trono, D Vella, S Walker, B Yeni, P AF Carpenter, C Feinberg, M Aubry, W Averitt, D Coffin, J Cooper, D Follansbee, S Hamburg, P Harrington, M Hidalgo, J Jaffe, H Landers, D Masur, H Pizzo, P Richman, D Saag, M Schooley, R Stone, V Thompson, M Trono, D Vella, S Walker, B Yeni, P CA NIH Panel Define Principles Therapy HIV Infect TI Report of the NIH Panel to Define Principles of Therapy of HIV Infection SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ZIDOVUDINE COMBINATION THERAPY; DYNAMICS IN-VIVO; TYPE-1 RNA LOAD; VIRAL LOAD; REVERSE-TRANSCRIPTASE; PROTEASE INHIBITOR; CUBIC MILLIMETER; CONTROLLED TRIAL; CLINICAL COURSE AB Recent research advances have afforded substantially improved understanding of the biology of HIV infection and the pathogenesis of AIDS. With the advent of sensitive tools for monitoring HIV replication in infected persons, the risk for disease progression and death can be assessed accurately and the efficacy of anti-HIV therapies can be determined directly. Furthermore, when used appropriately, combinations of newly available, potent antiviral therapies can effect prolonged suppression of detectable levels of HIV replication and circumvent the inherent tendency of HIV to generate drug-resistant viral variants. However, as antiretroviral therapy for HIV infection has become increasingly effective, it has also become increasingly complex. Familiarity with recent research advances is needed to ensure that newly available therapies are used in ways that most effectively improve the health and prolong the lives of HIV-infected persons. To enable practitioners and HIV-infected persons to best use rapidly accumulating new information about HIV disease pathogenesis and treatment, the Off ice of AIDS Research of the National Institutes of Health (NIH) sponsored the NIH Panel To Define Principles of Therapy of HIV Infection. This Panel was asked to define essential scientific principles that should be used to guide the most effective use of antiretroviral therapies and viral load testing in clinical practice. On the basis of detailed consideration of the most current data, the Panel delineated 11 principles that address issues of fundamental importance for the treatment of HIV infection. These principles provide the scientific basis for the specific treatment recommendations made by the Panel on Clinical Practices for the Treatment of HIV Infection sponsored by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The reports of both of these panels are provided in this supplement. Together, they summarize new data and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. This information will be of interest to health care providers, HIV-infected persons, HIV and AIDS educators, public health educators, public health authorities, and all organizations that fund medical care of HIV-infected persons. C1 Brown Univ, Providence, RI 02912 USA. Miriam Hosp, Providence, RI 02912 USA. NIH, Bethesda, MD 20892 USA. Blue Cross Blue Shield Assoc, San Francisco, CA USA. Womens Informat Serv & Exchange, Atlanta, GA USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. Davies Med Ctr, San Francisco, CA USA. New York City Dept Hlth, New York, NY 10013 USA. Treatment Act Grp, New York, NY USA. Ctr AIDS Serv Planning & Dev, Baltimore, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Magee Womens Hosp, Pittsburgh, PA USA. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Alabama, Birmingham, AL USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Brown Univ, Sch Med, Providence, RI 02912 USA. AIDS Res Consortium Atlanta, Atlanta, GA USA. Salk Inst Biol Studies, La Jolla, CA USA. Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. X Bichat Med Sch, Paris, France. RP Carpenter, C (reprint author), Brown Univ, Providence, RI 02912 USA. RI Vella, Stefano/D-4912-2015 OI Vella, Stefano/0000-0003-2347-5984 NR 107 TC 9 Z9 9 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 15 PY 1998 VL 128 IS 12 SU S BP 1057 EP 1078 PN 2 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA ZU477 UT WOS:000074201700002 ER PT J AU Bloch, M Schmidt, PJ Su, TP Tobin, MB Rubinow, DR AF Bloch, M Schmidt, PJ Su, TP Tobin, MB Rubinow, DR TI Pituitary-adrenal hormones and testosterone across the menstrual cycle in women with premenstrual syndrome and controls SO BIOLOGICAL PSYCHIATRY LA English DT Article DE premenstrual syndrome; testosterone; adrenocorticotropic hormone; beta-endorphin; cortisol; androgens ID PLASMA BETA-ENDORPHIN; ADRENOCORTICOTROPIC HORMONE; CORTISOL RESPONSES; TENSION SYNDROME; LUTEAL PHASE; AGE; DISORDER; ACTH; SEX AB Background: Premenstrual syndrome (PMS) is a cyclic mood disorder, widely believed yet not conclusively shown, to be of endocrine etiology. This study examines basal levels of several hormones reported, albeit inconsistently: to differ in women with PMS compared with controls, Methods: Subjects (10 PMS patients and 10 controls) had their blood drawn for one full menstrual cycle. Subjects' mood and behavioral symptoms were assessed by daily self-ratings and objective ratings, Plasma was assayed for total and free testosterone (T), beta-endolphin (P-EP), adrenocorticotropic hormone (ACTH), and cortisol. Results: No differences were observed between the PMS and control groups for P-EP, ACTH, or cortisol. PMS subjects had significantly lower total and free T plasma levels with a blunting of the normal periovulatory peak, a finding that may be epiphenomenal to age. Conclusions: This study does not confirm previous reports of abnormalities in plasma levels of either ACTH or P-EP in women with PMS; it also fails to replicate a previous observation of high free T levels in women with PMS. These results are not supportive of a primary endocrine abnormality in PMS patients. Published 1998 Society of Biological Psychiatry. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. RP Rubinow, DR (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Room 3N238,10 Ctr Dr MSC 1276, Bethesda, MD 20892 USA. NR 32 TC 55 Z9 56 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 1998 VL 43 IS 12 BP 897 EP 903 DI 10.1016/S0006-3223(98)00403-X PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ZT022 UT WOS:000074039800007 PM 9627744 ER PT J AU Zella, D Barabitskaja, O Burns, JM Romerio, F Dunn, DE Revello, MG Gerna, G Reitz, MS Gallo, RC Weichold, FF AF Zella, D Barabitskaja, O Burns, JM Romerio, F Dunn, DE Revello, MG Gerna, G Reitz, MS Gallo, RC Weichold, FF TI Interferon-gamma increases expression of chemokine receptors CCR1, CCR3, and CCR5, but not CXCR4 in monocytoid U937 cells SO BLOOD LA English DT Article ID IFN-GAMMA; T-CELLS; LYMPHOCYTE-T; HIV-1; REPLICATION; MIP-1-ALPHA; MIP-1-BETA; COFACTOR; RANTES AB Chemokine receptors (CR), which can mediate migration of immune cells to the site of inflammation, also function as coreceptors for human immunodeficiency virus (HIV) entry into CD4(+) T lymphocytes and antigen-presenting cells. We demonstrate here that interferon-gamma (IFN-gamma) increases the expression of chemokine receptors CCR1, CCR3, and CCR5 in monocytoid U937 cells as detected by cell surface molecule labeling and mRNA expression, as well as by intracellular calcium mobilization and cell migration in response to specific ligands. The increased expression of these chemokine receptors also results in an enhanced HIV-1 entry into cells. Our data provide evidence for a relationship of cellular pathways that are induced by IFN-gamma with those that regulate chemokine receptor expression. (C) 1998 by The American Society of Hematology. C1 Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. IRCCS, Policlin San Matteo, Viral Diagnost Serv, Pavia, Italy. RP Weichold, FF (reprint author), Univ Maryland, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM weichold@umbi.umd.edu NR 30 TC 63 Z9 66 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 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 1998 VL 91 IS 12 BP 4444 EP 4450 PG 7 WC Hematology SC Hematology GA ZT469 UT WOS:000074091000005 PM 9616137 ER PT J AU Chesi, M Bergsagel, PL Shonukan, OO Martelli, ML Brents, LA Chen, T Schrock, E Ried, T Kuehl, VM AF Chesi, M Bergsagel, PL Shonukan, OO Martelli, ML Brents, LA Chen, T Schrock, E Ried, T Kuehl, VM TI Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma SO BLOOD LA English DT Article ID CELL-LINE; CHROMOSOMAL TRANSLOCATIONS; GENE; PROTOONCOGENE; LEUKEMIA; LYMPHOMA; MODEL AB Dysregulation of oncogenes by translocation to an IgH (14q32) or IgL (kappa, 2p11 or lambda, 22q11) locus is a frequent event in the pathogenesis of B-cell tumors. Translocations involving an IgH locus and a diverse but nonrandom array of chromosomal loci occur in most multiple myeloma (MM) tumors even though the translocations often are not detected by conventional cytogenetic analysis. In a continuing analysis of translocations in 21 MM lines, we show that the novel, karyotypically silent t(14;16)(q32.3;q23) translocation is present in 5 MM lines, with cloned breakpoints from 4 lines dispersed over an approximately 500-kb region centromeric to the c-maf proto oncogene at 16q23. Another line has a t(16;22)(q23;q11), with the breakpoint telomeric to c-maf, so that the translocation breakpoints in these 6 lines bracket c-maf. Only these 6 lines overexpress c-maf mRNA. As predicted for dysregulation of c-maf by translocation, there is selective expression of one c-maf allele in 2 informative lines with translocations. This is the first human tumor in which the basic zipper c-maf transcription factor is shown to function as an oncogene. C1 USN Hosp, NCI, Med Branch, Dept Genet, Bethesda, MD 20889 USA. Cornell Univ, Coll Med, Dept Med, Div Hematol & Oncol, New York, NY USA. NIH, Natl Ctr Human Genome Res, Genome Technol Branch, Bethesda, MD 20892 USA. RP Kuehl, VM (reprint author), USN Hosp, NCI, Med Branch, Dept Genet, Bldg 8,Room 5101, Bethesda, MD 20889 USA. RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 NR 28 TC 290 Z9 294 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 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 1998 VL 91 IS 12 BP 4457 EP 4463 PG 7 WC Hematology SC Hematology GA ZT469 UT WOS:000074091000007 PM 9616139 ER PT J AU Elenitoba-Johnson, KSJ Gascoyne, RD Lim, MS Chhanabai, M Jaffe, ES Raffeld, M AF Elenitoba-Johnson, KSJ Gascoyne, RD Lim, MS Chhanabai, M Jaffe, ES Raffeld, M TI Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; ACUTE LYMPHOBLASTIC LEUKEMIAS; MALIGNANT-LYMPHOMAS; CELL; TUMORS; CLONING; CANCER; GENES; TRANSFORMATION; TRANSLOCATION AB Low-grade follicle center lymphoma (LGFCL) is characterized genetically by the t(14;18) translocation and an indolent clinical course. Histologic progression from LGFCL to an aggressive diffuse large B-cell lymphoma (DLCL) occurs in 60% to 80% of cases, and this transformation is associated with the accumulation of secondary genetic alterations. Using 10 polymorphic microsatellite markers spanning the chromosome 9p21 region harboring the p15 (p15(INK4B)/MTS. 2/CDKN2B) and p16 (p16(INK4A)/MTS-1/CDKN2) tumor-suppressor gene loci, we analyzed 11 matched pairs of LGFCL and their corresponding progressed DLCL biopsies for loss of heterozygosity and homozygous deletions at 9p21, A comparative multiplex polymerase chain reaction assay was also used for the detection of homozygous deletions. Deletions were identified in 8 of the 11 cases studied (73%): 6 homozygous (54%) and 2 hemizygous (18%), The deletions were identified exclusively in the progressed DLCL biopsies. Immunohistochemical studies showed an excellent correlation with the results from the genetic analyses. Of the 9 matched pairs of LGFCL and progressed DLCL with interpretable immunohistochemical staining, 9 of 9 (100%) of the LGFCL showed diffuse reactivity for p16. Four of the 9 (44%) immunohistochemically evaluable cases of progressed DLCL showed loss of or, in 1 case, markedly diminished p16 expression. All 4 of these cases correspondingly showed homozygous deletions at 9p21. Five of the 9 progressed DLCL cases showed p16 expression and demonstrated retention of one or both 9p21 alleles by genetic analysis. This is the first longitudinal series examining sequential biopsy specimens of low-grade and progressed FCL for genetic loss at 9p21 encompassing the p16 and p15 loci. The high frequency and exclusive occurrence of deletions involving p16 in the progressed DLCLs suggests that genetic loss at 9p21 targeting p16 and/or p15 is an important secondary genetic event in the histologic progression of FCL. C1 NCI, NIH, Hematopathol Sect, Pathol Lab, Bethesda, MD 20852 USA. British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. RP Raffeld, M (reprint author), NCI, NIH, Hematopathol Sect, Pathol Lab, Bldg 10,2N110,10 Ctr Dr,MSC 1500, Bethesda, MD 20852 USA. NR 32 TC 121 Z9 122 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 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 1998 VL 91 IS 12 BP 4677 EP 4685 PG 9 WC Hematology SC Hematology GA ZT469 UT WOS:000074091000033 PM 9616165 ER PT J AU Calafat, J Janssen, H Tool, A Dentener, MA Knol, EF Rosenberg, HF Egesten, A AF Calafat, J Janssen, H Tool, A Dentener, MA Knol, EF Rosenberg, HF Egesten, A TI The bactericidal/permeability-increasing protein (BPI) is present in specific granules of human eosinophils SO BLOOD LA English DT Article ID GRAM-NEGATIVE BACTERIA; HUMAN-BLOOD; NEUTROPHIL; GRANULOCYTES; LIPOPOLYSACCHARIDE; LOCALIZATION; DISEASE; IL-3 AB Eosinophils participate in the inflammatory response seen in allergy and parasitic infestation, but a role in host defense against bacterial infection is not settled. The bactericidal/permeability-increasing protein (BPI) has been demonstrated in neutrophils and it exerts bacteriostatic and bactericidal effects against a wide variety of Gram-negative bacterial species. Using the Western blot technique, a 55-kD band, corresponding to BPI, was detected in lysates from both neutrophils and eosinophils. The localization of BPI in immature and mature eosinophils was investigated using immunoelectron microscopy. BPI was found in immature and mature specific granules of eosinophils and was detected in phagosomes as well, indicating release of the protein from the granules into the phagosomes. Using a specific enzyme-linked immunosorbent assay, eosinophils were shown to contain 179 ng of BPI/5 x 10(6) eosinophils compared with 710 ng BPI/5 x 10(6) neutrophils. The presence of BPI in eosinophils suggests a role for these cells in host defense against Gram-negative bacterial invasion or may suggest a role for BPI against parasitic infestation. (C) 1998 by The American Society of Hematology. C1 Univ Hosp MAS, Dept Med, Univ Lund, S-20502 Malmo, Sweden. Netherlands Canc Inst, Div Cell Biol, Amsterdam, Netherlands. Netherlands Red Cross, Blood Transfus Serv, Cent Lab, Amsterdam, Netherlands. Maastricht Univ, Dept Pulm, Maastricht, Netherlands. NIAID, Host Def Lab, NIH, Bethesda, MD USA. RP Egesten, A (reprint author), Univ Hosp MAS, Dept Med, Univ Lund, S-20502 Malmo, Sweden. NR 27 TC 46 Z9 53 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 1998 VL 91 IS 12 BP 4770 EP 4775 PG 6 WC Hematology SC Hematology GA ZT469 UT WOS:000074091000044 PM 9616176 ER PT J AU Chandrasekaran, K Hatanpaa, K Brady, DR Stoll, J Rapoport, SI AF Chandrasekaran, K Hatanpaa, K Brady, DR Stoll, J Rapoport, SI TI Downregulation of oxidative phosphorylation in Alzheimer disease: loss of cytochrome oxidase subunit mRNA in the hippocampus and entorhinal cortex SO BRAIN RESEARCH LA English DT Article DE mitochondria; neurofibrillary tangles; neuritic plaque; mitochondrial DNA; synapse; neuronal activity; oxidative damage; mutation ID MITOCHONDRIAL-DNA EXPRESSION; NEUROFIBRILLARY TANGLES; GENE-EXPRESSION; FUNCTIONAL ALTERATIONS; POSITRON TOMOGRAPHY; NEURONAL-ACTIVITY; MESSENGER-RNA; MONKEY BRAIN; C-OXIDASE; METABOLISM AB Messenger RNA (mRNA) for cytochrome oxidase subunit II (COX II) was localized by in situ hybridization in the entorhinal cortex and hippocampal formation of postmortem brain tissue from normal human subjects and from patients with Alzheimer disease (AD). In the control entorhinal cortex, COX II mRNA was detected mainly in neuronal cell bodies of layers II and IV. In control hippocampal formation, highest levels were localized in neuronal cell bodies of the dentate gyrus and the CA3 and CA1 regions, neurons that are involved in the major input and output pathways of the hippocampal formation. In AD brain, COX II mRNA was markedly reduced in the entorhinal cortex and the hippocampal formation compared with control brain. In the AD hippocampal formation, reductions were in regions severely affected by AD pathology as well as in regions that were relatively spared. These results are consistent with the hypothesis that reduced mitochondrial energy metabolism reflects loss of neuronal connections in AD. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Rapoport, SI (reprint author), NIA, Neurosci Lab, NIH, Bldg 10,Rm 6C 103, Bethesda, MD 20892 USA. NR 48 TC 35 Z9 36 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 15 PY 1998 VL 796 IS 1-2 BP 13 EP 19 DI 10.1016/S0006-8993(98)00248-0 PG 7 WC Neurosciences SC Neurosciences & Neurology GA ZZ933 UT WOS:000074784000002 PM 9689449 ER PT J AU Rosen, JB Fanselow, MS Young, SL Sitcoske, M Maren, S AF Rosen, JB Fanselow, MS Young, SL Sitcoske, M Maren, S TI Immediate-early gene expression in the amygdala following footshock stress and contextual fear conditioning SO BRAIN RESEARCH LA English DT Article DE c-fos; NGFI-A; zif268; amygdala; fear; conditioning ID LONG-TERM POTENTIATION; CENTRAL NUCLEUS; C-FOS; ELECTRICAL-STIMULATION; TRANSCRIPTION FACTORS; DEFENSIVE REACTIONS; ACOUSTIC STARTLE; INDUCTION; BRAIN; RAT AB This study investigated the increase in expression in the amygdala of 2 immediate-early genes, c-fos and NGFI-A, following contextual fear conditioning. The immediate-shock freezing deficit paradigm was used to compare rats that received footshock after exploring a context to rats that received footshock immediately after placement in the chamber. The former procedure produces contextual fear conditioning while the latter does not. Rats were either handled (handled group), placed in a test chamber without receiving footshock (context-no-footshock group), received footshock immediately upon being placed in the chamber (immediate-footshock group), or received footshock after a 1 min delay (delayed-footshock group). Only the delayed-footshock group displayed a fear response (freezing behavior). Rats were sacrificed either 15 min after the experience or after a retention test 24 h later. The c-fos mRNA was increased in the medial nucleus of the amygdala in all of the groups that were placed in the test chamber. However, rats that received footshock (immediate- and delayed-footshock groups) had greater levels of c-fos mRNA expression than rats of the context-no-footshock group. The c-fos mRNA expression in the immediate- and delayed-footshock groups did not differ. However, after the retention test, the expression of c-fos mRNA in the medial nucleus of the amygdala did not differ between groups. In contrast to c-fos, NGFI-A mRNA expression in the lateral nucleus of the amygdala was greater in the delayed-footshock group than the handled and context-no-footshock groups 15 min after the footshock, This elevation in NGFI-A mRNA was not seen in the immediate-footshock group. This suggests that NGFI-A mRNA in the lateral nucleus of the amygdala may play a role in contextual fear conditioning. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Delaware, Dept Psychol, Newark, DE 19716 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. RP Rosen, JB (reprint author), Univ Delaware, Dept Psychol, 220 Wolf Hall, Newark, DE 19716 USA. EM jrosen@udel.edu RI Maren, Stephen/A-7091-2009; Maren, Stephen/B-6182-2014 OI Maren, Stephen/0000-0002-9342-7411; Maren, Stephen/0000-0002-9342-7411 NR 42 TC 127 Z9 129 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 15 PY 1998 VL 796 IS 1-2 BP 132 EP 142 DI 10.1016/S0006-8993(98)00294-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZZ933 UT WOS:000074784000016 PM 9689463 ER PT J AU Hamid, EH Hyde, TM Baca, SM Egan, MF AF Hamid, EH Hyde, TM Baca, SM Egan, MF TI Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia SO BRAIN RESEARCH LA English DT Article DE NMDA receptor; tardive dyskinesia; haloperidol; striatum; nucleus accumbens; vacuous chewing movements' syndrome; receptor autoradiography ID D-ASPARTATE RECEPTORS; EXTRACELLULAR GLUTAMATE; PARKINSONS-DISEASE; DOPAMINE RELEASE; RAT STRIATUM; HALOPERIDOL; SCHIZOPHRENIA; SYSTEMS; NEURONS; MOVEMENTS AB The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (-VCM). Rats from +VCM, -VCM groups and vehicle treated controls were selected for post mortem studies (n = 12 to 14 per group). NMDA receptor levels were assessed using [H-3]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that -VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia. (C) 1998 Elsevier Science B.V. All rights reserved. C1 St Elizabeth Hosp, NIMH, Neurosci Res Ctr, Clin Res Serv, Washington, DC 20032 USA. St Elizabeth Hosp, NIMH, Neurosci Res Ctr, Clin Brain Disorder Branch, Washington, DC USA. RP Egan, MF (reprint author), St Elizabeth Hosp, NIMH, Neurosci Res Ctr, Clin Res Serv, Washington, DC 20032 USA. NR 23 TC 10 Z9 10 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 JUN 15 PY 1998 VL 796 IS 1-2 BP 291 EP 295 DI 10.1016/S0006-8993(98)00196-6 PG 5 WC Neurosciences SC Neurosciences & Neurology GA ZZ933 UT WOS:000074784000033 PM 9689480 ER PT J AU Maxwell, GL Risinger, JI Gumbs, C Shaw, H Bentley, RC Barrett, JC Berchuck, A Futreal, PA AF Maxwell, GL Risinger, JI Gumbs, C Shaw, H Bentley, RC Barrett, JC Berchuck, A Futreal, PA TI Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias SO CANCER RESEARCH LA English DT Article ID MICROSATELLITE INSTABILITY; CARCINOMA; CANCER; P53 AB Mutation and deletion of the PTEN tumor suppressor gene occurs in about 40% of endometrial carcinomas. The purpose of this study was to determine whether PTEN mutations also are present in endometrial hyperplasias, which are premalignant precursors of invasive endometrial adenocarcinomas. Genomic DNA from 51 endometrial hyperplasias was extracted from paraffin blocks, and PCR was used to amplify the nine exons of the PTEN gene, These products were screened using single-strand conformation analysis, and variant bands were sequenced, Somatic mutations in the PTEN gene were seen in 10 of 51 cases (20%), and two mutations were found in one case. An identical 4-bp deletion in exon 8 was seen in three cases, and 8 of 11 PTEN mutations predicted truncated protein products. There was no higher frequency of PTEN mutations in endometrial hyperplasias with atypia (6 of 32; 19%) relative to those without atypia (4 of 19; 21%). These data suggest that inactivation of the PTEN tumor suppressor gene is an early event in the development of some endometrial cancers. C1 Duke Univ, Med Ctr, Div Gynecol Oncol, Dept Gynecol & Obstet, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Berchuck, A (reprint author), Duke Univ, Med Ctr, Div Gynecol Oncol, Dept Gynecol & Obstet, Box 3079, Durham, NC 27710 USA. NR 22 TC 151 Z9 161 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 JUN 15 PY 1998 VL 58 IS 12 BP 2500 EP 2503 PG 4 WC Oncology SC Oncology GA ZU255 UT WOS:000074178300003 PM 9635567 ER PT J AU Burke, L Khan, MA Freedman, AN Gemma, A Rusin, M Guinee, DG Bennett, WP Caporaso, NE Fleming, MV Travis, WD Colby, TV Trastek, V Pairolero, PC Tazelaar, HD Midthun, DE Liotta, LA Harris, CC AF Burke, L Khan, MA Freedman, AN Gemma, A Rusin, M Guinee, DG Bennett, WP Caporaso, NE Fleming, MV Travis, WD Colby, TV Trastek, V Pairolero, PC Tazelaar, HD Midthun, DE Liotta, LA Harris, CC TI Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer SO CANCER RESEARCH LA English DT Article ID P53 MUTATIONS; TUMOR-SUPPRESSOR; 3P DELETIONS; CARCINOMA; PATHOGENESIS; 3P14.2; SITES AB The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites, Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03), We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02), We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Inst Oncol, PL-44100 Gliwice, Poland. Univ Utah, Med Ctr, Salt Lake City, UT 84148 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Mayo Clin Scottsdale, Scottsdale, AZ 85259 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 2C05,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 27 TC 68 Z9 80 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 JUN 15 PY 1998 VL 58 IS 12 BP 2533 EP 2536 PG 4 WC Oncology SC Oncology GA ZU255 UT WOS:000074178300010 PM 9635574 ER PT J AU Yoshida, A Pourquier, P Pommier, Y AF Yoshida, A Pourquier, P Pommier, Y TI Purification and characterization of a Mg2+-dependent endonuclease (AN34) from etoposide-treated human leukemia HL-60 cells undergoing apoptosis SO CANCER RESEARCH LA English DT Article ID TOPOISOMERASE-II INHIBITORS; DNA FRAGMENTATION; CA2+/MG2+-DEPENDENT ENDONUCLEASE; POLY(ADP-RIBOSE) POLYMERASE; DIFFERENTIAL INDUCTION; DEOXYRIBONUCLEASE-I; DEATH; IDENTIFICATION; THYMOCYTES; ACTIVATION AB An important biochemical hallmark of apoptosis is the cleavage of chromatin into oligonucleosomal fragments. Here, we purified a Mg2+-dependent endonuclease from etoposide-treated HL-60 cells undergoing apoptosis, High levels of Mg2+-dependent endonuclease activity were detected in etoposide-treated HL-60 cells, and this activity increased in a time-dependent manner following etoposide treatment. Such an activity could not be detected in untreated cells or in cells treated with etoposide in the presence of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(OMe)-fluoromethyl ketone (zVAD-fmk) or the serine protease inhibitor tosyl-L-phenylalanine chloromethyl ketone (TPCK). This Mg2+-dependent endonuclease was purified by a series of chromatographic procedures. The enzyme preparation showed a single major protein band with M-r 34,000, determined by SDS-PAGE. The presence of the M-r 34,000 Mg2+-dependent endonuclease was also confirmed by activity gel analysis. The enzyme required only Mg2+ for full activity, pH optimum was in the range of 6.5-7.5. This enzyme introduced single-and double-strand breaks into SV40 DNA and produced internucleosomal DNA cleavage in isolated nuclei from untreated cells. The DNA breaks were terminated with 3'-OH, consistent with characteristic products of apoptotic chromatin fragmentation. We propose to designate this M-r 34,000 Mg2+-dependent endonuclease AN34 (apoptotic nuclease M-r 34,000). C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 48 TC 31 Z9 31 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 1998 VL 58 IS 12 BP 2576 EP 2582 PG 7 WC Oncology SC Oncology GA ZU255 UT WOS:000074178300017 PM 9635581 ER PT J AU Behan, KA Johnston, PG Allegra, CJ AF Behan, KA Johnston, PG Allegra, CJ TI Epitope mapping of a series of human thymidylate synthase monoclonal antibodies SO CANCER RESEARCH LA English DT Article ID ANTIGENIC STRUCTURES; CANCER; CHEMOTHERAPY; 5-FLUOROURACIL; QUANTITATION; PROTEINS; CELLS AB We have reported previously the development and application of several monoclonal antibodies to thymidylate synthase (TS). In this study, we used a series of overlapping 17-mer peptides that spanned the entire TS protein to map the epitope recognized bg three TS monoclonal antibodies (TS 106, TS 109, and TS 110). Using an ELISA, we identified two peptides (R-126-F-142 and L-131-R-147) that bound all three antibodies, which suggests that each antibody recognized a similar epitope on TS. A second set of peptides, representing sequential single-residue truncations from either the amino terminus or the carboxyl terminus starting with a G(129)-E-145 17-mer, was synthesized. A 10-amino acid sequence P-133-F-142 (PVYGFQWRHF) was identified as the binding epitope for all three antibodies. Further investigation via substitution mutational analysis of each residue within this epitope revealed that residues F-137, W-139, R-140, H-141, and F-142 mere critical for maximal binding of TS 106 and TS 110. TS 109 showed a similar pattern except in regard to R-140, with which there mas no apparent loss of binding. In addition to the utility of the three antibodies in detecting and measuring TS levels, identification of the binding locus permits the potential application of these antibodies in the investigation of TS enzymatic and regulatory function. C1 Natl Naval Med Ctr, Med Branch, NCI, Bethesda, MD 20889 USA. Queens Univ Belfast, Belfast City Hosp, Dept Oncol, Belfast BT9 7AB, Antrim, North Ireland. RP Allegra, CJ (reprint author), Natl Naval Med Ctr, Med Branch, NCI, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 16 TC 8 Z9 8 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 JUN 15 PY 1998 VL 58 IS 12 BP 2606 EP 2611 PG 6 WC Oncology SC Oncology GA ZU255 UT WOS:000074178300022 PM 9635586 ER PT J AU Carrasquillo, JA Lang, LX Whatley, M Herscovitch, P Wang, QC Pastan, I Eckelman, WC AF Carrasquillo, JA Lang, LX Whatley, M Herscovitch, P Wang, QC Pastan, I Eckelman, WC TI Aminosyn II effectively blocks renal uptake of F-18-labeled anti-Tac disulfide-stabilized Fv SO CANCER RESEARCH LA English DT Article ID SINGLE-CHAIN-FV; HUMAN T-CELLS; MONOCLONAL-ANTIBODY; IMMUNOGLOBULIN FRAGMENTS; ACID INFUSION; PROTEIN; FORMS; BIODISTRIBUTION; REDUCTION; ANALOG AB Because intact IgG has limitations as a tumor-imaging agent, radiolabeled Fv fragments are being evaluated. Due to the high renal accumulation of Fv fragments, methods to block renal uptake are being sought. This study evaluated how well Aminosyn II, a Food and Drug Administration-approved 15% amino acid solution, would block the renal accumulation of F-18 anti-Tac disulfide-stabilized Fv (dsFv) fragments (small fragments with high renal uptake). The anti-Tac dsFv is directed against the cu subunit of the interleukin 2 receptor. It was labeled at specific activities of 1.1-2.7 mCi/mg using N-succinimidyl 4-[F-18]fluoromethyl benzoate. Four adult baboons a ere injected i.v., with 0.7-1.9 mCi and 150 pg of dsFv. Each baboon was preinjected with Aminosyn II i.v. and, on a separate occasion, with a control solution. Thirty min before injection of F-18-labeled anti-Tac dsFv, a bolus of either solution was given, followed by a constant infusion of 13.3 ml/kg/h. Quantitative positron emission tomography imaging was performed. The amino acid levels in serum were measured serially. The baseline levels of lysine (and other amino acids) in plasma were not significantly different in either the Aminosyn Za or control infusion group and did not change during the control infusion. In the Aminosyn II group, lysine levels in plasma 5 min before anti-Tac dsFv infusion were 5-15 times higher than the baseline value and continued to rise during the infusion. The areas under the curve in blood of the F-18-labeled anti-Tac dsFv, from time of injection to end of imaging, expressed as percentage injected dose (%ID), were 28.94 +/- 4.05%ID x h/liter (mean +/- SD) for the control group and 32.09 +/- 11.15%ID x h/liter for the Aminosyn IH group (P = 0.54). The peak concentration of F-18-labeled anti-Tac dsFv in the kidney of the controls was 24.53 +/- 4.34%ID; the value in the Aminosyn II group was 5.39 +/- 1.89%ID, representing a mean decrease of 78.5%. The times to reach 90% of the peak levels of F-18 in the kidney were 5.6 +/- 3.0 min for the Aminosyn II group and 33.8 +/- 4.8 min for the control group. The amounts excreted in urine by 90 min were 47.7 +/- 8.55%ID and 78.5 +/- 12.8%ID (P = 0.01) for the controls and Aminosyn II group, respectively. In conclusion, Aminosyn Il effectively blocks the renal accumulation of F-18-labeled anti-Tac dsFv. Use of Aminosyn HI should allow much higher tracer administration for the same radiation exposure to the target organ (kidney). C1 NCI, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NCI, Positron Emiss Tomog Dept, NIH, Bethesda, MD 20892 USA. NCI, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Carrasquillo, JA (reprint author), NCI, Dept Nucl Med, NIH, Bldg 10,Room 1C496,10 Ctr Dr, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 38 TC 17 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 1998 VL 58 IS 12 BP 2612 EP 2617 PG 6 WC Oncology SC Oncology GA ZU255 UT WOS:000074178300023 PM 9635587 ER PT J AU Gratama, JW Orfao, A Barnett, D Brando, B Huber, A Janossy, G Johnsen, HE Keeney, M Marti, GE Preijers, F Rothe, G Serke, S Sutherland, DR Van der Schoot, CE Schmitz, G Papa, S AF Gratama, JW Orfao, A Barnett, D Brando, B Huber, A Janossy, G Johnsen, HE Keeney, M Marti, GE Preijers, F Rothe, G Serke, S Sutherland, DR Van der Schoot, CE Schmitz, G Papa, S CA European Working Grp Clinical Cell Anal TI Flow cytometric enumeration of CD34(+) hematopoietic stem and progenitor cells SO CYTOMETRY LA English DT Review DE CD34; hematopoietic stem cells; enumeration; flow cytometry; standardization ID UMBILICAL-CORD BLOOD; MOBILIZED PERIPHERAL-BLOOD; COLONY-STIMULATING FACTOR; BONE-MARROW; G-CSF; LEUKAPHERESIS PRODUCTS; MALIGNANT-LYMPHOMA; QUALITY ASSURANCE; NORMAL DONORS; IN-VITRO AB The need for a rapid and reliable marker for the engraftment potential of hematopoietic stem and progenitor cell (HPC) transplants has led to the development of flow cytometric assays to quantitate such cells on the basis of their expression of CD34, The variability associated with enumeration of low-frequency cells (i.e., as low as 0.1% or 5 cells/mu l) is exceedingly large, but recent developments have improved the accuracy and precision of the assay. Here, we review and compare the major techniques. Based on the current state of the art, we recommend i) bright fluorochrome conjugates of class II or III monoclonal antibodies (mAbs) that detect all glycoforms of CD34, 2) use of a vital nucleic acid dye to exclude platelets, unlysed red cells, and debris or use of 7-amino actinomycin D to exclude dead cells during data acquisition, 3) counterstaining with CD45 mAb to be included in the definition of HPC, 4) during list mode data analysis, Boolean gating to resolve the CD34(+) HPCs from irrelevant cell populations on the basis of the low levels of CD45 expression and low sideward light-scatter signals of HPCs, 5) inclusion of CD34(dim) and CD34(bright) populations in the CD34(+) cell count, 6) omission of the negative control staining, and 7) for apheresis products, enumeration of at least 100 CD34+ cells to ensure a 10% precision. Unresolved technical questions are 1) the replacement of conventional dual-platform by single-platform assay formats, i,e,, derivation of absolute CD34+ cell counts from a single flow cytometric assessment instead of from combined flow cytometer (percent CD34(+)) and hematology analyzer (absolute leukocyte count) data, 2) the cross-calibration of the available single-platform assays, and 3) the optimal method for sample preparation. An important clinical question to be addressed is the definition of the precise phenotypes and required numbers of HPCs responsible for short- and long-term recovery to optimize HPC transplant strategies. 1998. (C) 1998 Wiley-Liss, Inc. C1 Dr Daniel Den Hoed Canc Ctr, Dept Clin & Tumor Immunol, NL-3008 AE Rotterdam, Netherlands. Hosp Univ Salamanca, Serv Citometria, Hematol Lab, Salamanca, Spain. Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2JF, S Yorkshire, England. Osped Niguarda Ca Granda, Lab Unita Trapianto Renale, Milan, Italy. Kantonsspital, Zent Lab, Aarau, Switzerland. Royal Free Hosp, Sch Med, Dept Clin Immunol, London, England. Amtssygehus Herlev, Dept Hematol, Herlev, Denmark. London Hlth Sci Ctr, Dept Hematol, London, ON, Canada. NIH, Mol & Cellular Biol Lab, Ctr Biol Evaluat & Res, Food & Drug Adm, Bethesda, MD USA. Univ Nijmegen Hosp, Dept Hematol, NL-6500 HB Nijmegen, Netherlands. Univ Regensburg, Klinikum, Inst Klin Chem & Lab Med, D-8400 Regensburg, Germany. Humboldt Univ, Abt Hematol Onkol, Virchow Klinikum, Berlin, Germany. Toronto Hosp, Toronto, ON M5T 2S8, Canada. Dutch Res Cross Blood Transfus Serv, Dept Immunohematol, Cent Lab, Amsterdam, Netherlands. Univ Urbino, Ist Sci Morfol, I-61029 Urbino, Italy. RP Gratama, JW (reprint author), Dr Daniel Den Hoed Canc Ctr, Dept Clin & Tumor Immunol, POB 5201, NL-3008 AE Rotterdam, Netherlands. EM gratama@immh.azr.nl RI Preijers, F.W.M.B./L-4586-2015; OI Schmitz, Gerd/0000-0002-1325-1007 NR 109 TC 150 Z9 156 U1 2 U2 12 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 JUN 15 PY 1998 VL 34 IS 3 BP 128 EP 142 DI 10.1002/(SICI)1097-0320(19980615)34:3<128::AID-CYTO3>3.0.CO;2-D PG 15 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 102JN UT WOS:000074921200003 PM 9696157 ER PT J AU Lee-Kwon, W Park, D Bernier, M AF Lee-Kwon, W Park, D Bernier, M TI Nucleotide excision repair is not required for the antiapoptotic function of insulin-like growth factor 1 SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID DEPENDENT PROTEIN-KINASE; DISTINCT SIGNALING PATHWAYS; HAMSTER OVARY CELLS; DNA-REPAIR; INDUCED APOPTOSIS; PHOSPHATIDYLINOSITOL 3-KINASE; POLY(ADP-RIBOSE) POLYMERASE; CHO CELLS; IN-VIVO; P53 AB The expression of ERCC1, a member of the nucleotide excision repair (NER) family, is enhanced in cells transfected with insulin-like growth factor 1 (IGF-1) receptors. Of interest, an excellent concordance between ERCC1 expression and NER-mediated cell survival has been demonstrated. The two aims of the present study were to determine the signaling pathways used by IGF-1 to confer protection against apoptotic cell death in Chinese hamster ovary (CHO) cells and to assess the role of NER in this IGF-1 action. Experiments with pharmacological inhibitors indicated that phosphatidylinositol 3-kinase (PI 3-kinase) but not mitogen-activated protein kinase (ERK1/ERK2) mediates IGF-1 antiapoptotic activity. Using two series of CHO cells that have altered expression of ERCC1 or XPB/ERCC3, we examined IGF-1's ability to delay apoptotic death and reduction of mitochondrial oxidative function mediated by growth factor withdrawal. IGF-1 effectively blocked apoptosis, concomitant with increased MTT activity, in a pair of CHO cell lines expressing inactive ERCC1 (43-3B cells) and the transfected line of the mutant carrying the expressed human ERCC1 gene (83-G5 cells). Similarly, repair-deficient UV24 cells, which lack XPB/ERCC3, and their parental line AA8 were also responsive to the IGF-1's antiapoptotic capacity. In the presence of IGF-1, these cell lines became resistant to the cleavage of poly(ADP-ribose) polymerase, a key player in DNA damage recognition and DNA repair. These results suggest that PI 3-kinase activation plays a determinant role in the antiapoptotic function of IGF-1, but that functional NER does not play a critical part in mediating this IGF-1 response. (C) 1998 Academic Press. C1 NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. EM Bernierm@vax.grc.nia.nih.gov OI Bernier, Michel/0000-0002-5948-368X NR 64 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUN 15 PY 1998 VL 241 IS 2 BP 458 EP 466 DI 10.1006/excr.1998.4087 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA ZW008 UT WOS:000074364300019 PM 9637787 ER PT J AU Mochizuki, H Scherer, SW Xi, T Nickle, DC Majer, M Huizenga, JJ Tsui, LC Prochazka, M AF Mochizuki, H Scherer, SW Xi, T Nickle, DC Majer, M Huizenga, JJ Tsui, LC Prochazka, M TI Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence SO GENE LA English DT Article DE paraoxonase-2; exon-intron structure; alternative splicing; amino acid variants ID HUMAN SERUM PARAOXONASE; DEPENDENT DIABETES-MELLITUS; LIPOPROTEIN ASSOCIATED PARAOXONASE; LOW-DENSITY-LIPOPROTEIN; PIMA-INDIANS; INSULIN-RESISTANCE; MOLECULAR-BASIS; ARYLESTERASE; METABOLISM; PROTEIN AB We report the cloning and characterization of human PON2, a paraoxonase-related gene-2 that is physically linked with PON1 and PON3 on 7q21.3. PON2 is ubiquitously expressed and we identified several mRNA forms produced by alternative splicing, or by the use of a second transcription start site. We also describe two polymorphisms in the coding sequences that, in the protein deduced from the longest open reading frame, predict an alanine-to-glycine substitution at residue 147 and a serine-to-cysteine substitution at residue 310. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85016 USA. Hosp Sick Children, Dept Genet, Toronto, ON M5G 1X8, Canada. NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85016 USA. RP Prochazka, M (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, 4212 N 16Th St, Phoenix, AZ 85016 USA. RI Tsui, Lap-chee/A-1081-2010; Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013 OI Scherer, Stephen /0000-0002-8326-1999 NR 33 TC 106 Z9 122 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUN 15 PY 1998 VL 213 IS 1-2 BP 149 EP 157 DI 10.1016/S0378-1119(98)00193-0 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA ZX116 UT WOS:000074481000019 PM 9714608 ER PT J AU Robinson, GW Johnson, PF Hennighausen, L Sterneck, E AF Robinson, GW Johnson, PF Hennighausen, L Sterneck, E TI The C/EBP beta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland SO GENES & DEVELOPMENT LA English DT Article DE mammopoiesis; ductal morphogenesis; alveoli; milk proteins; gene deletion ID CCAAT/ENHANCER-BINDING-PROTEIN; INTERLEUKIN-6 PROMOTER; LEUCINE ZIPPER; CYCLIN D1; KAPPA-B; EXPRESSION; GENE; MICE; RECEPTOR; PREGNANCY AB Studies of C/EBP beta-deficient mice have demonstrated a pivotal role for this transcription factor in hematopoiesis, adipogenesis, and ovarian function. Here we show that C/EBP beta is also essential for normal development and function of the mammary gland. Ductal morphogenesis in virgin C/EBP beta-deficient mice was disrupted, with ducts displaying reduced growth and branching. To distinguish whether the effect of C/EBP beta deficiency on mammary epithelium is indirect or cell autonomous, we performed ovarian and mammary gland transplants. Transplants of wild-type ovaries into mutant females partially restored ductal morphogenesis during puberty but failed to support mammopoiesis during pregnancy. At term, mutant mice harboring wild-type ovaries exhibited reduced alveolar proliferation and impaired epithelial cell differentiation, including a complete absence of milk protein expression. Mammary gland transplant experiments demonstrated that development of C/EBP beta-deficient epithelium was defective within a wild-type stroma and host background. Cell proliferation during pregnancy was reduced and differentiation, as measured by the activity of milk protein genes, was inhibited. However, wild-type epithelium developed in a C/EBP beta-deficient stroma. Thus, C/EBP beta plays an essential, cell autonomous role in the proliferation and differentiation of mammary secretory epithelial cells and is required for the activation of milk protein genes. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. NCI, Eukaryot Transcript Regulat Grp, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Robinson, GW (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RI Johnson, Peter/A-1940-2012; Robinson, Gertraud/I-2136-2012 OI Johnson, Peter/0000-0002-4145-4725; NR 44 TC 185 Z9 190 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 1998 VL 12 IS 12 BP 1907 EP 1916 DI 10.1101/gad.12.12.1907 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA ZX336 UT WOS:000074505300016 PM 9637691 ER PT J AU Song, XY Gu, ML Jin, WW Klinman, DM Wahl, SM AF Song, XY Gu, ML Jin, WW Klinman, DM Wahl, SM TI Plasmid DNA encoding transforming growth factor-beta 1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE cytokine; inflammation; immunosuppression; gene therapy; arthritis ID FACTOR-BETA; SYNOVIAL INFLAMMATION; GENE-THERAPY; INTRAMUSCULAR INJECTION; SYSTEMIC DELIVERY; IN-VIVO; MICE; EXPRESSION; MUSCLE; HYPERPLASIA AB Transforming growth factor beta is a potent immunomodulator with both pro-and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-beta has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-beta, we administered a plasmid DNA encoding human TGF-beta 1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 mu g plasmid DNA encoding TGF-beta 1, but not vector DNA, administered at the peak of the acute phase profoundly suppressed the subsequent evolution of chronic erosive disease typified by disabling joint swelling and deformity (articular index = 8.17+/-0.17 vs. 1.25+/-0.76, n = 6, day 26, P < 0.01), Moreover, delivery of the TGF-beta 1 DNA even as the chronic phase commenced virtually eliminated subsequent inflammation and arthritis. Both radiologic and histopathologic as well as molecular evidence supported the marked inhibitory effect of TGF-beta 1 DNA on synovial pathology, with decreases in the inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and the expression of proinflammatory cytokines that characterize this model. Increases in TGF-beta 1 protein were detected in the circulation of TGF-beta 1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-beta 1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-beta 1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis. C1 NIDR, Oral Infect & Immunity Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Retrovirus Lab, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), Bldg 30,Room 332,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. NR 32 TC 93 Z9 95 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN 15 PY 1998 VL 101 IS 12 BP 2615 EP 2621 DI 10.1172/JCI2480 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZY285 UT WOS:000074604800002 PM 9637694 ER PT J AU Vendola, KA Zhou, J Adesanya, OO Weil, SJ Bondy, CA AF Vendola, KA Zhou, J Adesanya, OO Weil, SJ Bondy, CA TI Androgens stimulate early stages of follicular growth in the primate ovary SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE granulosa cells; folliculogenesis; mitosis; apoptosis; androgen ID MALE-TRANSSEXUALS; POLYCYSTIC OVARIES; CELL-PROLIFERATION; TREATED FEMALE; TESTOSTERONE; MORPHOLOGY; FOLLICLES; SECRETION; HORMONE; MONKEY AB The concept that androgens are atretogenic, derived from murine ovary studies, is difficult to reconcile with the fact that hyperandrogenic women have more developing follicles than normal-cycling women, To evaluate androgen's effects on primate follicular growth and survival, normal-cycling rhesus monkeys were treated with placebo-, testosterone-(T), or dihydrotestosterone-sustained release implants, and ovaries were taken for histological analysis after 3-10 d of treatment, Growing preantral and small antral follicles up to 1 mm in diameter were significantly and progressively increased in number and thecal layer thickness in T-treated monkeys from 3-10 d. Granulosa and thecal cell proliferation, as determined by immunodetection of the Ki67 antigen, were significantly increased in these follicles, Preovulatory follicles (> 1 mm), however, were not increased in number in androgen-treated animals, Follicular atresia was not increased and there were actually significantly fewer apoptotic granulosa cells in the T-treated groups. Dihydrotestosterone treatment had identical effects, indicating that these growth-promoting actions are mediated by the androgen receptor. These findings show that, over the short term at least, androgens are not atretogenic and actually enhance follicular growth and survival in the primate. These new data provide a plausible explanation for the pathogenesis of "polycystic" ovaries in hyperandrogenism. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bldg 10,Rm 10N262,10 Ctr Dr 1862, Bethesda, MD 20892 USA. NR 33 TC 331 Z9 347 U1 2 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN 15 PY 1998 VL 101 IS 12 BP 2622 EP 2629 DI 10.1172/JCI2081 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZY285 UT WOS:000074604800003 PM 9637695 ER PT J AU Novoradovskaya, N Lee, JH Yu, ZX Ferrans, VJ Brantly, M AF Novoradovskaya, N Lee, JH Yu, ZX Ferrans, VJ Brantly, M TI Inhibition of intracellular degradation increases secretion of a mutant form of alpha 1-antitrypsin associated with profound deficiency SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE alpha 1-antitrypsin; degradation; proteasome; cirrhosis; emphysema ID ENDOPLASMIC-RETICULUM; ALPHA-1-PROTEINASE INHIBITOR; PROTEIN-DEGRADATION; HUMAN-MONOCYTES; MESSENGER-RNA; PROTEASOME; VARIANT; PATHWAY; DEFECT; LIVER AB The mutant Z form of alpha 1-antitrypsin (alpha 1AT) is responsible for > 95% of all individuals with alpha 1AT deficiency, an important inherited cause of emphysema and liver disease. Since secreted Z alpha 1AT is a functional antiprotease, we hypothesized that interrupting catabolism of retained Z alpha 1AT might increase its transport out of cells, causing an increase in extracellular protease protection. Both the protein translation inhibitor cycloheximide and the specific inhibitor of proteasome function, lactacystin, prevented intracellular degradation of Z alpha 1AT, Moreover, this inhibition of degradation was associated with partial restoration of Z alpha 1AT vesicular transport. This effect was observed in a model system of transfected CHO cells as well as in human alveolar macrophages synthesizing Z alpha 1AT. This study supports the hypothesis that altering the intracellular fate of a mutant protein may be an option in the treatment of diseases associated with misfolded but potentially functional proteins. C1 NHLBI, Pulm Crit Care Med Branch, Clin Studies Sect, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Brantly, M (reprint author), NHLBI, Pulm Crit Care Med Branch, Clin Studies Sect, NIH, Bldg 10,10 Ctr Dr,MSC-1590,Room 6D03, Bethesda, MD 20892 USA. NR 43 TC 34 Z9 34 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN 15 PY 1998 VL 101 IS 12 BP 2693 EP 2701 DI 10.1172/JCI549 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA ZY285 UT WOS:000074604800011 PM 9637703 ER PT J AU Apte, RS Sinha, D Mayhew, E Wistow, GJ Niederkorn, JY AF Apte, RS Sinha, D Mayhew, E Wistow, GJ Niederkorn, JY TI Cutting edge: Role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; FACTOR MIF; LOCALIZATION; LENS; EYE AB The absence of MHC class I Ags on the corneal endothelium, which lines the anterior chamber of the eye, makes this cell layer potentially vulnerable to lysis by NK cells. However, aqueous humor (AH), which bathes the corneal endothelium, contains a 12-kDa protein which inhibits the NK-mediated lysis of corneal endothelial cells. An amino acid sequence analysis of AH revealed that this factor shared >90% homology,vith macrophage migration inhibitory factor (MIF). The NK inhibitory effect of AH was neutralized with anti-human MIF Ab, Moreover, mouse rMIF produced a similar inhibition of NK cell activity. However, neither rMIF nor AH inhibited the CTL-mediated lysis of allogeneic cells, rMIF prevented the release of perforin granules by NK cells but not CTLs, Although MIF displays proinflammatory properties, these results indicate that it can also inhibit at least one immune effector element, NK cells, and thereby contribute to immune privilege in the eye. C1 Univ Texas, SW Med Ctr, Dept Ophthalmol, Dallas, TX 75235 USA. NEI, Sect Mol Struct & Funct, NIH, Bethesda, MD 20892 USA. RP Niederkorn, JY (reprint author), Univ Texas, SW Med Ctr, Dept Ophthalmol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. FU NEI NIH HHS [EY 7641, EY05631] NR 19 TC 151 Z9 155 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 JUN 15 PY 1998 VL 160 IS 12 BP 5693 EP 5696 PG 4 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000001 PM 9637476 ER PT J AU Hathcock, KS Weng, NP Merica, R Jenkins, MK Hodes, R AF Hathcock, KS Weng, NP Merica, R Jenkins, MK Hodes, R TI Cutting edge: Antigen-dependent regulation of telomerase activity in murine T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IN-VIVO; EXPRESSION; MOUSE; HISTOCOMPATIBILITY; IDENTIFICATION; COSTIMULATION; ACTIVATION; INDUCTION; RECEPTOR; CANCER AB Telomeres, structures on the ends of linear chromosomes, function to maintain chromosomal integrity, Telomere shortening occurs with cell division and provides a mechanism for limiting the replicative potential of normal human somatic cells. Telomerase, a ribonucleoprotein enzyme, synthesizes telomeric repeats on chromosomal termini, potentially extending the capacity for cell division. The present study demonstrates that resting T cells express little/no activity, and optimal Ag-specific induction of telomerase activity in vitro requires both TCR and CD28-B7 costimulatory signals. Regulation of telomerase in T cells during in vivo Ag-dependent activation was also assessed by adoptive transfer of TCR transgenic T cells and subsequent Ag challenge. Under these conditions, telomerase was induced in transgenic T cells coincident with a phase of extensive clonal expansion, These findings suggest that telomerase may represent an adoptive response that functions to preserve replicative potential in Ag-reactive lymphocytes. C1 NIA, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Univ Minnesota, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. RP Hathcock, KS (reprint author), NIA, NIH, Room 4B10,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Jenkins, Marc/G-1063-2012 OI Jenkins, Marc/0000-0001-8009-7655 FU NIAID NIH HHS [AI07421, AI39614] NR 36 TC 57 Z9 59 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 1998 VL 160 IS 12 BP 5702 EP 5706 PG 5 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000003 PM 9637478 ER PT J AU Seder, RA Marth, T Sieve, MC Strober, W Letterio, JJ Roberts, AB Kelsall, B AF Seder, RA Marth, T Sieve, MC Strober, W Letterio, JJ Roberts, AB Kelsall, B TI Factors involved in the differentiation of TGF-beta-producing cells from naive CD4(+) T cells: IL-4 and IFN-gamma have opposing effects, while TGF-beta positively regulates its own production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; ORAL TOLERANCE; FACTOR-BETA-1 GENE; INTERFERON-GAMMA; TRANSGENIC MICE; TH1; INTERLEUKIN-12; ANTIBODIES AB TGF-beta has been shown to play a central role in regulating inflammatory responses; thus, understanding the factors involved in the generation of TGF-beta-producing cells could lead to interventions that are useful in effecting disease progression. In initial studies, the capacity of naive CD4(+) T cells from TCR transgenic (Tg) mice to produce TGF-beta following primary and secondary stimulation was assessed. TGF-beta, IL-4, or IFN-gamma production could not be detected from highly purified naive CD4+/lymphocyte endothelial cell adhesion molecule (LECAM)-1(high) cells following primary stimulation for 36 h with plate-bound anti-CD3, anti-CD28, and IL-2, This population was subsequently used to study the differentiation of TGF-beta-producing CD4(+) T cells. In further studies, naive CD4(+)/LECAM-1(high) cells from TCR transgenic mice of both the BALB/c and B10.A backgrounds were stimulated with T-depleted spleen cells (TDS) and specific peptide in the presence of various cytokines and/or cytokine antagonists for 5 days, restimulated, and TGF-beta, IL-4, and IFN-gamma production were measured. Priming conditions favoring high IL-4 production and/or low IFN-gamma production greatly enhanced TGF-beta production in secondary cultures. Furthermore, the presence of IL-10 in cultures was associated with an increase in TGF-beta production following restimulation, The importance of IL-4 and IFN-gamma in regulating TGF-beta production was confirmed in studies showing that cells from IFN-gamma(-/-) mice produced more TGF-beta, while cells from IL-4(-/-) mice produced less TGF-beta compared with wild-type controls. Finally, the addition of exogenous TGF-beta to priming cultures significantly enhanced the production of TGF-beta upon restimulation, demonstrating that TGF-beta has a role in self-regulating its own production. C1 NIAID, Lymphokine Regulat Unit, NIH, Bethesda, MD 20892 USA. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NCI, Chemoprevent Lab, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bldg 10,Room 11C215, Bethesda, MD 20892 USA. EM rseder@nih.gov NR 38 TC 172 Z9 179 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 JUN 15 PY 1998 VL 160 IS 12 BP 5719 EP 5728 PG 10 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000005 PM 9637480 ER PT J AU Kim, K Lee, C Sayers, TJ Muegge, K Durum, SK AF Kim, K Lee, C Sayers, TJ Muegge, K Durum, SK TI The trophic action of IL-7 on pro-T cells: Inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR-GAMMA CHAIN; LYMPHOID DEVELOPMENT; MOUSE THYMOCYTES; B-LYMPHOPOIESIS; DEFICIENT MICE; INTERLEUKIN-7; EXPRESSION; GENE; PROLIFERATION; PROGENITORS AB Signals from the IL-7R are essential for normal thymocyte development. We isolated thymocytes from early developmental stages and observed that suspensions of pro-T1, -T2, and -T3 cells rapidly died in culture. Addition of IL-7 promoted their survival, but did not induce cell division. Pro-T4 cells did not undergo rapid cell death, and their survival was therefore independent of IL-7, Death in the absence of IL-7 showed the hallmarks of apoptosis, including DNA fragmentation and annexin V binding; however, caspase inhibitors blocked DNA fragmentation, but did not block cell death. The trophic effect of IL-7 was partially inhibited by blocking protein synthesis. The p53 pathway was not involved in this death pathway, since pro-T cells from p53(-/-) mice also underwent cell death in the absence of IL-7. The Fas/Fas ligand pathway was not involved in cell death, since Fas-deficient pro-T cells died normally in the absence of IL-7, anti-Fas Abs did not protect cells from death in the absence of IL-7, and Fas expression was undetectable on cells at these stages. The IL-7 trophic affect correlated with increased intracellular levels of Bcl-2 and decreased levels of Bax, whereas no Bcl-X-L, Bcl-w, or Bad was detectable. Thus, maintaining a favorable Bcl-2/Bax ratio may account for the trophic action of IL-7. C1 NCI, Mol Immunoregulat Lab, Frederick Canc Res Facil, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Div Basic Sci, Ft Detrick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Mol Immunoregulat Lab, Frederick Canc Res Facil, Bldg 560,Room 31-45, Frederick, MD 21702 USA. RI Sayers, Thomas/G-4859-2015 NR 50 TC 139 Z9 140 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 JUN 15 PY 1998 VL 160 IS 12 BP 5735 EP 5741 PG 7 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000007 PM 9637482 ER PT J AU Hemmer, B Stefanova, I Vergelli, M Germain, RN Martin, R AF Hemmer, B Stefanova, I Vergelli, M Germain, RN Martin, R TI Relationships among TCR ligand potency, thresholds for effector function elicitation, and the quality of early signaling events in human T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; ALTERED PEPTIDE LIGANDS; POSITIVE SELECTION; AUTOIMMUNE ENCEPHALOMYELITIS; DIFFERENTIAL ACTIVATION; RECEPTOR ANTAGONISTS; MEDIATED-IMMUNITY; PARTIAL AGONISTS; ANTIGEN; ANALOG AB Determining how receptor ligand quality and quantity together control the biologic responses of T cells is central to understanding normal and pathologic T cell immunity. Here we have carefully examined how variations in antigenic peptide structure and dose affect multiple functional responses of human T cell clones and have correlated these observations with proximal TCR signaling events induced by the same set of related ligands, As the Ag concentration increases, effector functions are elicited according to a clone-specific hierarchy. The absolute amount of each peptide required to stimulate the entire set of effector functions (potency) differs markedly among ligands for a single TCR, correlating with the efficiency of TCR down-modulation and the extent of ZAP-70 activation. However, distinct patterns of TCR zeta-chain phosphorylation were observed, with the ratios of TCR zeta isoforms relating to ligand agonist potency. The appearance of partially phosphorylated TCR zeta isoforms was paralleled by relative changes in certain response thresholds within the hierarchy. Thus, a combination of density, potency, and quality of signaling all contribute to the distinct effects of agonist ligands on T cell immunity. C1 NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Martin, R (reprint author), NINCDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16,10 Ctr Dr MSC 1400, Bethesda, MD 20892 USA. NR 54 TC 123 Z9 123 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 JUN 15 PY 1998 VL 160 IS 12 BP 5807 EP 5814 PG 8 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000016 PM 9637491 ER PT J AU Hogaboam, G Kunkel, SL Strieter, RM Taub, DD Lincoln, P Standiford, TJ Lukacs, NW AF Hogaboam, G Kunkel, SL Strieter, RM Taub, DD Lincoln, P Standiford, TJ Lukacs, NW TI Novel role of transmembrane SCP for mast cell activation and eotaxin production in mast cell fibroblast interactions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID C-KIT LIGAND; INDUCED PULMONARY FIBROSIS; EXPRESSION; INFLAMMATION; CHEMOKINE; IDENTIFICATION; HISTAMINE; RECEPTOR; EOSINOPHILIA; MATURATION AB Mast cell activation can be induced by multiple mechanisms, including IgE-, complement-, and stem cell factor (SCF)-mediated pathways. In addition, the interaction of mast cells with particular cell populations, such as fibroblasts, have also demonstrated increased mast cell reactivity, In these studies, we have investigated the role of fibroblast-mast cell interaction for induction of histamine release and chemokine production and the specific role of SCF during this interaction. Primary pulmonary fibroblast cell lines were grown in culture and used throughout these studies. Mast cells were grown in parallel,vith fibroblasts by incubation of bone marrow cells with SCF and IL-3, During mast cell-fibroblast coculture, increased histamine release could be attenuated either by separation of the cell populations using a Trans-Well setup, which did not allow cellular contact, or by specific anti-SCF Ab, In addition, a significant increase in eotaxin, a potent eosinophil-specific C-C chemokine, was also observed during fibroblast-mast cell interaction. The production of eotaxin was cell contact dependent and could be inhibited using an anti-SCF Ab or specific antisense therapy. SCF was constitutively produced from fibroblasts in its transmembrane form and could be induced by TNF, SCF-coated plates induced significant mast cell-derived eotaxin production, whereas soluble SCF induced little or no eotaxin, suggesting a necessity for receptor cross-linking for activation. These studies indicate that fibroblast-mast cell contact plays a role in exacerbation of histamine release and eotaxin production. C1 Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Internal Med, Div Pulm & Crit Care, Ann Arbor, MI 48109 USA. NCI, Frederick, MD 21701 USA. RP Lukacs, NW (reprint author), Univ Michigan, Sch Med, Dept Pathol, 1301 Catherine, Ann Arbor, MI 48109 USA. NR 45 TC 39 Z9 39 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 1998 VL 160 IS 12 BP 6166 EP 6171 PG 6 WC Immunology SC Immunology GA ZU094 UT WOS:000074161000060 ER PT J AU Zipp, F Otzelberger, K Dichgans, J Martin, R Weller, M AF Zipp, F Otzelberger, K Dichgans, J Martin, R Weller, M TI Serum CD95 of relapsing remitting multiple sclerosis patients protects from CD95-mediated apoptosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE autoimmune disease; multiple sclerosis; apoptosis; CD95 ID FAS-MEDIATED APOPTOSIS; PROGRAMMED CELL-DEATH; AUTOIMMUNE ENCEPHALOMYELITIS; T-LYMPHOCYTES; ACTIVATION; TOLERANCE; MOLECULE; SYSTEM; GLIOMA; BRAIN AB Failure of CD95-mediated apoptosis as a potential negative regulatory mechanism of T cell expansion may be involved in T cell-mediated autoimmune diseases such as multiple sclerosis (MS). Recently, soluble CD95 has been shown to be elevated in MS patients with active disease. Here, we report that the sera of MS patients inhibit CD95 ligand-induced apoptosis of susceptible target cells in a concentration-dependent manner and dependent on the amount of serum CD95 levels. Thus, MS sera contain biologically active inhibitors of T cell apoptosis that may allow for prolonged abnormal immune responses. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Tubingen, Dept Neurol, D-72076 Tubingen, Germany. Natl Inst Neurol Dis, Neuroimmunol Branch, NIH, Bethesda, MD USA. RP Zipp, F (reprint author), Univ Tubingen, Dept Neurol, Hoppe Seyler Str 3, D-72076 Tubingen, Germany. RI Zipp, Frauke/C-9968-2015 OI Zipp, Frauke/0000-0002-1231-1928 NR 30 TC 49 Z9 49 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD JUN 15 PY 1998 VL 86 IS 2 BP 151 EP 154 DI 10.1016/S0165-5728(98)00032-0 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA ZX315 UT WOS:000074503200005 PM 9663560 ER PT J AU Battelle, BA Andrews, AW Calman, BG Sellers, JR Greenberg, RM Smith, WC AF Battelle, BA Andrews, AW Calman, BG Sellers, JR Greenberg, RM Smith, WC TI A myosin III from Limulus eyes is a clock-regulated phosphoprotein SO JOURNAL OF NEUROSCIENCE LA English DT Article DE myosin III; ninaC; Limulus polyphemus; photoreceptor cells; circadian rhythms; octopamine; unconventional myosin; cytoskeleton; Drosophila melanogaster; cAMP-dependent phosphorylation ID DROSOPHILA-NINAC KINASE; HEAVY-CHAIN HEAD; CIRCADIAN-RHYTHMS; VISUAL-SYSTEM; LATERAL EYE; VENTRAL PHOTORECEPTORS; CALMODULIN-BINDING; PROTEIN-KINASE; HORSESHOE-CRAB; EFFERENT NEUROTRANSMISSION AB The lateral eyes of the horseshoe crab Limulus polyphemus undergo dramatic daily changes in structure and function that lead to enhanced retinal sensitivity and responsiveness to light at night. These changes are controlled by a circadian neural input that alters photoreceptor acid pigment cell shape, pigment migration, and phototransduction. Clock input to the eyes also regulates photomechanical movements within photoreceptors, including membrane shedding. The biochemical mechanisms underlying these diverse effects of the clock on the retina are unknown, but a major biochemical consequence of activating clock input to the eyes is a rise in the concentration of cAMP in photoreceptors and the phosphorylation of a 122 kDa visual system-specific protein. We have cloned and sequenced cDNA encoding the clock-regulated 122 kDa phosphoprotein and show here that it is a new member of the myosin III family. We report that Limulus myosin III is similar to other unconventional myosins in that it binds to calmodulin in the absence of Ca2+; it is novel in that it is phosphorylated within its myosin globular head, probably by cAMP-dependent protein kinase. The protein is present throughout the photoreceptor, including the region occupied by the photosensitive rhabdom, We propose that the phosphorylation of Limulus myosin III is involved in one or more of the structural and functional changes that occur in Limulus eyes in response to clock input. C1 Univ Florida, Whitney Lab, St Augustine, FL 32086 USA. Univ Florida, Dept Neurosci, St Augustine, FL 32086 USA. NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Battelle, BA (reprint author), Univ Florida, Whitney Lab, 9505 Ocean Shore Blvd, St Augustine, FL 32086 USA. FU NEI NIH HHS [EY06454] NR 76 TC 34 Z9 34 U1 2 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 JUN 15 PY 1998 VL 18 IS 12 BP 4548 EP 4559 PG 12 WC Neurosciences SC Neurosciences & Neurology GA ZT273 UT WOS:000074068000012 PM 9614231 ER PT J AU Simpson, PB Mehotra, S Langley, D Sheppard, CA Russell, JT AF Simpson, PB Mehotra, S Langley, D Sheppard, CA Russell, JT TI Specialized distributions of mitochondria and endoplasmic reticulum proteins define Ca2+ wave amplification sites in cultured astrocytes SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE calreticulin; mitochondria; calcium homeostasis; ryanodine receptors ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; CALCIUM-BINDING PROTEINS; XENOPUS-LAEVIS OOCYTES; SARCOPLASMIC-RETICULUM; SUBCELLULAR-LOCALIZATION; GENE-EXPRESSION; SMOOTH-MUSCLE; CALRETICULIN; CELLS; CALSEQUESTRIN AB This study was undertaken to examine the expression and role of the endoplasmic reticulum (ER) proteins calreticulin and ryanodine receptors, and mitochondria, in cultured astrocytes. Using several lines of investigation, we have identified a key role for mitochondria in astrocyte Ca2+ signalling: (1) a significant correlation was found between sites of regenerative Ca2+ wave amplification (possessing high amplitude ER Ca2+ release) and the location of mitochondria in the cell; (2) norepinephrine (2 mu M) caused a rapid-onset increase in rhod 2 fluorescence in 34% of astrocyte mitochondria, indicating that cytosolic Ca2+ responses result in mitochondrial Ca2+ elevation; and (3) pretreatment with the protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone to inhibit mitochondrial activity markedly reduced the amplitude of subsequent norepinephrine-evoked cytosolic Ca2+ responses, We then investigated the roles of several ER proteins in Ca2+ signalling by immunocytochemistry, Ryanodine receptors and calreticulin were found to be expressed in heterogeneous patterns in astrocytes. The expression pattern of calreticulin corresponded closely,vith the distribution of mitochondria, whereas the expression of ryanodine receptors was not similar to that of either of these cellular factors. We measured Ca2+ wave kinetics in a single astrocyte, then assessed protein distribution by immunocytochemistry in the same cell. Cross-correlation between norepinephrine-evoked Ca2+ wave amplitude and calreticulin distribution indicated a close spatial relationship between this Ca2+-binding protein and sites of regenerative wave amplification. These results demonstrate that amplification sites for Ca2+ waves in astrocytes are identifiable by accumulations of calreticulin (and type 2 InsP(3)Rs), and by the presence of mitochondria, which may regulate the ER Ca2+ release process, (C) 1998 Wiley-Liss, Inc. C1 NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Russell, JT (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bdg 49 Rm 5A78,49 Convent Dr,MS4495, Bethesda, MD 20892 USA. EM james@helix.nih.gov NR 58 TC 46 Z9 46 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 15 PY 1998 VL 52 IS 6 BP 672 EP 683 PG 12 WC Neurosciences SC Neurosciences & Neurology GA ZW471 UT WOS:000074414300006 PM 9669316 ER PT J AU Bahring, R Mayer, ML AF Bahring, R Mayer, ML TI An analysis of philanthotoxin block for recombinant rat GluR6(Q) glutamate receptor channels SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID METHYL-D-ASPARTATE; NICOTINIC ACETYLCHOLINE-RECEPTORS; CA2+-PERMEABLE AMPA RECEPTORS; HIPPOCAMPAL-NEURONS; INWARD RECTIFICATION; NMDA RECEPTORS; SPIDER TOXINS; KAINATE; POLYAMINES; BRAIN AB 1. The action of philanthotoxin 343 (PhTX) on rat homomeric GluR6(Q) recombinant glutamate receptor channels was analysed using concentration-jump techniques and outside-out patches from HEK 293 cells. Both onset and recovery from block by external PhTX were dependent on the presence of agonist, indicating that channels must open for PhTX to bind and that channel closure can trap PhTX. 2. Block bg external PhTX developed with double-exponential kinetics. The rate of onset of the fast component of block showed an exponential increase per 27 mV hyperpolarization over the range -40 to -100 mV. The rate of onset of the slow component of block showed a nonlinear concentration dependence indicating a rate-limiting step in the blocking mechanism. 3. The extent of block by 1 mu m external PhTX was maximal at -40 mV and did not increase with further hyperpolarization; the rate of recovery from block by external PhTX increased 6-fold on hyperpolarization from -40 to -100 mV suggesting that PhTX permeates at negative membrane potentials. 4. Apparent K-d values for block by external PhTX estimated from dose-inhibition experiments decreased 300-fold on hyperpolarization from +40 mV (K-d, 19.6 mu m) to -40 mV (K-d, 69 nM); there was little further increase in affinity with hyperpolarization to -80 mV (K-d, 56 nM), consistent with permeation of PhTX at negative membrane potentials. 5. Block by internal PhTX showed complex kinetics and voltage dependence. Analysis with voltage ramps from -120 to +120 mV indicated a K-d at 0 mV of 20 mu M, decreasing e-fold per 16 mV depolarization. However, at +90 mV the extent of block by 1 and 10 mu M internal PhTX (73% and 95%, respectively) reached a maximum and did not increase with further depolarization. 6. Voltage-jump analysis of block by 100 mu M internal PhTX revealed partial trapping. With 100 ms jumps from -100 to -40 mV, onset and recovery from block were complete within 5 ms. With jumps of longer duration the extent of block increased, with a time constant of 8.1 s, reaching 84 % at 30 s. On repolarization to -100 mV, recovery from block showed fast and slow components. 7. The amplitude of the slow component of block by internal PhTX showed a biphasic voltage dependence, first increasing then decreasing with progressive depolarization. Maximum block was obtained at 0 mV. 8. Our results suggest that PhTX acts as an open channel blocker; however, provided that the to?rin remains bound to the channel, an allosteric mechanism destabilizes the open state, inducing channel closing and trapping PhTX. Strong depolarization for internal PhTX, or strong hyperpolarization for external PhTX, forces the toxin to permeate before it triggers entry into closed blocked states. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), Bldg 49,Room 5A78,49 Convent Dr,MSC 4495, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov RI Bahring, Robert/F-7146-2010; Mayer, Mark/H-5500-2013 NR 45 TC 56 Z9 57 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 15 PY 1998 VL 509 IS 3 BP 635 EP 650 DI 10.1111/j.1469-7793.1998.635bm.x PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZY390 UT WOS:000074616500002 PM 9596788 ER PT J AU Li, YX Schaffner, AE Walton, MK Barker, JL AF Li, YX Schaffner, AE Walton, MK Barker, JL TI Astrocytes regulate developmental changes in the chloride ion gradient of embryonic rat ventral spinal cord neurons in culture SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SUBUNIT MESSENGER-RNAS; DORSAL HORN NEURONS; HIPPOCAMPAL-NEURONS; GABA; CELLS; EXPRESSION; GLIA; DEPOLARIZATION; POTENTIALS; MODULATION AB 1. Embryonic rat ventral spinal cord neurons were dissociated at day 15 and grown on: (i) poly-D-lysine (PDL); (ii) a confluent monolayer of type I astrocytes; or (iii) PDL in astrocyte conditioned medium (ACM) to examine the influence of astroglia on the regulation of GABA(A) receptor/Cl- channel properties. 2. Potentiometric oxonol dye recordings of intact cells indicated that embryonic neurons were uniformly depolarized by muscimol. The depolarizing effects disappeared in cells dissociated during the early postnatal period and recovered in culture for 24 h. Similar recordings using the calcium-imaging dye fura-2 AM revealed that GABA or muscimol triggered a sustained rise in cytosolic Ca2+ (Ca-c(2+)) in embryonic neurons that was dependent on extracellular Ca2+, blocked by bicuculline and nifedipine and sensitive to changes in extracellular chloride. The incidence and amplitude of the Ca2+ response decreased with time in vitro and was accelerated in neurons cultured on astrocytes compared with those on PDL. 3. Perforated patch-clamp recordings revealed that GABA depolarized neurons in a Cl--dependent and bicuculline-sensitive manner. Both the resting membrane potential and the GABA equilibrium potential became more hyperpolarized with time in vitro. 4. Astrocytes and ACM accelerated the transformation of GABAergic potential responses from depolarizing to hyperpolarizing. The change occurred over the first 4 days in co-culture or in ACM but took more than 2 weeks in neurons cultured on PDL alone. 5. The intrinsic, elementary properties of GABA, receptor/Cl- channels including open time and unitary conductance changed independently of the presence of astrocytes or ACM. Mean open time of the dominant kinetic component decreased and conductance increased with time in vitro. 6. In sum, astrocytes accelerate the developmental change in the Cl- ion gradient extrinsic to GABA, receptor/Cl- channels, which is critical for triggering Ca2+ entry, without influencing parallel changes in the intrinsic properties of the channels. C1 National Institute Neurological Diseases & Stroke, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Barker, JL (reprint author), Bldg 36 Room 2C02,36 Convent Dr,MSC 4066, Bethesda, MD 20892 USA. EM jlbarker@codon.nih.gov NR 40 TC 28 Z9 29 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 15 PY 1998 VL 509 IS 3 BP 847 EP 858 DI 10.1111/j.1469-7793.1998.847bm.x PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA ZY390 UT WOS:000074616500018 PM 9596804 ER PT J AU Hudson, EK Tsuchiya, N Hansford, RG AF Hudson, EK Tsuchiya, N Hansford, RG TI Age-associated changes in mitochondrial mRNA expression and translation in the Wistar rat heart SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE mitochondrial protein synthesis; cytochrome c oxidase; mitochondrial gene expression; aging; heart ID PROTEIN-SYNTHESIS; TRANSCRIPTION FACTOR; LIPID OXIDATION; DNA; GENE; ACTIVATION; NUCLEAR; GENOME; IDENTIFICATION; BIOGENESIS AB The purpose of this research is to determine possible causes and mechanisms involved in the age-associated decline in mitochondrial activity. We have focused on cytochrome c oxidase because it is comprised of both nuclear and mitochondrial-encoded subunits and may provide some insight into the coordination of the two genomes. In agreement with previous reports, we show an approximate 30% decrease in cardiac cytochrome c oxidase activity at 24 months compared to 6 months with no change in the activity of the nuclear encoded citrate synthase of the mitochondrial matrix. The rate of mitochondrial protein synthesis as shown by [S-35]methionine incorporation decreased approximately 35% in the 24-month-old rat compared to the B-month-old rat. The decrease in protein synthesis was associated with a 30-50% reduction in the levels of most individually radiolabeled translation products including the COX subunits and specifically, a 23% decrease in COX1 protein steady-state levels according to Western analysis. Similarly, there was a decrease in the mRNA steady-state levels of both nuclear and mitochondrial-encoded subunits of cytochrome c oxidase. These results suggest that a number of different mechanisms are involved in the age-associated decrease in heart mitochondrial activity and these are discussed. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Mol Genet Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Hudson, EK (reprint author), NIA, Mol Genet Lab, Gerontol Res Ctr, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 38 TC 25 Z9 26 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing. Dev. PD JUN 15 PY 1998 VL 103 IS 2 BP 179 EP 193 DI 10.1016/S0047-6374(98)00043-8 PG 15 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 103AU UT WOS:000074959100006 PM 9701770 ER PT J AU Kamata, T Daar, IO Subleski, M Copeland, T Kung, HF Xu, RH AF Kamata, T Daar, IO Subleski, M Copeland, T Kung, HF Xu, RH TI Xenopus CRMP-2 is an early response gene to neural induction SO MOLECULAR BRAIN RESEARCH LA English DT Article DE Xenopus; XCRMP-2 gene; neural induction ID BONE MORPHOGENETIC PROTEIN-4; AXONAL GUIDANCE; SPINAL-CORD; VENTRALIZING FACTOR; ADHESION MOLECULES; UNC-33; SIGNALS; FAMILY; COLLAPSIN; OUTGROWTH AB A neural specific protein, CRMP-2 (for Collapsin Response Mediator Protein-2), is considered to mediate collapsin-induced growth cone collapse during neural development. We have isolated the Xenopus homologue of the CRMP-2 (XCRMP-2) cDNA and studied the expression of XCRMP-2 mRNA and protein during neural induction. Induction of XCRMP-2 mRNA and protein expression, like N-CAM, occurred at the midgastrula stage and increased through early neural developmental stages. Whole mount in situ hybridization demonstrated that expression of XCRMP-2 mRNA was localized in neural tissues such as the neural plate and tube at early stages, while its expression in the brain, spinal cord, and eyes was observed at later stages. Immunostaining of Xenopus embryos with the antibody against CRMP-2 also showed that the protein was specifically expressed in the neural tissues at early stages. XCRMP-2 expression was induced by neural inducers such as noggin and chordin which antagonize a neural inhibitor, BMP4. A dominant negative BMP receptor also induced XCRMP-2 expression, suggesting that transcription of XCRMP-2 gene was negatively regulated by the BMP4 signaling. These results indicate that expression of XCRMP-2 is an early response marking neural commitment, and that transcriptional control of XCRMP-2 gene, is one of the targets of BMP4 signaling. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NCI, IRSP, SAIC, FCRDC, Frederick, MD 21702 USA. NCI, LLB, DBS, FCRDC, Frederick, MD 21702 USA. NCI, ABL Basic Res Program, FCRDC, Frederick, MD 21702 USA. NCI, LBP, DBS, FCRDC, Frederick, MD 21702 USA. RP Kamata, T (reprint author), NCI, Lab Biochem Physiol, FCRDC, Bldg 567,Rm 152, Frederick, MD 21702 USA. RI Xu, Ren-He/M-3125-2016; OI Daar, Ira/0000-0003-2657-526X NR 30 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 15 PY 1998 VL 57 IS 2 BP 201 EP 210 DI 10.1016/S0169-328X(98)00082-5 PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZX899 UT WOS:000074566600003 ER PT J AU Smith, ER Belote, JM Schiltz, RL Yang, XJ Moore, PA Berger, SL Nakatani, Y Allis, CD AF Smith, ER Belote, JM Schiltz, RL Yang, XJ Moore, PA Berger, SL Nakatani, Y Allis, CD TI Cloning of Drosophila GCN5: conserved features among metazoan GCN5 family members SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HISTONE ACETYLTRANSFERASE; DNA-BINDING; TRANSCRIPTION; CBP; ACTIVATION; PROTEINS; GENE; IDENTIFICATION; ACETYLATION; COACTIVATOR AB PCAF and hGCN5 are distinct human genes that encode proteins related to the yeast histone acetyltransferase and transcriptional adapter GCN5. The PCAF protein shares extensive similarity with the 439 amino acids of yGCN5, hut it has an similar to 350 amino acid N-terminal extension that interacts with the transcriptional co-activator p300/CBP. Adenoviral protein E1a can disrupt PCAF-CBP interactions and prevent PCAF-dependent cellular differentiation. In this report, we describe the cloning and initial characterization of a Drosophila homolog of yGCN5. In addition to the homology to yGCN5, the Drosophila protein shares sequence similarity with the N-terminal portion of human PCAF that is involved in binding to CBP. In the course of characterizing dGCN5, we have discovered that hGCN5 also contains an N-terminal extension with significant similarity to PCAF. Interestingly, in the case of the hGCN5 gene, alternative splicing may regulate the production of full-length hGCN5. The presence of the N-terminal domain in a Drosophila GCN5 homolog and both human homologs suggests that it was part of the ancestral form of metazoan GCN5. C1 Univ Rochester, Dept Biol, Rochester, NY 14627 USA. Syracuse Univ, Dept Biol, Syracuse, NY 13244 USA. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Dept Mol Biol Human Genome Sci, Rockville, MD 20850 USA. Wistar Inst, Philadelphia, PA 19104 USA. RP Allis, CD (reprint author), Univ Rochester, Dept Biol, Rochester, NY 14627 USA. EM cdaa@uhura.cc.rochester.edu FU NIGMS NIH HHS [R01GM53512] NR 45 TC 56 Z9 59 U1 6 U2 8 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 JUN 15 PY 1998 VL 26 IS 12 BP 2948 EP 2954 DI 10.1093/nar/26.12.2948 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW066 UT WOS:000074370500017 PM 9611240 ER PT J AU Bhaumik, SR Chary, KVR Govil, G Liu, KL Miles, HT AF Bhaumik, SR Chary, KVR Govil, G Liu, KL Miles, HT TI A novel palindromic triple-stranded structure formed by homopyrimidine dodecamer d-CTTCTCCTCTTC and homopurine hexamer d-GAAGAG SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; HELIX-FORMING OLIGONUCLEOTIDES; DNA TRIPLEXES; ACIDS; NMR; CLEAVAGE; MACROMOLECULES; TRANSCRIPTION; ENDONUCLEASES; INHIBITION AB We have carried out NMR and molecular mechanics studies on a complex formed when a palindromic homopyrimidine dodecamer (d-CTTCTCCTCTTC) and a homopurine hexamer (d-GAAGAG) are mixed in 1:1 molar ratio in aqueous solutions. Such studies unequivocally establish that two strands of each oligomer combine to form a triple-stranded DNA structure with a palindromic symmetry and with six T.A:T and six C+.G:C hydrogen-bonded base triads, The two purine strands are placed head to head, with their 3' ends facing each other in the center of the structure. One-half of each pyrimidine strand contains protonated and the other half contains non-protonated cytosines, The two half segments containing protonated cytosines are hydrogen bonded to each of the two purine hexamers through Hoogsteen T.A and C+.G base pairing, The segments containing non-protonated cytosines are involved in Watson-Crick (A:T and G:C) base pairing, This leads to a palindromic tripler with a C2-dyad symmetry with respect to the center of the structure. The complex is less stable at neutral pH, but the cytosines involved in Hoogsteen base pairing remain protonated even under these conditions. Molecular mechanics calculations using NMR constraints have provided a detailed three-dimensional structure of the complex, The entire stretches of purine, and the pyrimidine nucleotides have a conformation close to B-DNA. C1 Tata Inst Fundamental Res, Dept Chem Sci, Bombay 400005, Maharashtra, India. NIDDKD, NIH, Bethesda, MD 20892 USA. Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China. RP Chary, KVR (reprint author), Tata Inst Fundamental Res, Dept Chem Sci, Homi Bhabha Rd, Bombay 400005, Maharashtra, India. EM chary@tifr.res.in NR 51 TC 11 Z9 13 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 JUN 15 PY 1998 VL 26 IS 12 BP 2981 EP 2988 DI 10.1093/nar/26.12.2981 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW066 UT WOS:000074370500021 PM 9611244 ER PT J AU Li, JW Liang, VCT Sedgwick, T Wong, JM Shi, YB AF Li, JW Liang, VCT Sedgwick, T Wong, JM Shi, YB TI Unique organization and involvement of GAGA factors in transcriptional regulation of the Xenopus stromelysin-3 gene SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EXTRACELLULAR-MATRIX; IV COLLAGENASE; METALLOPROTEINASE ACTIVITY; EXPRESSION; METAMORPHOSIS; APOPTOSIS; LAEVIS; CELLS; INHIBITORS; INVOLUTION AB Expression of the matrix metalloproteinase (MMP) gene stromelysin-3 (ST3) has been shown to be tightly associated with cell migration and apoptosis in mammals and amphibians. This contrasts with most other MMP genes. We demonstrate here that the Xenopus ST3 gene also has a structure distinct from other MMP genes, with its C-terminal half (the hemopexin domain) encoded by 4 instead of 6 exons, as in other MMP genes. Gear primer extension analysis reveals the existence of two transcription start sites and at least one is needed for transcription of the promoter in transient transfection assays. Furthermore, our deletion analysis has demonstrated a requirement for at least one GAGA factor binding site for promoter function. In vitro DNA binding and mutational studies have provided strong evidence for the participation of GAGA ok GAGA-like factors in transcriptional regulation of the frog ST3 gene. This contrasts with regulation of the human ST3 promoter. These results suggest that the ST3 gene evolved prior to most other metalloproteinase genes and uses distinct regulation pathways to achieve similar expression profiles and serve similar functions in mammals and amphibians. C1 NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Shi, YB (reprint author), NICHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. NR 52 TC 29 Z9 32 U1 1 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 JUN 15 PY 1998 VL 26 IS 12 BP 3018 EP 3025 DI 10.1093/nar/26.12.3018 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZW066 UT WOS:000074370500027 PM 9611250 ER PT J AU Green, JE Greenberg, NM Ashendel, CL Barrett, JC Boone, C Getzenberg, RH Henkin, J Matusik, R Janus, TJ Scher, HI AF Green, JE Greenberg, NM Ashendel, CL Barrett, JC Boone, C Getzenberg, RH Henkin, J Matusik, R Janus, TJ Scher, HI TI Workgroup 3: Transgenic and reconstitution models of prostate cancer SO PROSTATE LA English DT Article ID MICE; MOUSE; GENE C1 NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Cell Biol, Dallas, TX 75246 USA. Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. Abbott Labs, Abbott Pk, IL 60064 USA. Vanderbilt Univ, Dept Urol Surg, Nashville, TN USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bldg 41 Room C619,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 48 Z9 48 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 JUN 15 PY 1998 VL 36 IS 1 BP 59 EP 63 DI 10.1002/(SICI)1097-0045(19980615)36:1<59::AID-PROS11>3.0.CO;2-H PG 5 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA ZV861 UT WOS:000074349100010 PM 9650918 ER PT J AU Troendle, JF Legler, JM AF Troendle, JF Legler, JM TI A comparison of one-sided methods to identify significant individual outcomes in a multiple outcome setting: Stepwise tests or global tests with closed testing SO STATISTICS IN MEDICINE LA English DT Article ID CLINICAL-TRIALS; BONFERRONI PROCEDURE; ENDPOINTS; POWER AB We compare two approaches to the identification of individual significant outcomes when a comparison of two groups involves multiple outcome variables. The approaches are all designed to control the familywise error rate (FWE) with any subset of the null hypotheses being true (in the strong sense). The first approach is initially to use a global test of the overall hypothesis that the groups are equivalent for all variables, followed by an application of the closed testing algorithm of Marcus, Peritz and Gabriel. The global tests considered here are ordinary least squares (OLS), generalized least squares (GLS), an approximation to a likelihood ratio test (ALR), and a new test based on an approximation to the most powerful similar test for simple alternatives. The second approach is that of stepwise testing, which tests the univariate hypotheses in a specific order with appropriate adjustment to the univariate p-values for multiplicity. The stepwise tests considered include both step-down and step-up tests of a general type, and likewise permutation tests that incorporate the dependence structure of the data. We illustrate the tests with two examples of birth outcomes: a comparison of cocaine-exposed new-borns to control new-borns on neurobehavioural and physical growth variables, and, in a separate study, a comparison of babies born to diabetic mothers and babies born to non-diabetic mothers on minor malformations. After describing the methods and analysing the birth outcome data, we use simulations on Gaussian data to provide guidelines for the use of these procedures in terms of power and computation. (C) 1998 John Wiley & Sons, Ltd. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Biometry & Math Stat Branch, Bethesda, MD 20892 USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Biometry & Math Stat Branch, Bld 6100,Rm 7B13, Bethesda, MD 20892 USA. FU NIDA NIH HHS [R01DA06025] NR 29 TC 7 Z9 7 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUN 15 PY 1998 VL 17 IS 11 BP 1245 EP 1260 DI 10.1002/(SICI)1097-0258(19980615)17:11<1245::AID-SIM833>3.0.CO;2-Z PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA ZT158 UT WOS:000074055000005 PM 9670413 ER PT J AU Huang, K Kapadia, G Zhu, PP Peterkofsky, A Herzberg, O AF Huang, K Kapadia, G Zhu, PP Peterkofsky, A Herzberg, O TI A promiscuous binding surface: crystal structure of the IIA domain of the glucose-specific permease from Mycoplasma capricolum SO STRUCTURE WITH FOLDING & DESIGN LA English DT Article DE crystal structure; enzyme IIA(glc); glucose permease IIA domain; modeling; PEP, sugar phosphotransferase system; X-ray crystallography ID 3-DIMENSIONAL NMR-SPECTROSCOPY; SIGNAL-TRANSDUCING PROTEIN; BACTERIAL PHOSPHOTRANSFERASE SYSTEM; ESCHERICHIA-COLI; BACILLUS-SUBTILIS; PHOSPHOCARRIER PROTEIN; GLYCEROL KINASE; ENZYME-IIIGLC; SECONDARY STRUCTURE; PHOSPHOENOLPYRUVATE AB Background: The phosphoenolpyruvate: sugar phosphotransferase system (PTS) is a bacterial and mycoplasma system responsible for the uptake of some sugars, concomitant with their phosphorylation. The sugar-specific component of the system, enzyme II (EII), consists of three domains, EIIA, EIIB and EIIC. EIIA and EIIB are cytoplasmic and EIIC is an integral membrane protein that contains the sugar-binding site. Phosphoenolpyruvate (PEP) provides the source of the phosphoryl group, which is transferred via several phosphoprotein intermediates, eventually being transferred to the internalized sugar. Along the pathway, EIIA accepts a phosphoryl group from the phosphocarrier protein HPr and transfers it to EIIB. The structure of the glucose-specific EIIA (EIIA(glc)) from Mycoplasma capricolum reported here facilitates understanding of the nature of the interactions between this protein and its partners. Results: The crystal structure of EIIA(glc) from M. capricolum has been determined at 2.5 Angstrom resolution. Two neighboring EIIA(glc) molecules associate with one another in a front-to-back fashion, such that Glu149 of one molecule forms electrostatic interactions with the active-site histidine residues, His90 and His75, of the other. Glu149 is therefore considered to mimic the interaction that a phosphorylated histidine of a partner protein makes with EIIA. Another interaction, an ion pair between the active-site Asp94 and Lys168 of a neighboring molecule, may be analogous to the interaction between Asp94 of EIIA(glc) and Arg17 of HPr. Analysis of molecular packing in this crystal, and in the crystals of two other homologous proteins from Escherichia coli and Bacillus subtilis, reveals that in all cases active-site hydrophobic residues are involved in crystal contacts, but in each case a different region of the neighboring molecule is involved. The transition-state complexes of M. capricolum EIIA(glc) with HPr and EIIBglc have been modeled; in each case, different structural units are shown to interact with EIIA(glc). Many of the interactions are hydrophobic with no sequence specificity. The only specific interaction, other than that formed by the phosphoryl group, involves ion pairs between two invariant aspartate residues of EIIA(glc) and arginine/lysine residues of HPr or EIIBglc. Conclusions: The non-discriminating nature of the hydrophobic interactions that EIIA(glc) forms with a variety of partners may be a consequence of the requirement for interaction with a variety of proteins that show no sequence or structural similarity. Nevertheless, specificity is provided by an ion-pair interaction that is enhanced by the apolar nature of the interface. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Herzberg, O (reprint author), Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM osnat@carb.nist.gov NR 50 TC 15 Z9 16 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0969-2126 J9 STRUCT FOLD DES JI Struct. Fold. Des. PD JUN 15 PY 1998 VL 6 IS 6 BP 697 EP 710 DI 10.1016/S0969-2126(98)00072-0 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZZ471 UT WOS:000074732700004 PM 9705652 ER PT J AU Enoch, MA Kaye, WH Rotondo, A Greenberg, BD Murphy, DL Goldman, D AF Enoch, MA Kaye, WH Rotondo, A Greenberg, BD Murphy, DL Goldman, D TI 5-HT2A promoter polymorphism-1438G/A, anorexia nervosa, and obsessive-compulsive disorder SO LANCET LA English DT Article C1 NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Eating Disorders Unit, Pittsburgh, PA USA. Univ Pisa, Dept Psychiat, Pisa, Italy. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 4 TC 138 Z9 142 U1 0 U2 2 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 13 PY 1998 VL 351 IS 9118 BP 1785 EP 1786 DI 10.1016/S0140-6736(05)78746-8 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA ZU444 UT WOS:000074197600017 PM 9635956 ER PT J AU Brinton, LA AF Brinton, LA TI NIH follow-up study of women with augmentation mammoplasty: Investigator replies SO LANCET LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Brinton, LA (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 1 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 42 BEDFORD SQUARE, LONDON WC1B 3SL, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUN 13 PY 1998 VL 351 IS 9118 BP 1814 EP 1814 DI 10.1016/S0140-6736(05)78780-8 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA ZU444 UT WOS:000074197600058 PM 9635980 ER PT J AU Sweitzer, SM Hinshaw, JE AF Sweitzer, SM Hinshaw, JE TI Dynamin undergoes a GTP-dependent conformational change causing vesiculation SO CELL LA English DT Article ID PROTEIN-KINASE-C; MEDIATED ENDOCYTOSIS; ACIDIC PHOSPHOLIPIDS; BINDING-SITE; SH3 DOMAINS; DROSOPHILA; SHIBIRE; IDENTIFICATION; MUTATIONS AB The dynamin family of GTPases is essential for receptor-mediated endocytosis and synaptic vesicle recycling, and it has recently been shown to play a role in vesicle formation from the trans-Golgi network. Dynamin is believed to assemble around the necks of clathrin-coated pits and assist in pinching vesicles from the plasma membrane. This role would make dynamin unique among GTPases in its ability to act as a mechanochemical enzyme. Data presented here demonstrate that purified recombinant dynamin binds to a lipid bilayer in a regular pattern to form helical tubes that constrict and vesiculate upon GTP addition. This suggests that dynamin alone is sufficient for the formation of constricted necks of coated pits and supports the hypothesis that dynamin is the force-generating molecule responsible for membrane fission. C1 NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Sweitzer, SM (reprint author), NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. NR 39 TC 460 Z9 470 U1 7 U2 13 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 12 PY 1998 VL 93 IS 6 BP 1021 EP 1029 DI 10.1016/S0092-8674(00)81207-6 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZU514 UT WOS:000074205700013 PM 9635431 ER PT J AU Brodie, C Blumberg, PM Jacobson, KA AF Brodie, C Blumberg, PM Jacobson, KA TI Activation of the A(2A) adenosine receptor inhibits nitric oxide production in glial cells SO FEBS LETTERS LA English DT Article DE C6 cell; nitric oxide; adenosine agonist; adenosine receptor; tumor necrosis factor; cytokine ID CYCLIC-AMP ACCUMULATION; RAT ASTROCYTES; CYTOKINES AB Selective adenosine receptor agonists and antagonists have marked effects on the outcome of cerebral ischemia, and adenosine receptors are expressed on astrocytes. Zn this study we examined the effects of various adenosine receptor agonists on the production of nitric oxide and the induction of iNOS in astrocytes activated by LPS/IFN-gamma and TNF-alpha/IL-1 beta and on the production of TNF-alpha Treatment of the cells with the A(2A) receptor agonist CGS 21680 inhibited both NO production and iNOS expression induced by stimulation with either LPS/IFN-gamma or TNF-alpha/IL-1 beta, whereas the A(1) and A(3) receptor agonists, CPA and CI-IB-MECA, respectively, did not have significant inhibitory effects. The inhibitory effect of the A(2A) receptor agonist was antagonized by the specific A(2A) receptor antagonist CSC. The A(2A) agonist also exerted a small inhibitory effect on the production of TNF-alpha. Similar inhibitory effects on the production of NO were obtained by cyclic AMP-elevating reagents, such as forskolin and dibutyryl cyclic AMP. Our findings suggest that activation of the A(2A) receptor inhibits NO production and iNOS expression likely via increased cAMP. (C) 1998 Federation of European Biochemical Societies. C1 Bar Ilan Univ, Dept Life Sci, IL-52900 Ramat Gan, Israel. NCI, MMTP, LCCTP, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Brodie, C (reprint author), Bar Ilan Univ, Dept Life Sci, IL-52900 Ramat Gan, Israel. EM chaya@brosh.cc.biu.ac.il RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 27 TC 45 Z9 47 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 12 PY 1998 VL 429 IS 2 BP 139 EP 142 DI 10.1016/S0014-5793(98)00556-0 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZV756 UT WOS:000074338000003 PM 9650577 ER PT J AU Koval, AP Karas, M Zick, Y LeRoith, D AF Koval, AP Karas, M Zick, Y LeRoith, D TI Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOTYROSINE-BINDING DOMAIN; MYELOGENOUS LEUKEMIA-CELLS; TYROSINE PHOSPHORYLATION; ADAPTER PROTEINS; PC12 CELLS; C-CRK; SH2; RAS; SRC; SUBSTRATE-1 AB The closely related proto-oncogene proteins CrkII and CrkL consist of cane SH2 and two SI43 domains and share 60% overall homology with the highest identity within their functional domains. In this study we show that CrkL and CrkII may play overlapping but different roles in insulin-like growth factor (IGF)-I receptor-mediated signal transduction. While both proteins are substrates involved in IGF-I receptor signaling, they apparently demonstrate important different properties and different biological responses. Evidence supporting this hypothesis includes (a) the oncogenic potential of CrkL versus the absence of this potential in CrkII overexpressing cell lines, (b) the inhibition of IGF-I-dependent cell cycle progression by overexpression of CrkII, and (c) the differential regulation of the phosphorylation status of selective proteins in CrkII and CrkL overexpressing cell lines. In addition we demonstrate the specific association of CrkL and CrkII with the newly characterized IRS-4 protein, again in a differential manner. Whereas CrkL strongly interacts with IRS-4 via its SH2 and N-terminal SH3 domains, CrkII interacts only via its SH2 domain, possibly explaining the unstable nature of IRS-4-CrkII association. The results obtained snow us to propose a unique mechanism of CrkL and CrkII tyrosine phosphorylation in response to IGF-I stimulation. Thus these highly homologous proteins apparently possess structural features that allow for the differential association of each protein with different effector molecules, thereby activating different signaling pathways and resulting in unique biological roles of these proteins. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept MOl & Cell Biol, IL-76100 Rehovot, Israel. RP LeRoith, D (reprint author), NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. NR 52 TC 31 Z9 34 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 12 PY 1998 VL 273 IS 24 BP 14780 EP 14787 DI 10.1074/jbc.273.24.14780 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZU088 UT WOS:000074160400020 PM 9614078 ER PT J AU Fromm, SV Mey-Tal, SW Coligan, JE Schechter, C Ehrlich, R AF Fromm, SV Mey-Tal, SW Coligan, JE Schechter, C Ehrlich, R TI MHC class I heavy chain mRNA must exceed a threshold level for the reconstitution of cell surface expression of class I MHC complexes in cells transformed by the highly oncogenic adenovirus 12 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; HLA CLASS-I; INTRACELLULAR-TRANSPORT; T-CELLS; MONOCLONAL-ANTIBODIES; PEPTIDE TRANSPORTER; GENE-EXPRESSION; DOWN-REGULATION; MOLECULES; BETA-2-MICROGLOBULIN AB In primary embryonal fibroblasts from transgenic mice expressing H-2(b) genes and a miniature swine class I transgene (PD1), transformation with adenovirus 12 results in suppression of assembly and cell surface expression of all class I complexes. Cell surface expression of PD1 can be recovered by transfecting the cells with peptide transporter genes. However, reconstitution of the H-2K(b) gene expression requires, in. addition, a 2-fold increase in the steady state level of the H-2K(b) mRNA that can be attained by treatment of the cells with interferons or by transfecting them with the H-2K(b) gene. A detailed analyses of the biogenesis of class I molecules has revealed the steady state expression of free class I heavy chains that are not converted into conformed complexes even when peptide transporter genes are overexpressed, The fact that class I complex assembly seems to be highly inefficient in certain cell lines might be a major in vivo obstacle for the elimination of trans formed or virus-infected cells by cytotoxic T lymphocytes, especially in view of the fact that the level of class I gene transcription is often down-regulated in cancel cells and/or that assembly of class I major histocompatibility complexes can be subverted by virus-encoded proteins. C1 Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. NIAID, Mol Struct Lab, NIH, Bethesda, MD 20892 USA. RP Ehrlich, R (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel. NR 53 TC 7 Z9 7 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 JUN 12 PY 1998 VL 273 IS 24 BP 15209 EP 15216 DI 10.1074/jbc.273.24.15209 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZU088 UT WOS:000074160400077 PM 9614135 ER PT J AU Prasad, R Beard, WA Strauss, PR Wilson, SH AF Prasad, R Beard, WA Strauss, PR Wilson, SH TI Human DNA polymerase beta deoxyribose phosphate lyase - Substrate specificity and catalytic mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; ALDEHYDIC ABASIC SITES; ESCHERICHIA-COLI; PYRIDOXAL 5'-PHOSPHATE; APURINIC ENDONUCLEASE; BOVINE TESTIS; DAMAGED DNA; ACTIVE-SITE; LIGASE-I; BINDING AB DNA polymerase beta (beta-pol) cleaves the sugar-phosphate bond 3' to an intact apurinic/apyrimidinic (AP) site (i.e. AP lyase activity). The same bond is cleaved even if the AP site has been previously 5'-incised by AP endonuclease, resulting in a 5' 2-deoxyribose 5-phosphate (i.e. dRP lyase activity). We characterized these lyase reactions by steady-state kinetics with the aminoterminal 8-kDa domain of beta-pol and with the entire 39-kDa polymerase, Steady-state kinetic analyses show that the Michaelis constants for both the dRP and AP lyase activities of beta-pol are similar. However, k(cat) is approximately 200-fold lower for the AP lyase activity on an intact AP site than for an AP endonuclease-preincised site. The 8-kDa domain was also less efficient with an intact AP site than on a preincised site. The full-length enzyme and the 8-kDa domain efficiently remove the 5' dRP from a preincised AP site in the absence of Mg2+, and the pH profiles of beta-pol and 8-kDa domain dRP lyase catalytic efficiency exhibit a broad alkaline pH optimum. An inhibitory effect of pyridoxal 5'-phosphate on the dRP lyase activity is consistent with involvement of a primary amine (Lys(72)) as the Schiff base nucleophile during lyase chemistry. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm B246, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 54 TC 139 Z9 143 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 12 PY 1998 VL 273 IS 24 BP 15263 EP 15270 DI 10.1074/jbc.273.24.15263 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZU088 UT WOS:000074160400084 PM 9614142 ER PT J AU Boyes, J Omichinski, J Clark, D Pikaart, M Felsenfeld, G AF Boyes, J Omichinski, J Clark, D Pikaart, M Felsenfeld, G TI Perturbation of nucleosome structure by the erythroid transcription factor GATA-1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE chromatin; GATA-1; hypersensitive site; nucleosome disruption; transcription factor ID GLUCOCORTICOID RESPONSE ELEMENT; HOMEODOMAIN-DNA INTERACTIONS; FACILITATED BINDING; CRYSTAL-STRUCTURE; TRANSCRIBING POLYMERASE; HISTONE-BINDING; MMTV PROMOTER; COMPLEX; CORE; DISRUPTION AB The ability of transcription factors to gain access to their sites in chromatin requires the disruption or displacement of nucleosomes covering the promoter, signalled by the generation of a nuclease hypersensitive site. We characterise here the alterations in nucleosome structure caused by binding of the erythroid factor GATA-1 to a nucleosome carrying GATA-1 sites. DNase I and micrococcal nuclease probes show that GATA-1 binding causes extensive, cooperative breakage of the histone/DNA contacts to generate a complex very similar to that formed by the factor with free DNA. The only region which differs is confined to about 50 bp surrounding the nucleosome dyad axis which appears to be the domain of residual contact between the DNA and histone octamer. Despite considerable breakage of the histone/DNA contacts, the complex is completely stable in solution, and disruption of the nucleosome is entirely reversible: it is regenerated quantitatively upon removal of the transcription factor. Moreover, the histone 2A/2B component of the octamer does not exchange to external competitor. We suggest that formation of this complex may be a step in the generation of a fully hypersensitive site in viva over regulatory elements containing GATA family binding sites. (C) 1998 Academic Press Limited. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room 212, Bethesda, MD 20892 USA. NR 58 TC 47 Z9 48 U1 1 U2 1 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 12 PY 1998 VL 279 IS 3 BP 529 EP 544 DI 10.1006/jmbi.1998.1783 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV948 UT WOS:000074358400004 PM 9641976 ER PT J AU Lee, BM De Guzman, RN Turner, BG Tjandra, N Summers, MF AF Lee, BM De Guzman, RN Turner, BG Tjandra, N Summers, MF TI Dynamical behavior of the HIV-1 nucleocapsid protein SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE nucleocapsid protein; NMR; dynamics; structure; zinc knuckle ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEAR-MAGNETIC-RESONANCE; MURINE LEUKEMIA-VIRUS; N-15 NMR RELAXATION; TIME-RESOLVED FLUORESCENCE; RETROVIRAL GAG PROTEINS; AMINO-TERMINAL FRAGMENT; ACID-BINDING-PROTEINS; ZINC-FINGER PROTEIN; BACKBONE DYNAMICS AB The HIV-1 nucleocapsid protein (NC) contains two CCHC-type zinc knuckle domains that are essential for genome recognition, packaging and infectivity. The solution structure of the protein has been determined independently by three groups. Although the structures of the individual zinc knuckle domains are similar, two of the studies indicated that the knuckles behave as independently folded, non-interacting domains connected by a flexible tether, whereas one study revealed the presence of interknuckle NOE cross-peaks, which were interpreted in terms of a more compact structure in which the knuckles are in close proximity. We have collected multidimensional NMR data for the recombinant, isotopically labeled HIV-1 NC protein, and confirmed the presence of weak interknuckle NOEs. However, the NOE data are not consistent with a single protein conformation. N-15 NMR relaxation studies reveal that the two zinc knuckle domains possess different effective rotational correlation times, indicating that the knuckles are not tumbling as a single globular domain. Ln addition, the H-1 NMR chemical shifts of isolated zinc knuckle peptides are very similar to those of the intact protein. The combined results indicate that the interknuckle interactions, which involve the close;approach of the side-chains of Phe16 and Trp37, are transitory. The solution behavior of NC may be best considered as a rapid equilibrium between conformations with weakly interacting and non-interacting knuckle domains. This inherent conformational flexibility may be functionally important, enabling adaptive binding of NC to different recognition elements within the HIV-1 Psi-RNA packaging signal. (C) 1998 Academic Press Limited. C1 Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. RI Lee, Brian/F-8380-2013 OI Lee, Brian/0000-0002-0269-7812 FU NIGMS NIH HHS [GM42561] NR 106 TC 111 Z9 112 U1 1 U2 12 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 12 PY 1998 VL 279 IS 3 BP 633 EP 649 DI 10.1006/jmbi.1998.1766 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZV948 UT WOS:000074358400011 PM 9641983 ER PT J AU Shi, Q Chen, K Chen, X Brossi, A Verdier-Pinard, P Hamel, E McPhail, AT Tropsha, A Lee, KH AF Shi, Q Chen, K Chen, X Brossi, A Verdier-Pinard, P Hamel, E McPhail, AT Tropsha, A Lee, KH TI Antitumor agents. 183. Syntheses, conformational analyses, and antitubulin activity of allothiocolchicinoids SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID THIOCOLCHICINE ANALOGS; BIOLOGICAL EVALUATION; COLCHICINE; TUBULIN; BINDING; RING AB 7-O-Substituted analogues of allothiocochicine were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 6, a key compound in this study, was derived from thiocolchicone 5 by ring contraction. The structure of 6 was determined from spectral data. Optically active alcohols 7a and 7b were obtained by reduction of ketone 6 followed by chemical resolution including a separation of the camphanate diastereomers 8a and 8b and basic hydrolysis. The aR,7R configuration of 8b was verified by X-ray crystallographic analysis. Almost all compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 9.0 mu M. The camphanates, cyclohexanates, and, most notably, the 7S-benzoate ester (10a), were inactive with IC50 values >40 mu M. Compounds 6 and 7a also showed potent antitumor activity with GI(50) values at nM concentration range for most cell lines in NCI's in vitro screening. Generally, the 7S enantiomers of colchicinoids with a troplone C-ring showed greater activity than the 7R enantiomers. In the current allothiocolchicinoid (with a benzenoid C-ring) study, only small differences occurred between the two active enantiomers of each pair. The acyl esters with a 7S configuration were slightly more active than the 7R isomers. However, the aroyl ester with a 7S configuration was less active than the 7R isomer. NMR, optical rotation, and molecular modeling studies revealed two conformers in a solvent-dependent equilibrium for both 7S and 7R isomers. In polar solvents, the molecular chirality in esters with a 7-O-aroyl substituent was reversed from aS to aR or from aR to aS at an intensified rate. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Lab Mol Modeling, Chapel Hill, NC 27599 USA. NCI, Frederick Canc Res & Dev Ctr, Div Canc Treatment & Diagnosis, Dev Therapeut Program,Lab Drug Discovery Res & De, Frederick, MD 21702 USA. Duke Univ, Dept Chem, Paul M Gross Chem Lab, Durham, NC 27708 USA. RP Lee, KH (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Nat Prod Lab, Chapel Hill, NC 27599 USA. RI Tropsha, Alexander/G-6245-2014 NR 22 TC 28 Z9 29 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUN 12 PY 1998 VL 63 IS 12 BP 4018 EP 4025 DI 10.1021/jo980073p PG 8 WC Chemistry, Organic SC Chemistry GA ZV170 UT WOS:000074277100036 ER PT J AU Duesbery, N Vande Woude, G Leppla, S AF Duesbery, N Vande Woude, G Leppla, S TI How anthrax kills - Response SO SCIENCE LA English DT Letter C1 NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIDR, NIH, Bethesda, MD 20892 USA. RP Duesbery, N (reprint author), NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM woude@ncifcrf.gov; sleppla@irp30.nidr.nih.gov NR 8 TC 2 Z9 2 U1 0 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 JUN 12 PY 1998 VL 280 IS 5370 BP 1673 EP 1674 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZU446 UT WOS:000074197800003 ER PT J AU Courtney, SM Petit, L Ungerleider, LG Haxby, JV AF Courtney, SM Petit, L Ungerleider, LG Haxby, JV TI Areas of the brain: Movements and memories - Response SO SCIENCE LA English DT Letter C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Courtney, SM (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 12 PY 1998 VL 280 IS 5370 BP 1676 EP 1677 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZU446 UT WOS:000074197800007 ER PT J AU Choi, SK Lee, JH Zoll, WL Merrick, WC Dever, TE AF Choi, SK Lee, JH Zoll, WL Merrick, WC Dever, TE TI Promotion of Met-tRNA(i)(Met) binding to ribosomes by yIF2, a bacterial IF2 homolog in yeast SO SCIENCE LA English DT Article ID INITIATION FACTOR-II; SACCHAROMYCES-CEREVISIAE; TRANSLATIONAL-INITIATION; SHUTTLE VECTORS; CHROMOSOME-I; START-SITE; GENE; SEQUENCE; IDENTIFICATION; SELECTION AB Delivery of the initiator methionine transfer RNA (Met-tRNA(i)(Met)) to the ribosome is a key step in the initiation of protein synthesis. Previous results have indicated that this step is catalyzed by the structurally dissimilar translation factors in prokaryotes and eukaryotes-initiation factor 2 (IF2) and eukaryotic initiation factor 2 (eIF2), respectively. A bacterial IF2 homolog has been identified in both eukaryotes and archaea. By using a combination of molecular genetic and biochemical studies, the Saccharomyces cerevisiae IF2 homolog is shown to function in general translation initiation by promoting Met-tRNA(i)(Met) binding to ribosomes. Thus, the mechanism of protein synthesis in eukaryotes and prokaryotes is more similar than was previously realized. C1 NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. RP Dever, TE (reprint author), NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [GM08056]; PHS HHS [26796] NR 33 TC 99 Z9 101 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 12 PY 1998 VL 280 IS 5370 BP 1757 EP 1760 DI 10.1126/science.280.5370.1757 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZU446 UT WOS:000074197800043 PM 9624054 ER PT J AU Shrager, RI Hendler, RW AF Shrager, RI Hendler, RW TI Some pitfalls in curve-fitting and how to avoid them: A case in point SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE curve fitting; degree of error; independence of parameters; testing ID SINGULAR-VALUE DECOMPOSITION; TRANSITIONS; SPECTRA AB When curve-fitting is used to support a complex nonlinear model containing several exponential terms, some of which have closely-spaced time constants, a particular burden of proof must be assumed. Most important, the uniqueness of the solution must be explored and discussed. Statistical tests for the degree of error and independence of the parameters should be provided, as well as information relating to the steps actually used in the fitting procedures. As an example of the need for the procedures we recommend in this communication, we have chosen an important case in point that has been published recently, and which deals with the kinetics of electron transfer from fully-reduced cytochrome oxidase to O-2, analyzed by the method of SVD-based least squares. The problems we deal with in this case are applicable to a wide variety of other cases that involve curve-fitting to mathematical models. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Shrager, RI (reprint author), NIH, Math & Stat Comp Lab, Div Comp Res & Technol, Bethesda, MD 20892 USA. NR 11 TC 16 Z9 16 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD JUN 11 PY 1998 VL 36 IS 2-3 BP 157 EP 173 DI 10.1016/S0165-022X(98)00007-4 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 103TB UT WOS:000074973000008 PM 9711501 ER PT J AU Yarmola, E Chrambach, A AF Yarmola, E Chrambach, A TI Protein bandwidth in gel electrophoresis: A primary function of migration distance SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID DISPERSION AB By use of the fluorescent protein R-phycoerythrin, a number of factors have been investigated as potential sources of band broadening in agarose and polyacrylamide gels: temperature gradients, Joule heating, conductivity differences between analyte and buffer, electroendosmosis, microheterogeneity due to charge density differences; etc. It was found that none of these factors could be the major source of band broadening. Recently, it has been shown that diffusion is also not the predominant source of R-phycoerythrin band spreading in agarose gels and that the bandwidth depends linearly on migration distance and time (Yarmola, E.; Calabrese, P. P.; Chrambach, A.; Weiss, G. H. J. Phys. Chem. 1996, 101, 2381). The present data collected in agarose and polyacrylamide gels confirm the linear dependence of bandwidth on migration distance and describe the slope of this dependence as a function of electrophoretic conditions, Among all the factors studied that may impact on band spreading, only the interaction with the gel and microheterogeneity cannot be ruled out. This conclusion with regard to the mechanisms of band spreading agrees with that obtained recently by capillary electrophoresis in polymer solutions (Radko, S. P.; Weiss, G. H.; Chrambach, A. J. Chromatogr. A 1997, 781, 277-286). C1 NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Engelhardt Inst Mol Biol, Lab Biopolymer Phys, Moscow, Russia. RP Chrambach, A (reprint author), NICHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. NR 9 TC 9 Z9 9 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5647 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JUN 11 PY 1998 VL 102 IS 24 BP 4813 EP 4818 DI 10.1021/jp9804805 PG 6 WC Chemistry, Physical SC Chemistry GA ZV245 UT WOS:000074284900017 ER PT J AU Cole, ST Brosch, R Parkhill, J Garnier, T Churcher, C Harris, D Gordon, SV Eiglmeier, K Gas, S Barry, CE Tekaia, F Badcock, K Basham, D Brown, D Chillingworth, T Connor, R Davies, R Devlin, K Feltwell, T Gentles, S Hamlin, N Holroyd, S Hornby, T Jagels, K Krogh, A McLean, J Moule, S Murphy, L Oliver, K Osborne, J Quail, MA Rajandream, MA Rogers, J Rutter, S Seeger, K Skelton, J Squares, R Squares, S Sulston, JE Taylor, K Whitehead, S Barrell, BG AF Cole, ST Brosch, R Parkhill, J Garnier, T Churcher, C Harris, D Gordon, SV Eiglmeier, K Gas, S Barry, CE Tekaia, F Badcock, K Basham, D Brown, D Chillingworth, T Connor, R Davies, R Devlin, K Feltwell, T Gentles, S Hamlin, N Holroyd, S Hornby, T Jagels, K Krogh, A McLean, J Moule, S Murphy, L Oliver, K Osborne, J Quail, MA Rajandream, MA Rogers, J Rutter, S Seeger, K Skelton, J Squares, R Squares, S Sulston, JE Taylor, K Whitehead, S Barrell, BG TI Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence SO NATURE LA English DT Article ID ANTIGEN; RESISTANCE; SURVIVAL; LEPRAE; REPEAT; SEARCH; CELLS; GENES; DNA AB Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation. C1 Sanger Ctr, Hinxton CB10 1SA, England. Inst Pasteur, Unite Genet Mol Bacterienne, F-75724 Paris 15, France. Inst Pasteur, Unite Genet Mol Levures, F-75724 Paris 15, France. NIAID, TB Res Unit, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. RP Barrell, BG (reprint author), Sanger Ctr, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England. EM stcole@pasteur.fr; barrell@sanger.ac.uk RI Gordon, Stephen/E-6960-2011; Parkhill, Julian/G-4703-2011; Barry, III, Clifton/H-3839-2012; Tekaia, Fredj/H-4553-2012; Krogh, Anders/M-1541-2014; OI Gordon, Stephen/0000-0002-4833-5542; Parkhill, Julian/0000-0002-7069-5958; Krogh, Anders/0000-0002-5147-6282; Brosch, Roland /0000-0003-2587-3863 FU Intramural NIH HHS [Z01 AI000783-11]; Wellcome Trust NR 50 TC 4985 Z9 9107 U1 72 U2 430 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD JUN 11 PY 1998 VL 393 IS 6685 BP 537 EP + PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT988 UT WOS:000074150100041 PM 9634230 ER PT J AU Fan, SJ Wang, JA Yuan, RQ Ma, YX Meng, QH Erdos, MR Brody, LC Goldberg, ID Rosen, EM AF Fan, SJ Wang, JA Yuan, RQ Ma, YX Meng, QH Erdos, MR Brody, LC Goldberg, ID Rosen, EM TI BRCA1 as a potential human prostate tumor suppressor: modulation of proliferation, damage responses and expression of cell regulatory proteins SO ONCOGENE LA English DT Article DE prostate cancer; DU-145; BRCA1; DNA damage; apoptosis; p300 ID OVARIAN-CANCER; GENE BRCA1; TRANSCRIPTIONAL ACTIVATION; BREAST-CANCER; MUTATIONS; REGION; P53; FRAGMENTS; CARRIERS; FAMILIES AB In addition to breast and ovarian cancer in women, recent evidence suggests that germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) also confer an increased life-time risk for prostate cancer in male probands, However, it is not known if and how BRCA1 functions in prostate cancer, We stably expressed wildtype (wt) and tumor-associated mutant BRCA1 transgenes in DU-145, a human prostate cancer cell line with low endogenous expression of BRCA1, As compared with parental cells and vector transfected clones, wtBRCA1 clones exhibited: (1) a slightly decreased proliferation rate (doubling time = 25 h as compared with 22 h for control cells); (2) a (3-6)-fold increase in sensitivity to chemotherapy drugs (adriamycin, camptothecin, and taxol); (3) increased susceptibility to drug-induced apoptosis; (4) reduced repair of single-strand DNA strand breaks; and (5) alterations in expression of key cellular regulatory proteins (including BRCA2, p300, Mdm-2, p21(WAF1/CIP1), Bcl-2 and Bar). Clones transfected with the 5677insA breast cancer-associated mutant BRCA1 (insBRCA1) displayed a similar phenotype to wtBRCA1 clones, except that insBRCA1 clones had a significantly decreased proliferation rate (doubling time=42 h), On the other hand, cells transfected with with 185delAG mutant BRCA1 showed no obvious phenotype as compared with parental or vector transfected cells, These findings suggest that BRCA1 may function as a human prostate tumor suppressor by virtue of its ability to modulate proliferation and various components of the cellular damage response. They also suggest several potential target gene products for a BRCA1 prostate tumor suppressor function. C1 Long Isl Jewish Med Ctr, Albert Einstein Coll Med, Dept Radiat Oncol, New Hyde Park, NY 11040 USA. Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Fan, SJ (reprint author), Long Isl Jewish Med Ctr, Albert Einstein Coll Med, Dept Radiat Oncol, Long Isl Campus,270-05 76th Ave, New Hyde Park, NY 11040 USA. NR 47 TC 91 Z9 94 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 11 PY 1998 VL 16 IS 23 BP 3069 EP 3082 DI 10.1038/sj.onc.1202116 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZT782 UT WOS:000074125300014 PM 9662340 ER PT J AU Van Rompay, KKA Marthas, ML Lifson, JD Berardi, CJ Vasquez, GM Agatep, E Dehqanzada, ZA Cundy, KC Bischofberger, N Pedersen, NC AF Van Rompay, KKA Marthas, ML Lifson, JD Berardi, CJ Vasquez, GM Agatep, E Dehqanzada, ZA Cundy, KC Bischofberger, N Pedersen, NC TI Administration of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) for prevention of perinatal simian immunodeficiency virus infection in rhesus macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID POLYMERASE CHAIN-REACTION; ZIDOVUDINE TREATMENT; HIV-1 INFECTION; VERTICAL TRANSMISSION; SIV INFECTION; ANIMAL-MODEL; INFANT; TYPE-1; DIAGNOSIS; CULTURE AB Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model to explore novel strategies to reduce perinatal human immunodeficiency virus (HIV) infection. The availability of two easily distinguishable virus isolates, SIVmac251 and the simian/human immunodeficiency virus chimera SHIV-SF33, allows tracing the source of infection following inoculation with both viruses by different routes. In the present study, we evaluated the efficacy of pre-and postinoculation treatment regimens with 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) to protect newborn macaques against simultaneous oral SIVmac251 and intravenous SHIV-SF33 inoculation. Untreated newborns became persistently infected following virus inoculation. When three pregnant macaques were given a single subcutaneous dose of PMPA 2 hr before cesarean section, their newborns became SIV-infected following SIV and SHIV inoculation shortly after birth. In contrast, when four newborn macaques were inoculated simultaneously with SIV and SHIV, and started immediately on PMPA treatment for 2 weeks, only one animal became persistently SIV-infected; the remaining three PMPA-treated newborns, however, had some evidence of an initial transient virus infection but were seronegative and healthy at 8 months of age. Our data demonstrate that PMPA treatment can reduce perinatal SIV infection and suggest that similar strategies may also be effective against HIV. C1 Univ Calif Davis, Calif Reg Primate Res Ctr, Davis, CA 95616 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, AIDS Vaccine Program,Lab Retroviral Pathogenesis, Frederick, MD 21702 USA. Gilead Sci Inc, Foster City, CA 94404 USA. Univ Calif Davis, Dept Vet Med & Epidemiol, Davis, CA 95616 USA. RP Van Rompay, KKA (reprint author), Univ Calif Davis, Calif Reg Primate Res Ctr, Davis, CA 95616 USA. FU NCRR NIH HHS [RR00169]; PHS HHS [39109] NR 51 TC 65 Z9 65 U1 0 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 1998 VL 14 IS 9 BP 761 EP 773 DI 10.1089/aid.1998.14.761 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA ZT875 UT WOS:000074137100007 PM 9643376 ER PT J AU Elder, JH Dean, GA Hoover, EA Hoxie, JA Malim, MH Mathes, L Neil, JC North, TW Sparger, E Tompkins, MB Tompkins, WAF Yamamoto, J Yuhki, N Pedersen, NC Miller, RH AF Elder, JH Dean, GA Hoover, EA Hoxie, JA Malim, MH Mathes, L Neil, JC North, TW Sparger, E Tompkins, MB Tompkins, WAF Yamamoto, J Yuhki, N Pedersen, NC Miller, RH TI Lessons from the cat: Feline immunodeficiency virus as a tool to develop intervention strategies against human immunodeficiency virus type 1 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article C1 NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Scripps Inst, Dept Mol Biol, La Jolla, CA 92037 USA. N Carolina State Univ, Coll Vet Med, Dept Microbiol Pathol & Parasitol, Raleigh, NC 27695 USA. Colorado State Univ, Dept Pathol, Ft Collins, CO 80523 USA. Univ Penn, Dept Hematol & Oncol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. Univ Glasgow, Dept Vet Pathol, Glasgow G61 1QH, Lanark, Scotland. Univ Calif Davis, Sch Vet Med, Davis, CA 95694 USA. Univ Florida, Coll Vet Med, Gainesville, FL 32610 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21701 USA. RP Miller, RH (reprint author), NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. OI Malim, Michael/0000-0002-7699-2064 NR 0 TC 58 Z9 58 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 1998 VL 14 IS 9 BP 797 EP 801 DI 10.1089/aid.1998.14.797 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA ZT875 UT WOS:000074137100014 PM 9643379 ER PT J AU Rainov, NG Dobberstein, KU Sena-Esteves, M Herrlinger, U Kramm, CM Philpot, RM Hilton, J Chiocca, EA Breakefield, XO AF Rainov, NG Dobberstein, KU Sena-Esteves, M Herrlinger, U Kramm, CM Philpot, RM Hilton, J Chiocca, EA Breakefield, XO TI New prodrug activation gene therapy for cancer using cytochrome P450 4B1 and 2-aminoanthracene/4-ipomeanol SO HUMAN GENE THERAPY LA English DT Article ID SPECIES-DEPENDENT EXPRESSION; TARGET ORGAN ALKYLATION; THYMIDINE KINASE GENES; METABOLIC-ACTIVATION; BRAIN-TUMORS; LUNG-CANCER; CYTO-TOXIN; 2B1 GENE; 4-IPOMEANOL; RABBIT AB Vector-mediated transfer of prodrug-activating genes provides a promising means of cancer gene therapy. In a search for more selective and more potent bioactivating enzymes for gene therapy of malignant brain tumors, the toxicity-generating capacity of the rabbit cytochrome P450 isozyme CYP4B1 was investigated. Rabbit CYP4B1, but not rat or human isozymes, efficiently converts the inert prodrugs, 2-aminoanthracene (2-AA) and 4-ipomeanol (4-IM), into highly toxic alkylating metabolites. Toxicity of these two prodrugs was evaluated in culture in parental and genetically modified rodent (9L) and human (U87) glioma cell lines stably expressing CYP4B1, and in vivo in a subcutaneous 9L tumor model in nude mice. The most sensitive CYP4B1-expressing glioma clone, 9L4B1-60, displayed an LD50 of 2.5 mu M for 2-AA and 4-IM after 48 h of prodrug incubation, whereas 20 times higher prodrug concentrations did not cause any significant toxicity to control cells. Substantial killing of control tumor cells by 2-AA was achieved by co-culturing these cells with CYP4B1-expressing cells at a ratio of 100:1, and toxic metabolites could be transferred through medium. In both CYP4B1-expressing cells and cocultured control cells, prodrug bioactivation was associated with DNA fragmentation, as assayed by fluorescent TUNEL, assays and by annexin V staining. Alkaline elution of cellular DNA after exposure to 4-IM revealed extensive protein-DNA crosslinking with single-strand breakage. Growth of 9L-4B1 tumors in nude mice was inhibited by intraperitoneal Injection of 4-IM with minimal side effects. Potential advantages of the CYP4B1 gene therapy paradigm include: the low concentrations of prodrug needed to kill sensitized tumor cells; low prodrug conversion by human isozymes, thus reducing toxicity to normal cells; a tumor-killing bystander effect that can occur even without cell-to-cell contact; and the utilization of lipophilic prodrugs that can penetrate the blood-brain barrier. C1 Massachusetts Gen Hosp East, Ctr Neurosci, Serv Neurol, Mol Neurogenet Unit, Boston, MA 02129 USA. Martin Luther Univ, Fac Med, Dept Neurosurg, D-06097 Halle, Germany. Univ Dusseldorf, Pediat Clin, D-40225 Dusseldorf, Germany. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Johns Hopkins Univ, Ctr Oncol, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Mol Neurooncol Lab, Boston, MA 02114 USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp East, Ctr Neurosci, Serv Neurol, Mol Neurogenet Unit, 13th St,Bldg 149, Boston, MA 02129 USA. FU NCI NIH HHS [CA69246] NR 44 TC 58 Z9 58 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN 10 PY 1998 VL 9 IS 9 BP 1261 EP 1273 DI 10.1089/hum.1998.9.9-1261 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA ZU536 UT WOS:000074207900002 PM 9650611 ER PT J AU Arya, SK Zamani, M Kundra, P AF Arya, SK Zamani, M Kundra, P TI Human immunodeficiency virus type 2 lentivirus vectors for gene transfer: Expression and potential for helper virus-free packaging SO HUMAN GENE THERAPY LA English DT Article ID CIS-ACTING SEQUENCES; CELL-CYCLE ARREST; MUTATIONAL ANALYSIS; GENOMIC RNA; THERAPY; VPR; HIV-2; SITE; ENCAPSIDATION; REPLICATION AB In addition to the long-term expression of the transgene provided by all retroviral vectors, lentiviruses present the opportunity to transduce nondividing cells and potentially achieve regulated expression, The development of lentiviral vectors requires the design of transfer vectors to ferry the transgene with efficient encapsidation of the transgene RNA and with full expression capability, and of a packaging vector to provide packaging machinery in trans but without helper virus production. For both vectors, a knowledge of packaging signal is required-the signal to be included in the transfer vector but excluded from the packaging vector. Among the human lentiviruses, human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), we think HIV-2 is better suited for gene transfer than HIV-1, It is less pathogenic and thus safer during design and production; its desirable nuclear import and undesirable cell-cycle arrest functions are segregated on two separate genes. In HIV-1 infection, it is less likely to recombine with the resident HIV-1, and it may itself downregulate HIV-1 expression. Evidently, elements located both upstream and downstream of the splice donor site in the leader sequence participated in RNA encapsidation and these sequences appeared necessary and sufficient. Deletion of both sequence elements resulted in a dramatic curtailment of RNA encapsidation and helper virus production. This was accompanied by some but acceptable loss of gene expression capability. The helper virus-free phenotype and expression capability of the double mutant was maintained upon replacement of its 3' long terminal repeat with a minigene cassette containing a transcriptional termination signal and a drug resistance marker gene. Deletion of the splice donor site itself had a dramatic negative effect on gene expression, supporting the important role of this element in the life of RNA. C1 NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Arya, SK (reprint author), NCI, Basic Res Lab, Div Basic Sci, NIH, 37 Convent Dr MSC 4255,Bldg 37,Room 6A11, Bethesda, MD 20892 USA. NR 42 TC 42 Z9 42 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUN 10 PY 1998 VL 9 IS 9 BP 1371 EP 1380 DI 10.1089/hum.1998.9.9-1371 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA ZU536 UT WOS:000074207900012 PM 9650621 ER PT J AU DiPaolo, JA Woodworth, CD Coutlee, F Zimonic, DB Bryant, J Kessous, A AF DiPaolo, JA Woodworth, CD Coutlee, F Zimonic, DB Bryant, J Kessous, A TI Relationship of stable integration of herpes simplex virus-2 BglII N subfragment Xho2 to malignant transformation of human papillomavirus-immortalized cervical keratinocytes SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID TYPE-2; DNA; FRAGMENT; CANCER; CELLS; INFECTION; SEQUENCES; TUMORS; GENOME; GENE AB Transfection of the right end Xho2 subfragment of Bg/II N of herpes simplex virus-2 (HSV-2) into human genital keratinocytes immortalized by human papillomavirus (HPV) type 16 or 18 resulted in invasive and noninvasive indolent cystic squamous carcinomas when cells were injected into immunocompromised mice. Retention and expression of the right end portion of the Bg/II N fragment correlated with malignancy, as the corresponding HSV-2 sequences were integrated and transcribed in the tumorigenic cell lines. HPV-immortalized cells alone were not tumorigenic. In contrast, previous results have shown that using the entire Bg/II N region can malignantly transform HPV-immortalized cells, although HSV2 DNA was not retained. Together, these observations localize the transforming activity of Bg/II N to Xho2 and suggest that the remaining sequences have an inhibitory effect on stable integration. The XhoZ sequence is 2480 bp long and contains an open reading frame (ORF) extending from nucleotides 559 to 1797. The ORF encodes a putative protein of 412-aa with a m.w. of 42-43 kDa and is highly homologous to U(L)43 of HSV-1. The correlation of tumorigenicity with stable integration and expression of XhoZ DNA in HPV-immortalized cells indicates that HSV-2 should be investigated further for a possible role in cervical cancer. (C) 1998 Wiley-Liss, Inc.(dagger). C1 NCI, Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Univ Montreal, Dept Pathol, Montreal, PQ H3C 3J7, Canada. Univ Montreal, Dept Microbiol Immunol, Montreal, PQ H3C 3J7, Canada. NIDR, NIH, Baltimore, MD USA. RP DiPaolo, JA (reprint author), NCI, Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 2A19, Bethesda, MD 20892 USA. NR 21 TC 24 Z9 26 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 10 PY 1998 VL 76 IS 6 BP 865 EP 871 DI 10.1002/(SICI)1097-0215(19980610)76:6<865::AID-IJC16>3.0.CO;2-1 PG 7 WC Oncology SC Oncology GA ZR537 UT WOS:000073987500016 PM 9626354 ER PT J AU Wray, V Mertins, D Kiess, M Henklein, P Trowitzsch-Kienast, W Schubert, U AF Wray, V Mertins, D Kiess, M Henklein, P Trowitzsch-Kienast, W Schubert, U TI Solution structure of the cytoplasmic domain of the human CD4 glycoprotein by CD and H-1 NMR spectroscopy: Implications for biological functions SO BIOCHEMISTRY LA English DT Article ID TYPE-1 VPU PROTEIN; AMINO-TERMINAL DOMAIN; DOWN-REGULATION; CELL-SURFACE; ENDOPLASMIC-RETICULUM; SECONDARY STRUCTURE; CHEMICAL-SHIFT; KINASE P56LCK; U VPU; DEGRADATION AB The human T cell receptor CD4 is a type I integral membrane glycoprotein that is involved in T cell activation and also acts as the primary coreceptor for human immunodeficiency viruses (HIV), Here the structure of a synthetic 38 amino acid peptide corresponding to the complete cytoplasmic domain of CD4 (CD4(CYTO)) has been investigated under a variety of solution conditions using a combination of circular dichroism and homonuclear two-dimensional H-1 nuclear magnetic resonance spectroscopy. In the presence of the membrane mimetic 2,2,2-trifluoroethanol (TFE), a conformational change of CD4(CYTO) from a random coil to an a-helical structure was observed. In keeping with this, CD4(CYTO) has the potential to associate with membranes as demonstrated by binding studies of in vitro phosphorylated CD4(CYTO) with microsomal membranes. Both chemical shift and nuclear Overhauser enhancement data in 50% 2,2,2-trifluoroethanol solution provide direct experimental evidence for the predominance of a short amphiphatic alpha-helix that is approximately 4 turns in length and extends from positions Arg-402 to Lys-417. The present data provide, for the first time, compelling experimental evidence that only a fraction of CD4(CYTO) has a propensity for adopting secondary structure under conditions that are assumed to exist at or near to the membrane surface and that this a-helical structure is located in the membrane-proximal region of CD4(CYTO). The N-terminal residues, that link the alpha-helix to the transmembrane anchor of CD4, and a substantial C-terminal portion (14-18 residues) of CD4(CYTO) are unstructured under the solution conditions investigated. Correlation of our structural data with recent studies on the biological activity of CD4(CYTO) indicates that the alpha-helix is of crucial importance for the interaction of CD4 with Nef and Vpu in the process of HIV-mediated CD4 down-regulation. C1 Gesell Biotechnol Forsch GmbH, Abt Strukturforsch, Dept Mol Struct Res, D-38124 Braunschweig, Germany. Tech Fachhsch, Dept Chem, D-13353 Berlin, Germany. Humboldt Univ, Fac Med, Inst Pharmacol & Toxicol, D-10117 Berlin, Germany. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Univ Hamburg, Heinrich Pette Inst Expt Virol, D-20251 Hamburg, Germany. RP Wray, V (reprint author), Gesell Biotechnol Forsch GmbH, Abt Strukturforsch, Dept Mol Struct Res, Mascheroder Weg 1, D-38124 Braunschweig, Germany. NR 50 TC 23 Z9 24 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 9 PY 1998 VL 37 IS 23 BP 8527 EP 8538 DI 10.1021/bi9723111 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZU195 UT WOS:000074171800028 PM 9622505 ER PT J AU Chauhan, SS Ray, D Kane, SE Willingham, MC Gottesman, MM AF Chauhan, SS Ray, D Kane, SE Willingham, MC Gottesman, MM TI Involvement of carboxy-terminal amino acids in secretion of human lysosomal protease cathepsin L SO BIOCHEMISTRY LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTOR; PROCATHEPSIN-L; CYTOPLASMIC TAIL; ENDOPLASMIC-RETICULUM; CYSTEINE PROTEINASES; MURINE FIBROBLASTS; TRANSFORMED-CELLS; NEPHRON SEGMENTS; MEMBRANE-PROTEIN; MAMMALIAN-CELLS AB Cathepsin L, a lysosomal cysteine protease, is overexpressed and secreted by malignantly transformed cells. However, the reason for secretion of this man 6-phosphate-containing lysosomal protease into the extracellular medium is not clear. We wished to determine whether there is a region within the primary sequence of the proenzyme form of cathepsin L which affects its subcellular and extracellular localization. High-level transient expression of human procathepsin L in mouse NIH 3T3 cells results in the secretion of most of this protein into the extracellular medium. At the same time, the endogenous mouse procathepsin L in these nontransformed cells is found in its usual location in lysosomes. Mutants of human procathepsin L with carboxy-terminus deletions involving the last 11 amino acids are not secreted into the medium. Deletion of as little as two amino acids, Thr and Val, from the carboxy terminus, blocked the secretion of the protein but did not affect its enzyme activity, posttranslational processing, or subcellular distribution. Replacement of Thr-Val by two bulky amino acids Tyr-Asn allowed secretion of the procathepsin L, but the replacement of these two amino acids by nonbulky alanines prevented its secretion. Single alanine substitutions of the last six amino acids (ASYPTV) indicated that substitution by alanine of Y or T does not affect the secretion of hproCAT E, but alanine substitutions of S, P, or V completely blocked its secretion into the culture medium. We therefore conclude that the carboxy terminus of procathepsin L contains a sequence essential for its secretion. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. City Hope Natl Med Ctr, Dept Cell & Tumor Biol, Duarte, CA 91010 USA. Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1A09,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 50 TC 38 Z9 41 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 9 PY 1998 VL 37 IS 23 BP 8584 EP 8594 DI 10.1021/bi972251z PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZU195 UT WOS:000074171800033 PM 9622510 ER PT J AU Singh, RJ Karoui, H Gunther, MR Beckman, JS Mason, RP Kalyanaraman, B AF Singh, RJ Karoui, H Gunther, MR Beckman, JS Mason, RP Kalyanaraman, B TI Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu,Zn superoxide dismutase mutants and H2O2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOTOR-NEURON DISEASE; HYDROGEN-PEROXIDE; TYROSINE NITRATION; PEROXYNITRITE; GENE; ALS; INACTIVATION; MUTATIONS; LINKAGE; MODELS AB Amyotrophic lateral sclerosis (ALS) involves the progressive degeneration of motor neurons in the spinal cord and motor cortex. Mutations to Cu,Zn superoxide dismutase (SOD) linked with familial ALS are reported to increase hydroxyl radical adduct formation from hydrogen peroxide as measured by spin trapping with 5,5'-dimethyl-1-pyrrolline N-oxide (DMPO). In the present study, we have used oxygen-17-enriched water and H2O2 to reinvestigate the mechanism of DMPO/(OH)-O-. formation from the SOD and SOD mutants. The relative ratios of DMPO/(OH)-O-. 17 and DMPO/(OH)-O-. 16 formed in the Fenton reaction were 90% and 10%, respectively, reflecting the ratios of (H2O2)-O-17 to (H2O2)-O-16. The reaction of the WT SOD with (H2O2)-O-17 in bicarbonate/CO2 buffer yielded 63% DMPO/(OH)-O-. 17 and 37% DMPO/(OH)-O-. 16. Similar results were obtained from the reaction between familial ALS SOD mutants and (H2O2)-O-17:DMPO/(OH)-O-. 17 (64%); DMPO/(OH)-O-. 16 (36%) from A4V and DMPO/(OH)-O-. 17 (62%); and DMPO/(OH)-O-. 16 (38%) from G93A, These results were confirmed further by using 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide spin trap, a phosphorylated analog of DMPO. Contrary to earlier reports, the present results indicate that a significant fraction of DMPO/(OH)-O-. formed during the reaction of SOD and familial ALS SOD mutants with H2O2 is derived from the incorporation of oxygen from water due to oxidation of DMPO to DMPO/(OH)-O-. presumably via DMPO radical cation, No differences were detected between WT and mutant SODs, neither in the concentration of DMPO/(OH)-O-. or DEPMPO/(OH)-O-. formed nor in the relative incorporation of oxygen from H2O2 or water. C1 Med Coll Wisconsin, Biophys Res Inst, Milwaukee, WI 53226 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Alabama, Dept Anesthesiol Biochem & Mol Biol, Birmingham, AL 35233 USA. RP Kalyanaraman, B (reprint author), Med Coll Wisconsin, Biophys Res Inst, Milwaukee, WI 53226 USA. EM balarama@mcw.edu FU NCRR NIH HHS [RR01008]; NIGMS NIH HHS [GM22923] NR 50 TC 99 Z9 99 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 JUN 9 PY 1998 VL 95 IS 12 BP 6675 EP 6680 DI 10.1073/pnas.95.12.6675 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900021 PM 9618471 ER PT J AU Srivastava, RK Lee, YN Noguchi, K Park, YG Ellis, MJC Jeong, JS Kim, SN Cho-Chung, YS AF Srivastava, RK Lee, YN Noguchi, K Park, YG Ellis, MJC Jeong, JS Kim, SN Cho-Chung, YS TI The RII beta regulatory subunit of protein kinase A binds to cAMP response element: An alternative cAMP signaling pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HL-60 LEUKEMIA-CELLS; CYCLIC-AMP; RECEPTOR PROTEINS; SOMATOSTATIN GENE; GROWTH-INHIBITION; DIFFERENTIATION; TRANSCRIPTION; SITE; IDENTIFICATION; TRANSLOCATION AB cAMP, through the activation of cAMP-dependent protein kinase (PKA), is involved in transcriptional regulation. In eukaryotic cells, cAMP is not considered to alter the binding affinity of CREB/ATF to cAMP-responsive element (CRE) but to induce serine phosphorylation and consequent increase in transcriptional activity. In contrast, in prokaryotic cells, cAMP enhances the DNA binding of the catabolite repressor protein to regulate the transcription of several operons, The structural similarity of the cAMP binding sites in catabolite repressor protein and regulatory subunit of PKA type II (RII) suggested the possibility of a similar role for RII in eukaryotic gene regulation. Herein we report that RII beta subunit of PKA is a transcription factor capable of interacting physically and functionally with a CRE, In contrast to CREB/ATF, the binding of RII beta to a CRE was enhanced by cAMP, and in addition, RII beta exhibited transcriptional activity as a Gal4-RII beta fusion protein. These experiments identify RII beta as a component of an alternative pathway for regulation of CRE-directed transcription in eukaryotic cells. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B05, Bethesda, MD 20892 USA. EM chochung@helix.nih.gov NR 31 TC 21 Z9 21 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 1998 VL 95 IS 12 BP 6687 EP 6692 DI 10.1073/pnas.95.12.6687 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900023 PM 9618473 ER PT J AU Wang, LM Kuo, A Alimandi, M Veri, MC Lee, CC Kapoor, V Ellmore, N Chen, XH Pierce, JH AF Wang, LM Kuo, A Alimandi, M Veri, MC Lee, CC Kapoor, V Ellmore, N Chen, XH Pierce, JH TI ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPIDERMAL GROWTH-FACTOR; NEU DIFFERENTIATION FACTOR; FACTOR RECEPTOR FAMILY; HUMAN-BREAST-CANCER; EGF RECEPTOR; NEUREGULIN RECEPTOR; HEMATOPOIETIC-CELLS; CARDIAC DEVELOPMENT; CELLULAR-RESPONSE; FACTOR HEREGULIN AB Interleukin 3-dependent murine 32D cells do not detectably express members of the ErbB receptor family and do not proliferate in response to known ligands for these receptors, 32D transfectants were generated expressing human ErbB4 alone (32D.E4) or with ErbB2 (32D.E2/E4), Epidermal growth factor (EGF), neuregulin 1-beta (NRG1-beta), betacellulin (BTC), transforming growth factor-alpha (TGF-alpha), heparin binding-EGF (HB-EGF), and amphiregulin were analyzed for their ability to mediate mitogenesis in these transfectants. 32D.E4 responded mitogenically to NRG1-beta and BTC. Surprisingly, EGF also induced significant DNA synthesis and TGF-alpha was negligibly mitogenic on 32D.E4 cells, whereas HB-EGF and amphiregulin were inactive, Although coexpression of ErbB2 with ErbB4 in 32D.E2/E4 cells did not significantly alter DNA synthesis in response to NRG1-beta or BTC, it greatly enhanced mitogenesis elicited by EGF and TGF-alpha and unmasked the ability of HB-EGF to induce proliferation. EGF-related ligands that exhibited potent mitogenic activity on 32D.E2/E4 cells at low concentrations induced adherence, morphological alterations, and up-regulation of the Mac-1 integrin and Fc gamma RII/III at higher concentrations. While I-125-EGF could be specifically crosslinked to both 32D.E4 and 32D.E2/E4 cells, its crosslinking capacity was greatly enhanced in the cotransfected cells. The ability of the various ligands to mediate proliferation and/or adhesion in the two transfectants correlated with their capacity to induce substrate tyrosine phosphorylation and to initiate and sustain activation of mitogen-activated protein kinase, We conclude that the ability of ErbB4 to mediate signal transduction through EGF-like ligands is broader than previously assumed and can be profoundly altered by the concomitant expression of ErbB2. C1 NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. Univ La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy. Inst Tumori, Immunol Lab, Rome, Italy. RP Pierce, JH (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37,Room 1E24,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 55 TC 81 Z9 81 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 1998 VL 95 IS 12 BP 6809 EP 6814 DI 10.1073/pnas.95.12.6809 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900044 PM 9618494 ER PT J AU Herman, JG Umar, A Polyak, K Graff, JR Ahuja, N Issa, JPJ Markowitz, S Willson, JKV Hamilton, SR Kinzler, KW Kane, MF Kolodner, RD Vogelstein, B Kunkel, TA Baylin, SB AF Herman, JG Umar, A Polyak, K Graff, JR Ahuja, N Issa, JPJ Markowitz, S Willson, JKV Hamilton, SR Kinzler, KW Kane, MF Kolodner, RD Vogelstein, B Kunkel, TA Baylin, SB TI Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MISMATCH REPAIR GENES; CANCER CELL-LINES; MICROSATELLITE INSTABILITY; DNA METHYLATION; DEFECTS; COLON; HMSH2; INACTIVATION AB Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often;but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation. C1 Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21231 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ireland Canc Ctr, Cleveland, OH 44106 USA. Univ Calif San Diego, Sch Med, Ctr Canc, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. RP Herman, JG (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. RI Ahuja, Nita/H-1064-2011 FU NCI NIH HHS [CA43318, CA44704, CA54396, P50 CA062924, R01 CA043318, R01 CA054396]; NIGMS NIH HHS [R01 GM050006] NR 31 TC 1345 Z9 1403 U1 1 U2 44 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 JUN 9 PY 1998 VL 95 IS 12 BP 6870 EP 6875 DI 10.1073/pnas.95.12.6870 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900055 PM 9618505 ER PT J AU Winter, DB Phung, QH Umar, A Baker, SM Tarone, RE Tanaka, K Liskay, RM Kunkel, TA Bohr, VA Gearhart, PJ AF Winter, DB Phung, QH Umar, A Baker, SM Tarone, RE Tanaka, K Liskay, RM Kunkel, TA Bohr, VA Gearhart, PJ TI Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; POINT MUTATIONS; IMMUNE-RESPONSE; VARIABLE GENES; CELLS; MATURATION; EXTRACTS; INTRON; LINE AB Mutations are introduced into rearranged Ig variable genes at a frequency of 10(-2) mutations per base pair by an unknown mechanism. Assuming that DNA repair pathways generate or remove mutations, the frequency and pattern of mutation will be different in variable genes from mice defective in repair. Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2. High levels of mutation were found in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide excision repair nor mismatch repair pathways generate hypermutation. However, variable genes from PMS2-deficient mice had significantly more adjacent base substitutions than genes from wild-type or XPA-deficient mice. By using a biochemical assay, we confirmed that tandem mispairs were repaired by wild-type cells but not by Pms2(-/-) human or murine cells. The data indicate that tandem substitutions are produced by the hypermutation mechanism and then processed by a PMS2-dependent pathway. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Grad Program Immunol, Baltimore, MD 21205 USA. NIEHS, Div Nutr Sci & Toxicol, Res Triangle Pk, NC 27709 USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. Osaka Univ, Inst Mol & Cellular Biol, Suita, Osaka 565, Japan. Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. RP Gearhart, PJ (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM gearharp@grc.nia.nih.gov FU NIGMS NIH HHS [GM32741, GM45413, R37 GM032741, R01 GM045413, R01 GM032741] NR 43 TC 86 Z9 86 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 1998 VL 95 IS 12 BP 6953 EP 6958 DI 10.1073/pnas.95.12.6953 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900070 PM 9618520 ER PT J AU Schulick, AH Taylor, AJ Zuo, W Qiu, CB Dong, G Woodward, RN Agah, R Roberts, AB Virmani, R Dichek, DA AF Schulick, AH Taylor, AJ Zuo, W Qiu, CB Dong, G Woodward, RN Agah, R Roberts, AB Virmani, R Dichek, DA TI Overexpression of transforming growth factor beta 1 in arterial endothelium causes hyperplasia, apoptosis, and cartilaginous metaplasia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MEDIATED GENE-TRANSFER; SMOOTH-MUSCLE CELLS; IN-VIVO; MOUSE AORTA; FACTOR-BETA-1; EXPRESSION; INJURY; ATHEROSCLEROSIS; TGF-BETA-1; PROTEINS AB Uninjured rat arteries transduced with an adenoviral vector expressing an active form of transforming growth factor beta 1 (TGF-beta 1) developed a cellular and matrix-rich neointima, with cartilaginous metaplasia of the vascular media. Explant cultures of transduced arteries showed that secretion of active TGF-beta 1 ceased by 4 weeks, the time of maximal intimal thickening. Between 4 and 8 weeks, the cartilaginous metaplasia resolved and the intimal lesions regressed almost completely, in large part because of massive apoptosis, Thus, locally expressed TGF-beta 1 promotes intimal growth and appears to cause transdifferentiation of vascular smooth muscle cells into chondrocytes. Moreover, TGF-beta 1 withdrawal is associated with regression of vascular lesions. These data suggest an unexpected plasticity of the adult vascular smooth muscle cell phenotype and provide an etiology for cartilaginous metaplasia of the arterial wall, Our observations may help to reconcile divergent views of the role of TGF-beta 1 in vascular disease. C1 Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94141 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94141 USA. NHLBI, Mol Hematol Lab, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Washington, DC 20307 USA. NCI, Chemoprevent Lab, Bethesda, MD 20892 USA. RP Dichek, DA (reprint author), Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, POB 419100, San Francisco, CA 94141 USA. FU NHLBI NIH HHS [1F32HL09945-01, F32 HL009945, T32 HL007731, T32HL07731] NR 45 TC 144 Z9 150 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 1998 VL 95 IS 12 BP 6983 EP 6988 DI 10.1073/pnas.95.12.6983 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900075 PM 9618525 ER PT J AU Liang, BT Jacobson, KA AF Liang, BT Jacobson, KA TI A physiological role of the adenosine A(3) receptor: Sustained cardioprotection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SENSITIVE POTASSIUM CHANNELS; CARDIAC MYOCYTE; ISCHEMIA AB Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart. A newly recognized adenosine receptor, the A(3) subtype, is expressed on the cardiac ventricular cell, and its activation protects the ventricular heart cell against injury during a subsequent exposure to ischemia, A cultured chicken ventricular myocyte model was used to investigate the cardioprotective role of a novel adenosine A(3) receptor. The protection mediated by prior activation of A(3) receptors exhibits a significantly longer duration than that produced by activation of the adenosine A(1) receptor. Prior exposure of the myocytes to brief ischemia also protected them against injury sustained during a subsequent exposure to prolonged ischemia, The adenosine A(3) receptor-selective antagonist 3-ethyl 5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-( +/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) caused a biphasic inhibition of the protective effect of the brief ischemia, The concomitant presence of the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) converted the MRS1191-induced dose inhibition curve to a monophasic one. The combined presence of both antagonists abolished the protective effect induced by the brief ischemia. Thus, activation of both A(1) and A(3) receptors is required to mediate the cardioprotective effect of the brief ischemia. Cardiac atrial cells lack native A(3) receptors and exhibit a shorter duration of cardioprotection than do ventricular cells. Transfection of atrial cells with cDNA encoding the human adenosine A(3) receptor causes a sustained A(3) agonist-mediated cardioprotection. The study indicates that cardiac adenosine A(3) receptor mediates a sustained cardioprotective function and represents a new cardiac therapeutic target. C1 Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, 504 Johnson Pavil,3610 Hamilton Walk, Philadelphia, PA 19104 USA. EM liangb@mail.med.upenn.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20, Z99 DK999999]; NHLBI NIH HHS [R01 HL048225, R01-HL48225] NR 19 TC 166 Z9 166 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 9 PY 1998 VL 95 IS 12 BP 6995 EP 6999 DI 10.1073/pnas.95.12.6995 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT829 UT WOS:000074131900077 PM 9618527 ER PT J AU Cushman, WC Cutler, JA Hanna, E Bingham, SF Follmann, D Harford, T Dubbert, P Allender, PS Dufour, M Collins, JF Walsh, SM Kirk, GF Burg, M Felicetta, JV Hamilton, BP Katz, LA Perry, HM Willenberg, ML Lakshman, R Hamburger, RJ AF Cushman, WC Cutler, JA Hanna, E Bingham, SF Follmann, D Harford, T Dubbert, P Allender, PS Dufour, M Collins, JF Walsh, SM Kirk, GF Burg, M Felicetta, JV Hamilton, BP Katz, LA Perry, HM Willenberg, ML Lakshman, R Hamburger, RJ CA PATHS Grp TI Prevention and treatment of hypertension study (PATHS): effects of an alcohol treatment program on blood pressure SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; HEART-DISEASE; CONSUMPTION; LIPIDS; MORTALITY; SMOKING; MEN AB Objectives: To determine whether blood pressure is reduced for at least 6 months with an intervention to lower alcohol intake in moderate to heavy drinkers with above optimal to slightly elevated diastolic blood pressure, and whether reduction of alcohol intake can be maintained for 2 years. Design: A randomized controlled trial. Methods: Six hundred forty-one outpatient veterans with an average intake of 3 or more alcoholic drinks per day in the 6 months before entry into the study and with diastolic blood pressure 80 to 99 mm Hg were randomly assigned to a cognitive-behavioral alcohol reduction intervention program or a control observation group for 15 to 24 months. The goal of the intervention was the lower of 2 or fewer drinks daily or a 50% reduction in intake. A subgroup with hypertension was defined as having a diastolic blood pressure of 90 to 99 mm Hg, or 80 to 99 mm Hg if recently taking medication for hypertension. Results: Reduction in average weekly self-reported alcohol intake was significantly greater (P<.001) at every assessment from 3 to 24 months in the intervention group vs the control group: levels declined from 432 g/wk at baseline by 202 g/wk in the intervention group and from 445 g/wk by 78 g/wk in the control group in the first 6 months, with similar reductions after 24 months. The intervention group had a 1.2/0.7-mm Hg greater reduction in blood pressure than the control group (for each, P = .17 and P = .18) for the B-month primary end point; for the hypertensive stratum the difference was 0.9/0.7 mm Hg (for each, P = .58 and P = .44). Conclusions: The 1.3 drinks per day average difference between changes in self-reported alcohol intake observed in this trial produced only small nonsignificant effects on blood pressure. The results from the Prevention and Treatment of Hypertension Study (PATHS) do not provide strong support for reducing alcohol consumption in nondependent moderate drinkers as a sole method for the prevention or treatment of hypertension. C1 Vet Affairs Med Ctr 111Q, Memphis, TN 38104 USA. Dept Vet Affairs Med Ctr, Memphis, TN USA. NHLBI, Bethesda, MD 20892 USA. NIAAA, Rockville, MD 20852 USA. Perry Point Vet Affairs Cooperat Studies Program, Perry Point, MD USA. Vet Affairs Med Ctr, Jackson, MS USA. Vet Affairs Med Ctr, W Haven, CT USA. Vet Affairs Med Ctr, Phoenix, AZ USA. Vet Affairs Med Ctr, Baltimore, MD USA. Vet Affairs Med Ctr, New York, NY USA. Vet Affairs Med Ctr, St Louis, MO USA. Vet Affairs Med Ctr, Minneapolis, MN USA. Vet Affairs Med Ctr, Cent Lipids Lab, Washington, DC 20422 USA. Vet Affairs Med Ctr, Cent Renal lab, Boston, MA USA. RP Cushman, WC (reprint author), Vet Affairs Med Ctr 111Q, 1030 Jefferson Ave, Memphis, TN 38104 USA. NR 39 TC 52 Z9 60 U1 5 U2 8 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 JUN 8 PY 1998 VL 158 IS 11 BP 1197 EP 1207 DI 10.1001/archinte.158.11.1197 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA ZR234 UT WOS:000073953700006 PM 9625399 ER PT J AU Roccella, EJ AF Roccella, EJ TI The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and obstructive sleep apnea: Let their silence not be matched by the silence of the ordinary physician - In reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 NHLBI, Natl High Blood Pressure Educ Program, Bethesda, MD 20892 USA. RP Roccella, EJ (reprint author), NHLBI, Natl High Blood Pressure Educ Program, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 8 PY 1998 VL 158 IS 11 BP 1273 EP 1273 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA ZR234 UT WOS:000073953700019 ER PT J AU Chen, S Ren, YQ Bing, GY Hillman, DE AF Chen, S Ren, YQ Bing, GY Hillman, DE TI Transient c-fos gene expression in cerebellar development and functional stimulation SO BRAIN RESEARCH LA English DT Article DE immunohistochemistry; excitotoxicity; Purkinje cell; signal transduction; proto-oncogene; granule cell; stellate/basket cell; undercutting the cortex ID PURKINJE-CELL COMPARTMENTS; CENTRAL-NERVOUS-SYSTEM; ACID-INDUCED SEIZURES; ADULT-RAT CEREBELLUM; DNA-BINDING ACTIVITY; POSTNATAL-DEVELOPMENT; TRANSGENE EXPRESSION; MONKEY CEREBELLUM; RECEPTOR SUBUNITS; MOLECULAR LAYER AB This study examined the temporal appearance of c-fos expression in rat cerebella from birth to postnatal day 21 (P21) and following systemic kainic acid administration in adults. During development, Fos positive granule cells appeared first at P3 in caudal lobules and extended to all folia by P9. These reactive cells occurred in clusters throughout the granular layer and reached their highest reactivity by P15. In addition, Fos positive basket and stellate cells were seen in the molecular layer at this time. A steep decline in Fos protein labeling of the cerebellum began by P18 and was barely detectable in adulthood. In adult rats, systemic injection of kainic acid induced c-fos expression in granule cells and stellate/basket interneurons within 1 h of treatment. Fos reactive granule cells appeared in clusters with some forming distinct parasagittal bands in caudal folia. One day after unilateral cerebellar lesioning, a limited number of reactive cells were found on the lesion margins. A combination of lesioning and systemic kainic acid produced a strong, c-fos expression throughout the ipsilateral granular layer as well as in Purkinje cell nuclei. Contralateral to the lesion, the pattern of granule cell reactivity appeared the same but slightly stronger than those with kainate alone. We conclude that c-fos gene expression occurs transiently in granule cells during postnatal development and can be rapidly re-induced in the adult following systemic injection of glutamate agonists. The c-fos expression patterns suggest that subpopulations of granule cells are clustered and related to the parasagittal compartments of Purkinje cells. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NYU, Med Ctr, Dept Otolaryngol & Physiol Neurosci, New York, NY 10016 USA. NIEHS, Lab Environm Neurosci, NIH, Res Triangle Pk, NC 27709 USA. RP Hillman, DE (reprint author), NYU, Med Ctr, Dept Otolaryngol & Physiol Neurosci, 550 1st Ave, New York, NY 10016 USA. OI Bing, Guoying/0000-0003-0609-8152 FU NIA NIH HHS [AG-09480]; NINDS NIH HHS [NS-13742] NR 74 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 8 PY 1998 VL 795 IS 1-2 BP 87 EP 97 DI 10.1016/S0006-8993(98)00263-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 100FY UT WOS:000074806500011 PM 9622600 ER PT J AU Zhang, RX Wang, H Ruda, M Iadarola, MJ Qiao, JT AF Zhang, RX Wang, H Ruda, M Iadarola, MJ Qiao, JT TI C-Fos expression in NMDA receptor-contained neurons in spinal cord in a rat model of inflammation: a double immunocytochemical study SO BRAIN RESEARCH LA English DT Article DE N-methyl-D-aspartate receptor; immediate early gene; immunocytochemistry; pain; spinal cord; rat ID AMINO-ACID ANTAGONISTS; GLUTAMATE RECEPTORS; DORSAL HORN; BEHAVIORAL HYPERALGESIA; NOCICEPTION; MK-801; SUBUNITS; BRAIN; AMPA AB Double-labeling techniques were used to demonstrate the nociceptive activation of NMDA receptor-contained neurons in spinal dorsal horn by using c-Fos immunoreactivity as an indicator of this activation in a rat model of inflammation. About 25% and 55% of the c-Fos-immunoreactive neurons that were found in laminae I-II and lamina V showed NMDA receptor immunoreactivity, while about 4% and 11% of NMDA-receptor immunoreactive neurons in these two regions showed c-Fos immunoreactivity, respectively. The implication of the results was discussed. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Shanxi Med Univ, Dept Neurobiol, Taiyuan 030001, Shanxi, Peoples R China. NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Qiao, JT (reprint author), Shanxi Med Univ, Dept Neurobiol, Taiyuan 030001, Shanxi, Peoples R China. EM sydw@shanxi.ihep.ac.cn NR 29 TC 25 Z9 26 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 JUN 8 PY 1998 VL 795 IS 1-2 BP 282 EP 286 DI 10.1016/S0006-8993(98)00300-X PG 5 WC Neurosciences SC Neurosciences & Neurology GA 100FY UT WOS:000074806500032 PM 9622652 ER PT J AU Stearman, R Dancis, A Klausner, RD AF Stearman, R Dancis, A Klausner, RD TI YIpDCE1 - an integrating plasmid for dual constitutive expression in yeast SO GENE LA English DT Article DE two-hybrid method; tetrabrid; PGK promoter; ADE2 ID SACCHAROMYCES-CEREVISIAE; SHUTTLE VECTORS; SYSTEM; DNA AB YIpDCE1 (Dual Constitutive Expression), a novel Saccharomyces cerevisiae integrating plasmid, constitutively expresses two genes under the control of separate phosphoglycerate kinase promoters, YIpDCE1 contains the complete ADE2 gene which can be used as a marker for selecting integrants at mutant ade2 loci commonly present in laboratory yeast strains. The YIpDCE1 plasmid can be inserted into the ade2-101 locus of the HF7c strain used in two hybrid screens. Thus it could be useful for analysis of two hybrid interactions that occur in the context of additional protein components (e.g. modifying enzymes such as kinases or phosphatases, or multimeric complexes consisting of three or four distinct protein components). YIpDCE1 has been used to create strains simultaneously overexpressing the permease (ftrl) and oxidase (fet3) components of the yeast high-affinity iron uptake system. This confers constitutive high-affinity iron uptake on the transformed strains, bypassing the normal regulatory mechanisms. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. NCI, Off Director, NIH, Bethesda, MD 20892 USA. RP Stearman, R (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 17 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUN 8 PY 1998 VL 212 IS 2 BP 197 EP 202 DI 10.1016/S0378-1119(98)00179-6 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ZU192 UT WOS:000074171500005 PM 9611262 ER PT J AU Southan, GJ Srinivasan, A George, C Fales, HM Keefer, LK AF Southan, GJ Srinivasan, A George, C Fales, HM Keefer, LK TI N-nitrosated N-hydroxyguanidines are nitric oxide-releasing diazeniumdiolates SO CHEMICAL COMMUNICATIONS LA English DT Article ID RELAXING FACTOR; L-ARGININE; OXIDATION; GENERATION AB N-Hydroxyguanidines can be nitrosatively converted to zwitterionic diazeniumdiolates of crystallographically-confirmed structure H2N+=C[NHR][N(O)NO](-), whose hydrolytic dissociation at physiological pH leads to both NO and N2O; the results appear to account for the formation of the 'potential intercellular nitric oxide carrier' produced on exposing N-G-hydroxy-L-arginine (a metabolic intermediate in mammalian NO biosynthesis) to aerobic NO. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. NHLBI, Chem Lab, Bethesda, MD 20892 USA. RP Southan, GJ (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 11 TC 16 Z9 16 U1 0 U2 1 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON ROAD, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND SN 1359-7345 J9 CHEM COMMUN JI Chem. Commun. PD JUN 7 PY 1998 IS 11 BP 1191 EP 1192 DI 10.1039/a801543k PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA ZT211 UT WOS:000074060800012 ER PT J AU LeBeau, AP Robson, AB McKinnon, AE Sneyd, J AF LeBeau, AP Robson, AB McKinnon, AE Sneyd, J TI Analysis of a reduced model of corticotroph action potentials SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; ANTERIOR-PITUITARY-CELLS; CALCIUM OSCILLATIONS; RAT CORTICOTROPES; ADRENOCORTICOTROPIN SECRETION; ARGININE-VASOPRESSIN; CA2+ CHANNELS; ADENOMA CELLS; HORMONE; CAMP AB We have previously described a model for corticotroph plasma membrane electrophysiology [LeBeau ct al. (1997). Biophysical Journal 73, 1263-1275]. The model is a Hodgkin-Huxley-like formalism consisting of six coupled ordinary differential equations. Analysis of this model showed that Ca2+ action potentials could be induced by an increase in the L-type voltage-sensitive Ca2+ current. Thus we have demonstrated a putative causal link between an increase in the corticotroph Ca2+ current and action potential generation. We report here the reduction of the model to one with three equations, the behaviour of which was found to correspond well with that of the full model. The reduced model was then subjected to fast-slow subsystem analysis, which revealed the mechanistic interaction between the membrane potential and intracellular Ca2+ concentration that underlies action potential generation. Insights obtained from this analysis were used to investigate experimentally observed aspects of corticotroph electrophysiology such as spontaneous electrical activity, bursting action potentials, and observations from anode break excitation experiments. (C) 1998 Academic Press Limited. C1 Christchurch Sch Med, Dept Med, Div Endocrinol, Christchurch, New Zealand. Lincoln Univ, Ctr Comp & Biometr, Canterbury, New Zealand. Univ Canterbury, Dept Math & Stat, Biomath Res Ctr, Christchurch 1, New Zealand. RP LeBeau, AP (reprint author), NIDDK, NIH, Math Res Branch, BSA Bldg,Suite 350,9190 Wisconsin Ave, Bethesda, MD 20814 USA. RI Sneyd, James/C-8995-2009 OI Sneyd, James/0000-0001-7305-2862 NR 42 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD JUN 7 PY 1998 VL 192 IS 3 BP 319 EP 339 DI 10.1006/jtbi.1998.0656 PG 21 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA ZW493 UT WOS:000074416500005 PM 9650290 ER PT J AU Miller, M Leonard, EJ AF Miller, M Leonard, EJ TI Mode of receptor binding and activation by plasminogen-related growth factors SO FEBS LETTERS LA English DT Article DE hepatocyte growth factor; macrophage stimulating protein; plasminogen-related growth factor; tumorigenesis; receptor oligomerization ID MACROPHAGE-STIMULATING PROTEIN; FACTOR SCATTER FACTOR; MET PROTOONCOGENE PRODUCT; TYROSINE KINASE; EXTRACELLULAR DOMAIN; MITOGENIC ACTIVITY; HORMONE-RECEPTOR; RON RECEPTOR; IDENTIFICATION; FAMILY AB Hepatocyte growth factor/scatter factor (HGF/SF) and macrophage stimulating protein (MSP) are plasminogen-related kringle proteins that lost serine protease domain enzymatic activity and became ligands for cell surface tyrosine kinase receptors. They are activated by cleavage to disulfide-linked ap chains. Surprisingly, despite structural similarities, the high affinity receptor binding regions of the two proteins are different: a chain for HGF, and beta chain for MSP. We propose that after cleavage exposes a beta chain binding site (high affinity for MSP, low affinity for HGF), monomeric ligand induces receptor dimerization and activation via alpha and beta chain binding sites of different affinity. (C) 1998 Federation of European Biochemical Societies. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Immunobiol Lab, Frederick, MD 21702 USA. RP Miller, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Macromol Struct Lab, Frederick, MD 21702 USA. RI Miller, Maria/I-1636-2013 OI Miller, Maria/0000-0003-0252-5348 NR 30 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 5 PY 1998 VL 429 IS 1 BP 1 EP 3 DI 10.1016/S0014-5793(98)00533-X PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ZU956 UT WOS:000074253400001 PM 9657372 ER PT J AU Roy, S Garges, S Adhya, S AF Roy, S Garges, S Adhya, S TI Activation and repression of transcription by differential contact: Two sides of a coin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID OPEN-COMPLEX-FORMATION; COLI RNA-POLYMERASE; LAMBDA-PRM PROMOTER; ESCHERICHIA-COLI; LAC REPRESSOR; ALPHA-SUBUNIT; CONFORMATIONAL-CHANGES; BACTERIOPHAGE-LAMBDA; INITIATION; PROTEIN C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov NR 58 TC 72 Z9 73 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 JUN 5 PY 1998 VL 273 IS 23 BP 14059 EP 14062 DI 10.1074/jbc.273.23.14059 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZR856 UT WOS:000074021500001 PM 9603899 ER PT J AU Wong, JM Liang, VCT Sachs, LM Shi, YB AF Wong, JM Liang, VCT Sachs, LM Shi, YB TI Transcription from the thyroid hormone-dependent promoter of the Xenopus laevis thyroid hormone receptor beta A gene requires a novel upstream element and the initiator, but not a TATA box SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; AMPHIBIAN METAMORPHOSIS; MOLECULAR MECHANISMS; EXPRESSION; ALPHA; SUPERFAMILY; REPRESSION; ACTIVATION; PROTEIN AB The thyroid hormone receptor (TR) beta genes in Xenopus laevis are regulated by thyroid hormone in all organs of an animal during metamorphosis. This autoregulation appears to be critical for systematic transformations of different organs as a tadpole is transformed into a frog. To understand this autoregulation, we have previously identified a thyroid hormone response element in the hormone-dependent promoter of the X. laevis TR beta A gene. We report here the detailed characterization of the promoter. We have now mapped the transcription start site and demonstrated the existence of an initiator element at the start site critical for promoter function. More important, our deletion and mutational experiments revealed a novel upstream DNA element that is located 125 base pairs upstream of the start site and that is essential for active transcription from the promoter Promoter reconstitution experiments showed that this novel element does not function as an enhancer, but acts as a core promoter element, which, together with the initiator, directs accurate transcription from the promoter. Finally, we provide evidence for the existence of a protein(s) that specifically recognizes this element, Our studies thus demonstrate that the TR beta A promoter has a unique organization consisting of an initiator and a novel upstream promoter element. Such an organization may be important for the ubiquitous but tissue-dependent temporal regulation of the gene by thyroid hormone during amphibian metamorphosis. C1 NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Shi, YB (reprint author), NICHD, Mol Embryol Lab, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov NR 47 TC 22 Z9 22 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 JUN 5 PY 1998 VL 273 IS 23 BP 14186 EP 14193 DI 10.1074/jbc.273.23.14186 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZR856 UT WOS:000074021500022 PM 9603920 ER PT J AU Vance, CL Begg, CM Lee, WL Haase, H Copeland, TD McEnery, MW AF Vance, CL Begg, CM Lee, WL Haase, H Copeland, TD McEnery, MW TI Differential expression and association of calcium channel alpha(1B) and beta subunits during rat brain ontogeny SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CEREBELLAR GRANULE NEURONS; DEPENDENT CA2+ CHANNELS; DEVELOPMENTAL REGULATION; FUNCTIONAL EXPRESSION; GLUTAMATE RELEASE; SYNAPSE FORMATION; CA-2+ CHANNELS; MESSENGER-RNAS; GROWTH CONES; CURRENTS AB Calcium functions as an essential second messenger during neuronal development and synapse acquisition. Voltage-dependent calcium channels (VDCC), which are critical to these processes, are heteromultimeric complexes composed of alpha(1), alpha(2)/delta and beta subunits, beta subunits function to direct the VDCC complex to the plasma membrane as well as regulate its channel properties. The importance of beta to neuronal functioning was recently underscored by the identification of a truncated beta 4 isoform in the epileptic mouse lethargic (Ih) (Burgess, D. L., Jones, J. M., Meisler, M. H., and Noebels, J. L. (1997) Cell 88, 385-392). The goal of our study was to investigate the role of individual beta isoforms (beta 1b, beta 2, beta 3, and beta 4) in the assembly of N-type VDCC during rat brain development. By using quantitative Western blot analysis with anti-alpha(1B)-directed antibodies and [I-125-Tyr(22)]omega-conotoxin GVIA (I-125-CTX) radioligand binding assays, we observed that only a small fraction of the total alpha(1B) protein present in embryonic and early postnatal brain expressed high affinity I-125-CTX-binding sites. These results suggested that subsequent maturation of alpha(1B) or its assembly with auxiliary subunits was required to exhibit high affinity I-125-CTX binding. The temporal pattern of expression of beta subunits and their assembly with alpha(1B) indicated a developmental pattern of expression of beta isoforms: beta 1b increased 3-fold from PO to adult, beta 4 increased 10-fold, and both beta 2 and beta 3 expression remained unchanged, As the beta component of N-type VDCC changed during postnatal development, we were able to identify both immature and mature forms of N-type VDCC, At P2, the relative contribution of beta is beta 1b > beta 3 much greater than beta 2, whereas at P14 and adult the distribution is beta 3 > beta 1b = beta 4, Although we observed no beta 4 associated with the alpha(1B) at P2, beta 4 accounted for 14 and 25% of total alpha(1B)/beta subunit complexes in P14 and adult, respectively. Thus, of the beta isoforms analyzed, only the beta 4 was assembled with the rat a,, to form N-type VDCC with a time course that paralleled its level of expression during rat brain development. These results suggest a role for the beta 4 isoform in the assembly and maturation of the N-type VDCC. C1 Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. Max Delbruck Ctr Mol Med, D-13122 Berlin, Germany. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP McEnery, MW (reprint author), Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA. NR 78 TC 73 Z9 74 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 JUN 5 PY 1998 VL 273 IS 23 BP 14495 EP 14502 DI 10.1074/jbc.273.23.14495 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZR856 UT WOS:000074021500065 PM 9603963 ER PT J AU Ma, W Liu, QY Maric, D Sathanoori, RS Chang, YH Barker, JL AF Ma, W Liu, QY Maric, D Sathanoori, RS Chang, YH Barker, JL TI Basic FGF-responsive telencephalic precursor cells express functional GABA(A) receptor Cl- channels in vitro SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE neural stem cells; proliferation; BrdU; patch clamp; digital Ca2+ imaging ID RAT SPINAL-CORD; GROWTH-FACTOR; IMMUNOREACTIVITY; SUBUNIT AB We have previously described the expression of specific gamma-aminobutyric acid (GABA)(A) receptor subunits and their transcripts in the cortical neuroepithelium (Ma and Barker, 1995, 1998), However, it is not clear whether neural precursor cells exposed to basic fibroblast growth factor (bFGF) in vitro reproduce the biological properties of neuroepithelial cells in vivo within the embryonic ventricular zone. In the present study, neural precursor cells were isolated from the telencephalic neuroepithelium of embryonic day 13-13.5 rats and exposed to bFGF in serum-free medium. Basic FGF-responsive cells were capable of dividing and differentiating into neurons and astrocytes, The rapidly dividing cells formed multicellular spheres and then a rosette-like formation in which a majority of cells expressed GABA(A) receptor alpha 4, beta 1, or gamma 1 subunit proteins. We found in perforated patch-clamp recordings that GABA depolarized bromodeoxyundine (BrdU)(+) precursor cells, and under voltage-clamp induced a bicuculline-sensitive current that reversed at the Cl- equilibrium potential, GABA also increased cytoplasmic Ca2+ in a significant number of BrdU(+) cells that was blocked by bicuculline, The bicuculline sensitivity of these pharmacological effects implicates GABA(A) receptor/ Cl- channels, since bicuculline is a competitive GABA(A) antagonist at these channels in well-differentiated cells. It is possible that the three GABA(A) receptor subunits (alpha 4, beta 1, and gamma 1) found in precursor cells form the Cl- channels detected electrophysiologically. The functional GABAA receptor/Cl- channels and associated regulation of their cytoplasmic Ca2+ levels via bicuculline-sensitive mechanisms may play significant roles in the regulation of neural cell proliferation in this model neuroepithelium. (C) 1998 John Wiley & Sons, Inc. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Biotechnol Res & Applicat Div, Rockville, MD 20850 USA. RP Ma, W (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C-02, Bethesda, MD 20892 USA. NR 24 TC 48 Z9 50 U1 1 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 JUN 5 PY 1998 VL 35 IS 3 BP 277 EP 286 DI 10.1002/(SICI)1097-4695(19980605)35:3<277::AID-NEU5>3.0.CO;2-W PG 10 WC Neurosciences SC Neurosciences & Neurology GA ZP550 UT WOS:000073764700005 PM 9622011 ER PT J AU Khrebtukova, I Michaud, EJ Foster, CM Stark, KL Garfinkel, DJ Woychik, RP AF Khrebtukova, I Michaud, EJ Foster, CM Stark, KL Garfinkel, DJ Woychik, RP TI Utilization of microhomologous recombination in yeast to generate targeting constructs for mammalian genes SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE microhomologous recombination; yeast; targeting construct; targeted mutagenesis; mouse mutation; functional genomics ID EMBRYONIC STEM-CELLS; POLYCYSTIC KIDNEY-DISEASE; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; SHUTTLE VECTORS; MOUSE; MICE; MUTAGENESIS; REPLACEMENT; DELETION AB We have developed a new procedure utilizing microhomologous recombination in yeast to generate targeting constructs for producing targeted mutations in mice. This procedure is rapid and efficient, and should be directly applicable to all mammalian genes. Moreover, only minimal information about the locus being targeted is required. The feasibility of this approach was demonstrated by producing another allele of the mouse Tg737 polycystic kidney gene. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM rpw@po.cwru.edu NR 40 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 5 PY 1998 VL 401 IS 1-2 BP 11 EP 25 DI 10.1016/S0027-5107(98)00053-0 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA ZY520 UT WOS:000074630000002 PM 9639665 ER PT J AU Mdluli, K Slayden, RA Zhu, YQ Ramaswamy, S Pan, X Mead, D Crane, DD Musser, JM Barry, CE AF Mdluli, K Slayden, RA Zhu, YQ Ramaswamy, S Pan, X Mead, D Crane, DD Musser, JM Barry, CE TI Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid SO SCIENCE LA English DT Article ID CATALASE-PEROXIDASE GENE; ACYL CARRIER PROTEIN; DRUG-RESISTANCE; CELL-GROWTH; FATTY-ACID; TARGET; INHA; MUTATIONS; KATG; BIOSYNTHESIS AB Although isoniazid (isonicotinic acid hydrazide, INH) is widely used for the treatment of tuberculosis, its molecular target has remained elusive. In response to INH treatment, saturated hexacasanoic acid (C26:0) accumulated on a 12-kilodalton acyl carrier protein (AcpM) that normally carried mycolic acid precursors as long as C50. A protein species purified from INH-treated Mycobacterium tuberculosis was shown to consist of a covalent complex of INH, AcpM, and a beta-ketoacyl acyl carrier protein synthase, KasA. Amino acid-altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, TB Res Unit,NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Inst Study Bacterial Pathogenesis, Houston, TX 77030 USA. RP Barry, CE (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, TB Res Unit,NIH, Hamilton, MT 59840 USA. RI Barry, III, Clifton/H-3839-2012; Slayden, Richard/O-8626-2016 OI Slayden, Richard/0000-0001-6857-7277 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI37004] NR 28 TC 301 Z9 317 U1 1 U2 23 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 JUN 5 PY 1998 VL 280 IS 5369 BP 1607 EP 1610 DI 10.1126/science.280.5369.1607 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT213 UT WOS:000074061200042 PM 9616124 ER PT J AU Tamura, M Gu, JG Matsumoto, K Aota, S Parsons, R Yamada, KM AF Tamura, M Gu, JG Matsumoto, K Aota, S Parsons, R Yamada, KM TI Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN SO SCIENCE LA English DT Article ID INTEGRINS; KINASE AB The tumor suppressor PTEN is a phosphatase with sequence similarity to the cytoskeletal protein tensin. Here the cellular roles of PTEN were investigated. Overexpression of PTEN inhibited cell migration, whereas antisense PTEN enhanced migration. Integrin-mediated cell spreading and the formation of focal adhesions were down-regulated by wild-type PTEN but not by PTEN with an inactive phosphatase domain. PTEN interacted with the focal adhesion kinase FAK and reduced its tyrosine phosphorylation. Overexpression of FAK partially antagonized the effects of PTEN. Thus, PTEN phosphatase may function as a tumor suppressor by negatively regulating cell interactions with the extracellular matrix. C1 NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. RP Tamura, M (reprint author), NIDR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bldg 30,Room 421,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. EM mtamura@yoda.nidr.nih.gov; kyamada@yoda.nidr.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 NR 25 TC 858 Z9 965 U1 5 U2 32 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 JUN 5 PY 1998 VL 280 IS 5369 BP 1614 EP 1617 DI 10.1126/science.280.5369.1614 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZT213 UT WOS:000074061200044 PM 9616126 ER PT J AU Gragerov, A Kino, T Ilyina-Gragerova, G Chrousos, GP Pavlakis, GN AF Gragerov, A Kino, T Ilyina-Gragerova, G Chrousos, GP Pavlakis, GN TI HHR23A, the human homologue of the yeast repair protein RAD23, interacts specifically with Vpr protein and prevents cell cycle arrest but not the transcriptional effects of Vpr SO VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SACCHAROMYCES-CEREVISIAE; MUTATIONAL ANALYSIS; GENE RAD23; NUCLEAR-LOCALIZATION; PRODUCTIVE INFECTION; PHASE; G(2); MACROPHAGES; REQUIREMENT AB Yeast two-hybrid selection of proteins interacting with human immunodeficiency virus type 1 Vpr identified HHR23A, a human homologue of the yeast DNA repair protein RAD23, as a specific interactor. A small 57-amino-acid C-terminal portion of HHR23A was sufficient for Vpr interaction. When introduced into human cells by transfection, full-length HHR23A or its C-terminal fragments were able to alleviate Vpr-induced cell cycle arrest, suggesting that HHR23A may participate in the pathway leading to G2 arrest by Vpr. We have also examined the effects of HHR23 on the recently identified transcription coactivator function of Vpr. The two Vpr functions are independent, since we have identified mutants lacking either the cell cycle arrest or the coactivator function. Our analysis showed that excess of HHR23A does not affect the coactivator function of Vpr, while it affects the cell cycle arresting function. Therefore, a simple sequestering model for Vpr in the presence of excess HHR23A is not supported, we propose that the interaction of HHR23A with Vpr may affect specifically pathways leading to cell cycle regulation. (C) 1998 Academic Press. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NICHHD, Sect Pediat Endocrinol, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Pavlakis, GN (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Bldg 535,Room 210,POB B, Frederick, MD 21702 USA. NR 49 TC 50 Z9 50 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUN 5 PY 1998 VL 245 IS 2 BP 323 EP 330 DI 10.1006/viro.1998.9138 PG 8 WC Virology SC Virology GA ZU337 UT WOS:000074186800015 PM 9636371 ER PT J AU Sim, BC Aftahi, N Reilly, C Bogen, B Schwartz, RH Gascoigne, NRJ Lo, D AF Sim, BC Aftahi, N Reilly, C Bogen, B Schwartz, RH Gascoigne, NRJ Lo, D TI Thymic skewing of the CD4/CD8 ratio maps with the T-cell receptor alpha-chain locus SO CURRENT BIOLOGY LA English DT Article ID POSITIVE SELECTION; GENETIC-CONTROL; MOUSE STRAINS; HAPLOTYPES; LINEAGES; COMMITMENT; THYMOCYTES; ANTIBODY; FAMILY; CD4 AB The thymic preference for CD4(+) T cells over CD8(+) T cells is often attributed to a default pathway favouring CD4(+) T cells [1] or to homeostatic mechanisms [2,3] It is also clear, however, that T-cell receptor (TCR) preferences for major histocompatibility complex (MHC) class I versus class II binding will strongly influence an individual clone's skewing to the CD4 or CD8 subset [4] The variable region of each TCR alpha chain (V alpha) studied to date is found to be overrepresented in either CD4(+) [5-7] or CD8(+) cells [7-9], suggesting that each V alpha element can Interact more favourably with either MHC class I or class II molecules [10], Indeed, TCRs appear to have an intrinsic ability to interact with MHC molecules [11,12], and single amino acid residues present in germline-encoded complementarity determining region 1 (CDR1) and CDR2 of the V alpha element can be responsible for determining MHC specificity [13]. Interestingly, the degree of CD4/CD8 skewing is variable among different mouse strains [14,15] and in human populations [16], Here, we have shown that polymorphism in CD4/CD8 skewing between Be and BALB/c mice is determined by the stem cell genotype and not by environmental effects, and that it maps in or near the TCR alpha-chain complex, Tcra, This was confirmed by comparing Tcra(b) with Tcra(a) or Tcra(c) haplotypes in congenic mice. We propose that the array of V alpha genes in various Tcra haplotypes exerts influence over the proportion of CD4 and CD8 subsets generated and may account in part for the observed thymic skewing. Thus, while it has been suggested that the TCR genes have been selected by evolution for MHC binding, our results further indicate selection for class II MHC preference. C1 Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Univ Oslo, Inst Immunol & Rheumatol, N-0172 Oslo, Norway. NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lo, D (reprint author), Scripps Res Inst, Dept Immunol, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. FU NIAID NIH HHS [AI38375, AI29689]; NIGMS NIH HHS [R01 GM48002] NR 28 TC 39 Z9 39 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 4 PY 1998 VL 8 IS 12 BP 701 EP 704 DI 10.1016/S0960-9822(98)70276-3 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZT760 UT WOS:000074122900018 PM 9637921 ER PT J AU Imhof, A Wolffe, AP AF Imhof, A Wolffe, AP TI Transcription: Gene control by targeted histone acetylation SO CURRENT BIOLOGY LA English DT Article ID YEAST; LYSINES; GCN5P AB A transcriptional regulator in yeast, Gcn5p, activates transcription by targeted acetylation of specific lysine residues in the amino-terminal tails of histones, This targeted modification is restricted to nucleosomes assembled on the promoters of Gcn5p-responsive genes. C1 NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Imhof, A (reprint author), NICHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. OI Imhof, Axel/0000-0003-2993-8249 NR 13 TC 63 Z9 66 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 4 PY 1998 VL 8 IS 12 BP R422 EP R424 DI 10.1016/S0960-9822(98)70268-4 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZT760 UT WOS:000074122900011 PM 9637914 ER PT J AU Pei, XF Gupta, TH Badio, B Padgett, WL Daly, JW AF Pei, XF Gupta, TH Badio, B Padgett, WL Daly, JW TI 6 beta-acetoxynortropane: A potent muscarinic agonist with apparent selectivity toward M-2-receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GONG-TENG-A; RECEPTORS; ANTAGONISTS; MECHANISMS; NORTROPANE; BINDING AB A series of tropane derivatives, related in structure to baogongteng A (1), an alkaloid from a Chinese herb, were synthesized. 6 beta-Acetoxynortropane (5) had weak affinity (K-i 22 mu M) for central (M-1) muscarinic receptors in a [H-3]quinuclidinyl benzilate binding assay but had extremely high affinity (K-i 2.6 nM) and selectivity for M-2-muscarinic receptors expressed in CHO cells. It had 13-fold lower affinity for M-4-receptors, 260-fold lower affinity for M-3-receptors, and 8200-fold lower affinity for M-1-receptors expressed in CHO cells. The 6 beta-carbomethoxy analogue (14) of baogongteng A had only weak affinity for M-2-muscarinic receptors, as did 6 beta-carbomethoxynortropane (13) and 6 beta-acetoxytropane (4). In transfected CHO cells, 6 beta-acetoxynortropane (5) was an agonist at M-2-receptors, based on a GTP-elicited decrease in affinity, and a full agonist with an IC50 of 11 nM at M-4-receptors, based on inhibition of cyclic AMP accumulation, while being a full agonist at M-1-receptors with an EC50 Of 23 nM and a partial agonist at M-3-receptors with an EC50 Of 3.6 nM, based in both cases on stimulation of phosphoinositide breakdown. All of the 16 tropane derivatives had weak affinities for central alpha(4) beta(2)-nicotinic receptors with 6 beta-carbomethoxynortropane (13) having the highest affinity, which was still 150-fold less than that of nicotine. 6 beta-carbomethoxynortropane (5) represents a potent muscarinic agonist with apparent selectivity toward M-2-receptors. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Rm 1A17, Bethesda, MD 20892 USA. NR 22 TC 18 Z9 22 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 4 PY 1998 VL 41 IS 12 BP 2047 EP 2055 DI 10.1021/jm9705115 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZT494 UT WOS:000074093500006 PM 9622546 ER PT J AU Cushman, M Casimiro-Garcia, A Hejchman, E Ruell, JA Huang, MJ Schaeffer, CA Williamson, K Rice, WG Buckheit, RW AF Cushman, M Casimiro-Garcia, A Hejchman, E Ruell, JA Huang, MJ Schaeffer, CA Williamson, K Rice, WG Buckheit, RW TI New alkenyldiarylmethanes with enhanced potencies as anti-HIV agents which act as non-nucleoside reverse transcriptase inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 HIV-1; BIOLOGICAL EVALUATION; NONNUCLEOSIDE INHIBITORS; SELECTIVE-INHIBITION; REPLICATION; DERIVATIVES; RESISTANCE; SERIES; RESOLUTION AB Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3 "-dichloro-4',4 "-dimethoxy-5', 5 "-bis(methoxycarbonyl)-6, (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 mu M but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations. C1 Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Lab Antiviral Drug Mechanisms, Frederick, MD 21702 USA. Frederick Res Ctr, So Res Inst, Virol Res Grp, Frederick, MD 21701 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmacal Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. FU NCI NIH HHS [N01-CM-17513, N01-CO-56000]; NIAID NIH HHS [R01-AI-36624] NR 49 TC 32 Z9 34 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUN 4 PY 1998 VL 41 IS 12 BP 2076 EP 2089 DI 10.1021/jm9800595 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA ZT494 UT WOS:000074093500009 PM 9622549 ER PT J AU Hyman, SE AF Hyman, SE TI Neurobiology - A new image for fear and emotion SO NATURE LA English DT Editorial Material C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Hyman, SE (reprint author), NIMH, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 11 TC 13 Z9 13 U1 0 U2 4 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD JUN 4 PY 1998 VL 393 IS 6684 BP 417 EP 418 DI 10.1038/30855 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZR842 UT WOS:000074020000025 PM 9623995 ER PT J AU Ridge, JP Di Rosa, F Matzinger, P AF Ridge, JP Di Rosa, F Matzinger, P TI A conditioned dendritic cell can be a temporal bridge between a CD4(+) T-helper and a T-killer cell SO NATURE LA English DT Article ID ANTIGEN-PRESENTING CELLS; INVIVO; TOLERANCE; INDUCTION; RESPONSES; ABSENCE; REQUIREMENTS; GENERATION; ACTIVATION; MECHANISM AB To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each other's presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both(1-3). This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum, We found that the three cells need not meet simultaneously but that the helper cell can first engage and 'condition' the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the longstanding paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals. C1 NIAID, Ghost Lab, Sect T Cell Tolerance & Memory, Lab Cellular & Mol Immunol,NIH, Bethesda, MD 20892 USA. RP Ridge, JP (reprint author), NIAID, Ghost Lab, Sect T Cell Tolerance & Memory, Lab Cellular & Mol Immunol,NIH, Bldg 4 Room 111,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jridge@atlas.niaid.nih.gov RI Di Rosa, Francesca/J-8116-2014 NR 30 TC 1654 Z9 1692 U1 3 U2 23 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD JUN 4 PY 1998 VL 393 IS 6684 BP 474 EP 478 DI 10.1038/30989 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ZR842 UT WOS:000074020000046 PM 9624003 ER PT J AU Zhang, HT O'Rourke, DM Zhao, HZ Murali, R Mikami, Y Davis, JG Greene, MI Qian, XL AF Zhang, HT O'Rourke, DM Zhao, HZ Murali, R Mikami, Y Davis, JG Greene, MI Qian, XL TI Absence of autophosphorylation site Y882 in the p185(neu) oncogene product correlates with a reduction of transforming potential SO ONCOGENE LA English DT Article DE p185(neu); tyrosine kinase; Y882; transformation ID EPIDERMAL GROWTH-FACTOR; TYROSINE KINASE-ACTIVITY; FACTOR-I RECEPTOR; NEU-ONCOGENE; SIGNAL-TRANSDUCTION; INTERMOLECULAR ASSOCIATION; CELL-TRANSFORMATION; RET PROTOONCOGENE; PROTEIN-KINASE; POINT MUTATION AB Autophosphorylation of type I receptor tyrosine kinases (RTKs) comprises one step in the signaling events mediated by erbB receptors such as p185(neu) and EGFR. Previous analysis of p185(neu) has indicated that there are at least five tyrosine autophosphorylation sites, Y882, Y1028, E1143, Y1226/7 and Y1253, of which Y882 might be important because of its location in the kinase activity domain. We have specifically analysed the effect of a Y882F (phenylalanine substituted for tyrosine at position 882) mutation in the enzymatic active domain. We also deleted the carboxyl terminal 122 amino acids which contained three other autophosphorylation sites (TAPstop) and combined mutants of that deletion with Y882F (Y882F/APstop). Both in vitro and in vivo transformation assays showed that substitution of tyrosine(882) by phenylalanine significantly decreased the transforming potential of activated, oncogenic p185(neu), although no significant difference in the total phosphotyrosine levels of the mutant proteins were observed. To analyse mitogenic signaling in response to ligand, the intracellular domains of p185(neu) and Y882F were fused with the extracellular domain of the EGF receptor. The proliferation of cells expressing these chimeric receptors was EGF-dependent, and cells expressing EGFR/Y882F chimeric receptors were less responsive to EGF stimulation than those expressing EGFR/neu receptors. In vitro kinase assays demonstrated that abolishing the autophosphorylation site Y882 diminished the enzymatic tyrosine kinase activity of p185(neu). These studies, taken together with the phenotypic inhibition observed with cells expressing Y882F, suggest that the tyrosine(882). residue may be important for p185(neu)-mediated transformation by affecting the enzymatic kinase function of the p185(neu) receptor. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Greene, MI (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 36th & Hamilton Walk, Philadelphia, PA 19104 USA. NR 42 TC 15 Z9 16 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 4 PY 1998 VL 16 IS 22 BP 2835 EP 2842 DI 10.1038/sj.onc.1201820 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA ZR544 UT WOS:000073988200002 PM 9671404 ER PT J AU Penninx, BWJH Guralnik, JM Ferrucci, L Simonsick, EM Deeg, DJH Wallace, RB AF Penninx, BWJH Guralnik, JM Ferrucci, L Simonsick, EM Deeg, DJH Wallace, RB TI Depressive symptoms and physical decline in community-dwelling older persons SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RISK-FACTORS; IMMUNE-SYSTEM; DISABILITY; PERFORMANCE; ANXIETY; FALLS; CARE AB Context.-Significant symptoms of depression are common in the older community-dwelling population. Although depressive symptoms and disability may commonly occur in the same person, whether depressive symptoms contribute to subsequent functional decline has not been elucidated, Objective.-To determine whether depressive symptoms in older persons increase the risk of subsequent decline in physical function as measured by objective performance-based tests. Design.-A 4-year prospective cohort study. Setting.-The communities of Iowa and Washington counties, Iowa. Participants.-A total of 1286 persons aged 71 years and older who completed a short battery of physical performance tests in 1988 and again 4 years later. Main Outcome Measures.-Baseline depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale. Physical performance tests included an assessment of standing balance, a timed 2.4-m (8-ft) walk, and a timed test of 5 repetitions of rising from a chair and sitting down. Results.-After adjustment far baseline performance score, health status, and sociodemographic factors, increasing levels of depressive symptoms were predictive of greater decline in physical performance over 4 years (odds ratio for decline in those with depressed mood vs those without, 1.55; 95% confidence interval [CI], 1.02-2.34), Even among those at the high end of the functional spectrum, who reported no disability, the severity of depressive symptoms predicted subsequent decline in physical performance (odds ratio for decline, 1.03; 95% CI, 1.00-1.08). Conclusions.-This study provides evidence that older persons who report depressive symptoms are at higher risk of subsequent physical decline, These results suggest that prevention or reduction of depressed mood could play a role in reducing functional decline in older persons. C1 NIA, Epidemiol Demogr & Biometry Program, Bethesda, MD 20892 USA. INRCA, Dept Geriatr, Florence, Italy. Vrije Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. Vrije Univ Amsterdam, Dept Psychiat, Amsterdam, Netherlands. Univ Iowa, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. RP Guralnik, JM (reprint author), NIA, Epidemiol Demogr & Biometry Program, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-02107, N01-AG-02106, N01-AG-0215] NR 42 TC 486 Z9 492 U1 3 U2 15 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 JUN 3 PY 1998 VL 279 IS 21 BP 1720 EP 1726 DI 10.1001/jama.279.21.1720 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA ZQ544 UT WOS:000073878700033 PM 9624025 ER PT J AU Chatfield, DC Szabo, A Brooks, BR AF Chatfield, DC Szabo, A Brooks, BR TI Molecular dynamics of staphylococcal nuclease: Comparison of simulation with N-15 and C-13 NMR relaxation data SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MAGNETIC-RESONANCE RELAXATION; MODEL-FREE APPROACH; DIFFRACTION STRUCTURE DETERMINATION; CONTEMPORARY ENZYMOLOGY; BACKBONE DYNAMICS; PROTEIN DYNAMICS; CRYSTAL-STRUCTURE; ACID COMPONENTS; FORCE-FIELD; SPECTROSCOPY AB Motional parameters for the atomic-level dynamics of staphylococcal nuclease are calculated from an Is-ns molecular dynamics simulation of the liganded enzyme and from a 3.75-ns simulation of the unliganded enzyme and compared with motional parameters calculated from C-13 and N-15 NMR relaxation data. Order parameters for backbone N-H and C-alpha-H bond vectors are on average in good agreement with experiment, indicating a similar degree of backbone flexibility. Somewhat greater flexibility is seen in the simulation of unliganded SNase, consistent with some experimental data. Alanine C-alpha-C-beta and C-alpha-H order parameters agree to within 5% for simulation while NMR finds the former to be 30% smaller than the latter; thus experimental reexamination of (CH3)-C-13 relaxation may be worthwhile. Average simulated and experimental rotation rates for the more rapidly rotating alanine and leucine methyl groups are in agreement. However, simulation predicts a much larger range of methyl rotation rates than is observed experimentally. Analysis of methyl rotations in a variety of environments indicates that the variation in the simulated methyl rotation rates is due to steric (van der Waals) interactions. C1 Florida Int Univ, Dept Chem, Miami, FL 33199 USA. NIDDKD, Struct Biol Lab, Div Comp Res & Technol, NIH, Bethesda, MD 20892 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Chatfield, DC (reprint author), Florida Int Univ, Dept Chem, Miami, FL 33199 USA. RI Szabo, Attila/H-3867-2012 NR 54 TC 93 Z9 93 U1 0 U2 14 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 JUN 3 PY 1998 VL 120 IS 21 BP 5301 EP 5311 DI 10.1021/ja972215n PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA ZT015 UT WOS:000074039100020 ER PT J AU Warren, JL Riley, GF Potosky, AL Klabunde, CN Richter, E Ballard-Barbash, R AF Warren, JL Riley, GF Potosky, AL Klabunde, CN Richter, E Ballard-Barbash, R TI Trends and outcomes of outpatient mastectomy in elderly women SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID MODIFIED RADICAL-MASTECTOMY; EARLY DISCHARGE; BREAST-CANCER; AMBULATORY SURGERY; SERVICES; CARE; ADVANTAGES; DECLINE; COSTS; STAY AB Background: Considerable public attention has focused on the use of outpatient mastectomy and has resulted in numerous legislative proposals to mandate a minimum hospital stay following mastectomy, To date, only limited scientific data are available regarding the use and the outcomes of outpatient mastectomy, The purpose of this study was to provide population-based information on trends and outcomes for outpatient mastectomy in elderly women. Methods: Medicare data for elderly women with fee-for-service coverage were examined for trends and regional variation in the use of outpatient mastectomy, Logistic regression was used to identify patient and provider characteristics associated with having an outpatient mastectomy, and outcomes were assessed by calculating the risk of being rehospitalized and the reasons for rehospitalization. Results: From 1986 through 1995, the proportion of mastectomies performed on an outpatient basis increased from virtually 0% to 10.8%, Outpatient mastectomies were more likely to be performed on women with no coexisting health problems in hospitals that were for-profit or non-teaching or in large metropolitan statistical areas. Women undergoing outpatient mastectomy had substantially higher rates of rehospitalization within 30 days than women with a 1-day stay in the hospital. Both groups had comparable rates of rehospitalization for complications definitely related to their surgery. The percentage of women who required rehospitalization was low, and the actual number of women rehospitalized was relatively small. Conclusions: We conclude that the risks from outpatient mastectomy are modest, although ongoing monitoring of outcomes and assessment of patient satisfaction are needed. C1 NCI, Appl Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. US Hlth Care Financing Adm, Baltimore, MD 21207 USA. RP Warren, JL (reprint author), NIH, Execut Plaza N,Rm 313, Bethesda, MD 20892 USA. NR 44 TC 50 Z9 50 U1 1 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 3 PY 1998 VL 90 IS 11 BP 833 EP 840 DI 10.1093/jnci/90.11.833 PG 8 WC Oncology SC Oncology GA ZR701 UT WOS:000074005100011 PM 9625171 ER PT J AU Scudiero, DA Monks, A Sausville, EA AF Scudiero, DA Monks, A Sausville, EA TI Cell line designation change: Multidrug-resistant cell line in the NCI anticancer screen SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID DRUG SCREEN C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, Div Canc Treatment Diag & Ctr, Bethesda, MD 20892 USA. RP Scudiero, DA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Box B,Bldg 432, Frederick, MD 21702 USA. NR 5 TC 74 Z9 74 U1 1 U2 1 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 3 PY 1998 VL 90 IS 11 BP 862 EP 862 PG 1 WC Oncology SC Oncology GA ZR701 UT WOS:000074005100016 PM 9625176 ER PT J AU Dall'Acqua, W Goldman, ER Lin, WH Teng, C Tsuchiya, D Li, HM Ysern, X Braden, BC Li, YL Smith-Gill, SJ Mariuzza, RA AF Dall'Acqua, W Goldman, ER Lin, WH Teng, C Tsuchiya, D Li, HM Ysern, X Braden, BC Li, YL Smith-Gill, SJ Mariuzza, RA TI A mutational analysis of binding interactions in an antigen-antibody protein-protein complex SO BIOCHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; DOUBLE-MUTANT CYCLES; EGG-WHITE LYSOZYME; FUNCTIONAL EPITOPE; CRYSTAL-STRUCTURES; FREE-ENERGY; INTERFACE; NEURAMINIDASE; FV; RENATURATION AB Alanine scanning mutagenesis, double mutant cycles, and X-ray crystallography were used to characterize the interface between the anti-hen egg white lysozyme (HEL) antibody D1.3 and HEL. Twelve out of the 13 nonglycine contact residues on HEL, as determined by the high-resolution crystal structure of the D1.3-HEL complex, were individually truncated to alanine. Only four positions showed a Delta Delta G (Delta G(mutant) - Delta G(wild-type)) of greater than 1.0 kcal/mol, with HEL residue Gln121 proving the most critical for binding (Delta Delta G = 2.9 kcal/mol). These residues form a contiguous patch at the periphery of the epitope recognized by D1.3. To understand how potentially disruptive mutations in the antigen are accommodated in the D1.3-HEL interface, we determined the crystal structure to 1.5 Angstrom resolution of the complex between D1.3 and HEL mutant Asp18 --> Ala. This mutation results in a Delta Delta G of only 0.3 kcal/mol, despite the loss of a hydrogen bond and seven van der Waals contacts to the Asp18 side chain. The crystal structure reveals that three additional water molecules ape stably incorporated in the antigen-antibody interface at the site of the mutation. These waters help fill the cavity created by the mutation and form part of a rearranged solvent network linking the two proteins. To further dissect the energetics of specific interactions in the D1.3-HEL interface, double mutant cycles were carried out to measure the coupling of 14 amino acid pairs, 10 of which are in direct contact in the crystal structure. The highest coupling energies, 2.7 and 2.0 kcal/mol, were measured between HEL residue Gln121 and D1.3 residues V(L)Trp92 and V(L)Tyr32, respectively. The interaction between Gln121 and V(L)Trp92 consists of three van der Waals contacts, while the interaction of Gln121 with V(L)Tyr32 is mediated by a hydrogen bond. Surprisingly, however, most cycles between interface residues in direct contact in the crystal structure showed no significant coupling. In particular, a number of hydrogen-bonded residue pairs were found to make no net contribution to complex stabilization. We attribute these results to accessibility of the mutation sites to water, such that the mutated residues exchange their interaction with each other to interact with water. This implies that the strength of the protein-protein hydrogen bonds in these particular cases is comparable to that of the protein-water hydrogen bonds they replace. Thus, the simple fact that two residues are in direct contact in a protein-protein interface cannot be taken as evidence that there necessarily exists a productive interaction between them. Rather, the majority of such contacts may be energetically neutral, as in the D1.3-HEL complex. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. Bowie State Univ, Bowie, MD 20715 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. OI Li, Hongmin/0000-0002-8684-5308 FU NIGMS NIH HHS [GM5280] NR 53 TC 122 Z9 122 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 2 PY 1998 VL 37 IS 22 BP 7981 EP 7991 DI 10.1021/bi980148j PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT215 UT WOS:000074061600008 PM 9609690 ER PT J AU Xie, L Schoenberg, M AF Xie, L Schoenberg, M TI Binding of SH1-SH2-modified myosin subfragment-1 to actin SO BIOCHEMISTRY LA English DT Article ID RABBIT PSOAS FIBERS; ADENOSINE-TRIPHOSPHATASE; PHENYLMALEIMIDE; CROSSBRIDGES; FORCE; SITE AB Myosin subfragment-1 (S1) was labeled with NPM in the presence of ATP or with pPDM in the presence of ADP at 0 degrees C, conditions which favor linking of maleimide groups to both Cys-707 (SH1) and Cys-697 (SH2). Unmodified S1 was removed by sedimentation with a small amount of F-actin, and the modified protein in the supernatant thoroughly dialyzed. The myosin high-salt EDTA and calcium ATPase activities of the isolated modified S1 were close to zero, suggesting nearly complete modification of SH1 and SH2. The binding of control and these modified myosins to actin was measured at 100 mM ionic strength using a co-sedimentation assay. In the presence of high MgATP concentration, control and NPM- and pPDM-reacted S1 all bind weakly to actin, with binding constants K-2 of 4.9, 2.2, and 1.9 x 10(4) M-1, respectively. In the absence of MgATP, the binding constant K-2 of pPDM-reacted S1 remains weak, 4.6 x 10(4) M-1, while that of NPM-reacted and control S1 becomes strong, 4.7 and 31 x 10(6) M-1, respectively. The binding constant for ATP to acto-NPM-reacted-S1 is similar to 2 x 10(4) M-1. Our data suggest that the binding of NPM-S1 to F-actin, in contrast to that of pPDM-S1, is ATP sensitive and can be quite strong at very low ATP concentration. They also suggest that while simple alkylation of SH1 and SH2 may be sufficient to inhibit myosin's ability to hydrolyze ATP, actual covalent linkage of SH1 and SH2 may be necessary to inhibit the weakly to strongly binding conformational change. C1 NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. RP Schoenberg, M (reprint author), NIAMSD, Phys Biol Lab, NIH, Bldg 6,Rm 408, Bethesda, MD 20892 USA. EM mark@lpb.niams.nih.gov NR 23 TC 7 Z9 7 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 2 PY 1998 VL 37 IS 22 BP 8048 EP 8053 DI 10.1021/bi980319k PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT215 UT WOS:000074061600016 PM 9609698 ER PT J AU Tiktopulo, EI Kajava, AV AF Tiktopulo, EI Kajava, AV TI Denaturation of type I collagen fibrils is an endothermic process accompanied by a noticeable change in the partial heat capacity SO BIOCHEMISTRY LA English DT Article ID MOLECULAR PACKING; INVITRO; MODEL; TROPOCOLLAGEN; TRANSITIONS; MICROFIBRIL; SCATTERING; STABILITY; MONOMERS AB Thermal transitions of typo I collagen fibrils were investigated by differential scanning calorimetry and spectrophotometry of turbidity within a wide range of external conditions. The advanced microcalorimeter allowed us to carry out the measurements at low concentrations of collagen (0.15-0.3 mg/mL), At these concentrations of collagen and under fibril-forming conditions, the melting curves display two pronounced heat adsorption peaks (at 40 and 55 degrees C). The low-temperature peak was assigned to the melting of monomeric collagen, while the high-temperature peak was assigned to the denaturation of collagen fibrils. It was shown that the denaturation of fibrils, in contrast to the monomeric collagen, is accompanied by a noticeable change in the partial specific heat capacity. Surprisingly, comparison of the collagen calorimetric curves in the fibril-forming and nonforming conditions revealed that Delta C-p of fibril denaturation is caused by a decrease in the C-p of collagen at premelting temperatures. This suggests the existence of an intermediate structural state of collagen in a transparent solution preceding fibril formation. Our study also shows thar collagen fibrils formed prior to heating have thermodynamic parameters different from those of fibrils formed and denatured during heating in the calorimeter. Analysis of the data allowed us to determine the denaturation enthalpy of the mature fibrils and to conclude that the enthalpy plays a more important role in fibril stabilization than was previously assumed. The observed large Delta C-p value of fibril denaturation as well as the difference between thermodynamic parameters of the mature and newly formed fibrils is readily explained by the presence of water molecules in the fibril structure. C1 Russian Acad Sci, Inst Prot Res, Pushchino 142292, Russia. Swiss Inst Expt Canc Res, CH-1066 Epalinges, Lausanne, Switzerland. RP Kajava, AV (reprint author), NIH, Ctr Mol Modeling, DCRT, Bldg 12A,Room 2011, Bethesda, MD 20892 USA. EM akjava@isrec-sun1.unil.ch RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 NR 43 TC 50 Z9 53 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 2 PY 1998 VL 37 IS 22 BP 8147 EP 8152 DI 10.1021/bi980360n PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT215 UT WOS:000074061600028 PM 9609710 ER PT J AU Broocks, A Pigott, TA Hill, JL Canter, S Grady, TA L'Heureux, F Murphy, DL AF Broocks, A Pigott, TA Hill, JL Canter, S Grady, TA L'Heureux, F Murphy, DL TI Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive-compulsive disorder(OCD): behavioral and biological results SO PSYCHIATRY RESEARCH LA English DT Article DE obsessive-compulsive disorder; meta-chlorophenylpiperazine hydrochloride; ondansetron; anxiety; cortisol; norepinephrine; serotonin ID M-CHLOROPHENYLPIPERAZINE; 5-HT3 RECEPTORS; META-CHLOROPHENYLPIPERAZINE; RECOGNITION SITES; SEROTONERGIC RESPONSIVITY; CLOMIPRAMINE TREATMENT; HEALTHY-VOLUNTEERS; OCD PATIENTS; RAT-BRAIN; NEUROENDOCRINE AB Obsessive-compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT3 receptor antagonist, the present study was undertaken to investigate 5-HT3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP + placebo, m-CPP + ondansetron, ondansetron + placebo and placebo + placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIMH, Clin Sci Lab, Sect Clin Neuropharmacol, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Psychiat, Galveston, TX 77550 USA. Natl Inst Drug Abuse, Rockville, MD USA. Duke Univ, Sch Med, Dept Psychiat, Durham, NC USA. RP Broocks, A (reprint author), Univ Lubeck, Psychiat Klin Med, Ratzeburger Allee 160, D-23538 Lubeck, Germany. NR 45 TC 28 Z9 29 U1 1 U2 2 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 JUN 2 PY 1998 VL 79 IS 1 BP 11 EP 20 DI 10.1016/S0165-1781(98)00029-8 PG 10 WC Psychiatry SC Psychiatry GA ZY660 UT WOS:000074646400002 PM 9676822 ER PT J AU Weerda, HG Gamberger, TI Siegner, A Gjuric, M Tamm, ER AF Weerda, HG Gamberger, TI Siegner, A Gjuric, M Tamm, ER TI Effects of transforming growth factor-beta 1 and basic fibroblast growth factor on proliferation of cell cultures derived from human vestibular nerve schwannoma SO ACTA OTO-LARYNGOLOGICA LA English DT Article DE neurinoma; transforming growth factor-beta 1; basic fibroblast growth factor; cell culture ID FACTOR-BETA; GROWTH-FACTOR-BETA-1; STIMULATION; EXPRESSION; MITOGENS; GENE AB The influence of transforming growth factor-beta 1 (TGF-beta 1) and basic fibroblast growth factor (bFGF) on growth of cell cultures derived from unilateral vestibular nerve schwannomas was investigated. Cell cultures were initiated from 9 schwannomas and characterized immunocytochemically with antibodies against S-100 and type IV collagen. The effects of TGF-beta 1 and bFGF on DNA synthesis in chemically defined serum-free medium were assessed by measuring the incorporation of 5-bromo-2'-deoxy-uridine (BRDU) into cellular DNA. Cell proliferation was evaluated with an electronic cell counter. Reverse transcription polymerase chain reaction (RT-PCR) was performed using oligonucleotide primers specific for TGF-beta 1 and TGF-beta 2. TGF-beta 1 stimulated DNA synthesis in a dose dependent manner. Maximal stimulation was observed at a concentration of 1 ng/ml, which induced a nearly 2-fold increase in DNA content. This effect was not seen when TGF-beta 1 was added in the presence of neutralizing antibodies. In addition, antibodies against TGF-beta 1 significantly reduced DNA synthesis in control cultures without supplemented exogenous growth factors, bFGF alone had no significant effects on DNA synthesis. In contrast, when TGF-beta 1 and bFGF were added together, the mitogenic response was much greater than produced by TGF-beta 1 alone. RT-PCR showed that the cultured cells expressed mRNA for both TGF-beta 1 and TGF-beta 2. We hypothesize that TGF-beta 1 is an autocrine growth factor for human vestibular nerve schwannomas in culture. A similar mechanism might be involved in the growth of these tumors in situ. C1 Univ Erlangen Nurnberg, Dept Anat, D-8520 Erlangen, Germany. Univ Erlangen Nurnberg, Dept Otorhinolaryngol, D-8520 Erlangen, Germany. RP Tamm, ER (reprint author), NEI, Mol & Dev Biol Lab, Bldg 6 Room 204,6 Ctr Dr,MSC 2730, Bethesda, MD 20892 USA. NR 25 TC 19 Z9 19 U1 0 U2 2 PU SCANDINAVIAN UNIVERSITY PRESS PI OSLO PA PO BOX 2959 TOYEN, JOURNAL DIVISION CUSTOMER SERVICE, N-0608 OSLO, NORWAY SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD JUN PY 1998 VL 118 IS 3 BP 337 EP 343 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA ZT564 UT WOS:000074100500008 PM 9655207 ER PT J AU Heishman, SJ Henningfield, JE Kendler, KS Le Houezec, J Malin, DH Pomerleau, OF Schneider, NG AF Heishman, SJ Henningfield, JE Kendler, KS Le Houezec, J Malin, DH Pomerleau, OF Schneider, NG TI Society for research on nicotine and tobacco SO ADDICTION LA English DT Editorial Material AB The goal of the third annual scientific conference of the Society for Research on Nicotine and Tobacco was to provide a forum for the exchange of information across the spectrum of nicotine and tobacco research. Five symposia covered the following topics: animal and human models of nicotine dependence, use of nicotine as a therapeutic agent in disorders associated with ageing and psychopathology, public health strategies to reduce morbidity and mortality caused by smoking by reducing exposure to tobacco smoke, new pharmacological treatments and treatment combinations that are being tested for smoking cessation and the integration of behavioral and molecular genetic approaches to explain nicotine dependence. The genetic epidemiology of smoking initiation and nicotine dependence was the topic of an invited address. The findings presented at the conference clearly demonstrated the wide range of nicotine and tobacco research programs. C1 NIDA, Addict Res Ctr, Clin Pharmacol Branch, Intramural Res Program, Baltimore, MD 21224 USA. Pinney Associates Inc, Bethesda, MD USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Hop La Pitie Salpetriere, CNRS URA 1957, Paris, France. Univ Houston Clear Lake, Houston, TX 77058 USA. Univ Michigan, Ann Arbor, MI 48109 USA. VA Med Ctr, Los Angeles, CA USA. RP Heishman, SJ (reprint author), NIDA, Addict Res Ctr, Clin Pharmacol Branch, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sheish@irp.nida.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 1998 VL 93 IS 6 BP 907 EP 910 DI 10.1046/j.1360-0443.1998.93690712.x PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA ZV421 UT WOS:000074302900012 PM 9766927 ER PT J AU Pickworth, WB Fant, RV Chenoweth, RNM Rohrer, M Stephenson, K AF Pickworth, WB Fant, RV Chenoweth, RNM Rohrer, M Stephenson, K TI Effects of a smoking cessation product (Take Out?) on nicotine delivery and smoking characteristics SO ADDICTION LA English DT Meeting Abstract C1 Carleton Coll, NIDA, Intramural Res Program, Northfield, MN 55057 USA. Coll Notre Dame, Belmont, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARFAX PUBL CO PI ABINGDON PA PO BOX 25, ABINGDON, OXFORDSHIRE, ENGLAND OX14 3UE SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 1998 VL 93 IS 6 BP 920 EP 920 PG 1 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA ZV421 UT WOS:000074302900049 ER PT J AU Radzius, A Sosnow, K Henning-Field, J Gazaway, P Svikis, D AF Radzius, A Sosnow, K Henning-Field, J Gazaway, P Svikis, D TI Availability of nicotine and cotinine to fetus of smoking mothers SO ADDICTION LA English DT Meeting Abstract C1 NIDA, DIR, NIH, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Pinney Associates, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARFAX PUBL CO PI ABINGDON PA PO BOX 25, ABINGDON, OXFORDSHIRE, ENGLAND OX14 3UE SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 1998 VL 93 IS 6 BP 920 EP 920 PG 1 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA ZV421 UT WOS:000074302900051 ER PT J AU Shoaib, M AF Shoaib, M TI The glutamate release inhibitor riluzole prevents the development but not the expression of behavioural sensitization to nicotine in rats SO ADDICTION LA English DT Meeting Abstract C1 Inst Psychiat, Sect Behav Pharmacol, London, England. NIDA, Addict Res Ctr, Preclin Pharmacol Lab, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARFAX PUBL CO PI ABINGDON PA PO BOX 25, ABINGDON, OXFORDSHIRE, ENGLAND OX14 3UE SN 0965-2140 J9 ADDICTION JI Addiction PD JUN PY 1998 VL 93 IS 6 BP 922 EP 922 PG 1 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA ZV421 UT WOS:000074302900057 ER PT J AU Shearer, GM Clerici, M AF Shearer, GM Clerici, M TI Cytokine profiles in HIV type 1 disease and protection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROGRAMMED CELL-DEATH; T-CELLS; HELPER ACTIVITY; INFECTION; AIDS; DYSFUNCTION; INDIVIDUALS; INTERLEUKIN-2; PATHOGENESIS C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Milan, Cattedra Immunol, I-20157 Milan, Italy. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 40 TC 33 Z9 33 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN PY 1998 VL 14 SU 2 BP S149 EP S152 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA ZX734 UT WOS:000074549300004 PM 9672232 ER PT J AU Gonzales, RA McNabb, J Yim, HJ Ripley, T Bungay, PM AF Gonzales, RA McNabb, J Yim, HJ Ripley, T Bungay, PM TI Quantitative microdialysis of ethanol in rat striatum SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE microdialysis; mathematical model; rat; brain; clearance ID INDUCED DOPAMINE RELEASE; FREELY MOVING RATS; NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; BLOOD-FLOW; BRAIN; WATER; PERMEABILITY; SEROTONIN; GLUTAMATE AB We have applied a steady-state theory of microdialysis to characterize the diffusion of ethanol through a microdialysis membrane and through rat striatum. Quantitative characterization required measurement of in vitro and in vivo extraction fractions for ethanol and determination of the clearance of ethanol from brain tissue during steady-state perfusion through a microdialysis probe. Extraction fraction of ethanol was determined in vitro by perfusing a known concentration of ethanol through probes immersed in water at 37 degrees C with stirring. The in vitro extraction fraction yielded a probe permeability value of 0.046 +/- 0.004 cm/min that is comparable with an estimate from published measurements for similar dialysis membranes. The in vivo extraction fraction was determined for probes placed in the striatum. Clearance of ethanol and a brain slice concentration profile of ethanol were determined by measurement of the amount of ethanol remaining in the brain tissue during steady-state perfusion of the probe. Steady state was achieved within 10 min after beginning the ethanol perfusion in vivo, and the extraction fraction was not altered by sedation of the Pat with pentobarbital. The tissue concentration profile was symmetrical around the probe hack, and ethanol was detected 1 mm from the probe. The experimental clearance rate constant value obtained for ethanol (2.0 +/- 0.3 min(-1)) was higher than that expected for removal solely by loss to the blood. The tissue diffusivity for ethanol, D,, derived from the experimental measurements was 1.2 +/- 0.2 x 10(-5) cm(2)/seo. This value is greater than expected for interstitial diffusion, suggesting a substantial contribution by transcellular diffusion of ethanol as well. The predicted tissue concentration profile bad a higher peak value and did not extend into the tissue (0.5 mm) as much as the experimental profile (1 mm), although there was reasonable agreement between experiment and theory. Our quantitative characterization of the microdialysis behavior of ethanol in brain provides a framework for interpretation of brain microdialysis experiments using ethanol by supplying, inter alia, a means for estimating the ethanol concentration achieved in the tissue volume being sampled by the probe. C1 Univ Texas, Coll Pharm, Inst Neurosci, Neuropharmacol Program, Austin, TX 78712 USA. NIH, Biomed Engn & Instrumentat Program, Bethesda, MD 20892 USA. RP Gonzales, RA (reprint author), Univ Texas, Coll Pharm, Inst Neurosci, Neuropharmacol Program, Austin, TX 78712 USA. FU NIAAA NIH HHS [AA08484, AA00147] NR 32 TC 18 Z9 18 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 1998 VL 22 IS 4 BP 858 EP 867 DI 10.1097/00000374-199806000-00014 PG 10 WC Substance Abuse SC Substance Abuse GA ZV333 UT WOS:000074294100016 PM 9660313 ER PT J AU Birman, D AF Birman, D TI Biculturalism and perceived competence of Latino immigrant adolescents SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE biculturalism; acculturation; self-competence; adjustment; immigrants; Latinos; Hispanics; adolescents ID MEXICAN-AMERICAN ADOLESCENTS; PSYCHOLOGICAL DISTRESS; UNITED-STATES; YOUNG-ADULTS; ACCULTURATION; ADJUSTMENT; IDENTIFICATION; HISPANICS; CHILDREN; SCALE AB The present study investigated acculturation to the Hispanic and American cultures and self-perceptions of competence among 123 Latino immigrant adolescents. The study tested a contextual model of biculturalism by examining whether different acculturation styles predicted perceived competence in life spheres with different cultural demands. Perceived competence was assessed using Hal-ter's (1988) Self-Perceptions of Competence Profile for Adolescents for the life spheres of school, peers (both Latino and non-Latino), and global self-worth. In addition, an analogous scale to assess perceptions of competence in the family was constructed for that sphere. The study found some support for a contextual model of acculturation. Acculturation to American culture predicted positive self-perceptions of competence with American peers, while acculturation to Hispanic culture predicted positive self-perceptions of competence with Latino peers. Perceived family competence, however was predicted by acculturation to American rather than Hispanic culture. Results with respect to biculturalism are tentative, with a trend relating biculturalism to positive self-perceptions of global self-worth. However because,many of the conditions stipulated by the model were not met, results with respect to biculturalism raise questions about current approaches to operationalizing the construct. C1 NIMH, Bethesda, MD 20892 USA. RP Birman, D (reprint author), Room 17C-14,5600 Fishers Lane, Rockville, MD 20857 USA. RI Birman, Dina/E-4628-2015 OI Birman, Dina/0000-0003-2513-3048 NR 49 TC 68 Z9 71 U1 1 U2 7 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD JUN PY 1998 VL 26 IS 3 BP 335 EP 354 DI 10.1023/A:1022101219563 PG 20 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA 112VF UT WOS:000075514800001 PM 9726112 ER PT J AU Lee, ET Cowan, LD Welty, TK Sievers, M Howard, WJ Oopik, A Wang, WY Yeh, JL Devereux, RB Rhoades, ER Fabsitz, RR Go, O Howard, BV AF Lee, ET Cowan, LD Welty, TK Sievers, M Howard, WJ Oopik, A Wang, WY Yeh, JL Devereux, RB Rhoades, ER Fabsitz, RR Go, O Howard, BV TI All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45-74 years, 1984-1988 - The Strong Heart Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; Indians, North American; mortality ID ACUTE MYOCARDIAL-INFARCTION; NEW-YORK STATE; DIABETES-MELLITUS; PIMA-INDIANS; RISK-FACTORS; TRENDS; FRAMINGHAM; PREVALENCE; FAILURE; PROGRAM AB Community mortality surveillance for 1984-1988 was conducted by researchers of the Strong Heart Study, which examined the incidence, prevalence, and risk factors of cardiovascular disease in three American Indian populations, aged 45-74 years, in Arizona, Oklahoma, and South/North Dakota. All-cause and cardiovascular disease mortality rates were determined through the use of death certificate data. Cardiovascular disease deaths were confirmed by independent systematic review of medical records. In all three populations, men had higher all-cause and cardiovascular disease mortality rates than did women. Oklahoma exhibited slightly lower 5-year, age-adjusted, all-cause mortality (96/1,000) than did Arizona (107/1,000) and South/North Dakota (114/1,000). The leading cause of death among both sexes in Oklahoma and in South/North Dakota was cardiovascular disease. Diabetes mellitus led among Arizona women. The other major causes of death were cancer, liver disease including cirrhosis, and injury. When compared with the rates in each state, average annual all-cause mortality rates were higher for the American Indian populations in almost every age group. The all-cause annual mortality rates in the three Indian populations were close to rates in the US black population and higher than the rates of the entire US population and of US whites. This trend was amplified in the 45- to 64-year age group. Only in the 65- to 74-year age group did mortality rates in the Indian population approach those of the US population. Cardiovascular disease mortality rates were close to the US averages in Arizona and Oklahoma, but they were more than two times higher in South/North Dakota among those between 45 and 64 years of age. Thus, American Indians in Arizona, Oklahoma, and South/North Dakota exhibit high all-cause mortality rates. In particular, the South/North Dakota population cardiovascular disease death rate appears to present a potential target for community-based programs to intervene on known risk factors to promote healthy lifestyles. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Biostat & Epidemiol, Oklahoma City, OK 73190 USA. Aberdeen Area Indian Hlth Serv, Program Epidemiol, Rapid City, SD USA. NIDDKD, NIH, Phoenix, AZ USA. Medlant Res Inst, Washington, DC USA. Cornell Med Ctr, Dept Med, New York, NY USA. Univ Oklahoma, Hlth Sci Ctr, Coll Med, Oklahoma City, OK 73190 USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. RP Lee, ET (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, POB 26091, Oklahoma City, OK 73190 USA. FU NHLBI NIH HHS [U01HL 41642, U01HL 41652, U01HL 41654] NR 27 TC 116 Z9 116 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 BP 995 EP 1008 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZQ373 UT WOS:000073854700001 PM 9620042 ER PT J AU Modan, B Ron, E Lerner-Geva, L Blumstein, T Menczer, J Rabinovici, J Oelsner, G Freedman, L Mashiach, S Lunenfeld, B AF Modan, B Ron, E Lerner-Geva, L Blumstein, T Menczer, J Rabinovici, J Oelsner, G Freedman, L Mashiach, S Lunenfeld, B TI Cancer incidence in a cohort of infertile women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; endometrial neoplasms; infertility; ovarian neoplasms; ovulation induction ID STATES CASE-CONTROL; EPITHELIAL OVARIAN-CANCER; COLLABORATIVE ANALYSIS; FOLLICULAR STIMULATION; GONADOTROPIN THERAPY; ENDOMETRIAL CANCER; PUBLICATION BIAS; RISK-FACTORS; WHITE WOMEN; CARCINOMA AB Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval(CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded. C1 Chaim Sheba Med Ctr, Dept Clin Epidemiol, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Stanley Steyer Inst Canc Epidemiol & Res, IL-69978 Tel Aviv, Israel. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Edith Wolfson Med Ctr, Dept Gynecol, Holon, Israel. Chaim Sheba Med Ctr, Dept Obstet & Gynecol, IL-52621 Tel Hashomer, Israel. Bar Ilan Univ, Ramat Gan, Israel. RP Modan, B (reprint author), Chaim Sheba Med Ctr, Dept Clin Epidemiol, IL-52621 Tel Hashomer, Israel. FU NIMHD NIH HHS [263-MD-335190] NR 35 TC 165 Z9 176 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 BP 1038 EP 1042 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZQ373 UT WOS:000073854700006 PM 9620047 ER PT J AU Harris, TB Langlois, JA Kiel, DP Hannan, MT Roubenoff, R AF Harris, TB Langlois, JA Kiel, DP Hannan, MT Roubenoff, R TI Re: "Epidemiology of insulin-like growth factor-I in elderly men and women. The Rancho Bernardo Study" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID HEALTHY OLDER MEN; PHYSICAL-ACTIVITY; HORMONE; AGE C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Harvard Univ, Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Harris, TB (reprint author), NIA, Epidemiol Demog & Biometry Program, Gateway Bldg,3C-309, Bethesda, MD 20892 USA. OI Kiel, Douglas/0000-0001-8474-0310 NR 13 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 BP 1093 EP 1094 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZQ373 UT WOS:000073854700013 PM 9620054 ER PT J AU Baird, DD Schectman, JM Dixon, D Sandler, DP Hill, MC AF Baird, DD Schectman, JM Dixon, D Sandler, DP Hill, MC TI African Americans at higher risk than whites for uterine fibroids: Ultrasound evidence. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 13 Z9 13 U1 0 U2 2 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 358 BP S90 EP S90 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800358 ER PT J AU Butler, LM Potischman, NA Brinton, LA AF Butler, LM Potischman, NA Brinton, LA TI Menstrual risk factors and early-onset breast cancer. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Environm Epidemiol Branch, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 360 BP S90 EP S90 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800359 ER PT J AU Cooper, GS Schildkraut, JM Whittemore, AS AF Cooper, GS Schildkraut, JM Whittemore, AS TI Pregnancy regency, menopausal status, and risk of ovarian cancer. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 357 BP S90 EP S90 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800356 ER PT J AU Cooper, GS Ephross, SA Weinberg, CR Baird, DD Whelan, EA Sandler, DP AF Cooper, GS Ephross, SA Weinberg, CR Baird, DD Whelan, EA Sandler, DP TI Menstrual and reproductive risk factors for ischemic heart disease. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 200 BP S50 EP S50 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800201 ER PT J AU Evans, JC Larson, MG Levy, D AF Evans, JC Larson, MG Levy, D TI Cigarette smoking and myocardial infarction in the elderly: Two explanations for diminishing risk over age 65. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NHLBI, Framingham Study, Framingham, MA 01702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 275 BP S69 EP S69 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800274 ER PT J AU Garcia-Closas, M Rothman, N Lubin, J AF Garcia-Closas, M Rothman, N Lubin, J TI Impact of misclassification in studies of gene-environment interaction. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 260 BP S65 EP S65 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800260 ER PT J AU Hartman, T Dorgan, J Taylor, PR Heinonen, OP Chandler, DW Galmarini, M Tangrea, J Virtamo, J Albanes, D AF Hartman, T Dorgan, J Taylor, PR Heinonen, OP Chandler, DW Galmarini, M Tangrea, J Virtamo, J Albanes, D TI Serum vitamin E as a predictor of serum androgens and estrogens in older men. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 2 Z9 2 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 208 BP S52 EP S52 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800209 ER PT J AU Hoffman, HJ Reed, GW Kol, CW Tambs, K Borchgrevink, H AF Hoffman, HJ Reed, GW Kol, CW Tambs, K Borchgrevink, H TI Hearing loss and aging: A population-based study of adults (> 20 years old) in Nord Trondelag county, Norway SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIDCD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Prevent Med, Nashville, TN 37232 USA. Natl Inst Publ Hlth, N-0462 Oslo, Norway. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 5 BP S2 EP S2 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800006 ER PT J AU Hoppin, JA Tolbert, PE Holly, EA Taylor, JA AF Hoppin, JA Tolbert, PE Holly, EA Taylor, JA TI Potential bias in use of tumor blocks in molecular epidemiology studies. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Calif San Francisco, San Francisco, CA 94109 USA. Emory Univ, Atlanta, GA 30322 USA. RI Tolbert, Paige/A-5676-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 137 BP S35 EP S35 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800138 ER PT J AU Ishii, EK MacTurk, RH Hoffman, HJ Reed, GW AF Ishii, EK MacTurk, RH Hoffman, HJ Reed, GW TI Audiometric test-retest reliability for children in NHANES III. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIDCD, Epidemiol Branch, NIH, Bethesda, MD 20852 USA. Vanderbilt Univ, Dept Prevent Med, Nashville, TN 37232 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 51 BP S13 EP S13 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800051 ER PT J AU Kamel, F Umbach, DM Hu, H Munsat, TL Shefner, JM Sandler, DP AF Kamel, F Umbach, DM Hu, H Munsat, TL Shefner, JM Sandler, DP TI Lead exposure and amyotrophic lateral sclerosis (ALS). SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 298 BP S75 EP S75 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800299 ER PT J AU Keifer, MC Zahm, SH AF Keifer, MC Zahm, SH TI Comparison of a traditional questionnaire with an icon/calendar-based questionnaire to assess occupational history. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Occupat Med Program, Dept Med, Seattle, WA 98195 USA. Univ Washington, Occupat Med Program, Dept Environm Hlth, Seattle, WA 98195 USA. NCI, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 88 BP S22 EP S22 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800089 ER PT J AU Nalluswami, K Ko, CW Hou, JR Hoffman, HJ AF Nalluswami, K Ko, CW Hou, JR Hoffman, HJ TI Very low birth weight (VLBW) infants are at increased risk for frequent ear infection. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIDCD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 63 BP S16 EP S16 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800063 ER PT J AU Pietinen, P Alfthan, G Ripatti, S Albanes, D Virtamo, J AF Pietinen, P Alfthan, G Ripatti, S Albanes, D Virtamo, J TI Methylmercury exposure and risk of myocardial infarction. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Natl Publ Hlth Inst, Helsinki, Finland. NCI, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 3 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 280 BP S70 EP S70 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800280 ER PT J AU Sandler, DP Shore, DL Solansky, I Rericha, V Hnizdo, E Sram, R AF Sandler, DP Shore, DL Solansky, I Rericha, V Hnizdo, E Sram, R TI Lung cancer incidence in Czech uranium miners with low-level radon exposure. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. RI Sram, Radim/H-2455-2014 OI Sram, Radim/0000-0003-4256-3816 NR 0 TC 1 Z9 1 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 342 BP S86 EP S86 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800342 ER PT J AU Shu, XO Wen, W Buckley, J Brondum, J Linet, M Robison, L AF Shu, XO Wen, W Buckley, J Brondum, J Linet, M Robison, L TI Lifestyle and risk of acute lymphocytic leukemia in children SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Univ S Carolina, Columbia, SC 29203 USA. Univ So Calif, Los Angeles, CA 90033 USA. Univ Minnesota, Minneapolis, MN 55455 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 37 BP S10 EP S10 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800038 ER PT J AU Sinha, R Kulldorff, M Chow, WH Denobile, J Lang, NP Kadlubar, FF Hoover, RN Rothman, N AF Sinha, R Kulldorff, M Chow, WH Denobile, J Lang, NP Kadlubar, FF Hoover, RN Rothman, N TI Heterocyclic amines (HCAs), metabolic variation and risk of colorectal adenomas. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Bethesda, MD 20892 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RI Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 258 BP S65 EP S65 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800259 ER PT J AU Stolzenberg-Solomon, RZ Albanes, D Hartman, T Rautalahti, M Sehlub, J Tangrea, J Nieto, FJ Taylor, P AF Stolzenberg-Solomon, RZ Albanes, D Hartman, T Rautalahti, M Sehlub, J Tangrea, J Nieto, FJ Taylor, P TI Pancreatic cancer risk and methyl-group availability indicators. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 34 BP S9 EP S9 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800036 ER PT J AU Tseng, M Weinberg, CR Longnecker, MP AF Tseng, M Weinberg, CR Longnecker, MP TI Estimation of adjusted population attributable risk (PAR) using effect estimates from meta-analysis. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 319 BP S80 EP S80 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800318 ER PT J AU Velie, E Schatzkin, A Li, L Kulldorff, M Troisi, R Albanes, D Schairer, C AF Velie, E Schatzkin, A Li, L Kulldorff, M Troisi, R Albanes, D Schairer, C TI Dietary fat and breast cancer: The breast cancer detection demonstration project follow-up study, 1987-95. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Rockville, MD 20852 USA. RI Kulldorff, Martin/H-4282-2011; Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 147 BP S37 EP S37 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800147 ER PT J AU Weinberg, CR Umbach, DM AF Weinberg, CR Umbach, DM TI Pooled exposure assessment: An efficient strategy for case-control studies that must rely on an expensive assay. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 281 BP S71 EP S71 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800281 ER PT J AU Woodson, K Albanes, D Virtamo, J Taylor, PR AF Woodson, K Albanes, D Virtamo, J Taylor, PR TI The association between alcohol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 1998 VL 147 IS 11 SU S MA 35 BP S9 EP S9 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA ZR584 UT WOS:000073992800035 ER PT J AU Greenhouse, S Rankin, T Dean, J AF Greenhouse, S Rankin, T Dean, J TI Genetic causes of female infertility: Targeted mutagenesis in mice SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; ZONA-PELLUCIDA; MUTATION; AMENORRHEA C1 NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Obstet & Gynecol, Washington, DC USA. RP Greenhouse, S (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bldg 6,Room B1-26,6 Ctr Dr,MSC 2715, Bethesda, MD 20892 USA. NR 24 TC 9 Z9 9 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 1998 VL 62 IS 6 BP 1282 EP 1287 DI 10.1086/301893 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ZU224 UT WOS:000074174700003 PM 9585621 ER PT J AU Stephens, JC Reich, DE Goldstein, DB Shin, HD Smith, MW Carrington, M Winkler, C Huttley, GA Allikmets, R Schriml, L Gerrard, B Malasky, M Ramos, MD Morlot, S Tzetis, M Oddoux, C di Giovine, FS Nasioulas, G Chandler, D Aseev, M Hanson, M Kalaydjieva, L Glavac, D Gasparini, P Kanavakis, E Claustres, M Kambouris, M Ostrer, H Duff, G Baranov, V Sibul, H Metspalu, A Goldman, D Martin, N Duffy, D Schmidtke, J Estivill, X O'Brien, SJ Dean, M AF Stephens, JC Reich, DE Goldstein, DB Shin, HD Smith, MW Carrington, M Winkler, C Huttley, GA Allikmets, R Schriml, L Gerrard, B Malasky, M Ramos, MD Morlot, S Tzetis, M Oddoux, C di Giovine, FS Nasioulas, G Chandler, D Aseev, M Hanson, M Kalaydjieva, L Glavac, D Gasparini, P Kanavakis, E Claustres, M Kambouris, M Ostrer, H Duff, G Baranov, V Sibul, H Metspalu, A Goldman, D Martin, N Duffy, D Schmidtke, J Estivill, X O'Brien, SJ Dean, M TI Dating the origin of the CCR5-Delta 32 AIDS-resistance allele by the coalescence of haplotypes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CYSTIC-FIBROSIS MUTATION; CHEMOKINE RECEPTOR GENE; MITOCHONDRIAL-DNA; HIV-1 INFECTION; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; MODERN HUMANS; HUMAN GENOME; POPULATIONS; MIP-1-ALPHA AB The CCR5-Delta 32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a dine of CCR5-Delta 32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta 32-containing ancestral haplotype to be similar to 700 years ago, with an estimated range of 275-1,875 years. The geographic dine of CCR5-Delta 32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g., an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Hosp Duran Reynals, IRO, Dept Mol Genet, Barcelona, Spain. Med Hsch Hannover, Inst Humangenet, Hannover, Germany. Univ Athens, St Sophias Childrens Hosp, Dept Pediat 1, GR-10679 Athens, Greece. Univ Athens, Sch Med, Dept Hyg & Epidemiol, Natl Retrovirus Reference Ctr, GR-10679 Athens, Greece. NYU, Med Ctr, Human Genet Program, Dept Pediat, New York, NY 10016 USA. Univ Sheffield, Dept Mol & Med Genet, Sheffield, S Yorkshire, England. Edith Cowan Univ, Ctr Human Genet, Perth, WA, Australia. Russian Acad Med Sci, Inst Obstet & Gynecol, St Petersburg, Russia. Univ Ljubljana, Lab Mol Pathol, Ljubljana, Slovenia. IRCCS, CSS Hosp, Natl Med Genet Serv, San Giovanni Rotondo, Italy. CNRS, UPR 9008, Biochim Genet Lab, F-9008 Montpellier, France. King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. Tartu State Univ, Estonian Bioctr, EE-202400 Tartu, Estonia. Tartu State Univ, Childrens Hosp, EE-202400 Tartu, Estonia. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. Royal Brisband Hosp, Queensland Inst Med Res, Herston, Qld, Australia. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov RI LABO, U827/A-8632-2008; Smith, Michael/B-5341-2012; Estivill, Xavier/E-2957-2012; Dean, Michael/G-8172-2012; Estivill, Xavier/A-3125-2013; Huttley, Gavin/G-5169-2015; Duffy, David/B-7392-2013; Goldman, David/F-9772-2010 OI Martin, Nicholas/0000-0003-4069-8020; Dean, Michael/0000-0003-2234-0631; Estivill, Xavier/0000-0002-0723-2256; Huttley, Gavin/0000-0001-7224-2074; Duffy, David/0000-0001-7227-632X; Goldman, David/0000-0002-1724-5405 NR 64 TC 324 Z9 338 U1 5 U2 50 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 1998 VL 62 IS 6 BP 1507 EP 1515 DI 10.1086/301867 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA ZU224 UT WOS:000074174700029 PM 9585595 ER PT J AU Sidransky, E Burgess, C Ikeuchi, T Lindblad, K Long, RT Philibert, RA Rapoport, J Schalling, M Tsuji, S Ginns, EI AF Sidransky, E Burgess, C Ikeuchi, T Lindblad, K Long, RT Philibert, RA Rapoport, J Schalling, M Tsuji, S Ginns, EI TI A triplet repeat on 17q accounts for most expansions detected by the repeat-expansion-detection technique SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter ID CHILDHOOD-ONSET SCHIZOPHRENIA; EXPANDED CAG REPEATS; DISORDER C1 NIMH, Clin Neurosci Branch, IRP, NIH, Bethesda, MD 20892 USA. NIMH, Child Psychiat Branch, IRP, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Dept Mol Med, S-10401 Stockholm, Sweden. Niigata Univ, Dept Neurol, Brain Res Inst, Niigata, Japan. RP Sidransky, E (reprint author), NIMH, Clin Neurosci Branch, IRP, NIH, Bldg 49,Room B1EE16,49 Convent Dr,MSC 4405, Bethesda, MD 20892 USA. NR 17 TC 32 Z9 33 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 1998 VL 62 IS 6 BP 1548 EP 1551 DI 10.1086/301876 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA ZU224 UT WOS:000074174700036 PM 9585604 ER PT J AU Shriver, MD Smith, MW Jin, L AF Shriver, MD Smith, MW Jin, L TI Difficulties in the estimation of ethnic affiliation - Reply SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Letter C1 Allegheny Univ Hlth Sci, Dept Human Genet, Pittsburgh, PA 15212 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD USA. Univ Texas, Ctr Human Genet, Houston, TX USA. RP Shriver, MD (reprint author), Allegheny Univ Hlth Sci, Dept Human Genet, 3290 William Pitt Way,Bldg B4,Room 125, Pittsburgh, PA 15212 USA. RI Smith, Michael/B-5341-2012; Jin, Li/C-1468-2009 OI Jin, Li/0000-0002-4546-2415 NR 3 TC 4 Z9 4 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 1998 VL 62 IS 6 BP 1560 EP 1561 DI 10.1086/301894 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA ZU224 UT WOS:000074174700041 ER PT J AU Moser, M Ramsay, LE Elliott, WJ Weber, MA Black, H Roccella, E AF Moser, M Ramsay, LE Elliott, WJ Weber, MA Black, H Roccella, E TI Current recommendations for initial therapy in hypertension: Are they still valid? Discussion SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Editorial Material C1 Yale Univ, Sch Med, New Haven, CT 06520 USA. Royal Hallamshire Hosp, Sheffield S10 2JF, S Yorkshire, England. Brookdale Univ Hosp & Med Ctr, Brooklyn, NY USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. NHLBI, Natl High Blood Pressure Educ Program, Bethesda, MD 20892 USA. RP Moser, M (reprint author), 13 Murray Hill Rd, Scarsdale, NY 10583 USA. NR 10 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD JUN PY 1998 VL 11 IS 6 SU S BP 95S EP 100S PN 2 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ZW399 UT WOS:000074407100005 ER PT J AU Samaniego, F Markham, PD Gendelman, R Watanabe, Y Kao, V Kowalski, K Sonnabend, JA Pintus, A Gallo, RC Ensoli, B AF Samaniego, F Markham, PD Gendelman, R Watanabe, Y Kao, V Kowalski, K Sonnabend, JA Pintus, A Gallo, RC Ensoli, B TI Vascular endothelial growth factor and basic fibroblast growth factor present in Kaposi's sarcoma (KS) are induced by inflammatory cytokines and synergize to promote vascular permeability and KS lesion development SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR NECROSIS FACTOR; GENE-EXPRESSION; SPINDLE CELLS; ADHESION MOLECULE-1; INTERFERON-GAMMA; HOMOSEXUAL MEN; HIV-INFECTION; ONCOSTATIN-M; FACTOR-ALPHA; NUDE-MICE AB All forms of Kaposi's sarcoma (KS) are characterized by spindle cell proliferation, angiogenesis, inflammatory cell infiltration, and edema. We have previously reported that spindle cells of primary KS lesions and KS-derived spindle cell cultures express high levels of basic fibroblast growth factor (bFGF), which is promoted by the inflammatory cytokines identified in these lesions. These cytokines, namely, tumor necrosis factor, interleukin-1, and interferon-gamma, induce production and release of bFGF, which stimulates angiogenesis and spindle cell growth in an autocrine fashion. Here we show that both AIDS-KS and classical KS lesions co-express vascular endothelial growth factor (VEGF) and bFGF. VEGF production by KS cells is promoted synergistically by inflammatory cytokines present in conditioned media from activated T cells and in KS lesions. KS cells show synthesis of VEGF isoforms that are mitogenic to endothelial cells but not to KS spindle cells, suggesting a prevailing paracrine effect of this cytokine, This may be due to the level of expression of the flt-1-VEGF receptor that is down-regulated in KS cells as compared with endothelial cells. KS-derived bFGF and VEGF synergize in inducing endothelial cell growth as shown by studies using both neutralizing antibodies and antisense oligodeoxynucleotides directed against these cytokines, In addition, VEGF and bFGF synergize to induce angiogenic;KS-like lesions in nude mice and vascular permeability and edema in guinea pigs, These results indicate that inflammatory cytokines present in KS lesions stimulate the production of bFGF and VEGF, which, in turn, cooperate to induce angiogenesis, edema, and KS lesion formation. C1 Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. NCI, NIH, Tumor Cell Biol Lab, Bethesda, MD 20892 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Adv BioSci Labs Inc, Kensington, MD USA. Community Res Initiat AIDS, New York, NY USA. Univ Cagliari, Inst Clin Med, Cagliari, Italy. Ist Super Sanita, Virol Lab, I-00161 Rome, Italy. RP Ensoli, B (reprint author), Ist Super Sanita, Virol Lab, Viale Regina Elena 299, I-00161 Rome, Italy. EM ensoli@virus1.net.iss.it RI Ensoli, Barbara/J-9169-2016 OI Ensoli, Barbara/0000-0002-0545-8737 NR 53 TC 136 Z9 140 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 1998 VL 152 IS 6 BP 1433 EP 1443 PG 11 WC Pathology SC Pathology GA ZR873 UT WOS:000074023300006 PM 9626048 ER PT J AU Spong, CY Rasul, C Collea, JV Eglinton, GS Ghidini, A AF Spong, CY Rasul, C Collea, JV Eglinton, GS Ghidini, A TI Characterization and prognostic significance of variable decelerations in the second stage of labor SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE variable decelerations; fetal heart rate tracing; second stage of labor ID AMNIOINFUSION; RELIEF AB The characteristics of variable decelerations (VD) in the second stage of labor and the relationship between the number, frequency or severity and neonatal outcome have not been studied. We have analyzed the characteristics of VD in the second stage of labor and their prognostic significance in the prediction of Apgar scores. In this descriptive study, fetal heart tracings containing VD from 250 singleton, vaginal deliveries between June 1994 and July 1996 were reviewed blinded to outcome information. Excluded were: (1) deliveries at <36 weeks, (2) uninterpretable tracing, (3) absence of VD in second stage of labor, and (4) absence of exam establishing beginning of second stage of labor. VD characteristics evaluated: shape (U, V, W); anterior and posterior "shoulders"; slow return to baseline (less than or equal to 30-degree curve); cumulative depth of VD per 10 min, second stage oxytocin dose. Outcome information collected: method of delivery, birth weight and Apgar scores. Statistical analysis included regression and analysis of variance (ANOVA). The mean maternal age was 32 +/- 5 years and gestational age 39 +/- 1.3 week. In the second stage of labor, the mean oxytocin dose was 3 +/- 5 mu/min, length of the second stage 65 +/- 57 min, total number of VD averaged 21 +/- 17 and uterine contractions 26 +/- 22 per patient. The percentage of VD <100 bpm was 50 +/- 27%, VD <70 bpm 13 +/- 20%, anterior shoulders 76 +/- 30%, posterior shoulders 75 +/- 30% and slow return to baseline 12 +/- 17%. The number of VD significantly increased with the length of the second stage of labor (r = 0.85, p <0.001). The total number and percentage of VD <70 bpm were inversely correlated with 5-min Apgar score (p = 0.038, 0.015 respectively). The sum of the depth of VD/length of second stage as well as the percentage of VD with anterior and/or posterior shoulders and slow return to baseline were not significantly related to Apgar sco es (p = 0.08, 0.72, 0.73, 0.99, respectively). Patients with a higher percentage of decelerations with slow return to baseline had a higher rate of operative vaginal deliveries (20 vs. 11%, p = 0.002); but no significant differences in Apgar scores compared with those with spontaneous delivery (p = 0.9). Second stage VD <70 bpm were significantly associated with lower 5-min Apgar scores. Although the presence of VD with a slow return to baseline was significantly associated with operative delivery, there was no difference in 5-min Apgar scores. C1 NICHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Spong, CY (reprint author), NICHD, Dev Neurobiol Lab, NIH, 9000 Rockville Pike,Bldg 49,5A-38,MSC 4480, Bethesda, MD 20892 USA. NR 11 TC 6 Z9 6 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD JUN PY 1998 VL 15 IS 6 BP 369 EP 374 DI 10.1055/s-2007-993959 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 110BZ UT WOS:000075360500005 PM 9722057 ER PT J AU Philp, NJ Yoon, H Grollman, EF AF Philp, NJ Yoon, H Grollman, EF TI Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE retinal pigment epithelium; lactate; anion; pH; water homeostasis ID RETINAL-PIGMENT EPITHELIUM; LACTATE TRANSPORT; CELLS; COTRANSPORT; METABOLISM; EXPRESSION; GLUCOSE; CLONING; GLUT1 AB The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier and regulates the movement of nutrients, water, and ions between the choroidal blood supply and the retina. The transport properties of the RPE maintain retinal adhesion and regulate the pH and osmolarity in the space surrounding the photoreceptor cell outer segments. In this report we identify two monocarboxylate transporters, MCT1 and MCTS, expressed in rat RPE. On the basis of Northern and Western blot analyses, MCT1 is expressed in both the neural retina and the RPE, whereas the expression of MCT3 is restricted to the RPE. Using indirect immunolocalization we show that the two transporters are polarized to distinct membrane domains. MCT1 antibody labels the apical surface and the apical processes of the RPE. A polyclonal antibody produced against the carboxy terminus of rat MCTS labels only the basolateral membrane of the RPE. The demonstration of MCT1 on the apical membrane and MCT3 on the basal membrane identifies specific proteins involved in the discriminate and critical regulation of water and lactate transport from the retina to the choroid. C1 Penn Coll Optometry, Philadelphia, PA 19141 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. RP Philp, NJ (reprint author), Penn Coll Optometry, 1200 W Godfrey Ave, Philadelphia, PA 19141 USA. NR 26 TC 75 Z9 77 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD JUN PY 1998 VL 274 IS 6 BP R1824 EP R1828 PG 5 WC Physiology SC Physiology GA ZQ835 UT WOS:000073907700038 PM 9841555 ER PT J AU Ecelbarger, CA Chou, CL Lee, AJ DiGiovanni Sr Verbalis, JG Knepper, MA AF Ecelbarger, CA Chou, CL Lee, AJ DiGiovanni, SR Verbalis, JG Knepper, MA TI Escape from vasopressin-induced antidiuresis: role of vasopressin resistance of the collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE antidiuretic hormone; aquaporin-2; adenosine 3 ',5 '-cyclic monophosphate; osmotic water permeability; urinary concentrating mechanism ID WATER PERMEABILITY; RAT; ACTIVATION; INCREASES; CHANNEL; KIDNEY AB Previously, we demonstrated that escape from vasopressin-induced antidiuresis ("vasopressin escape") in rats is associated with a large, selective decrease in whole kidney expression of aquaporin-2, the vasopressin-regulated water channel. Here, we show that isolated perfused inner medullary collecting ducts (IMCDs) from vasopressin-escape rats {desamino-[D-arginine]vasopressin (DDAVP)/water-loaded} have dramatically reduced vasopressin-dependent osmotic water permeabilities [46% of control rats (DDAVP alone)], which coincides with a fall in inner medullary aquaporin-2 protein abundance as measured by immunoblotting in the opposite kidney Furthermore, we demonstrate in IMCD suspensions that cAMP accumulation in response to DDAVP is substantially reduced in the vasopressin-escape rats both in the presence and absence of the phosphodiesterase inhibitor IBMX. By immunoblotting, we show that the abundance of two proteins important in cAMP generation: the stimulatory heterotrimeric G protein subunit G(s) alpha and adenylyl cyclase type VI, do not change. We conclude that vasopressin escape is associated with relative vasopressin resistance of the collecting duct cells manifested by decreased intracellular cAMP levels. The decreased cAMP levels can contribute to the demonstrated decrease in collecting duct water permeability in two ways: 1)by causing a decrease in aquaporin-2 expression and 2) by limiting the acute action of vasopressin to increase collecting duct water permeability. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Internal Med, Div Nephrol, Richmond, VA 23298 USA. Georgetown Univ, Div Endocrinol, Washington, DC 20007 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603 Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NIDDK NIH HHS [K01 DK002672, R01-DK-38094] NR 18 TC 53 Z9 55 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 1998 VL 274 IS 6 BP F1161 EP F1166 PG 6 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA ZT310 UT WOS:000074071600021 PM 9841509 ER PT J AU Tsai, GCE Ragan, P Chang, R Chen, S Linnoila, VMI Coyle, JT AF Tsai, GCE Ragan, P Chang, R Chen, S Linnoila, VMI Coyle, JT TI Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CEREBELLAR GRANULE CELLS; LONG-TERM POTENTIATION; CHRONIC ETHANOL-CONSUMPTION; INDUCED LIPID-PEROXIDATION; ACETYL-ASPARTYL-GLUTAMATE; EXCITATORY AMINO-ACIDS; RAT HIPPOCAMPAL SLICES; NEUROPSYCHIATRIC DISORDERS; RECEPTOR FUNCTION; NMDA RECEPTORS AB Objective: Neurophysiological and pathological effects of ethanol may be mediated to art important extent, via the glutamatergic system. Animal studies indicate the acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Persistent attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in the compensatory up-regulation of NMDA receptors. Whether glutamatergic neurotransmission and oxidative stress are enhanced during ethanol withdrawal in humans is unknown. Method: CSF teas obtained from 18 matched comparison subjects and from 28 patients with alcohol dependence 1 week and 1 month after cessation of ethanol ingestion. CSF samples were analyzed for excitatory neurotransmitters, gamma-aminobutyric acid (GABA), and markers for oxidative stress. Results: The alcohol-dependent patients' CSF levels of aspartate, glycine, and N-acetylaspartylglutamate were all higher than those of the comparison subjects, and their concentration of GABA was lower. In addition, there were significant correlations between excitatory neurotransmitters and oxidative stress markers, which suggest that the two mechanisms may play an interactive role in neurotoxicity mediated by ethanol withdrawal. Conclusions: The data suggest that augmentations of excitatory neurotransmission may lead to enhanced oxidative stress, which, in concert with reduced inhibitory neurotransmission, may contribute to the symptoms of ethanol withdrawal and associated neurotoxicity in humans. Whether these abnormalities represent a trait- or state-dependent marker of ethanol dependence remains to be resolved. C1 MGH CNY, Dept Psychiat, Lab Mol & Dev Neurosci, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. NIAAA, Clin Studies Lab, Div Intramural Clin & Biol Res, Bethesda, MD 20892 USA. RP Tsai, GCE (reprint author), MGH CNY, Dept Psychiat, Lab Mol & Dev Neurosci, Rm 2504,149 13th St, Charlestown, MA 02129 USA. EM TSAIG@Helix.MGH.Harvard.edu FU NINDS NIH HHS [NS-13584] NR 62 TC 126 Z9 129 U1 0 U2 3 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 1998 VL 155 IS 6 BP 726 EP 732 PG 7 WC Psychiatry SC Psychiatry GA ZR224 UT WOS:000073952700004 PM 9619143 ER PT J AU Buchanan, RW Breier, A Kirkpatrick, B Ball, P Carpenter, WT AF Buchanan, RW Breier, A Kirkpatrick, B Ball, P Carpenter, WT TI Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID TREATMENT-REFRACTORY SCHIZOPHRENICS; OUTPATIENTS; INSTRUMENT; VIEW AB Objective: In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life. Method: Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, pal allel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a I-year open-label clozapine study. Results: For patients who completed the IO-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life. Conclusions: For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome. C1 Univ Maryland, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21228 USA. NIMH, Sect Clin Studies, Bethesda, MD 20892 USA. RP Buchanan, RW (reprint author), Univ Maryland, Maryland Psychiat Res Ctr, Dept Psychiat, POB 21247, Baltimore, MD 21228 USA. FU NIMH NIH HHS [MH-40279, MH-45074] NR 31 TC 181 Z9 183 U1 2 U2 4 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 1998 VL 155 IS 6 BP 751 EP 760 PG 10 WC Psychiatry SC Psychiatry GA ZR224 UT WOS:000073952700007 PM 9619146 ER PT J AU Mentis, MJ Alexander, GE Krasuski, J Pietrini, P Furey, ML Schapiro, MB Rapoport, SI AF Mentis, MJ Alexander, GE Krasuski, J Pietrini, P Furey, ML Schapiro, MB Rapoport, SI TI Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; PARVOCELLULAR CONTRIBUTIONS; GLUCOSE-UTILIZATION; ENERGY-METABOLISM; SENILE DEMENTIA; FRONTAL-CORTEX; STRIATE CORTEX; SYNAPSE LOSS; SPINAL-CORD AB Objective: The authors examined the Interaction of Alzheimer's disease severity and visual stimulus complexity in relation to regional brain function. Method: Each subject had five positron emission tomography [(15)]H(2)O scans while weaving goggles containing a grid of red lights embedded into each lens. Regional cerebral blood flow, (CBF) was measured at 0 Hz and while lights were flashed alternately Into the two eyes at 1, 4, 7, and 14 Hz. Changes in regional CBF from the 0-Hz baseline were measured at each frequency in 19 healthy subjects (mean age=65 years, SD=11), 10 patients with mild Alzheimer's disease (mean age=69, SD=5; Mini-Mental State score greater than or equal to 20), and 11 patients with moderate to severe Alzheimer's disease (mean age=73, SD=12; A Mini-Mental State score less than or equal to 19). Results: As pattern-flash frequency increased, CBF responses in the comparison group included biphasic rising then falling in the striate cortex, linear increase in visual association areas, linear decrease in many anterior areas, and a peak at 1 Hz in V5/MT. Despite equivalent resting CBF and CBF responses to low frequencies among all groups, the groups with Alzheimer's disease had significantly smaller CBF responses than the comparison group at the frequency producing the largest response in the comparison group in many brain regions. Also, patients with moderate/severe dementia had smaller responses at frequencies producing intermediate responses in comparison subjects. Conclusions: Functional failure was demonstrated In patients with mild dementia when large neural responses were required and in patients with moderate/severe dementia when large and intermediate responses were required. C1 NIA, Neurosci Lab, Bethesda, MD 20892 USA. RP Mentis, MJ (reprint author), N Shore Univ Hosp, Dept Neurol, Suite 206,444 Community Dr, Manhasset, NY 11030 USA. EM movdis@aol.com RI Furey, Maura/H-5273-2013 NR 54 TC 58 Z9 58 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 1998 VL 155 IS 6 BP 785 EP 794 PG 10 WC Psychiatry SC Psychiatry GA ZR224 UT WOS:000073952700012 PM 9619151 ER PT J AU Sethna, NF Liu, MW Gracely, R Bennett, GJ Max, MB AF Sethna, NF Liu, MW Gracely, R Bennett, GJ Max, MB TI Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects SO ANESTHESIA AND ANALGESIA LA English DT Article ID POSTOPERATIVE ANALGESIA; NMDA ANTAGONIST; CANCER PAIN; MORPHINE; HYPERALGESIA; INJECTION; INFUSIONS; ALLODYNIA; PLACEBO; SYNERGY AB Combinations of opioids and N-methyl-D-aspartate (NMDA) antagonists enhance acute antinodception and seduce opioid tolerance in some animal experiments but have received little rigorous study in humans. To quantitatively assess the nature of the interaction of these two classes of drugs in producing analgesia and cognitive impairment, we compared IV infusions of ketamine, alfentanil, and ketamine-alfentanil combinations in 12 normal volunteers after an intradermal injection of capsaicin. Drug doses for a 70-kg subject in this six-session, randomized, double-blind, cross-over study were: ketamine 20 mg, ketamine 5 mg, alfentanil 2 mg alfentanil 0.5 mg ketamine 10 mg + alfentanil 1 mg, and ketamine 2.5 mg + alfentanil 0.25 mg, given over 35 min. Outcome measures were background pain, area and magnitude of hyperalgesia to pinprick, and cognitive performance on the Digit Symbol Substitution Test and the Perception Speed Test. The results demonstrated simple additivity for the effects of ketamine and alfentanil on pain, pinprick hyperalgesia, and cognitive impairment. We conclude that, at least in this experimental pain model, there is no clear advantage or disadvantage of a ketamine-alfentanil combination over equianalgesic doses of either component. Implications: In a double-blind, controlled trial, we administered doses of an opioid analgesic (alfentanil), an N-methyl-D-aspartate receptor antagonist (ketamine), or their combination to normal volunteers and found no advantage of the combination over a larger dose of either drug alone in relieving pain caused by painful chemical stimulation. C1 NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Anesthesia, Boston, MA USA. Univ Penn, Dept Anesthesia, Philadelphia, PA 19104 USA. RP Max, MB (reprint author), NIDR, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 10,3C-405, Bethesda, MD 20892 USA. NR 28 TC 61 Z9 64 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JUN PY 1998 VL 86 IS 6 BP 1250 EP 1256 DI 10.1097/00000539-199806000-00022 PG 7 WC Anesthesiology SC Anesthesiology GA ZQ584 UT WOS:000073882700021 PM 9620514 ER PT J AU Yost, CS Hampson, AJ Leonoudakis, D Koblin, DD Bornheim, LM Gray, AT AF Yost, CS Hampson, AJ Leonoudakis, D Koblin, DD Bornheim, LM Gray, AT TI Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity but does not alter minimum alveolar anesthetic concentration SO ANESTHESIA AND ANALGESIA LA English DT Article ID RAT-BRAIN; XENOPUS OOCYTES; INDUCE SLEEP; SUBUNIT; MAC; EXPRESSION; BINDING; HETEROGENEITY; HALOTHANE; POTENCY AB A naturally occurring brain lipid, cis-9,10-octadeceamide-oleamide (OA) is found in increased concentrations in the cerebrospinal fluid of sleep-deprived cats, which suggests that it may be an endogenous sleep-inducing substance. We studied the effects of this fatty-add derivative on the function of cloned gamma-aminobutyric add (GABA(A)) receptors expressed in Xenopus oocytes. Oocytes were injected with cRNA synthesized in vitro to express simple GABA(A) receptors (alpha 1 beta 1, alpha 3 beta 1, alpha 5 beta 1, and alpha 1 beta 2 subunit combinations) and receptors in which the GABA-induced chloride currents were potentiated in the presence of benzodiazepines (alpha 1 beta 1 gamma 2s and alpha 1 beta 2 gamma 2s subunit combinations). OA only produced significant potentiation of the peak Cl- current when applied with GABA to benzodiazepine-sensitive GABA(A) receptors. The peak currents of the simple GABA(A) receptors in the presence of OA were either unaffected or slightly inhibited by OA, but the overall mean currents were not significantly altered. Oleic add was also capable of potentiating benzodiazepine-sensitive GABA(A) receptor function. The function of other ligand-gated ion channels, such as the N-methyl-D-aspartate receptor (NR1 + NR2A or 2C) and the 5-HT3 receptor expressed in Xenopus oocytes, were unaffected by OA. Sprague-Dawley rats receiving intraperitoneal injections of oleamide (10, 20, or 100 mg/kg) showed no change in the minimum alveolar anesthetic concentration (MAC) of desflurane required to abolish movement in response to noxious (tail clamp) stimulation (control MAC 6.48% +/- 1.28% atm; 100 mg/kg OA MAC 7.05% +/- 0.42% atm). These results reinforce the view that oleyl compounds may be natural modulators of inhibitory ion channel function, but that these effects contribute little to the central nervous system depression produced by volatile anesthetics as measured by MAC. Implications: The putative sleep inducing substance, oleamide, potentiates benzodiazepine sensitive gamma-aminobutyric acid receptor function but does not alter desflurane minimum alveolar anesthetic concentration in rats. C1 Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. Vet Affairs Med Ctr Ft Miley, San Francisco, CA USA. NIMH, Cell Biol Lab, Bethesda, MD USA. RP Yost, CS (reprint author), Univ Calif San Francisco, Dept Anesthesia, 513 Parnassus Ave, San Francisco, CA 94143 USA. FU NIGMS NIH HHS [GMS-51372, GMS-47818] NR 24 TC 58 Z9 59 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD JUN PY 1998 VL 86 IS 6 BP 1294 EP 1300 DI 10.1097/00000539-199806000-00031 PG 7 WC Anesthesiology SC Anesthesiology GA ZQ584 UT WOS:000073882700030 PM 9620523 ER PT J AU Werner, P Raducha, MG Prociuk, U Lyons, LA Kehler, JS Henthorn, PS Patterson, DF AF Werner, P Raducha, MG Prociuk, U Lyons, LA Kehler, JS Henthorn, PS Patterson, DF TI RXRA and HSPA5 map to the telomeric end of dog chromosome 9 SO ANIMAL GENETICS LA English DT Article DE canine; comparative gene mapping; dog chromosome; CFA9; HSPA5; RXRA ID LOCALIZATION; KARYOTYPE; ALPHA AB Previous results showed that loci from human chromosome 17q (HSA17q) map to the centromeric two-thirds of dog chromosome 9 (CFA9). In these studies fluorescence in situ hybridization (FISH) using a human total chromosome 17 painting probe, indicated that the telomeric one-third of CFA9 must have homology to one or more human chromosomes other than HSA17. Here we report that this distal part of CFA9 contains a segment syntenic to the telomeric end of HSA9q and mouse chromosome 2 (MMU2). The gene loci encoding retinoid X receptor, alpha (RXRA) and heat shock protein 5 (HSPA5 or GRP78), which are found on HSA9q34 and MMU2, occupy a region on CFA9 distal to NF1 and CRYBA1. FISH of a canine specific genomic cosmid clone for RXRA demonstrated the more telomeric localization of this locus to NF1 on CFA9. A linkage map developed for the distal region of CFA9 included: NF1-(2.7 cM)-CRYBA1-(6.5 cM)-RXRA-(22 cM)-HSPA5. The next best order, RXRA-NF1-CRYBA1-HSPA5 with a difference in the log odds of 1.43 does not correspond to our findings with FISH. The most probable map order places HSPA5 distal to RXRA on CFA9 whereas in humans it lies centromeric of RXRA on HSA9q34. C1 Univ Penn, Sch Vet Med, Ctr Comparat Med Genet, Philadelphia, PA 19104 USA. Univ Penn, Sch Vet Med, Med Genet Sect, Philadelphia, PA 19104 USA. NCI, Lab Genom Divers, Ft Detrick, MD 21702 USA. RP Patterson, DF (reprint author), Univ Penn, Sch Vet Med, Ctr Comparat Med Genet, Philadelphia, PA 19104 USA. FU NCRR NIH HHS [RR02512]; NHLBI NIH HHS [HL18848] NR 15 TC 5 Z9 6 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0268-9146 J9 ANIM GENET JI Anim. Genet. PD JUN PY 1998 VL 29 IS 3 BP 220 EP 223 DI 10.1046/j.1365-2052.1998.00328.x PG 4 WC Agriculture, Dairy & Animal Science; Genetics & Heredity SC Agriculture; Genetics & Heredity GA 108CR UT WOS:000075248900010 PM 9720182 ER PT J AU Pettit, GR Srirangam, JK Barkoczy, J Williams, MD Boyd, MR Hamel, E Pettit, RK Hogan, F Bai, RL Chapuis, JC McAllister, SC Schmidt, JM AF Pettit, GR Srirangam, JK Barkoczy, J Williams, MD Boyd, MR Hamel, E Pettit, RK Hogan, F Bai, RL Chapuis, JC McAllister, SC Schmidt, JM TI Antineoplastic agents 365. Dolastatin 10 SAR probes SO ANTI-CANCER DRUG DESIGN LA English DT Article DE antineoplastic agents; dolastatin 10; structural modifications ID PEPTIDE DOLASTATIN-10; DOLABELLA-AURICULARIA; CHIRAL ISOMERS; TUBULIN; BINDING; DOLAPHENINE; SEGMENTS; ANALOGS AB The remarkable anticancer drug dolastatin 10(1a) from the Indian Ocean sea hare Dolabella auricularia is currently undergoing phase I clinical trials Thirty-eight new structural modifications of this unusual peptide have been synthesized and evaluated against a variety of human and murine cancer cell lines, and for their ability to inhibit tubulin polymerization and vinblastine and GTP binding to tubulin. Dolastatin 10 and one structural modification was found to have antifungal activity, while one other structural modification of the parent compound exhibited antibacterial activity. Some of the new peptides approximated the antineoplastic potency of dolastatin 10, especially those based on replacement of the Doe unit with Met, Phe or an appropriately substituted phenylethylamide. C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem, Tempe, AZ 85287 USA. NCI, Lab Drug Discovery Res & Dev, DTP,DCTDC, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Western Oregon State Coll, Dept Biol, Monmouth, OR 97361 USA. RP Pettit, GR (reprint author), Arizona State Univ, Canc Res Inst, Box 872404, Tempe, AZ 85287 USA. FU NCI NIH HHS [CA44344-01-09] NR 32 TC 52 Z9 52 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0266-9536 J9 ANTI-CANCER DRUG DES JI Anti-Cancer Drug Des. PD JUN PY 1998 VL 13 IS 4 BP 243 EP 277 PG 35 WC Biochemistry & Molecular Biology; Oncology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy GA ZU073 UT WOS:000074158500001 PM 9627667 ER PT J AU Hughes, W Dorenbaum, A Yogev, R Beauchamp, B Xu, J McNamara, J Moye, J Purdue, L van Dyke, R Rogers, M Sadler, B AF Hughes, W Dorenbaum, A Yogev, R Beauchamp, B Xu, J McNamara, J Moye, J Purdue, L van Dyke, R Rogers, M Sadler, B CA Pediat AIDS Clinical Trials Grp TI Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PNEUMOCYSTIS-CARINII PNEUMONIA; TRIMETHOPRIM-SULFAMETHOXAZOLE; AIDS; 566C80; HYDROXYNAPHTHOQUINONE; TOXOPLASMOSIS; EFFICACY AB A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body, weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24, Prior studies with adults suggest that the average plasma atovaquone concentration of 15 mu g/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 mu g/ml in children ages 1 to 3 months and 2 to 12 gears, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 35 mg/kg/day. C1 St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Chicago Childrens Mem Hosp, Chicago, IL USA. Univ Puerto Rico, San Juan, PR 00936 USA. Harvard Univ, Sch Med, Boston, MA USA. NIAID, Bethesda, MD 20892 USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. Glaxo Wellcome, Res Triangle Pk, NC USA. RP Hughes, W (reprint author), St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. OI moye, john/0000-0001-9976-8586 NR 18 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 1998 VL 42 IS 6 BP 1315 EP 1318 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ZR221 UT WOS:000073952400002 PM 9624466 ER PT J AU Nash, T Rice, WG AF Nash, T Rice, WG TI Efficacies of zinc-finger-active drugs against Giardia lamblia SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID TETRAETHYLTHIURAM DISULFIDE; ANTIGENIC VARIATION; SURFACE-PROTEINS; BINDING; INFECTIONS; INHIBITORS; MICE AB Twenty-nine of 34 (85%) Zn-finger-active compounds at 300 mu M or less inhibited the growth of Giardia lamblia. The most active compound, disulfiram (Antabuse), was cidal at 1.23 +/- 0.32 mu M. In the adult mouse model, significant in vivo activity was demonstrated by increased cure rates and decreased parasite burdens. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Antiviral Drug Mechanisms, SAIC Frederick, Frederick, MD 21702 USA. RP Nash, T (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Rm 81-01, Bethesda, MD 20892 USA. NR 31 TC 23 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 1998 VL 42 IS 6 BP 1488 EP 1492 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ZR221 UT WOS:000073952400035 PM 9624499 ER PT J AU Reichelderfer, PS Coombs, RW AF Reichelderfer, PS Coombs, RW TI Cartesian coordinate analysis of viral burden and CD4+ T-cell count in human immunodeficiency virus type-1 infection SO ANTIVIRAL RESEARCH LA English DT Article; Proceedings Paper CT Consensus Conference on Antiviral Therapy CY JUL, 1995 CL LISBON, PORTUGAL DE Cartesian coordinate analysis; CD4+ cell; HIV-1 RNA; viral burden; virulence; virologic response modifiers; pathogenesis; clinical trials ID ACTIVE ANTIRETROVIRAL THERAPY; SYNCYTIUM-INDUCING PHENOTYPE; POLYMERASE CHAIN-REACTION; P24 ANTIGEN LEVELS; PLASMA HIV-1 RNA; DISEASE PROGRESSION; ZIDOVUDINE RESISTANCE; CLINICAL PROGRESSION; LYMPHOCYTE COUNTS; CONTROLLED TRIAL AB We have used a Cartesian coordinate plot to analyze the inverse relationship between viral burden (x-axis) and peripheral blood CD4 + cell count (y-axis) to extend our understanding of the mechanisms of antiviral drugs and differences in outcome resulting from variability in virus and host responses. Each of 186 subjects studied were assigned to one of four response quadrants. Quadrants A (x -, y +) and D (x +, y -) defined the effect of a change in virus load on the inverse change in CD4 + cell count expected from the natural history of HIV infection or antiretroviral therapy. Quadrants B (x +, y +) and C (,x -, y - ) defined the dissociation of the inverse relationship between the relative changes in CD4 + cell count and viral load that resulted from the hypothesized effect of putative virologic or immunologic response modifiers. Of the response modifiers studied, only the syncytium-inducing phenotype resulted in a complete dissociation of this inverse relationship. The analysis provided an integrated virological and immunological approach to better understand therapeutic responses and potential dissociation between changes in viral RNA and CD4 + cell count. This type of analysis may be helpful for individualizing patient management as well as designing and analyzing studies of HIV-1 antiretroviral drugs and disease pathogenesis. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Coombs, RW (reprint author), Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. FU NIAID NIH HHS [UO1-AI-27664, P30-AI-27757, N01-AI-05065] NR 68 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JUN PY 1998 VL 38 IS 3 BP 181 EP 194 DI 10.1016/S0166-3542(98)00010-2 PG 14 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 114RJ UT WOS:000075622400002 PM 9754887 ER PT J AU Barditch-Crovo, PA Petty, BG Gambertoglio, J Nerhood, LJ Kuwahara, S Hafner, R Lietman, PS Kornhauser, DM AF Barditch-Crovo, PA Petty, BG Gambertoglio, J Nerhood, LJ Kuwahara, S Hafner, R Lietman, PS Kornhauser, DM TI The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet SO ANTIVIRAL RESEARCH LA English DT Article DE foscarnet; bioavailability; antiviral; H2-blocker; ranitidine ID HUMAN IMMUNODEFICIENCY VIRUS; PHARMACOKINETICS; INFECTION AB For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 mu M) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD USA. Univ Calif San Francisco, Div Clin Pharmacol, San Francisco, CA 94143 USA. Univ Utah, Salt Lake City, UT USA. National Institute Allergy & Infectious Diseases, NIH, Rockville, MD USA. RP Barditch-Crovo, PA (reprint author), Johns Hopkins Hosp, Harvey 502,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCRR NIH HHS [M01-RR00722, M01-RR00035] NR 11 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JUN PY 1998 VL 38 IS 3 BP 209 EP 212 DI 10.1016/S0166-3542(98)00024-2 PG 4 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 114RJ UT WOS:000075622400004 PM 9754889 ER PT J AU Weiss, GH AF Weiss, GH TI Statistical properties of the penetration of photons into a semi-infinite turbid medium: a random-walk analysis SO APPLIED OPTICS LA English DT Article ID MIGRATION; TRANSILLUMINATION AB Statistical properties of the expected amount of time spent by a photon at different depths of a semiinfinite turbid medium are derived with formalism based on the continuous-time random walk. The formalism is applied to the study of both cw and time-gated experiments. Earlier analytical results relating to cw experiments are reproduced with a single approximation, rather than the more complicated approach used in earlier research based on the discrete-time random walk. The distribution of the occupancy of different depths in a time-gated experiment is found to have a convenient scaling form. C1 NIH, Bethesda, MD 20892 USA. RP NIH, Bethesda, MD 20892 USA. NR 18 TC 17 Z9 17 U1 0 U2 1 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD JUN 1 PY 1998 VL 37 IS 16 BP 3558 EP 3563 DI 10.1364/AO.37.003558 PG 6 WC Optics SC Optics GA ZQ398 UT WOS:000073857200028 PM 18273324 ER PT J AU Middaugh, S Haythornthwaite, J Thompson, B Hill, D Freedman, R Attanasio, V Scheier, M Jacob, R Canner, J Smith, E AF Middaugh, S Haythornthwaite, J Thompson, B Hill, D Freedman, R Attanasio, V Scheier, M Jacob, R Canner, J Smith, E TI The Raynaud's Treatment Study: Acquisition and clinical application of temperature biofeedback skills SO APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK LA English DT Meeting Abstract DE Raynaud's phenomenon; temperature biofeedback; treatment outcome C1 Med Univ S Carolina, Dept Phys Med & Rehabil, Charleston, SC 29425 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. NHLBI, Bethesda, MD 20892 USA. Wayne State Univ, Detroit, MI 48202 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PLENUM PUBL CORP PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-0586 J9 APPL PSYCHOPHYS BIOF JI Appl. Psychophysiol. Biofeedback PD JUN PY 1998 VL 23 IS 2 BP 122 EP 123 PG 2 WC Psychology, Clinical SC Psychology GA 125YQ UT WOS:000076265500039 ER PT J AU Neumeister, A Turner, EH Matthews, JR Postolache, TT Barnett, RL Rauh, M Vetticad, RG Kasper, S Rosenthal, NE AF Neumeister, A Turner, EH Matthews, JR Postolache, TT Barnett, RL Rauh, M Vetticad, RG Kasper, S Rosenthal, NE TI Effects of tryptophan depletion vs catecholamine depletion in patients with seasonal affective disorder in remission with light therapy SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID METHYL-PARA-TYROSINE; ANTIDEPRESSANT-INDUCED REMISSION; AMINO-ACID MIXTURES; DEPRESSED-PATIENTS; BRAIN TRYPTOPHAN; BEHAVIORAL-RESPONSES; PLASMA TRYPTOPHAN; RAT-BRAIN; SEROTONIN; CHLOROPHENYLPIPERAZINE AB Background: Although hypotheses about the therapeutic mechanism of action of light therapy have focused on serotonergic mechanisms, the potential role, if any, of catecholaminergic pathways has not been fully explored. Methods: Sixteen patients with seasonal affective disorder who had responded to a standard regimen of daily 10000-lux light therapy were enrolled in a double-blind, placebo-controlled, randomized crossover study. We compared the effects of tryptophan depletion with catecholamine depletion and sham depletion. Ingestion of a tryptophan-free amino acid beverage plus amino acid capsules was used to deplete tryptophan. Administration of the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine was used to deplete catecholamines. Diphenhydramine hydrochloride was used as an active placebo during sham depletion. The effects of these interventions were evaluated with measures of depression, plasma tryptophan levels, and plasma catecholamine metabolites. Results: Tryptophan depletion significantly decreased plasma total and free tryptophan levels. Catecholamine depletion significantly decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Both tryptophan depletion and catecholamine depletion, compared with sham depletion, induced a robust increase (P < .001, repeated-measures analysis of variance) in depressive symptoms as measured with the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version. Conclusions: The beneficial effects of light therapy in the treatment of seasonal affective disorder are reversed by both tryptophan depletion and catecholamine depletion. These findings confirm previous work showing that serotonin plays an important role in the mechanism of action of light therapy and provide new evidence that brain catecholaminergic systems may also be involved. C1 Univ Vienna, Dept Gen Psychiat, A-1090 Vienna, Austria. NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Dept Pediat, D-8520 Erlangen, Germany. RP Neumeister, A (reprint author), Univ Vienna, Dept Gen Psychiat, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM alexander.neumeister@akh-wien.ac.at RI Turner, Erick/A-4848-2008; OI Turner, Erick/0000-0002-3522-3357; Rauh, Manfred/0000-0002-4852-7157 NR 55 TC 89 Z9 93 U1 0 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 JUN PY 1998 VL 55 IS 6 BP 524 EP 530 DI 10.1001/archpsyc.55.6.524 PG 7 WC Psychiatry SC Psychiatry GA ZT661 UT WOS:000074111200006 PM 9633671 ER PT J AU Caruso, RC Zujewski, J Iwata, F Podgor, MJ Conley, BA Ayres, LM Kaiser-Kupfer, MI AF Caruso, RC Zujewski, J Iwata, F Podgor, MJ Conley, BA Ayres, LM Kaiser-Kupfer, MI TI Effects of fenretinide (4-HPR) on dark adaptation SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID SYNTHETIC RETINOID FENRETINIDE AB Objectives: To assess the alterations in dark adaptation induced by low (200 mg/d) doses of fenretinide (4-HPR), to assess whether these effects were cumulative and whether they were reversible, and to attempt to elucidate the mechanism underlying the changes in night vision. Design: Case series. Setting: Outpatient eye clinic. Patients: Twenty-two women enrolled in a breast cancer chemoprevention trial, and 18 normal control subjects. Intervention: Measurements of absolute luminance thresholds during dark adaptation. Main Outcome Measures: Parameters of an exponential model of the dark-adaptation function before, during, and after administration of fenretinide. Results: The most conspicuous effect of fenretinide on dark adaptation was a significant delay in the timing of the rod-cone break (P<.001), A minimal elevation of the final cone threshold was also observed. These effects were reversible after fenretinide therapy was discontinued and did not seem to be cumulative. An inverse relationship between delay of the rod-cone break and plasma retinol concentration was found. Conclusion: The dose of fenretinide used in this study produced clearly measurable, but not severe, changes in night vision, which were rarely symptomatic. C1 NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. NEI, Div Biometry & Epidemiol, Stat Methods & Anal Sect, Bethesda, MD 20892 USA. NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Clin Invest Branch, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Caruso, RC (reprint author), NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bldg 10,Room 10N226,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. NR 10 TC 20 Z9 20 U1 0 U2 2 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 JUN PY 1998 VL 116 IS 6 BP 759 EP 763 PG 5 WC Ophthalmology SC Ophthalmology GA ZU461 UT WOS:000074199400006 PM 9639444 ER PT J AU Rintala, DH Loubser, PG Castro, J Hart, KA Fuhrer, MJ AF Rintala, DH Loubser, PG Castro, J Hart, KA Fuhrer, MJ TI Chronic pain in a community-based sample of men with spinal cord injury: Prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article ID LIFE SATISFACTION; DYSESTHETIC PAIN; ADJUSTMENT; ORIGINS AB Objective: To assess the prevalence, severity, and correlates of chronic pain in a community-based sample of men with spinal cord injury (SCI). Design: Survey. Setting: Community. Participants: Seventy-seven men with SCI randomly selected from a sampling frame solicited from the community. Method: Participants completed standardized questionnaires assessing many areas of life, were interviewed in their homes, and underwent a physical examination at a hospital. There they were interviewed by an anesthesiologist regarding chronic pain, and a nurse administered objective pain measures. Results: Seventy-five percent of the men reported chronic pain. Chronic pain was associated with more depressive symptoms, more perceived stress, and poorer self-assessed health. Greater intensity of pain was related to less paralytic impairment, violent etiology, and more perceived stress. Area of the body affected by pain was related to independence and mobility. Conclusions: Because of the high prevalence of chronic pain in the population with SCI and its relation to disability, handicap, and quality of Life, health care providers need to give this issue the same priority given to other SCI health issues. Analysis of individual pain components provides better information than assessing overall pain. It is futile to treat SCI pain without giving full attention to subjective factors. (C) 1998 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. C1 Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77027 USA. Baylor Coll Med, Dept Anesthesiol, Houston, TX 77027 USA. Texas Womans Univ, Inst Rehabil & Res, Houston, TX USA. Texas Womans Univ, Coll Nursing, Houston, TX USA. NICHHD, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. RP Rintala, DH (reprint author), Baylor Coll Med, Dept Phys Med & Rehabil, 3555 Timmons Lane,Suite 820, Houston, TX 77027 USA. FU PHS HHS [H133B40011-95, H133B80020] NR 49 TC 154 Z9 159 U1 6 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD JUN PY 1998 VL 79 IS 6 BP 604 EP 614 DI 10.1016/S0003-9993(98)90032-6 PG 11 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA ZT554 UT WOS:000074099500002 PM 9630137 ER PT J AU Felson, DT Couropmitree, NN Chaisson, CE Hannan, MT Zhang, YQ McAlindon, TE LaValley, M Levy, D Myers, RH AF Felson, DT Couropmitree, NN Chaisson, CE Hannan, MT Zhang, YQ McAlindon, TE LaValley, M Levy, D Myers, RH TI Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID KNEE OSTEO-ARTHRITIS; II PROCOLLAGEN GENE; WOMEN; COLLAGEN; COL2A1 AB Objective, To investigate the inheritance of generalized osteoarthritis (OA), Methods. OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade greater than or equal to 2, The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA, Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. Results. A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306, In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models), The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. Conclusion. These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors. C1 Boston Univ, Arthrit Ctr, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. NHLBI, Framingham, MA USA. RP Felson, DT (reprint author), Boston Univ, Arthrit Ctr, Boston, MA 02215 USA. OI Hannan, Marian/0000-0002-9586-6928 FU NHLBI NIH HHS [N01-HC-38038]; NIA NIH HHS [AG-09300]; NIAMS NIH HHS [AR-20613] NR 24 TC 132 Z9 133 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 1998 VL 41 IS 6 BP 1064 EP 1071 DI 10.1002/1529-0131(199806)41:6<1064::AID-ART13>3.0.CO;2-K PG 8 WC Rheumatology SC Rheumatology GA ZR876 UT WOS:000074023700012 PM 9627016 ER PT J AU Nietert, PJ Sutherland, SE Silver, RM Pandey, JP Knapp, RG Hoel, DG Dosemeci, M AF Nietert, PJ Sutherland, SE Silver, RM Pandey, JP Knapp, RG Hoel, DG Dosemeci, M TI Is occupational organic solvent exposure a risk factor for scleroderma? SO ARTHRITIS AND RHEUMATISM LA English DT Article ID PROGRESSIVE SYSTEMIC-SCLEROSIS; MEDIATED IMMUNE STATUS; WATER; MICE; TRICHLOROETHYLENE; ASSOCIATION; CHEMICALS; SYMPTOMS; BINDING; MATRIX AB Objective, The primary objective was to determine whether occupational exposure to organic solvents is related to an increased risk of systemic sclerosis (SSc; scleroderma), Methods. Occupational histories were obtained front 178 SSc patients and 200 controls, Exposure scores were computed for each individual using job exposure matrices, which were validated by an industrial expert, Results. Among men, those,vith SSc were more likely than controls to have a high cumulative intensity score (odds ratio [OR] 2.9, 95% confidence interval [95% CI] 1.1-7.6) and a high maximum intensity score (OR 2.9, 95% CI 1.2-7.1) for any solvent exposure. They were also more likely than controls to have a high maximum intensity score for trichloroethylene exposure (OR 3.3, 95% CI 1.0-10.3), Among men and women, significant solvent-disease associations were observed among SSc patients who tested positive for the anti-Scl-70 autoantibody; these trends mere not observed among the men and women who tested negative for anti-Scl-70, Conclusion. These results provide evidence that occupational solvent exposure may be associated,vith an increased risk of SSc. C1 Med Univ S Carolina, Ctr Hlth Care Res, Charleston, SC 29425 USA. NCI, Bethesda, MD 20892 USA. RP Nietert, PJ (reprint author), Med Univ S Carolina, Ctr Hlth Care Res, 171 Ashley Ave, Charleston, SC 29425 USA. OI Nietert, Paul/0000-0002-3933-4986 NR 35 TC 82 Z9 82 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 1998 VL 41 IS 6 BP 1111 EP 1118 DI 10.1002/1529-0131(199806)41:6<1111::AID-ART19>3.0.CO;2-J PG 8 WC Rheumatology SC Rheumatology GA ZR876 UT WOS:000074023700018 PM 9627022 ER PT J AU Genter, MB Liang, HC Gu, J Ding, XX Negishi, M McKinnon, RA Nebert, DW AF Genter, MB Liang, HC Gu, J Ding, XX Negishi, M McKinnon, RA Nebert, DW TI Role of CYP2A5 and 2G1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the Cyp1a2(-/-) mouse SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE olfactory mucosa; CYP2A5; Cyp1a2(-/-) knockout mouse; acetaminophen; CYP2G1; metabolism ID ACUTE-RENAL-FAILURE; RABBIT NASAL MICROSOMES; COVALENT BINDING; REACTIVE METABOLITE; DIALLYL SULFIDE; CYTOCHROME-P-450; HEPATOTOXICITY; LIVER; P450; RAT AB Acetaminophen (AP) is a widely-used analgesic agent that has been linked to human liver and kidney disease with prolonged or high-dose usage. In rodents, the target organs that are affected include liver, kidney, and the olfactory mucosa. AP toxicity requires cytochrome P450(CYP)-mediated metabolic activation, and the isozymes CYP1A2, 2E1, and 3A are known to activate AP in the human. In the present study, we determined that olfactory mucosal toxicity of AP was not different between the Cyp1a2(+/+) wild-type and the Cyp1a2(-/-) knockout mouse, whereas the hepatic toxicity of AP was significantly diminished in Cyp1a2(-/-) mice. Western blots of olfactory mucosa revealed that CYP2E1 and CYP3A levels are similar between untreated Cyp1a2(+/+) and Cyp1a2(-/-) mice. Diallyl sulfide (DAS), a known inhibitor of CYP2E1 and of CYP2A10/2A11 (the rabbit orthologue of mouse CYP2A5), completely eliminated olfactory toxicity of AP in both the Cyp1a2(-/-) and wild-type mouse olfactory mucosa. We found that heterologously expressed mouse CYP2A5 and CYP2G1 enzymes (known to be present in olfactory mucosa) form 3-hydroxyacetaminophen (3 OH-AP) and 3-(glutathion-S-yl)acetaminophen (GS-AP); CYP2A5 is considerably more active than 2G1. Addition of GSH caused increases in GS-AP proportional to decreases in 3-OH-AP, suggesting that these two metabolites arise from a common precursor or are formed by way of competing pathways. We also found that both CYP2A5 and CYP2G1 are inhibitable by DAS in vitro. These studies provide strong evidence that, in addition to CYP2E1, CYP2A5 and 2G1 are important in AP bioactivation in the mouse olfactory mucosa and that CYP1A2 appears to be of minor importance for AP olfactory toxicity. (C) 1998 Elsevier Science Inc. C1 Univ Cincinnati, Dept Mol & Cellular Physiol, Cincinnati, OH 45267 USA. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. Univ Cincinnati, Ctr Environm Genet, Cincinnati, OH 45267 USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. SUNY Albany, Sch Publ Hlth, Albany, NY 12001 USA. NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Genter, MB (reprint author), Univ Cincinnati, Dept Mol & Cellular Physiol, ML 670576, Cincinnati, OH 45267 USA. EM MaryBeth.Genter@UC.Edu RI McKinnon, Ross /B-9340-2009 OI McKinnon, Ross /0000-0002-3725-793X FU NIA NIH HHS [R01 AG13837]; NIEHS NIH HHS [ES06321, ES07462] NR 46 TC 36 Z9 38 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUN 1 PY 1998 VL 55 IS 11 BP 1819 EP 1826 DI 10.1016/S0006-2952(98)00004-5 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZU342 UT WOS:000074187500010 PM 9714300 ER PT J AU Bauer, KS Dixon, SC Figg, WD AF Bauer, KS Dixon, SC Figg, WD TI Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE angiogenesis; thalidomide; aorta; metabolism ID PLASMA PHARMACOKINETICS; TUMOR ANGIOGENESIS; METASTASIS; CARCINOMA; DISEASE; CANCER; ASSAY AB Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents. (C) 1998 Elsevier Science Inc. C1 NCI, Med Branch, Div Clin Sci, 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 27 TC 229 Z9 239 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUN 1 PY 1998 VL 55 IS 11 BP 1827 EP 1834 DI 10.1016/S0006-2952(98)00046-X PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZU342 UT WOS:000074187500011 PM 9714301 ER PT J AU Fu, QL Mcphie, P Gowda, DC AF Fu, QL Mcphie, P Gowda, DC TI Methionine modification impairs the C5-cleavage function of cobra venom factor-dependent C3/C5 convertase SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article DE cobra venom factor; methionine modification; complement activity; C5 binding; impaired C5 cleavage ID MONOCLONAL-ANTIBODY; CIRCULAR-DICHROISM; HUMAN-COMPLEMENT; 3RD COMPONENT; PROTEINS; OLIGOSACCHARIDE; CONJUGATION; ACTIVATION; INVITRO; ACID AB The complement-mediated lysis of guinea pig erythrocytes by cobra venom factor (CVF) decreased by 50-60% within 2 min of treatment with 5 mM sodium periodate at 0 degrees C. This loss of activity paralleled modification of 3-4 Met; other amino acids and sugar residues of the oligosaccharide chains were not affected. Treatment with N-chlorosuccinimide or chloramine-T under conditions that specifically modified 3-4 readily-oxidizable Met also caused 50-60% loss of CVF activity. The secondary structure of CVF was not altered by these modifications. Methionine-modified CVF (MetCVF) supported the cleavage of factor B by factor D with equal efficiency as that of untreated CVF to form C3/C5 convertase (MetCVF,Bb) of the alternative pathway. MetCVF,Bb and CVF,Bb were indistinguishable with respect to C3 cleavage. However, the C5-cleavage ability of MetCVF,Bb was significantly lower than that of CVF,Bb. These results suggest the involvement of Met in CVF binding of C5. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gowda, DC (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NR 33 TC 5 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS AUST PI MARRICKVILLE PA LOCKED BAG 16, MARRICKVILLE, NSW 2204, AUSTRALIA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD JUN PY 1998 VL 45 IS 1 BP 133 EP 144 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT872 UT WOS:000074136800013 PM 9635137 ER PT J AU Kondrashin, AA Nesterova, MV Cho-Chung, YS AF Kondrashin, AA Nesterova, MV Cho-Chung, YS TI Subcellular distribution of the R-subunits of cAMP-dependent protein kinase in LS-174T human colon carcinoma cells SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article DE cAMP-dependent protein kinase; regulatory subunits; subcellular localization ID REGULATORY SUBUNIT; RECEPTOR; MEMBRANE; PHOSPHORYLATION; EXPRESSION; LIGAND AB The analysis of the particulate preparations of LS-174T human colon carcinoma cells in confluent stage of growth revealed different distribution for regulatory subunits (R) of cAMP-dependent protein kinase (PKA) in the subcellular compartments. The LS-174T cell lysates were subjected to differential and discontinuous sucrose density gradient centrifugation. The obtained fractions were assayed for marker enzymes and photoaffinity labeled with 8-N-3[P-32]cAMP. The whole lysates and cytoplasmic fraction exhibited the presence of both RI alpha and RII alpha - subunits of PKA. The fractions exhibiting high activity of the marker enzymes for plasma membranes, Golgi apparatus and mitochondria contained mainly RII alpha. In the fractions of lysosomes and microsomes RI alpha and RII alpha were found in nearly equal amounts. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bldg 10,Rm 5B05, Bethesda, MD 20892 USA. NR 27 TC 6 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS AUST PI MARRICKVILLE PA LOCKED BAG 16, MARRICKVILLE, NSW 2204, AUSTRALIA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD JUN PY 1998 VL 45 IS 2 BP 237 EP 244 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX793 UT WOS:000074556000003 PM 9678244 ER PT J AU Doanes, AM Irani, K Goldschmidt-Clermont, PJ Finkel, T AF Doanes, AM Irani, K Goldschmidt-Clermont, PJ Finkel, T TI A requirement for rac1 in the PDGF-stimulated migration of fibroblasts and vascular smooth cells SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article DE adenovirus; migration; Rac1; PDGF; signal transduction ID GROWTH-FACTOR; PHOSPHATIDYLINOSITOL-3 KINASE; SIGNALING PATHWAYS; RECEPTOR-BETA; MUSCLE CELLS; ACTIVATION; BINDING; PROTEIN; PHOSPHORYLATION; GENE AB Rad is a member of the Rho family of small GTPases. Although rad has been demonstrated to regulate the cytoskeleton, relatively little is known regarding its role in directional migration of mammalian cells. To address this issue, we have used recombinant adenoviruses to transiently express in fibroblasts either a dominant negative (N17rac1) or constitutively active (V12rac1) isoform of the small GTP-binding protein rac1. Expression of N17rac1 is demonstrated to inhibit PDGF-stimulated migration of rat fibroblasts. Surprisingly, expression of V12rac1 also inhibited, albeit to a lesser degree, the chemotactic response to PDGF. In contrast, expression of N17rac1 had no effect on PDGF stimulation of mitogen activated protein kinase (MAPK) or the adherence of cells to plastic or fibronectin coated surfaces. Similar to what was observed in fibroblasts, expression of N17rac1 inhibited the PDGF-stimulated migration of primary vascular smooth muscle cells. These results identify rac1 as an important downstream mediator of PDGF-induced chemotaxis. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Sch, Div Cardiol, Baltimore, MD USA. Ohio State Univ, Heart & Lung Inst, Columbus, OH 43210 USA. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 7B15,MSC 1650, Bethesda, MD 20892 USA. NR 30 TC 29 Z9 36 U1 0 U2 1 PU ACADEMIC PRESS AUST PI MARRICKVILLE PA LOCKED BAG 16, MARRICKVILLE, NSW 2204, AUSTRALIA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD JUN PY 1998 VL 45 IS 2 BP 279 EP 287 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZX793 UT WOS:000074556000008 PM 9678249 ER PT J AU Green Goldman, RD Forgacs, G Chen, C Stewart, M Steinert, PM AF Green Goldman, RD Forgacs, G Chen, C Stewart, M Steinert, PM TI Intermediate filament cytoskeletal system: Dynamic and mechanical properties - Discussion SO BIOLOGICAL BULLETIN LA English DT Editorial Material C1 Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Cell Mol & Struct Biol, Chicago, IL 60611 USA. Clarkson Univ, Dept Phys, Potsdam, NY 13676 USA. Columbia Univ, Coll Phys & Surg, Dept Anat & Cell Biol, New York, NY 10032 USA. MRC Ctr, Mol Biol Lab, Cambridge CB2 2QH, England. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Boston, MA 02115 USA. RP Green (reprint author), Northwestern Univ, Sch Med, Dept Pathol, 303 E Chicago Ave, Chicago, IL 60611 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARINE BIOLOGICAL LABORATORY PI WOODS HOLE PA 7 MBL ST, WOODS HOLE, MA 02543 USA SN 0006-3185 J9 BIOL BULL JI Biol. Bull. PD JUN PY 1998 VL 194 IS 3 BP 362 EP 363 PG 2 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA ZZ709 UT WOS:000074759100033 ER PT J AU Steinert, PM AF Steinert, PM TI Structural-mechanical integration of keratin intermediate filaments with cell peripheral structures in the cornified epidermal keratinocyte SO BIOLOGICAL BULLETIN LA English DT Article; Proceedings Paper CT Workshop on the Cytoskeleton - Mechanical, Physical, and Biological Interactions CY NOV 15-17, 1996 CL MARINE BIOL LAB, WOODS HOLE, MASSACHUSETTS SP Marine Biol Lab, Ctr Adv Studies Space Life Sci, NASA HO MARINE BIOL LAB ID PROLINE-RICH PROTEIN-1; ENVELOPE; EXPRESSION; LORICRIN C1 NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steinert, PM (reprint author), NIAMSD, Skin Biol Lab, NIH, Bldg 6,Room 425, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 6 U1 0 U2 1 PU MARINE BIOLOGICAL LABORATORY PI WOODS HOLE PA 7 MBL ST, WOODS HOLE, MA 02543 USA SN 0006-3185 J9 BIOL BULL JI Biol. Bull. PD JUN PY 1998 VL 194 IS 3 BP 367 EP 368 DI 10.2307/1543115 PG 2 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA ZZ709 UT WOS:000074759100036 PM 9664665 ER PT J AU Coulombe, PA Steinert, PM Goldman, RD Green Janmey, PA Borisy, GB AF Coulombe, PA Steinert, PM Goldman, RD Green Janmey, PA Borisy, GB TI Structural-mechanical integration of keratin intermediate filaments with cell peripheral structures in the cornified epidermal keratinocyte - Discussion SO BIOLOGICAL BULLETIN LA English DT Editorial Material C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Univ Wisconsin, Dept Mol Biol & Zool, Madison, WI 53706 USA. Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Cell Mol & Struct Biol, Chicago, IL 60611 USA. Brigham & Womens Hosp, Div Expt Med, Boston, MA 02115 USA. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Coulombe, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARINE BIOLOGICAL LABORATORY PI WOODS HOLE PA 7 MBL ST, WOODS HOLE, MA 02543 USA SN 0006-3185 J9 BIOL BULL JI Biol. Bull. PD JUN PY 1998 VL 194 IS 3 BP 369 EP 370 PG 2 WC Biology; Marine & Freshwater Biology SC Life Sciences & Biomedicine - Other Topics; Marine & Freshwater Biology GA ZZ709 UT WOS:000074759100037 ER PT J AU Adler, CM Goldberg, TE Malhotra, AK Pickar, D Breier, A AF Adler, CM Goldberg, TE Malhotra, AK Pickar, D Breier, A TI Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers SO BIOLOGICAL PSYCHIATRY LA English DT Article DE N-methyl-D-aspartate; ketamine; cognition; thought disorder; working memory ID SCHIZOPHRENIC-PATIENTS; DYSFUNCTION AB Background: The N-methyl-D-aspartate receptor antagonist, ketamine, produces a clinical syndrome of thought disorder perceptual distortion, and cognitive impairment. Methods: We have administered ketamine to healthy volunteers to characterize the formal thought disorder and specific memory dysfunction associated with ketamine. Ten healthy volunteers underwent a double-blind, placebo-controlled, ketamine infusion (0.12 mg/kg bolus and 0.65 mg/kg/hour). Thought disorder was evaluated with the Scale for the Assessment of Thought, Language and Communication. Cognitive resting involved working and semantic memory tasks. Results: Ketamine produced a formal thought disorder, as well as impairments in working and semantic memory. The degree of ketamine-induced thought disorder significantly correlated with ketamine-induced decreases in working memory and did not correlate with ketamine-induced impairments in semantic memory. Conclusions: This study characterizes the formal thought disorder associated with ketamine and may suggest that ketamine-induced deficits in working memory are associated with ketamine-induced thought disorder. Published 1998 Society of Biological Psychiatry. C1 NIMH, Expt Therapeut Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Malhotra, AK (reprint author), Hillside Hosp, 75-59 263rd St, Glen Oaks, NY 11004 USA. NR 23 TC 151 Z9 155 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 1998 VL 43 IS 11 BP 811 EP 816 DI 10.1016/S0006-3223(97)00556-8 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ZP304 UT WOS:000073738900005 PM 9611670 ER PT J AU Wehr, TA Turner, EH Shimada, JM Lowe, CH Barker, C Leibenluft, E AF Wehr, TA Turner, EH Shimada, JM Lowe, CH Barker, C Leibenluft, E TI Treatment of a rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep SO BIOLOGICAL PSYCHIATRY LA English DT Article DE rapidly cycling bipolar disorder; depression; mania; sleep; sleep deprivation; motor activity; light; photoperiod; circadian rhythm ID AFFECTIVE-DISORDERS; PHASE ADVANCE; WAKE CYCLE; ILLNESS; MOOD; MANIA AB Background: The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night. Methods: We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings. Results: The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark. Conclusions: Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients. Published 1998 Society of Biological Psychiatry. C1 NIMH, Clin Psychobiol Branch, Bethesda, MD 20892 USA. RP Wehr, TA (reprint author), NIMH, Clin Psychobiol Branch, Room 3S-231,Bldg 10,10 Ctr Dr MSC1390, Bethesda, MD 20892 USA. RI Turner, Erick/A-4848-2008 OI Turner, Erick/0000-0002-3522-3357 NR 28 TC 86 Z9 90 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 1 PY 1998 VL 43 IS 11 BP 822 EP 828 DI 10.1016/S0006-3223(97)00542-8 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA ZP304 UT WOS:000073738900007 PM 9611672 ER PT J AU Dunson, DB AF Dunson, DB TI Dose-dependent number of implants and implications in developmental toxicity SO BIOMETRICS LA English DT Article DE data augmentation; generalized estimating equations; multiple imputations; teratology ID TOXICOLOGICAL EXPERIMENTS; TERATOLOGICAL EXPERIMENTS; RESPONSE MODELS; DISTRIBUTIONS AB This paper proposes a method for assessing risk in developmental toxicity studies with exposure prior to implantation. The method proposed in this paper was developed to account for a dose-dependent trend in the number of implantation sites per dam, which is a common problem in studies with exposure prior to implantation. Toxins may have the effect of interfering with the early reproductive process, which can prevent implantation in the uterine wall. An imputation procedure is presented for estimating the number of potential fetuses by sampling from the empirical distribution of the number of implants per litter in the control group. The marginal death outcomes and the joint malformation and survival outcomes for each potential fetus can be estimated using multiple imputation or the chained data augmentation algorithm. Legit models can then be fit and used to estimate the effect of dose on reducing the probability of a normal birth. These models accommodate multiple covariate effects and can be applied to low-dose extrapolation. A simulation study is done to evaluate the properties of model-based estimators of the mean response and the virtually safe dose level (VSD). It was found that both estimates were good approximations of the underlying dose effect. A dominant lethal assay data set (Luning et al., 1966, Mutation Research 3, 444-451) is analyzed, and the results are compared with those of Rai and Van Ryzin (1985, Biometrics 41, 1-9). C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03, Res Triangle Pk, NC 27709 USA. EM dunson@calvin.niehs.nih.gov NR 20 TC 7 Z9 7 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 808 17TH ST NW SUITE 200, WASHINGTON, DC 20006-3910 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 1998 VL 54 IS 2 BP 558 EP 569 DI 10.2307/3109763 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA ZU099 UT WOS:000074161600013 PM 9629644 ER PT J AU Kaulin, YA Schagina, LV Bezrukov, SM Malev, VV Feigin, AM Takemoto, JY Teeter, JH Brand, JG AF Kaulin, YA Schagina, LV Bezrukov, SM Malev, VV Feigin, AM Takemoto, JY Teeter, JH Brand, JG TI Cluster organization of ion channels formed by the antibiotic syringomycin E in bilayer lipid membranes SO BIOPHYSICAL JOURNAL LA English DT Article ID CONDUCTANCE STATES; PSEUDOMONAS-SYRINGAE; SODIUM-CHANNEL; PHYTOTOXIN; MECHANISM AB The cyclic lipodepsipeptide, syringomycin E, when incorporated into planar lipid bilayer membranes, forms two types of channels (small and large) that are different in conductance by a factor of sixfold. To discriminate between a cluster organization-type channel structure and other possible different structures for the two channel types, their ionic selectivity and pore size were determined. Pore size was assessed using water-soluble polymers, ion selectivity was found to be essentially the same for both the small and large channels. Their reversal (zero current) potentials with the sign corresponding to anionic selectivity did not differ by more than 3 mV at a twofold electrolyte gradient across the bilayer. Reduction in the single-channel conductance induced by poly(ethylene glycol)s of different molecular weights demonstrated that the aqueous pore sizes of the small and large channels did not differ by more than 2% and were close to 1 nm. Based on their virtually identical selectivity and size, we conclude that large syringomycin E channels are clusters of small ones exhibiting synchronous opening and closing. C1 Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. NICHD, NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Nucl Phys, Gatchina 188350, Russia. Utah State Univ, Logan, UT 84322 USA. Univ Penn, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Brand, JG (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM brand@monell.org RI Takemoto, Jon/A-5309-2011 OI Takemoto, Jon/0000-0001-9919-9168 FU NIDCD NIH HHS [DC-00356, DC-01838] NR 25 TC 66 Z9 69 U1 1 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 1998 VL 74 IS 6 BP 2918 EP 2925 PG 8 WC Biophysics SC Biophysics GA ZT214 UT WOS:000074061500020 PM 9635746 ER PT J AU Frisbie, SM Xu, S Chalovich, JM Yu, LC AF Frisbie, SM Xu, S Chalovich, JM Yu, LC TI Characterizations of cross-bridges in the presence of saturating concentrations of MgAMP-PNP in rabbit permeabilized psoas muscle SO BIOPHYSICAL JOURNAL LA English DT Article ID X-RAY-DIFFRACTION; INSECT FLIGHT-MUSCLE; ACTOMYOSIN ADENOSINE-TRIPHOSPHATASE; RELAXED FIBER STIFFNESS; P-N-P; SKELETAL-MUSCLE; MYOSIN SUBFRAGMENT-1; F-ACTIN; TROPONIN-TROPOMYOSIN; ROTATIONAL-DYNAMICS AB Several earlier studies have led to different conclusions about the complex of myosin with MgAMP-PNP. It has been suggested that subfragment 1 of myosin (S1)-MSAMP-PNP forms an S1-MgADP-like state, an intermediate between the myosin S1-MgATP and myosin S1-MgADP states or a mixture of cross-bridge states. We suggest that the different states observed result from the failure to saturate S1 with MgAMP-PNP. At saturating MgAMP-PNP, the interaction of myosin S1 with actin is very similar to that which occurs in the presence of MgATP. 1) At 1 degrees C and 170 mM ionic strength the equatorial x-ray diffraction intensity ratio I-11/I-10 decreased with an increasing MgAMP-PNP concentration and leveled off by similar to 20 mM MgAMP-PNP. The resulting ratio was the same for MgATP-relaxed fibers. 2) The two dimensional x-ray diffraction patterns from MgATP-relaxed and MgAMP-PNP-relaxed bundles are similar. 3) The affinity of S1-MgAMP-PNP for the actin-tropomyosin-troponin complex in solution in the absence of free calcium is comparable with that of S1-MgATP. 4) In the presence of calcium, I-11/I-10 decreased toward the relaxed value with increasing MgAMP-PNP, signifying that the affinity between cross-bridge and actin is weakened by MgAMP-PNP. 5) The degree to which the equatorial intensity ratio decreases as the ionic strength increases is similar in MgAMP-PNP and MgATP. Therefore, results from both fiber and solution studies suggest that MgAMP-PNP acts as a non hydrolyzable MgATP analogue for myosin. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. E Carolina Univ, Sch Med, Greenville, NC 27834 USA. RP Yu, LC (reprint author), NIAMSD, NIH, Bldg 6,Room 408, Bethesda, MD 20892 USA. EM lcyu@helix.nih.gov OI Chalovich, Joseph/0000-0002-1243-4055 FU NIAMS NIH HHS [AR35126, R01 AR035216] NR 50 TC 10 Z9 10 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 JUN PY 1998 VL 74 IS 6 BP 3072 EP 3082 PG 11 WC Biophysics SC Biophysics GA ZT214 UT WOS:000074061500035 PM 9635761 ER PT J AU Xia, P Bungay, PM Gibson, CC Kovbasnjuk, ON Spring, KR AF Xia, P Bungay, PM Gibson, CC Kovbasnjuk, ON Spring, KR TI Diffusion coefficients in the lateral intercellular spaces of Madin-Darby canine kidney cell epithelium determined with caged compounds SO BIOPHYSICAL JOURNAL LA English DT Article ID FLUORESCENCE PHOTOBLEACHING RECOVERY; FLOW; MONOLAYERS; MOBILITY; RELEASE AB The diffusion coefficients of two caged fluorescent dyes were measured in free solution and in the lateral intercellular spaces (LIS) of cultured Madin-Darby canine kidney (MDCK) cells after photoactivation by illumination with a continuous or pulsed UV laser. Both quantitative video imaging and a new photometric method were utilized to determine the rates of diffusion of the caged fluorescent dyes: 8-((4,5-dimethoxy-2-nitrobenzyl)oxy)pyrene-1,3,6-trisulfonic acid (DMNB-HPTS) and (4,5-dimethoxy-2-nitrobenzyl) fluorescein dextran (10,000 MW) (DMNB-caged fluorescein dextran). The diffusion coefficients at 37 degrees C in free solution were 3.3 x 10(-6) cm(2)/s (HPTS) and 0.98 x 10(-6) cm(2)/s (10,000 MW dextran). Diffusion of HPTS within nominally linear stretches of the LIS of MDCK cells grown on glass coverslips was indistinguishable from that in free solution, whereas dextran showed a 1.6 +/- 0.5-fold reduction in diffusivity. Measurements of HPTS diffusion within the LIS of multicellular regions also exhibited a diffusivity comparable to the free solution value. The restriction to diffusion of the dextran within the LIS may be due to molecular hindrance. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Res Resources, Biomed Engn & Instrumentat Program, Bethesda, MD 20892 USA. RP Spring, KR (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. NR 23 TC 30 Z9 30 U1 0 U2 1 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 1998 VL 74 IS 6 BP 3302 EP 3312 PG 11 WC Biophysics SC Biophysics GA ZT214 UT WOS:000074061500058 PM 9635784 ER PT J AU Sasaki, CY Passaniti, A AF Sasaki, CY Passaniti, A TI Identification of anti-invasive but noncytotoxic chemotherapeutic agents using the tetrazolium dye MTT to quantitate viable cells in Matrigel SO BIOTECHNIQUES LA English DT Article ID COMPONENTS; GROWTH; ASSAY AB Screening methods for chemotherapeutic agents usually rely on the cytotoxic properties of the drugs. However; agents that inhibit invasion may have more efficacy and cause fewer side effects. Various cellular invasion assays have been used to evaluate these types of compounds, including the modified Boyden chamber; monolayer wound models and Matrigel outgrowth assays. In this report, we have combined the use of the Matrigel outgrowth assay with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) visualization and cell viability dye to visualize invasive cells on Matrigel without magnification. Extraction of the dye to formazan by-product allows cell viability to be assessed. Using several invasive and noninvasive cell lines, the utility of the method for various target cells was verified. Several established chemotherapeutic agents were also screened for their anti-invasive and/or cytotoxic effects when cultured on Matrigel. Our results suggest that this method may be an easy, inexpensive and nonradioactive alternative for both enumerating cells on Matrigel and screening various tumor cell lines treated with chemotherapeutic agent to look for compounds with noncytotoxic but anti-invasive properties. C1 NIA, NIH, Gerontol Res Ctr, Biol Chem Lab, Baltimore, MD 21224 USA. RP Sasaki, CY (reprint author), NIA, NIH, Gerontol Res Ctr, Biol Chem Lab, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 9 TC 23 Z9 23 U1 1 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 JUN PY 1998 VL 24 IS 6 BP 1038 EP 1043 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA ZT019 UT WOS:000074039500026 PM 9631200 ER PT J AU Fowler, DH Whitfield, B Livingston, M Chrobak, P Gress, RE AF Fowler, DH Whitfield, B Livingston, M Chrobak, P Gress, RE TI Non-host-reactive donor CD8(+) T cells of Tc2 phenotype potently inhibit marrow graft rejection SO BLOOD LA English DT Article ID ALLOGENEIC MARROW; LYMPHOCYTES-T; EFFECTOR POPULATIONS; VETO CELLS; TRANSPLANTATION; DISEASE; EXPRESSION; MICE; PREVENTION; MECHANISM AB Donor CD8(+) T cells capable of host reactivity inhibit marrow graft rejection, but also generate graft-versus-host disease (GVHD). To evaluate whether the Tc1- and Tc2-type subsets of CD8 cells might inhibit rejection without host reactivity, we established an F1 into-parent murine bone marrow transplant model. Donor Tc1 and Tc2 cells were generated that preferentially secreted type I or type II cytokines; both subsets possessed potent cytolytic function, and clonally deleted host-type allospecific precursor CTL in vitro, B6 hosts receiving 950 cGy irradiation did not reject the donor marrow (F1 chimerism of 78.6%; n = 10), whereas hosts receiving 650 cGy rejected the donor marrow (3.8% chimerism; n = 8). At 650 cGy irradiation, the addition of Tc2 cells to the F1 marrow resulted in extensive F1 chimerism (70.8%) in 8 of 8 recipients; in contrast, alloengraftment was not consistently observed in mice receiving Tc1 cells or unmanipulated CD8 cells. Furthermore, when the preparative regimen was further reduced to 600 cGy, only hosts receiving the Tc2-type cells did not reject the F1 marrow. We conclude that Tc2 cells potently inhibit marrow graft rejection without inducing an alloaggressive response and that non-host-reactive Tc2 cells therefore facilitate engraftment across genetic barriers with reduced GVHD. (C) 1998 by The American Society of Hematology. C1 NCI, Transplantat Therapy Sect, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Fowler, DH (reprint author), NCI, Transplantat Therapy Sect, Med Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. NR 26 TC 22 Z9 25 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 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 1998 VL 91 IS 11 BP 4045 EP 4050 PG 6 WC Hematology SC Hematology GA ZP871 UT WOS:000073797000005 PM 9596648 ER PT J AU Kim, MJ Cooper, DD Hayes, SF Spangrude, GJ AF Kim, MJ Cooper, DD Hayes, SF Spangrude, GJ TI Rhodamine-123 staining in hematopoietic stem cells of young mice indicates mitochondrial activation rather than dye efflux SO BLOOD LA English DT Article ID GLYCOPROTEIN GENE LEADS; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; TUMOR-CELLS; BONE-MARROW; REPOPULATING ABILITY; PROGENITOR CELLS; IN-VIVO; TRANSPORTER; LYMPHOCYTES AB Low-intensity fluorescence of rhodamine-123 (Rh-123) discriminates a quiescent hematopoietic stem cell (HSC) population in mouse bone marrow, which provides stable, longterm hematopoiesis after transplantation. Rh-123 labels mitochondria with increasing intensity proportional to cellular activation, however the intensity of staining also correlates with the multidrug resistance (MDR) phenotype, as Rh-123 is a substrate for P-glycoprotein (P-gp). To address the mechanisms of long-term repopulating HSC discrimination by Rh-123, mouse bone marrow stem and progenitor cells were isolated based on surface antigen expression and subsequently separated into subsets using various fluorescent probes sensitive to mitochondrial characteristics and/or MDR function. We determined the cell cycle status of the separated populations and tested for HSC function using transplantation assays. Based on blocking studies using MDR modulators, we observed little efflux of Rh-123 from HSC obtained from young (3- to 4-week-old) mice, but significant efflux from HSC derived from older animals. A fluorescent MDR substrate (Bodipy-verapamil, BodVer) and Rh-123 both segregated quiescent cells into a dim-staining population, however Rh-123-based separations resulted in better enrichment of HSC function. Similar experiments using two other fluorescent probes with specificity for either mitochondrial mass or membrane potential indicated that mitochondrial activation is more important than either mitochondrial mass or MDR function in defining HSC in young mice. This conclusion was supported by morphologic studies of cell subsets separated by Rh-123 staining. (C) 1998 by The American Society of Hematology. C1 Univ Utah, Dept Pathol, Div Cell Biol & Immunol, Salt Lake City, UT 84132 USA. Univ Utah, Dept Med, Div Hematol Oncol, Salt Lake City, UT 84132 USA. NIAID, Microscopy Branch, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Spangrude, GJ (reprint author), Univ Utah, Dept Pathol, Div Cell Biol & Immunol, Room 5C 130 SOM, Salt Lake City, UT 84132 USA. FU NCI NIH HHS [P30 CA42014]; NHLBI NIH HHS [R01 HL56857]; NIDDK NIH HHS [P50 DK49219] NR 43 TC 100 Z9 101 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 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 1998 VL 91 IS 11 BP 4106 EP 4117 PG 12 WC Hematology SC Hematology GA ZP871 UT WOS:000073797000013 PM 9596656 ER PT J AU Laethem, RM Hannun, YA Jayadev, S Sexton, CJ Strum, JC Sundseth, R Smith, GK AF Laethem, RM Hannun, YA Jayadev, S Sexton, CJ Strum, JC Sundseth, R Smith, GK TI Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843 SO BLOOD LA English DT Article ID CERAMIDE-INDUCED APOPTOSIS; NECROSIS-FACTOR-ALPHA; SIGNALING PATHWAY; DOWNSTREAM TARGET; ANTICANCER DRUGS; LEUKEMIA-CELLS; PROTEIN; DEATH; RECEPTOR; 1843U89 AB Thymidylate synthase (TS) inhibition causes cell death, and this enzyme is the target for the important chemotherapy regime 5-fluorouracil/leucovorin. GW1843 (1843U89) is a potent and specific folate analog TS inhibitor in clinical development. Because of the importance of TS as a chemotherapy target, we are studying the mechanism of TS inhibition-induced cell death by GW1843. Ceramide:is a regulatory lipid generated by the action of sphingomyelinase and is believed to signal apoptosis. The role of the ceramide in apoptotic signaling was studied in Molt-4 human T-cell leukemia cells undergoing cell death after treatment with GW1843. In response to GW1843, Molt-4 cells undergo apoptosis with both acidic pH, Mg2+-independent sphingomyelinase (ASMase) and neutral pH, Mg2+-dependent sphingomyelinase (NSMase) activities elevated as early steps in the initiation of apoptosis before Molt-4 commitment to death. These activities lead to ceramide production with kinetics consistent with a role as an effector molecule signaling the initiation of apoptosis in Molt-C cells. These changes were found to be independent of caspase 3-like (CPP32/apopain) activity and DNA degradation, but were not separable from membrane blabbing or cell lysis in this cell line. In this report, kinetic evidence is provided for a role of ceramide in initiating GW1843-induced cell death of Molt-4 T cell leukemia cells. (C) 1998 by The American Society of Hematology. C1 Glaxo Wellcome Inc, Int Sci Dev Grp, Res Triangle Pk, NC 27709 USA. Glaxo Wellcome Inc, Dept Mol Sci, Res Triangle Pk, NC 27709 USA. Glaxo Wellcome Inc, Dept Funct Genet, Res Triangle Pk, NC 27709 USA. Glaxo Wellcome Inc, Dept Mol Biochem, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Andcare Inc, Durham, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Laethem, RM (reprint author), Glaxo Wellcome Inc, Int Sci Dev Grp, 5 Moore Dr, Res Triangle Pk, NC 27709 USA. NR 53 TC 28 Z9 29 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 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 1998 VL 91 IS 11 BP 4350 EP 4360 PG 11 WC Hematology SC Hematology GA ZP871 UT WOS:000073797000041 PM 9596684 ER PT J AU Hoshino, T Wang, JX Devetten, MP Iwata, N Kajigaya, S Wise, RJ Liu, JM Youssoufian, H AF Hoshino, T Wang, JX Devetten, MP Iwata, N Kajigaya, S Wise, RJ Liu, JM Youssoufian, H TI Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression SO BLOOD LA English DT Article ID ENDOPLASMIC-RETICULUM; GLYCOPROTEIN-B; GENE; COMPLEMENTATION; CELLS; FACC; LOCALIZATION; INDUCTION; GRP78; INTERFERON AB The FAC protein encoded by the gene defective in Fanconi anemia (FA) complementation group C binds to at least three ubiquitous cytoplasmic proteins in vitro. We used here the complete coding sequence of FAC in a yeast two-hybrid screen to identify interacting proteins. The molecular chaperone GRP94 was isolated twice from a B-lymphocyte cDNA library. Binding was confirmed by coimmunoprecipitation of FAC and GRP94 from cytosolic, but not nuclear, lysates of transfected COS-1 cells, as well as from mouse liver cytoplasmic extracts. Deletion mutants of FAC showed that residues 103-308 were required for interaction with GRP94, and a natural splicing mutation within the IVS-4 of FAC that removes residues 111-148 failed to bind GRP94. Ribozyme-mediated inactivation of GRP94 in the rat NRK cell line led to significantly reduced levels of immunoreactive FAC and concomitant hypersensitivity to mitomycin C, similar to the cellular phenotype of FA. Our results demonstrate that GRP94 interacts with FAC both in vitro and in vivo and regulates its intracellular level in a cell culture model. In addition, the pathogenicity of the IVS-4 splicing mutation in the FAC gene may be mediated in part by its inability to bind to GRP94. (C) 1998 by The American Society of Hematology. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Hematol Oncol, Boston, MA USA. RP Youssoufian, H (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL52138, P01 HL42443] NR 50 TC 47 Z9 47 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 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 1998 VL 91 IS 11 BP 4379 EP 4386 PG 8 WC Hematology SC Hematology GA ZP871 UT WOS:000073797000045 PM 9596688 ER PT J AU Passweg, JR Rowlings, PA Atkinson, KA Barrett, AJ Gale, RP Gratwohl, A Jacobsen, N Klein, JP Ljungman, P Russell, JA Schaefer, UW Sobocinski, KA Vossen, JM Zhang, MJ Horowitz, MM AF Passweg, JR Rowlings, PA Atkinson, KA Barrett, AJ Gale, RP Gratwohl, A Jacobsen, N Klein, JP Ljungman, P Russell, JA Schaefer, UW Sobocinski, KA Vossen, JM Zhang, MJ Horowitz, MM TI Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia SO BONE MARROW TRANSPLANTATION LA English DT Article DE allogeneic bone marrow transplantation; infection prophylaxis; protective isolation ID LAMINAR AIR-FLOW; VERSUS-HOST DISEASE; PROPHYLACTIC SYSTEMIC ANTIBIOTICS; EARLY INFECTIOUS COMPLICATIONS; RECIPIENTS; GRAFT; RISK; DECONTAMINATION; COLONIZATION; CULTURES AB Various isolation strategies are used to prevent infections during bone marrow transplantation; data on their efficacy are lacking. We studied whether use of high efficiency particulate air filtration (HEPA) and/or laminar airflow (LAF) units affect transplant-related mortality (TRM) or survival in the first year after allogeneic transplantation. 5065 patients with leukemia receiving bone marrow transplants from an HLA identical sibling (n = 3982) or alternative related or unrelated donors (n = 1083) between 1988 and 1992 were reported to the International Bone Marrow Transplant Registry by 222 teams. Two types of isolation were considered: (1) conventional protective isolation with single patient room and any combination of hand-washing, gloves, mask and gown; and (2) HEPA and/or LAF. Cox proportional hazards regression models were used to determine the relative risks (RRs) of transplant-related mortality (TRM) and of deaths from any cause in patients treated in HEPA/LAF units compared to patients treated in conventional isolation. HLA-identical sibling and alternative donor transplants were analyzed separately. Risks of TRM and overall mortality in the first 100 days post-transplant were significantly lower among patients treated in HEPA/LAF units than in those treated conventionally. RRs of TRM were 0.76 (P = 0.009) for recipients of HLA-identical sibling transplants and 0.65 (P = 0.003) for recipients of alternative donor transplants. Correspondingly RRs of overall mortality were 0.80 (P = 0.02) and 0.65 (P = 0.0006). Decreased risks of TRM and of death in the first 100 days post-transplant resulted in significantly higher 1-year survival rates in patients treated in HEPA/LAF rather than in conventional isolation units. Use of HEPA and/or LAF to prevent infections decreases TRM and increases survival after allogeneic bone marrow transplants for leukemia. C1 Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Hlth Policy Inst, Milwaukee, WI 53226 USA. NHLBI, Bethesda, MD 20892 USA. St Vincents Hosp, Dept Med, Darlinghurst, NSW 2010, Australia. Salick Hlth Care, Div Bone Marrow & Stem Cell Transplantat, Los Angeles, CA USA. Kantonsspital, CH-4031 Basel, Switzerland. Rigshosp, Dept Haematol, DK-2100 Copenhagen, Denmark. Huddinge Hosp, Dept Med, S-14186 Huddinge, Sweden. Alberta Bone Marrow Transplant Program, Calgary, AB, Canada. Univ Essen Gesamthsch, Dept Bone Marrow Transplantat, D-4300 Essen 1, Germany. Univ Leiden Hosp, Dept Pediat, NL-2300 RC Leiden, Netherlands. RP Horowitz, MM (reprint author), Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Hlth Policy Inst, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. FU NCI NIH HHS [P01-CA-40053] NR 35 TC 69 Z9 69 U1 0 U2 2 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JUN PY 1998 VL 21 IS 12 BP 1231 EP 1238 DI 10.1038/sj.bmt.1701238 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA ZX054 UT WOS:000074475600011 PM 9674857 ER PT J AU Meyer-Lindenberg, A Bauer, U Krieger, S Lis, S Vehmeyer, K Schuler, G Gallhofer, B AF Meyer-Lindenberg, A Bauer, U Krieger, S Lis, S Vehmeyer, K Schuler, G Gallhofer, B TI The topography of non-linear cortical dynamics at rest, in mental calculation and moving shape perception SO BRAIN TOPOGRAPHY LA English DT Article DE electroencephalography; nonlinear dynamics; correlation dimension; mental calculation; shape perception; cognition ID NONLINEAR EEG MEASURES; TIME-SERIES; STRANGE ATTRACTORS; BRAIN ACTIVITY; SURROGATE DATA; VISUAL-MOTION; ACALCULIA; LOCALIZATION; ACTIVATION; COMPLEXITY AB Differential cortical activation by cognitive processing was studied using dimensional complexity, a measure derived from nonlinear dynamics that indicates the degrees of freedom (complexity) of a dynamic system. We examined the EEG of 32 healthy subjects at rest, during a visually presented calculation task, and during a moving shape perception task. As a nonlinear measure of connectivity, the mutual dimension of selected electrode pairs was used. The first Lyapunov coefficient was also calculated. Data were tested for non-linearity using a surrogate data method and compared to spectral EEG measures (power, coherence). Surrogate data testing confirmed the presence of nonlinear structure in the data. Cognitive activation led to a highly significant rise in dimensional complexity. While both tasks activated central, parietal and temporal areas, mental arithmetic showed frontal activation and an activity maximum at T3, while the moving shape task led to occipital activation and a right parietal activity maximum. Analysis of mutual dimension showed activation of a bilateral temporal-right frontal network in calculation. The Lyapunov coefficient showed clear topographic variation, but was not significantly changed by mental tasks (p<.09). While dimensional complexity was almost unrelated to power values, nonlinear (mutual dimension) and linear (coherence) measures of connectivity shared up to 37% of variance. Data are interpreted in terms of increased cortical complexity as a result of recruitment of asynchronously active, distributed neuronal assemblies in cognition. The topography of nonlinear dynamics are related to neuropsychological and neuroimaging findings on mental calculation and moving shape perception. C1 Univ Giessen, Sch Med, Ctr Psychiat, Giessen, Germany. RP NIMH, Unit PET, Clin Brain Disorders Branch, Bldg 10,Room 4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM meyera@intra.nimh.nih.gov OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Lis, Stefanie/0000-0002-8051-2756 NR 52 TC 22 Z9 26 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 EI 1573-6792 J9 BRAIN TOPOGR JI Brain Topogr. PD SUM PY 1998 VL 10 IS 4 BP 291 EP 299 DI 10.1023/A:1022227108139 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ZX552 UT WOS:000074529500006 PM 9672228 ER PT J AU Phillips, HA MacCallum, J Burns, D Cho-Chung, YS Miller, WR AF Phillips, HA MacCallum, J Burns, D Cho-Chung, YS Miller, WR TI Absence of mutations in sites of key functional importance of the RI alpha and RII beta regulatory subunits of protein kinase A in human breast cancers SO BREAST LA English DT Article ID CYCLIC-AMP BINDING; AMINO-ACID SEQUENCE; ESTROGEN-RECEPTOR; MOLECULAR-CLONING; POINT MUTATIONS; HUMAN TESTIS; GROWTH; POLYMORPHISMS; EXPRESSION; RII(BETA) AB There is evidence that the regulatory subunits (R) of cyclic AMP-dependent protein kinase A (PKA) are important in the biology of breast cancer and that mutations of both RI alpha and RII beta, alter cellular behaviour. Consequently, a PCR-SSCP assay was established to screen for the presence of mutations in and around two functionally important sites: the pseudophosphorylation site of RI alpha and the autophosphorylation site of RII beta, In a cohort of 45 breast cancers, no mutations were found in either area screened. It is concluded that mutation at either of these particular sites is a rare event and is therefore unlikely to be influential in the natural history of most breast cancers. However, the relationship between PKA and breast cancer suggests that it will be important to look for mutations elsewhere as well as identifying factors that influence the relative expression of the regulatory subunits. C1 Univ Edinburgh, Western Gen Hosp, Dept Clin Oncol, ICRF Med Oncol Unit, Edinburgh EH4 2XU, Midlothian, Scotland. NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Phillips, HA (reprint author), Univ Edinburgh, Western Gen Hosp, Dept Clin Oncol, ICRF Med Oncol Unit, Edinburgh EH4 2XU, Midlothian, Scotland. NR 25 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD JUN PY 1998 VL 7 IS 3 BP 139 EP 142 DI 10.1016/S0960-9776(98)90024-8 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ZZ532 UT WOS:000074739000005 ER PT J AU Alexandroff, AB McIntyre, CA Porter, JC Zeuthen, J Vile, RG Taub, DD AF Alexandroff, AB McIntyre, CA Porter, JC Zeuthen, J Vile, RG Taub, DD TI Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE gene and adoptive cancer immunotherapy; cell adhesion; chemotaxis; apoptosis; natural killer cells ID INTEGRIN ALPHA-4-BETA-1; PHYSIOLOGICAL FLOW; MELANOMA-CELLS; T-CELLS; RECEPTORS; ADHESION; LIGAND; LYMPHOCYTES; METASTASIS; EXPRESSION AB The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination, In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimulation, gene and adoptive immunotherapy were also addressed. The purpose of this report is to outline current trends in tumour immunology. C1 Univ Edinburgh, Dept Surg, Edinburgh, Midlothian, Scotland. Univ Sheffield, Sch Med, Inst Canc Studies, Sheffield, S Yorkshire, England. Imperial Canc Res Fund, Leukocyte Adhes Lab, London, England. Danish Canc Soc, Div Canc Biol, DK-2100 Copenhagen, Denmark. Hammersmith Hosp, Imperial Canc Res Fund, Oncol Unit, Lab Mol Therapy, London, England. NIA, Gerontol Res Ctr, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Alexandroff, AB (reprint author), Univ Edinburgh, Royal Infirm Edinburgh, Dept Surg, Lister Labs, Edinburgh EH3 9YW, Midlothian, Scotland. RI Porter, Joanna/C-7162-2009 OI Porter, Joanna/0000-0002-7307-169X NR 31 TC 14 Z9 14 U1 0 U2 0 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 JUN PY 1998 VL 77 IS 11 BP 1806 EP 1811 DI 10.1038/bjc.1998.300 PG 6 WC Oncology SC Oncology GA 194RP UT WOS:000080207600013 PM 9667650 ER PT J AU Cattaneo, M Baglietto, L Zighetti, ML Bettega, D Robertson, C Costa, A Mannucci, PM Decensi, A AF Cattaneo, M Baglietto, L Zighetti, ML Bettega, D Robertson, C Costa, A Mannucci, PM Decensi, A TI Tamoxifen reduces plasma homocysteine levels in healthy women SO BRITISH JOURNAL OF CANCER LA English DT Article DE tamoxifen; homocysteine; chemoprevention; breast cancer; cardiovascular disease ID BREAST-CANCER; POSTMENOPAUSAL WOMEN; ENDOMETRIAL CANCER; ADJUVANT TAMOXIFEN; RANDOMIZED TRIAL; RISK FACTOR; PREVENTION; THROMBOSIS; MORBIDITY; SERUM AB Treatment with tamoxifen is associated with reduced incidence of myocardial infarction, As plasma homocysteine is an independent risk factor for cardiovascular disease, we studied the effects of tamoxifen on plasma homocysteine in 66 healthy women participating in the Italian prevention trial of breast cancer who were randomized in a double-blind manner to tamoxifen 20 mg day(-1) or placebo for 5 years. They were aged between 35 and 70 years, had undergone previous hysterectomy for non-malignant conditions and had no contraindications to the use of tamoxifen. Plasma levels of total homocysteine (tHcy) were measured at randomization and after 2 and 6 months. The mean +/- s.d. plasma levels of tHcy were 7.59 +/- 1.71 mu mol l(-1), 7.25 +/- 1.61 and 7.09 +/- 1.33 in the tamoxifen group and 8.07 +/- 2.06, 7.93 +/- 1.77 and 8.12 +/- 2.04 in the placebo group at 0, 2 and 6 months (P = 0.008 for the between-group difference over time). The higher the baseline tHcy level, the greater was the lowering effect of tamoxifen. No statistically significant effect of age, body mass index or smoking habit on baseline tHcy levels and its variation over time was found, In conclusion, tamoxifen (20 mg day(-1) for 6 months) decreased plasma tHcy levels in healthy women, This effect may contribute to its protective effect on myocardial infarction. C1 Univ Milan, Inst Internal Med, Osped Maggiore, IRCCS,Angelo Bianchi Bonomi Haemophilia & Thrombo, I-20122 Milan, Italy. European Inst Oncol, FIRC Chemoprevent Unit, Div Epidemiol & Biostat, I-20141 Milan, Italy. Natl Canc Inst, Dept Med Oncol 2, I-16132 Genoa, Italy. RP Cattaneo, M (reprint author), Haemophilia & Thrombosis Ctr, Via Pace 9, I-20122 Milan, Italy. RI Mannucci, Pier/C-3102-2014; OI Cattaneo, Marco/0000-0002-7343-4534 NR 29 TC 33 Z9 33 U1 1 U2 1 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 JUN PY 1998 VL 77 IS 12 BP 2264 EP 2266 DI 10.1038/bjc.1998.376 PG 3 WC Oncology SC Oncology GA ZU851 UT WOS:000074242000029 PM 9649143 ER PT J AU Anzai, H Kikuchi, A Kinoshita, A Nishikawa, T AF Anzai, H Kikuchi, A Kinoshita, A Nishikawa, T TI Recurrent annular erythema in juvenile chronic myelogenous leukaemia SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID CHRONIC GRANULOCYTIC-LEUKEMIA; ALLOGENEIC MARROW TRANSPLANTATION; NEUROFIBROMATOSIS; CHILDREN; MYELODYSPLASIA AB Juvenile chronic myelogenous leukaemia (JCML) is a rare haematological malignancy of myelomonocytic lineage that affects patients less than 4 years of age and is known as an entity different from adult-type chronic myelogenous leukaemia. In JCML, skin manifestations are relatively common but most of them have been reported as a non-specific eruption, which histologically may show changes resembling neurofibromatosis or xanthogranuloma. We present a 2-year-old boy with JCML who developed a recurrent annular erythema in which leukaemic infiltrates were confirmed histologically, even though his bone marrow examination suggested that he remained in haematological remission. C1 Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan. Keio Univ, Sch Med, Dept Pediat, Tokyo, Japan. RP Kikuchi, A (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. NR 18 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JUN PY 1998 VL 138 IS 6 BP 1058 EP 1060 PG 3 WC Dermatology SC Dermatology GA ZX811 UT WOS:000074557800023 PM 9747374 ER PT J AU Mavroudis, DA Dermime, S Molldrem, J Jiang, YZ Raptis, A van Rhee, F Hensel, N Fellowes, V Eliopoulos, G Barrett, AJ AF Mavroudis, DA Dermime, S Molldrem, J Jiang, YZ Raptis, A van Rhee, F Hensel, N Fellowes, V Eliopoulos, G Barrett, AJ TI Specific depletion of alloreactive T cells in HLA-identical siblings: a method for separating graft-versus-host and graft-versus-leukaemia reactions SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE graft-versus-host disease; graft-versus-leukaemia; T-cell depletion; specific tolerance ID BONE-MARROW TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; CHRONIC MYELOGENOUS LEUKEMIA; LYMPHOCYTES-T; RECOMBINANT IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; SELECTIVE DEPLETION; DISEASE; PRECURSORS; PREVENTION AB Accumulating evidence indicates that alloreactive donor T cells confer both graft-versus-host (GVH) and graft-versus-leukaemia (GVL) reactivity following allogeneic bone marrow transplantation. We have developed a method to deplete alloreactive donor T cells with an immunotoxin targeting the alpha chain of the IL-2 receptor. In patients with chronic myeloid leukaemia and their HLA-identical sibling donors, we measured donor helper T-lymphocyte precursor frequencies (HTLPf) against recipient peripheral blood mononuclear cells (PBMNC; donor versus host), recipient leukaemia cells (donor versus leukaemia) and third-party PBMNC, before and after the depletion. In seven pairs there was a 4.3-fold reduction of donor-versus-host HTLPf (P = 0.017), without a significant change in the donor frequencies against third party (P = 0.96). In eight further donor-recipient pairs, immunotoxin-depleted donor versus patient PBMNC HTLPf 4.5-fold (mean 1/1 5 5 000 before and 1/839 000 after depletion, P = 0.007). There was a smaller non-significant 1.8-fold reduction in donor-versus-leukaemia HTLPf from 1/192 000 to 1/334 000 (P = 0.19). These results suggest that selective T-cell depletion can significantly deplete donor anti-host reactivity while conserving antileukaemia reactivity in HLA-matched donor-recipient pairs. C1 NHLBI, NIH, Bone Marrow Transplantat Unit, Hematol Branch, Bethesda, MD 20894 USA. NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Hosp Heraklion, Sch Med, Dept Haematol, Crete, Greece. RP Barrett, AJ (reprint author), NHLBI, NIH, Bone Marrow Transplantat Unit, Hematol Branch, 10,7C103,9000 Rockville Pike, Bethesda, MD 20894 USA. RI Dermime, Said/C-6235-2009 OI Dermime, Said/0000-0002-5526-7496 NR 22 TC 54 Z9 56 U1 0 U2 0 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 JUN PY 1998 VL 101 IS 3 BP 565 EP 570 PG 6 WC Hematology SC Hematology GA ZU799 UT WOS:000074236100027 PM 9633903 ER PT J AU Pokharel, GP Regmi, G Shrestha, SK Negrel, AD Ellwein, LB AF Pokharel, GP Regmi, G Shrestha, SK Negrel, AD Ellwein, LB TI Prevalence of blindness and cataract surgery in Nepal SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article AB Background-A national eye care programme was launched in Nepal in the early 1980s. The impact of this programme on blindness and cataract surgery prevalence was evaluated in two geographic zones. Methods-People aged 45 years and older were sampled using a stratified cluster design. Within randomly selected clusters, door to door enumeration was followed by visual acuity measurement and eye examinations at conveniently located sites. The full survey was preceded by a pilot study where operational methods were refined and quality assurance measures carried out. Results-Of the 5112 enumerated individuals 90% were examined. Blindness, defined as presenting visual acuity less than 6/60 in both eyes, was found in 5.3% (95% CI 3.6, 6.8) of individuals examined, with cataract being the principal cause in at least one eye in 78% of cases. Considering both cataract operated and unoperated cataract blind cases, surgical coverage was approximately 42%. Conclusion-The findings suggest that blindness prevalence may have decreased slightly from that estimated in a 1981 national survey, both overall and cataract related. Similarly, cataract surgical coverage may have increased somewhat. None of these changes, however, are at statistically significant levels. Accordingly, the blindness problem remains challengingly high. C1 NEI, Bethesda, MD 20892 USA. Fdn Eye Care, Kathmandu, Nepal. New Era Ltd, Kathmandu, Nepal. Lumbini Rana Ambika Eye Hosp, Bhairahawa, Nepal. WHO, CH-1211 Geneva, Switzerland. RP Ellwein, LB (reprint author), NEI, 31 Ctr Dr,MSC 2510,Bldg 31,Rm 6A-04, Bethesda, MD 20892 USA. FU NEI NIH HHS [N01-EY-2103] NR 4 TC 74 Z9 79 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUN PY 1998 VL 82 IS 6 BP 600 EP 605 DI 10.1136/bjo.82.6.600 PG 6 WC Ophthalmology SC Ophthalmology GA ZU407 UT WOS:000074194000008 PM 9797657 ER PT J AU Pokharel, GP Selvaraj, S Ellwein, LB AF Pokharel, GP Selvaraj, S Ellwein, LB TI Visual functioning and quality of life outcomes among cataract operated and unoperated blind populations in Nepal SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article AB Background-Visual acuity and vision related quality of life outcomes in cataract surgery were evaluated in a population based survey in two geographic zones in Nepal. Methods-Case finding was based on random sampling using a stratified cluster design with door to door enumeration of people aged greater than or equal to 45 years followed by eye examinations at village sites. All aphakics/ pseudophakics, those with visual acuity less than 6/60 in either eye, and a sample of those with normal visual acuity were administered visual functioning (VF) and quality of life (QOL) questionnaires. Results-15% of the 159 cataract operated cases had presenting visual acuity greater than or equal to 6/18 in both eyes, 38% with best corrected visual acuity. 21% were still blind with presenting visual acuity <6/60 in both eyes, 7% with best correction. On a 0-100 scale, mean VF and QOL scores were 87.2 and 93.9 respectively in normally sighted unoperated individuals, dropping to 15.6 and 29.5 for those severely blind (<3/60). Among the cataract operated, mean VF and QOL scores were 47.5 and 55.4, respectively. VF and QOL scores correlated with vision status at statistically significant levels (p <0.0001) Conclusion-Cataract surgery outcomes, whether measured by traditional visual acuity or by patient reported VF/QOL, are at levels many would consider unacceptably low. It is apparent that in the quest to reduce cataract blindness much more attention must be given to improving surgery outcomes. C1 NEI, Bethesda, MD 20892 USA. Fdn Eye Care, Kathmandu, Nepal. Aravind Eye Hosp, Madurai, Tamil Nadu, India. RP Ellwein, LB (reprint author), NEI, 31 Ctr Dr,MSC 2510,Bldg 31,Rm 6A-04, Bethesda, MD 20892 USA. FU NEI NIH HHS [N01-EY-2103] NR 7 TC 72 Z9 82 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUN PY 1998 VL 82 IS 6 BP 606 EP 610 DI 10.1136/bjo.82.6.606 PG 5 WC Ophthalmology SC Ophthalmology GA ZU407 UT WOS:000074194000009 PM 9797658 ER PT J AU Wyatt, RJ Damiani, LM Henter, ID AF Wyatt, RJ Damiani, LM Henter, ID TI First-episode schizophrenia - Early intervention and medication discontinuation in the context of course and treatment SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID LONG-TERM COURSE; FOLLOW-UP; 1ST-EPISODE SCHIZOPHRENIA; EXPRESSED EMOTION; TREATMENT RESPONSE; NATURAL-HISTORY; NORTHWICK PARK; 1ST ADMISSIONS; 1ST-ADMISSION; PREDICTORS AB Background The concept that early intervention with antipsychotic medications improves the long-term course of schizophrenia is discussed. Method This report reviews the literature concerning early intervention with antipsychotic medications for people with first episodes, and how it affects longterm morbidity. It also studies the effects of discontinuing antipsychotic medications on relapse for people with first episodes. Results Early intervention with antipsychotic medications appears to decrease the long-term morbidity of schizophrenia. Conclusions Early intervention with antipsychotic medications should be encouraged for people experiencing their first episode of schizophrenia.This report proposes that studying the various phases of subject response to treatment can be helpful in elucidating when antipsychotic medications should be tapered or withdrawn. C1 NIMH, Neurosci Ctr St Elizabeths, Washington, DC 20032 USA. Univ Virginia, Dept Psychiat, Charlottesville, VA USA. RP Wyatt, RJ (reprint author), NIMH, Neurosci Ctr St Elizabeths, Washington, DC 20032 USA. NR 66 TC 49 Z9 51 U1 2 U2 3 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON, ENGLAND SW1X 8PG SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD JUN PY 1998 VL 172 SU 33 BP 77 EP 83 PG 7 WC Psychiatry SC Psychiatry GA ZU668 UT WOS:000074221200014 PM 9764131 ER PT J AU De Lucca, AJ Bland, JM Grimm, C Jacks, TJ Cary, JW Jaynes, JM Cleveland, TE Walsh, TJ AF De Lucca, AJ Bland, JM Grimm, C Jacks, TJ Cary, JW Jaynes, JM Cleveland, TE Walsh, TJ TI Fungicidal properties, sterol binding, and proteolytic resistance of the synthetic peptide D4E1 SO CANADIAN JOURNAL OF MICROBIOLOGY LA English DT Article DE peptides; fungicidal; Aspergillus spp.; Fusarium spp.; sterols ID ANTIBACTERIAL PEPTIDES; INSECT IMMUNITY; CECROPIN-B; PIG INTESTINE; ASPERGILLUS; MYCOTOXINS; SEQUENCE; PROTEINS; CONIDIA; PUPAE AB The fungicidal properties of the synthetic peptide D4E1 were studied with nongerminated and germinating conidia of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Fusarium moniliforme, and Fusarium oxysporum. The minimal lethal concentrations (MLC) needed to kill 100% of germinating conidia of A. fumigatus, A. flavus, and A. niger were 12.5, 12.5, and 25 mu M, respectively. The MLC value for nongerminated and germinating conidia of both Fusarium spp. was 3.0 mu M. Except for A. fumigatus, D4E1 was inactive against the nongerminated conidia of the Aspergillus spp. Physicochemical studies showed D4E1 complexed with ergosterol, a sterol present in conidial walls. Cholesterol, present in nongerminated conidia of F. moniliforme, had a greater affinity for D4E1 than did ergosterol. D4E1 was more resistant to fungal and plant protease degradation than the natural peptide, cecropin A. These in vitro results suggest D4E1 is a candidate for transgenic expression in plants to enhance host resistance to fungal infection. C1 ARS, So Reg Res Ctr, USDA, New Orleans, LA 70124 USA. Demeter Biotechnol Ltd, Res Triangle Pk, NC 27709 USA. NCI, Immunocompromised Host Sect, NIH, Bethesda, MD 20892 USA. RP De Lucca, AJ (reprint author), ARS, So Reg Res Ctr, USDA, 1100 Robert E Lee Blvd, New Orleans, LA 70124 USA. NR 34 TC 34 Z9 35 U1 1 U2 5 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0008-4166 J9 CAN J MICROBIOL JI Can. J. Microbiol. PD JUN PY 1998 VL 44 IS 6 BP 514 EP 520 DI 10.1139/cjm-44-6-514 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology; Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology; Microbiology GA 114VP UT WOS:000075630100002 PM 9734302 ER PT J AU Yancik, R Wesley, MN Ries, LAG Havlik, RJ Long, S Edwards, BK Yates, JW AF Yancik, R Wesley, MN Ries, LAG Havlik, RJ Long, S Edwards, BK Yates, JW TI Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients - A population-based study SO CANCER LA English DT Article DE colon carcinoma; elderly; comorbidity; aging ID HOSPITAL MORTALITY; CANCER-PATIENTS; OLDER PATIENTS; BREAST-CANCER; STAGE; SURVIVAL AB BACKGROUND. Colon carcinoma primarily affects persons 65 years and older. Seventy-five percent of the incident tumors affect persons in this age group. Because of their advanced age, older patients already may be coping with other concomitant major physical illnesses. This article documents preexisting diseases in older colon carcinoma patients at diagnosis and evaluates the effects of their comorbidity burden on early mortality. METHODS. Prevalence of comorbid conditions was assessed by a retrospective medical records review of an age-stratified random sample of male and female patients aged 55-64 years, 65-74 years, and 75+ years (males, n = 799; females, n = 811). Data were collected on comorbidity by the National Institute on Aging (NIA) and National Cancer Institute (NCI) and merged with NCI Surveillance, Epidemiology, and End Results (SEER) tumor registry data. RESULTS. Hypertension, high impact heart conditions, gastrointestinal problems, arthritis, and chronic obstructive pulmonary disease emerged as the most prominent comorbid conditions in the NIA/NCI SEER Study sample. The prevalence of comorbidity in the number and type of conditions was similar for both men and women (e.g., 40% of each gender had greater than or equal to 5 comorbidities). Within 2 years of diagnosis, 28% (n = 454) of the patients had died. The number of comorbid conditions was significant in predicting early mortality in a model including age, gender, and disease stage (P = 0.0007). Certain comorbidities, classified as "current problem," added significantly to a basic model (e.g., heart problems, alcohol abuse, liver disease, and deep vein thrombosis). CONCLUSIONS. Although disease stage at time of diagnosis of colon carcinoma is a crucial determinant of patient outcome, comorbidity increases the complexity of cancer management and affects survival duration. Cancer control and treatment research questions should address comorbidity issues pertinent to the age group primarily afflicted with colon carcinoma (i.e., the elderly). (C) 1998 American Cancer Society. C1 NIA, Geriatr Program, NIH, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. NCI, Canc Control Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NIA, Epidemiol Biometry & Demog Program, NIH, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Yancik, R (reprint author), NIA, Geriatr Program, NIH, Gateway Bldg,Suite 3E327,7201 Wisconsin Ave MSC 9, Bethesda, MD 20892 USA. NR 41 TC 272 Z9 279 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 0008-543X J9 CANCER JI Cancer PD JUN 1 PY 1998 VL 82 IS 11 BP 2123 EP 2134 DI 10.1002/(SICI)1097-0142(19980601)82:11<2123::AID-CNCR6>3.3.CO;2-N PG 12 WC Oncology SC Oncology GA ZP472 UT WOS:000073756900006 PM 9610691 ER PT J AU Shields, PG Lerman, C Audrain, J Bowman, ED Main, D Boyd, NR Caporaso, NE AF Shields, PG Lerman, C Audrain, J Bowman, ED Main, D Boyd, NR Caporaso, NE TI Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NOVELTY SEEKING; NICOTINE DEPENDENCE; NO EVIDENCE; DRD4 GENE; ASSOCIATION; SCHIZOPHRENIA; POLYMORPHISM; POPULATION; CLOZAPINE; CESSATION AB An understanding of why people smoke cigarettes can have an important impact on smoking prevention and cessation. People smoke cigarettes to maintain nicotine levels in the body, and nicotine has been implicated in the stimulation of brain reward mechanisms via central neuronal dopaminergic pathways. In this study, we evaluated the association of smoking and smoking cessation with a dopamine D4 receptor 48-bp variable nucleotide tandem repeat polymorphism in which the seven-repeat allele (04.7) reduces dopamine affinity. Smokers (n = 283) and nonsmokers (n = 192) were recruited through local media for a case-control study of smoking. After giving informed consent and answering a behavioral questionnaire, smokers underwent a single minimal-contact session of smoking cessation counseling and then were followed for up to 1 year. The frequency of the dopamine D4 receptor genetic polymorphism using PCR was determined, and individuals were classified by the number of repeat alleles (two to five repeats as S and six to eight repeats as L), Persons with those genotypes including only S alleles (homozygote S/S) were compared with those with at least one L allele (heterozygote S/L and homozygote L/L). chi(2) tests of association, Fisher's exact test, and Student's t test were used. Ps were two-tailed. The data show that African-Americans (n = 72) who had at least one L allele had a higher risk of smoking (odds ratio, 7.7; 95% confidence interval, 1.5-39.9; P = 0.006), shorter time to the first cigarette in the morning (P = 0.03), and earlier age at smoking initiation (P = 0.09) compared with homozygote S/S genotypes, After smoking cessation counseling, none of the African-American smokers with an L allele were abstinent at 2 months, compared with 35% of the smokers who were homozygote S/S (P = 0.02), The analysis of Caucasians (n = 403) did not suggest a similar smoking risk for the D4 genotypes (odds ratio, 1.0; 95% confidence interval, 0.6-1.6; P = 0.90), or smoking cessation (P = 0.75), Although the number of African-Americans is small, this study is consistent with the hypothesis that the L alleles increase the risk of smoking because these individuals are prone to use nicotine to stimulate synaptic dopamine transmission. If replicated, the data indicate that a single minimal-contact session of cessation counseling, similar to what is typically provided in primary care physician offices, is ineffective in African-American smokers who have at least one L allele, The finding of an effect for these polymorphic loci in African-Americans, but not Caucasians, suggests that the variable nucleotide tandem repeat studied here is a marker for another polymorphic site in African-Americans, but not in Caucasians. C1 NCI, Mol Epidemiol Sect, Human Carcinogenesis Lab, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Pharmacogenet Sect, Genet Epidemiol Branch, Div Canc epidemiol & Genet, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19020 USA. RP Shields, PG (reprint author), NCI, Mol Epidemiol Sect, Human Carcinogenesis Lab, Div Basic Sci, Bldg 37,Room 2C16, Bethesda, MD 20892 USA. RI Shields, Peter/I-1644-2012 FU PHS HHS [R0163562] NR 53 TC 112 Z9 119 U1 1 U2 6 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 JUN PY 1998 VL 7 IS 6 BP 453 EP 458 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA ZR916 UT WOS:000074029000001 PM 9641486 ER PT J AU Byrne, C Sinha, R Platz, EA Giovannucci, E Colditz, GA Hunter, DJ Speizer, FE Willett, WC AF Byrne, C Sinha, R Platz, EA Giovannucci, E Colditz, GA Hunter, DJ Speizer, FE Willett, WC TI Predictors of dietary heterocyclic amine intake in three prospective cohorts SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AROMATIC-AMINES; FRIED MEAT; BIOLOGICAL SIGNIFICANCE; CYTOCHROME P4501A2; COLORECTAL-CANCER; COLON-CANCER; COOKED FOODS; RISK; CARCINOGENICITY; TEMPERATURE AB Cooking meat creates heterocyclic amines (HCAs) through pyrolysis of amino acids and creatinine. Although recognized as mutagenic, the etiological role of HCA in human cancer is unclear, due to the lack of information on the effect of typical food cooking methods on HCA concentrations and on variation in HCA exposure in populations. We estimated overall daily dietary HCA intake and variation in intake between individuals, using recent data on HCA concentrations in various meats prepared by cooking methods, temperatures, and times common in United States in the 1990s. Random samples of 250 participants from each of three large prospective cohorts were mailed a questionnaire to assess frequency of consumption, cooking method, and typical outside appearance of pan-fried, broiled, and grilled or barbecued chicken, fish, hamburger, and steak; fried, microwaved, and broiled bacon; fried sausage; roast beef; and homemade gravy. The 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 2-amino-3,4,8-trimethylimidazo[4,5,f]quinoxaline (DiMeIQx) concentrations, measured in composite samples by solid-phase extraction and high-performance liquid chromatography, were assigned to each food, cooking method, and doneness level. The dietary reports showed similar to 30-fold relative variation in 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline intake, 20-fold for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and over 110-fold for 2-amino-3,4,8-trimethylimidazo[4,5,f]quinoxaline, when the 10th and 90th percentiles of HCA intake were compared (90th/10th percentile value). These reported variations in HCA exposure among participants in these three large cohorts indicates that estimation of HCA intake and determination of association with disease risk are feasible, if additional information on meat cooking methods is obtained. C1 Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Byrne, C (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. RI Sinha, Rashmi/G-7446-2015; Byrne, Celia/K-2964-2015; Colditz, Graham/A-3963-2009 OI Sinha, Rashmi/0000-0002-2466-7462; Byrne, Celia/0000-0001-8289-4252; Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 40356, CA 50385, CA 55075] NR 28 TC 49 Z9 49 U1 1 U2 7 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 JUN PY 1998 VL 7 IS 6 BP 523 EP 529 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA ZR916 UT WOS:000074029000012 PM 9641497 ER PT J AU Poirier, MC Weston, A Schoket, B Shamkhani, H Pan, CF McDiarmid, MA Scott, BG Deeter, DP Heller, JM Jacobson-Kram, D Rothman, N AF Poirier, MC Weston, A Schoket, B Shamkhani, H Pan, CF McDiarmid, MA Scott, BG Deeter, DP Heller, JM Jacobson-Kram, D Rothman, N TI Biomonitoring of United States Army soldiers serving in Kuwait in 1991 SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AROMATIC HYDROCARBON-DNA; WHITE BLOOD-CELLS; BURNING OIL-WELLS; HUMAN LUNG; HUMAN-PLACENTA; ADDUCT LEVELS; DIOL-EPOXIDE; BENZOPYRENE; POLYMORPHISM; CONSUMPTION AB Biomarkers of polycyclic aromatic hydrocarbon (PAH) exposure and genetic biomarkers of potential cancer susceptibility were determined in a group of United States Army soldiers who were deployed to Kuwait and Saudi Arabia in 1991 in the aftermath of the Persian Gulf War. Because hundreds of oil well fires were still burning, there was concern that ground troops stationed in Kuwait might he exposed to high levels of PAHs and other toxicants, The United States Army Environmental Hygiene Agency monitored air and soil for ambient PAHs, In addition, a group of 61 soldiers was involved in the biomonitoring study reported here. These soldiers kept diaries of daily activities and provided blood and urine samples in Germany (June) before deployment to Kuwait, after 8 weeks in Kuwait (August), and 1 month after the return to Germany (October). Here we present data for PAM-DNA adducts measured by immunoassay in blood cell DNA samples obtained at all three sampling times from 22 soldiers and bulky aromatic adducts measured by P-32-postlabeling in blood cell DNA samples from 20 of the same soldiers. Urinary 1-hydroxypyrene-glucuronide levels were determined by synchronous fluorescence spectrometry in a matched set of samples from 33 soldiers. Contrary to expectations, environmental monitoring showed low ambient PAH levels in the areas where these soldiers were working in Kuwait. For both DNA adduct assays, levels were the lowest in Kuwait in August and increased significantly after the soldiers returned to Germany (October), Urinary 1-hydroxypyrene-glucuronide levels were also lowest in Kuwait and highest in Germany, but the differences were not statistically significant. The PAM-exposure biomarker levels were not significantly influenced by polymorphic variations of CYP1A1 (MspI) and glutathione S-transferases M1 and T1. Overall, the data suggest that this group of soldiers was not exposed to elevated levels of PAHs while deployed in Kuwait. C1 NCI, Carcinogen DNA Interact Sect, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bethesda, MD 20892 USA. NIOSH, Ctr Dis Control, Hlth Effects Lab Div, Morgantown, WV 26505 USA. Johan Bela Natl Inst Publ Hlth, Dept Biochem, H-1097 Budapest, Hungary. Kaiser Permanente, Dept Internal Med, Gaithersburg, MD 20877 USA. CUNY, Mt Sinai Med Ctr, Dept Community Med, New York, NY 10029 USA. Univ Maryland, Sch Med, Occupat Hlth Project, Baltimore, MD 21201 USA. USA, Command & Gen Staff Coll, Ft Leavenworth, KS 66027 USA. USA Med Act, Redstone Arsenal, AL 35809 USA. USA, Ctr Hlth Promot & Prevent Med, Edgewood Area, Aberdeen Proving Ground, MD 21010 USA. MA Bioserv Inc, Rockville, MD 20850 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bldg 37,Room 3B25,MSC-4255,37 Convent Dr, Bethesda, MD 20892 USA. NR 32 TC 39 Z9 40 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 JUN PY 1998 VL 7 IS 6 BP 545 EP 551 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA ZR916 UT WOS:000074029000015 PM 9641500 ER PT J AU Tseng, M AF Tseng, M TI Dietary iron and recurrence of colorectal adenomas (vol 6, pg 1029, 1997) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Correction ID FOOD C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Tseng, M (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RI Tseng, Marilyn/B-9334-2016 OI Tseng, Marilyn/0000-0002-9969-9055 NR 3 TC 0 Z9 0 U1 1 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 JUN PY 1998 VL 7 IS 6 BP 556 EP 556 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA ZR916 UT WOS:000074029000017 ER PT J AU Khan, J Parsa, NZ Harada, T Meltzer, PS Carter, NP AF Khan, J Parsa, NZ Harada, T Meltzer, PS Carter, NP TI Detection of gains and losses in 18 meningiomas by comparative genomic hybridization SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID HOMOGENEOUSLY STAINING REGIONS; TUMOR-SUPPRESSOR GENE; NEUROFIBROMATOSIS TYPE-2; NF2 GENE; CHROMOSOME-ABNORMALITIES; SPORADIC MENINGIOMAS; CYTOGENETIC ANALYSIS; GERMLINE DELETION; DNA-SEQUENCES; PROGRESSION AB Comparative genomic hybridization (CGH) was used to examine gains and losses in 18 meningioma tumors that had been previously analyzed for loss of heterozygosity (LOH) at 22q12. partial or complete losses were seen by CGH in only 9 of 18 cases on chromosome 22. This compares with 11 of 18 losses of single or more loci by LOH. The discrepancy in these results is probably explained by the increased sensitivity of LOH by using microsatellite markers that are able to defect small deletions, whereas losses on the order of 10-15 megabases are required for confident identification by CGH. There was no consistent pattern of gains or losses by CGH, including those tumors that lacked LOH at 22q12. In one tumor of interest in which CGH and LOH studies failed to demonstrate loss on chromosome 22, CGH identified an area of amplification at 17q22-23. (C) Elsevier Science Inc., 1998. C1 Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. Addenbrookes NHS Trust, Acad Dept Pediat, Cambridge CB2 2QQ, England. Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. Sanger Ctr, Cambridge, England. RP Khan, J (reprint author), Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bldg 49,49 Covenent Dr,Msc 4470,Room 4A15, Bethesda, MD 20892 USA. FU Wellcome Trust NR 36 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JUN PY 1998 VL 103 IS 2 BP 95 EP 100 DI 10.1016/S0165-4608(97)00394-4 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA ZQ255 UT WOS:000073839000002 PM 9614906 ER PT J AU Ning, Y Liang, JC Nagarajan, L Schrock, E Ried, T AF Ning, Y Liang, JC Nagarajan, L Schrock, E Ried, T TI Characterization of 5q deletions by subtelomeric probes and spectral karyotyping SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID CHROMOSOME-5 C1 Natl Human Genome Res Inst, Genome Technol Branch, Bethesda, MD USA. Univ Texas, Md Anderson Canc Ctr, Sect Cytogenet, Div Lab Med, Houston, TX USA. Univ Texas, Md Anderson Canc Ctr, Div Med, Sect Mol Hematol & Therapy, Houston, TX USA. RP Ning, Y (reprint author), George Washington Univ, GeneCare Wilson Genet Ctr, 2300 I St NW,Suite 455, Washington, DC 20037 USA. FU NCI NIH HHS [CA55164, CA66982] NR 12 TC 30 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JUN PY 1998 VL 103 IS 2 BP 170 EP 172 DI 10.1016/S0165-4608(97)00417-2 PG 3 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA ZQ255 UT WOS:000073839000015 PM 9614919 ER PT J AU Sun, XY Plouzek, CA Henry, JP Wang, TTY Phang, JM AF Sun, XY Plouzek, CA Henry, JP Wang, TTY Phang, JM TI Increased UDP-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin A in prostate cancer cells SO CANCER RESEARCH LA English DT Article ID STEROID GLUCURONIDE LEVELS; ANDROGEN METABOLISM; PLASMA; LNCAP; TISSUE; LINE; MEN; DIHYDROTESTOSTERONE; 5-ALPHA-REDUCTASE; HYPERPLASIA AB Our laboratory has characterized androgen metabolism in an androgen-responsive prostate cancer cell line (LNCaP) and showed that these cells accumulated intracellular testosterone primarily as glucuronidated metabolites. Using a cell-free assay with testosterone as substrate, we showed that LNCaP had UDP-glucuronosyltransferase (UDPGT) activity. Because dietary factors, such as flavonoids in soy products, may reduce the risk for hormone-dependent cancers, we studied the effects of flavonoids on testosterone-UDPGT activity. LNCaP cells were exposed to selected flavonoids for up to 6 days. The increase in UDPGT-specific activity was linear over this period, Of the compounds tested, biochanin A was the most potent, with increased activity at concentration range 0.5-50 mu M. Activities were linear for time and protein and were unaffected by flavonoids added directly to the assay. Kinetics studies showed no change in K-m for testosterone in the face of these large increases in specific activity. Cellular metabolism of testosterone reflected the increase in enzyme activity, Intact cells treated with biochanin A produced testosterone-glucuronide from testosterone at twice the rate of controls. The steroid form of the UDPGT transcript was expressed in LNCaP cells and was enhanced in biochanin A-treated LNCaP cells. Additionally, biochanin A markedly decreased prostate specific antigen (PSA) level against the effect of testosterone on PSA production, Biochanin A significantly decreased the testosterone-stimulated release of PSA, presumably because biochanin A increased UDPGT and increased the intracellular glucuronidation of testosterone, These studies suggest that the modulation of hormone metabolism by dietary factors may be important in the prevention and treatment of prostate cancer. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Nutr & Mol Regulat, NIH, Frederick, MD 21702 USA. RP NCI, Frederick Canc Res & Dev Ctr, Lab Nutr & Mol Regulat, NIH, Bldg 560,Room 12-91, Frederick, MD 21702 USA. NR 34 TC 66 Z9 69 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 1998 VL 58 IS 11 BP 2379 EP 2384 PG 6 WC Oncology SC Oncology GA ZR703 UT WOS:000074005300023 PM 9622078 ER PT J AU Loftus, DJ Squarcina, P Nielsen, MB Geisler, C Castelli, C Odum, N Appella, E Parmiani, G Rivoltini, L AF Loftus, DJ Squarcina, P Nielsen, MB Geisler, C Castelli, C Odum, N Appella, E Parmiani, G Rivoltini, L TI Peptides derived from self-proteins as partial agonists and antagonists of human CD8(+) T-cell clones reactive to melanoma/melanocyte epitope MART1(27-35) SO CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; INTERLEUKIN (IL)-4; RECEPTOR OCCUPANCY; MELANOMA PATIENTS; PERIPHERAL-BLOOD; ANTIGEN; MART-1; IDENTIFICATION; STIMULATION; ACTIVATION AB The self-peptide MART1(27-35) derives from the melanocyte/melanoma protein Melan A/MART1 and is a target epitope of CD8(+) T cells, commonly recovered from tumor-infiltrating lymphocytes of HLA-A2.1(+) melanoma patients. Despite their prevalence in such patients, these CTLs generally appear to be ineffective in mediating tumor regression in vivo. We have noted previously that numerous peptides from both endogenous and foreign proteins are similar to MART1(27-35) and, potentially, are capable of productively engaging the T-cell receptors of patient-derived CTLs. This observation raised the question of whether CTLs in vivo might encounter self-peptide analogues of MART1(27-35) that lack full agonist activity, perhaps to the detriment of the antitumor CTL response. This possibility was evaluated using cloned, patient-derived CTLs with a panel of self-derived natural analogues of MART1(27-35) in assays for cytolysis, cytokine release, and phosphorylation of T-cell receptor signaling constituents. Several peptides were identified as partial agonists, capable of eliciting cytolysis and/or release of cytokines tumor necrosis factor-a and IFN-gamma but not interleukin 2, Several other peptides showed antagonist behavior, effectively inhibiting cytolysis of MART1(27-35)-pulsed targets, but did not inhibit killing of cells prepulsed with a synthetic, heteroclitic variant of MART1(27-35). Some of these antagonists also had lasting effects on interleukin 2 secretion by CTLs under experimental conditions involving sequential exposure to ligands. Together, these observations suggest that encounters with self-peptide analogues of MART1(27-35) may contribute to the peripheral maintenance of these CTLs, while ultimately impairing the efficacy of this antitumor T-cell response. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Ist Nazl Tumori, Div Expt Oncol D, I-20133 Milan, Italy. Univ Copenhagen, Panum Inst, Inst Med Microbiol & Immunol, DK-2200 Copenhagen, Denmark. RP Loftus, DJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1B03,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Geisler, Carsten/A-7056-2012; castelli, chiara/K-6899-2012; OI castelli, chiara/0000-0001-6891-8350; Rivoltini, Licia/0000-0002-2409-6225 NR 52 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 JUN 1 PY 1998 VL 58 IS 11 BP 2433 EP 2439 PG 7 WC Oncology SC Oncology GA ZR703 UT WOS:000074005300030 PM 9622085 ER PT J AU Mock, BA Lowry, DT Rehman, I Padlan, C Yuspa, SH Hennings, H AF Mock, BA Lowry, DT Rehman, I Padlan, C Yuspa, SH Hennings, H TI Multigenic control of skin tumor susceptibility in SENCARA/Pt mice SO CARCINOGENESIS LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GENETIC DISSECTION; MOUSE SKIN; COMPLEX TRAITS; PROMOTION; ALLELOTYPE; HEAD; NECK; CARCINOGENESIS; DISSOCIATION AB Skin tumors induced in mice by initiation-promotion (2 mu g DMBA-2 mu g TPA) protocols were found to be under multigenic control, Eighty-one N2 mice from the cross (BALB/cAnPt X SENCARA/Pt)F1 X SENCARA/Pt that were either solidly resistant (no papillomas) or highly susceptible (greater than or equal to 7 papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite markers to check for associations with susceptible and resistant phenotypes, A locus on Chr 5 (Skts4) was found to control the susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to papilloma formation. In addition, higher than expected linkage scores were seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is required to establish whether genes determining papilloma formation are located in these regions of the genome, In general, no evidence was seen for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in 17 microdissected papillomas from (BALB/c X SENCARA)F1 hybrid mice. C1 NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, DBS, NIH, Bethesda, MD 20892 USA. RP Mock, BA (reprint author), NCI, Genet Lab, NIH, Bldg 37,Rm 2B-08,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 47 TC 30 Z9 30 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUN PY 1998 VL 19 IS 6 BP 1109 EP 1115 DI 10.1093/carcin/19.6.1109 PG 7 WC Oncology SC Oncology GA ZV977 UT WOS:000074361300021 PM 9667751 ER PT J AU Forander, P Hoffer, B Stromberg, I AF Forander, P Hoffer, B Stromberg, I TI Nerve fiber formation and catecholamine content in adult rat adrenal medullary transplants after treatment with NGF, NT-3, NT-4/5, bFGF, CNTF, and GDNF SO CELL AND TISSUE RESEARCH LA English DT Article DE chromaffin cells; trophic factors; NGF; NT-3; NT-4/5; CNTF; GDNF; bFGF; rat (Sprague Dawley) ID CULTURED CHROMAFFIN CELLS; TYROSINE PROTEIN-KINASE; GROWTH-FACTOR; NEUROTROPHIC FACTOR; MESSENGER-RNA; NEURAL CREST; ROTATIONAL BEHAVIOR; PERIPHERAL-TISSUES; TRK PROTOONCOGENE; STORING CELLS AB Adrenal chromaffin cells have been characterized by the ability to change the phenotype in response to neurotrophic factor stimulation. The adrenal,oland expresses numerous trophic factors endogenously, but there is still a lack of knowledge as to how the adrenal medullary cells respond to these factors. Accordingly, we evaluated nerve fiber outgrowth and cell morphology, and measured catecholamine content in adult rat adrenal medullary tissue transplanted to the anterior chamber of the eye after exposure to neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), or glial cell line-derived neurotrophic factor (GDNF) compared with the effects after exposure to recombinant human nerve growth factor (rhNGF). The results show that rhNGF was the most potent factor in inducing neurite outgrowth from the grafted chromaffin cells. CNTF was also a powerful inducer of nerve fiber formation, while NT-4/5, GDNF and bFGF were less potent. NT-3 did not produce neurite outgrowth above that seen in vehicle-treated eyes. Combining two neurotrophins, rhNGF and NT-3, reduced nerve fiber formation. Tyrosine hydroxylase (TH) immunohistochemistry revealed good cell survival in all grafts, and no morphological differences were detected with the different treatments. The adrenaline: noradrenaline: dopamine ratio was approximately 49%. 49%: 2%, independent of treatment, and the catecholamine content was equal irrespective of treatment. In conclusion, all neurotrophic factors used, except for NT-3, promoted neurite outgrowth from adult rat chromaffin transplants. Differences in outgrowth induced by the various trophic factors did not, however, change the catecholamine content in grafts when analyzed together with the graft-derived nerve plexus. C1 Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Natl Inst Drug Abuse, Baltimore, MD 21224 USA. RP Forander, P (reprint author), Karolinska Inst, Dept Neurosci, Doktorsringen 12,Plan 6, S-17177 Stockholm, Sweden. EM petter.forander@neuro.ki.se NR 59 TC 10 Z9 11 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD JUN PY 1998 VL 292 IS 3 BP 503 EP 512 DI 10.1007/s004410051079 PG 10 WC Cell Biology SC Cell Biology GA ZT529 UT WOS:000074097000008 PM 9582407 ER PT J AU Laskey, AD Roth, BJ Simpson, PB Russell, JT AF Laskey, AD Roth, BJ Simpson, PB Russell, JT TI Images of Ca2+ flux in astrocytes: evidence for spatially distinct sites of Ca2+ release and uptake SO CELL CALCIUM LA English DT Article ID SALIVARY-GLAND CELLS; CALCIUM WAVES; ENDOPLASMIC-RETICULUM; POLARIZED EXPRESSION; ELEMENTARY EVENTS; SKELETAL-MUSCLE; (I) WAVES; CARDIAC-MUSCLE; MITOCHONDRIA; PROPAGATION AB In this study, we have developed a mathematical method to derive the Ca2+ fluxes underlying agonist-evoked Ca2+ waves in cultured rat cortical astrocytes. Astrocytes were stimulated with norepinephrine (100 nM) to evoke Ca2+ waves, which were recorded by measuring Fluo-3 fluorescence changes with high spatial and temporal resolution. Normalized fluorescence (Delta F/F) was analyzed in discrete cellular spaces in a series of successive slices along the length of the cell. From these data, Ca2+ flux was then calculated using a one dimensional reaction-diffusion equation which utilizes the temporal and spatial derivatives of the fluorescence data and the diffusion coefficient of Ca2+ in the cytosol. This method identified distinct sites of positive flux (Ca2+ release into the cytosol) and of negative flux (Ca2+ removal from cytosol) and showed that in astrocytes, sites of Ca2+ release from stores regularly alternate with sites of Ca2+ removal from the cytosol. Cross correlation analysis of the two distribution patterns gave positive correlation at 2 mu m out of phase and a negative correlation in phase. Thapsigargin-induced Ca2+ waves were analyzed to determine if the negative flux was due to Ca2+ uptake via thapsigargin-sensitive Ca2+ pumps. Negative flux sites were still found under these conditions, suggesting that multiple mechanisms of Ca2+ removal from the cytosol may contribute to negative flux sites. This method of calculation of flux may serve as a means to describe the distribution of functional ion channels and pumps participating in cellular Ca2+ signalling. C1 NICHD, Sect Neuronal Secretory Syst, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Phys & Astron, Nashville, TN 37235 USA. RP Russell, JT (reprint author), NICHD, Sect Neuronal Secretory Syst, Lab Cellular & Mol Neurophysiol, NIH, 49 Convent Dr,MSC 4495,Bldg 49,Rm 5A32, Bethesda, MD 20892 USA. EM james@helix.nih.gov RI Roth, Bradley/A-4920-2008 NR 35 TC 17 Z9 18 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD JUN PY 1998 VL 23 IS 6 BP 423 EP 432 DI 10.1016/S0143-4160(98)90099-9 PG 10 WC Cell Biology SC Cell Biology GA 111EH UT WOS:000075424000008 PM 9924634 ER PT J AU Szabo, E Goheer, A Witschi, H Linnoila, RI AF Szabo, E Goheer, A Witschi, H Linnoila, RI TI Overexpression of CC10 modifies neoplastic potential in lung cancer cells SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID FOCAL ADHESION KINASE; IV COLLAGENASE; MESSENGER-RNA; SQUAMOUS-CELL; GELATINASE-A; CLARA CELLS; IN-VITRO; PROTEIN; EXPRESSION; UTEROGLOBIN AB CC10 is infrequently expressed in non-small cell lung cancer cell lines, despite being abundantly produced by progenitor cells for normal and neoplastic airway epithelium. We overexpressed CC10 cDNA in the non-small cell lung cancer cell line A549 to determine its effect on the neoplastic phenotype. A549 cells transfected with CC10 demonstrated a marked reduction in invasiveness that was paralleled by diminished 92-kDa and absent 72-kDa metalloproteinase activity by zymography. Western analysis revealed the near absence of the corresponding matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in the CC10-transfected cell lines, but not in the vector-transfected cell lines. The CC10-transfected cell lines also demonstrated decreased adhesiveness to fibronectin compared with the controls. CC10 expression was associated with decreased anchorage-independent growth but not with decreased anchorage-dependent growth. These data suggest that loss of CC10 may contribute to carcinogenesis, because CC10 antagonizes the neoplastic phenotype. C1 NCI, Dept Cell & Canc Biol, Med Branch, Div Clin Sci, Rockville, MD 20850 USA. Univ Calif Davis, Inst Toxicol & Environm Hlth, Davis, CA 95616 USA. RP Szabo, E (reprint author), NCI, Dept Cell & Canc Biol, Med Branch, Div Clin Sci, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. EM szaboe@bprb.nci.nih.gov FU NIEHS NIH HHS [ES-05707] NR 61 TC 40 Z9 41 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD JUN PY 1998 VL 9 IS 6 BP 475 EP 485 PG 11 WC Cell Biology SC Cell Biology GA ZW443 UT WOS:000074411500004 PM 9663466 ER PT J AU Schulte, TW Akinaga, S Soga, S Sullivan, W Stensgard, B Toft, D Neckers, LM AF Schulte, TW Akinaga, S Soga, S Sullivan, W Stensgard, B Toft, D Neckers, LM TI Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin SO CELL STRESS & CHAPERONES LA English DT Article ID PROGESTERONE-RECEPTOR; PROTEIN-KINASE; STEROID-RECEPTOR; IN-VIVO; COMPLEX; TRANSFORMATION; HETEROCOMPLEX; RENATURATION; ANSAMYCINS; GRP94 AB The molecular chaperone Hsp90 plays an essential role in the folding and function of important cellular proteins including steroid hormone receptors, protein kinases and proteins controlling the cell cycle and apoptosis, A 15 Angstrom deep pocket region in the N-terminal domain of Hsp90 serves as an ATP/ADP-binding site and has also been shown to bind geldanamycin, the only specific inhibitor of Hsp90 function described to date. We now show that radicicol, a macrocyclic antifungal structurally unrelated to geldanamycin, also specifically binds to Hsp90. Moreover, radicicol competes with geldanamycin for binding to the N-terminal domain of the chaperone, expressed either by in vitro translation or as a purified protein, suggesting that radicicol shares the geldanamycin binding site. Radicicol, as does geldanamycin, also inhibits the binding of the accessory protein p23 to Hsp90, and interferes with assembly of the mature progesterone receptor complex. Radicicol does not deplete cells of Hsp90, but rather increases synthesis as well as the steady-state level of this protein, similar to a stress response. Finally, radicicol depletes SKBR3 cells of p185(erbB2), Raf-l and mutant p53, similar to geldanamycin. Radicicol thus represents a structurally unique antibiotic, and the first non-benzoquinone ansamycin, capable of binding to Hsp90 and interfering with its function. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Nagaizumi, Shizuoka 411, Japan. Mayo Clin & Mayo Grad Sch Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. RP Schulte, TW (reprint author), NCI, Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 38 TC 257 Z9 265 U1 2 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1355-8145 J9 CELL STRESS CHAPERON JI Cell Stress Chaperones PD JUN PY 1998 VL 3 IS 2 BP 100 EP 108 DI 10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2 PG 9 WC Cell Biology SC Cell Biology GA ZW979 UT WOS:000074468200004 PM 9672245 ER PT J AU Tagamets, MA Horwitz, B AF Tagamets, MA Horwitz, B TI Integrating electrophysiological and anatomical experimental data to create a large-scale model that simulates a delayed match-to-sample human brain imaging study SO CEREBRAL CORTEX LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; HUMAN EXTRASTRIATE CORTEX; VISUAL WORKING-MEMORY; PREFRONTAL CORTEX; STRIATE CORTEX; FUNCTIONAL-ORGANIZATION; NEURAL MECHANISMS; NETWORK ANALYSIS; CORTICAL AREAS; MACAQUE MONKEY AB We propose a model that draws together experimental evidence from anatomical, electrophysiological and imaging experiments in order to understand better the neural substrate of human imaging studies using positron electron tomography (PET) and functional magnetic resonance imaging (fMRI). First, we define a simple local circuit that reflects the major role that local connectivity plays in producing PET and fMRI data, which are thought to mainly reflect synaptic activity. Second, in order to account for the role of varying behaviors during the course of a typical imaging experiment, we propose a local circuit that can perform a delayed match-to-sample task. The elements of this circuit behave very much like neurons that have been found in the prefrontal cortex during similar tasks in monkeys. One subpopulation responds selectively only when stimuli are present. Two different populations show the two types of delay-period activity that have been identified, one with high activity both during the cue and the delay period, the other with a rise during the delay period only. Last, a subpopulation shows a brief response only if the second stimulus matches the first, thus mediating the decision about whether the stimuli match. We show that in addition to performing the task, the integrated summed synaptic activities of the model are similar to experimental PET data. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Tagamets, MA (reprint author), Georgetown Univ, Georgetown Inst Cognit & Computat Sci, Washington, DC 20057 USA. EM malle@giccs.georgetown.edu NR 57 TC 97 Z9 101 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 1998 VL 8 IS 4 BP 310 EP 320 DI 10.1093/cercor/8.4.310 PG 11 WC Neurosciences SC Neurosciences & Neurology GA ZQ260 UT WOS:000073839500003 PM 9651128 ER PT J AU Lin, B Doan, LX Yagi, H Jerina, DM Whalen, DL AF Lin, B Doan, LX Yagi, H Jerina, DM Whalen, DL TI Halide effects in the hydrolysis reactions of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID MUTAGENIC 7,8-DIOL 9,10-EPOXIDES; ANTI-BENZOPYRENE DIOL EPOXIDE; PRODUCT DISTRIBUTIONS; BENZOPYRENE; HYDROCARBONS; NUCLEOPHILES; ION AB Rates of reaction of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8, (DE-2) have been determined in 1:9 dioxane-water solutions containing 1.0 M KCI, 0.5 M KBr, and 0.1 M NaI over the pH range 4-13. These pH-rate profiles are more complicated than those for reaction of DE-2 in 0.2 M NaClO4 solutions and are interpreted in part by mechanisms in which halide ion attacks the diol epoxide as a nucleophile at intermediate pH, resulting in the formation of a trans-halohydrin. Reaction of DE-2 in these halide solutions at pH < ca. 5 occurs by rate-limiting carbocation formation, followed by capture of the intermediate carbocation by halide ion. The relative magnitudes of the rate constants for reaction of the intermediate carbocation with halide ions are estimated from product studies. The halohydrins are unstable intermediates and react quickly in subsequent reactions to yield tetrols in a ratio different than that formed from reaction of the carbocation with solvent. Nucleophilic attacks of 1.0 M Cl-, 0.5 M Br-, and 0.1M I- on DE-2 are the principal reactions in the pH range cat 6-9, leading to intermediate trans-halohydrins that hydrolyze to tetrols. At pH ca. 9-11, halohydrin formed from attack of halide ion on DE-2 reverts back to epoxide, leading to a negative break in the pH-rate profile. The main product-forming reaction of DE-2 at pH 11.3 is the spontaneous reaction. At pH > 12, the rate of reaction of DE-S increases due to a second-order reaction of HO- with DE-2. C1 Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Whalen, DL (reprint author), Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA. OI Lin, Binshan/0000-0002-8481-302X NR 26 TC 8 Z9 8 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JUN PY 1998 VL 11 IS 6 BP 630 EP 638 DI 10.1021/tx9701743 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA ZV403 UT WOS:000074301100006 PM 9625731 ER PT J AU Moon, KY Moschel, RC AF Moon, KY Moschel, RC TI Effect of ionic state of 2 '-deoxyguanosine and solvent on its aralkylation by benzyl bromide SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; NUCLEIC-ACIDS; INACTIVATION; SELECTIVITY; DERIVATIVES; ALKYLATION; GUANOSINE; MODEL; SITES AB To extend studies of the aralkylation of nucleic acid components under a variety of solvent conditions, we determined product distributions from the reactions of benzyl bromide with 2'-deoxyguanosine and the anion of 2'-deoxyguanosine in 2,2,2-trifluoroethanol (TFE) and compared these distributions with those from the reaction of the anion with benzyl bromide in N'\N-dimethylacetamide (DMA). 7-Benzylguanine was the only benzylated product detected in the reaction with the neutral nucleoside in TFE, In striking contrast, the reaction of the anion of 2'-deoxyguanosine with benzyl bromide in TFE produced N-2-benzyl-2'-deoxyguanasine in significant yield and with high selectivity. The reaction of the anion of 2'-deoxyguanosine with benzyl bromide in DMA produced products derived only from reaction at the 1- and/or 7-position of the nucleoside. The weakly nucleophilic but protic polar solvent TFE and the iminolate tautomeric form of the 2'-deoxyguanosine anion appear to be essential for benzylation at the exocyclic N-2-position. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Chem Carcinogenesis Lab, Frederick, MD 21701 USA. RP Moschel, RC (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Chem Carcinogenesis Lab, POB B, Frederick, MD 21701 USA. NR 28 TC 23 Z9 23 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JUN PY 1998 VL 11 IS 6 BP 696 EP 702 DI 10.1021/tx980012m PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA ZV403 UT WOS:000074301100013 PM 9625738 ER PT J AU Scow, RO Schultz, CJ Park, JW Blanchette-Mackie, EJ AF Scow, RO Schultz, CJ Park, JW Blanchette-Mackie, EJ TI Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article; Proceedings Paper CT Conference on Lipases and Lipids - Structure, Specificity and Applications in Biocatalysis CY SEP 20, 1997 CL VILLA OLMO, ITALY DE lipoprotein lipase; hepatic lipase; combined lipase deficiency; dimerization; endoplasmic reticulum; brefeldin A ID HEPARIN-RELEASABLE LIPASE; CULTURED BROWN ADIPOCYTES; BREFELDIN-A; INTRACELLULAR-TRANSPORT; RAT HEPATOCYTES; NEWBORN MICE; LIVER; MOUSE; SECRETION; INHIBITION AB Lipoprotein lipase (LPL) and hepatic lipase (HL), which act on plasma lipoproteins, belong to the same gene family as pancreatic lipase. LPL is synthesized in heart, muscle and adipose tissue, while HL is synthesized primarily in liver. LPL is also synthesized in liver of newborn rodents. The active form of LPL is a dimer, whereas that of HL has not been established. Combined lipase deficiency (CLD) is an autosomal recessive mutation (cld) in mice which impairs post-translational processing of LPL and HL. Cld/cld mice have very low LPL and HL activities (< 5% of normal), yet normal pancreatic lipase activity. They develop massive hypertriglyceridemia and die within 3 days after birth. The CLD mutation allows synthesis, glycosylation and dimerization of LPL, but blocks activation and secretion of the lipase. Thus, dimerization per se does not result in production of active LPL. Immunofluoresence studies showed that LPL is retained in endoplasmic reticulum (ER) in cld/cld cells. Translocation of Golgi components to ER by treatment with brefeldin A (BFA) enabled synthesis of active LPL in cultured cld/cld brown adipocytes. Thus, production of inactive LPL in cld/cld cells results from inability of the cells to transport LPL from ER. The CLD mutation allows synthesis and glycosylation of HL, but blocks activation of the lipase. Immunofluoresence studies located HL mostly outside of cells in liver, liver cell cultures and incubated adrenal tissue of normal and cld/cld mice and mostly inside of cells in liver cell cultures and adrenal tissues treated with monensin (to block secretion of protein). These findings demonstrate synthesis and secretion of HL by both liver and adrenal cells of normal and cld/cld mice. Thus, the CLD mutation allows secretion of inactive HL by liver and adrenals. However, it does not block synthesis or secretion of active pancreatic lipase. Our findings indicate that LPL, HL and pancreatic lipase, although closely related, are processed differently. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. Chonnam Natl Univ, Sch Med, Dept Biochem, Chonju 560182, South Korea. RP Scow, RO (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bldg 8,Room 309, Bethesda, MD 20892 USA. NR 47 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD JUN PY 1998 VL 93 IS 1-2 BP 149 EP 155 DI 10.1016/S0009-3084(98)00039-5 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 106NT UT WOS:000075136300016 PM 9720257 ER PT J AU Berkowitz McCann Kerns Elvik Dubowitz Muram Finkel Hitchcock AF Berkowitz McCann Kerns Elvik Dubowitz Muram Finkel Hitchcock TI The appearance of acute, healing, and healed anogenital trauma SO CHILD ABUSE & NEGLECT LA English DT Editorial Material C1 Univ Calif Los Angeles, Sch Med, Torrance, CA 90509 USA. Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. Univ Calif Davis, Med Ctr, Child Protect Team, Sacramento, CA 95817 USA. Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. Santa Clara Valley Med Ctr, Ctr Children Protect, San Jose, CA 95128 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Harbor UCLA Med Ctr, Child Crisis Ctr, Torrance, CA 90509 USA. Univ Maryland, Sch Med, Child Protect Program, Baltimore, MD 21201 USA. Univ Tromso, Tromso, Norway. Univ Med & Dent New Jersey, Sch Osteopath Med, Ctr Childrens Support, Stratford, NJ 08084 USA. NIAID, Sexually Transmitted Dis Branch, Rockville, MD USA. RP Berkowitz (reprint author), Univ Calif Los Angeles, Sch Med, Torrance, CA 90509 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUN PY 1998 VL 22 IS 6 BP 621 EP 622 PG 2 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA ZP681 UT WOS:000073777800026 ER PT J AU Kerns Ingram Muram Hammerschlag Britton Chadwick Finkel Hitchcock Chalk AF Kerns Ingram Muram Hammerschlag Britton Chadwick Finkel Hitchcock Chalk TI The transmissiblity of sexually transmitted diseases in sexually abused children SO CHILD ABUSE & NEGLECT LA English DT Editorial Material C1 Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. Santa Clara Valley Med Ctr, Ctr Child Protect, San Jose, CA 95128 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ N Carolina, Sch Med, Dept Pediat, Div Pediat Infect Dis, Chapel Hill, NC USA. Univ Tromso, Tromso, Norway. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Univ Utah, Med Ctr, Salt Lake City, UT USA. Primary Childrens Med Ctr, Child Protect Team, Salt Lake City, UT 84103 USA. Childrens Hosp, Ctr Child Protect, San Diego, CA USA. Univ Med & Dent New Jersey, Sch Osteopath Med, Ctr Childrens Support, Stratford, NJ 08084 USA. NIAID, Sexually Transmitted Dis Branch, Rockville, MD USA. Inst Med, Natl Res Council, Board Children Youth & Families, Washington, DC USA. RP Kerns (reprint author), Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUN PY 1998 VL 22 IS 6 BP 641 EP 643 PG 3 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA ZP681 UT WOS:000073777800029 ER PT J AU Britton Myers De Jong, AR Chadwick, DL Runyan, DK Muram, D Leventhal, JM Kerns, DL Sternberg Levitt, C Keltner AF Britton Myers De Jong, AR Chadwick, DL Runyan, DK Muram, D Leventhal, JM Kerns, DL Sternberg Levitt, C Keltner TI Impact of child sexual abuse examinations on the dependency and criminal systems SO CHILD ABUSE & NEGLECT LA English DT Editorial Material C1 Univ Utah, Med Ctr, Salt Lake City, UT 84112 USA. Primary Childrens Med Ctr, Child Protect Team, Salt Lake City, UT 84103 USA. Univ Pacific, McGeorge Sch Law, Sacramento, CA USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Childrens Hosp, Ctr Child Protect, San Diego, CA USA. Univ N Carolina, Chapel Hill, NC USA. Univ Tromso, Tromso, Norway. Yale Univ, Sch Med, New Haven, CT USA. Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. Santa Clara Valley Med Ctr, Ctr Child Protect, San Jose, CA 95128 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. NICHHD, Sect Social & Emot Dev, Bethesda, MD 20892 USA. Childrens Hlth Care, Midw Childrens Resource Ctr, St Paul, MN USA. Legacy Hlth Syst, CARES Program, Portland, OR USA. RP Britton (reprint author), Univ Utah, Med Ctr, Salt Lake City, UT 84112 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUN PY 1998 VL 22 IS 6 BP 657 EP 660 PG 4 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA ZP681 UT WOS:000073777800032 ER PT J AU Huffman, LC Bryan, YE del Carmen, R Pedersen, FA Doussard-Roosevelt, JA Porges, SW AF Huffman, LC Bryan, YE del Carmen, R Pedersen, FA Doussard-Roosevelt, JA Porges, SW TI Infant temperament and cardiac vagal tone: Assessments at twelve weeks of age SO CHILD DEVELOPMENT LA English DT Article ID STABILITY; DIFFICULTNESS; ATTACHMENT; REACTIVITY; RATINGS AB Sixty 12-week-old infants participated in a laboratory study to explore the relations between temperament and cardiac vagal tone. Temperament was evaluated via laboratory observations and maternal ratings. Cardiac vagal tone, measured as the amplitude of respiratory sinus arrhythmia, was quantified from beat-to-beat heart period data collected during a resting baseline period and during the laboratory assessment of temperament. Specific hypotheses were investigated relating temperament to both basal cardiac vagal tune and changes in cardiac vagal tone during social/attention challenges. Infants with higher baseline cardiac vagal tone were rated in the laboratory as showings fewer negative behaviors and were less disrupted by the experimental procedure. Infants who decreased cardiac vagal tone during the laboratory assessment were rated on maternal report temperament scales as having longer attention spans, and being more easily soothed. C1 Stanford Univ, Comparat Ethol Lab, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. Stanford Univ, Comparat Ethol Lab, Sch Med, Childrens Hlth Council, Palo Alto, CA 94304 USA. Lehigh Valley Hosp Ctr, Allentown, PA 18102 USA. Natl Inst Mental Hlth, Rockville, MD USA. Univ Maryland, College Pk, MD 20742 USA. RP Huffman, LC (reprint author), Stanford Univ, Comparat Ethol Lab, Sch Med, Dept Pediat, 700 Sand Hill Rd, Palo Alto, CA 94304 USA. EM lynne.huffman@stanford.edu FU NICHD NIH HHS [HD22628]; PHS HHS [MCJ240622] NR 61 TC 140 Z9 142 U1 1 U2 9 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 JUN PY 1998 VL 69 IS 3 BP 624 EP 635 DI 10.2307/1132194 PG 12 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 100VW UT WOS:000074836900010 PM 9680676 ER PT J AU Bornstein, MH Haynes, OM AF Bornstein, MH Haynes, OM TI Vocabulary competence in early childhood: Measurement, latent construct, and predictive validity SO CHILD DEVELOPMENT LA English DT Article ID DEVELOPMENTAL LANGUAGE SCALES; INFANT TEMPERAMENT; SPEECH SAMPLES; MOTHER; INTELLIGENCE; SPECIFICITY; PLAY; PERFORMANCE; UTTERANCE; CHECKLIST AB Mr, systematically examined relations among 6 measures of child language derived from 3 sources, including observations of the child's speech with mother, experimenter assessments, and maternal reports. A total of 184 20-month-olds and their mothers contributed complete information about child language comprehension and expression Correlations of child language measures with socioeconomic status and maternal education were accounted for, as were correlations of child language measures with mothers' verbal intelligence, maternal report measures with mothers' tendency to respond in a socially desirable fashion, and experimenter assessments with child social competence. Structural equation modeling supported (1) strong relations among child language measures derived from observations of the child's speech with mother, experimenter assessments, and maternal reports; (2) the loading of multiple measures of child language from different sources on a single latent construct of vocabulary competence; and (3) the predictive validity of the vocabulary competence latent variable at 20 months, as well as receptive vocabulary specifically, for both verbal and performance IQ (verbal better than performance) at 48 months. Neither an index of child monologing (a nonvocabulary language measure) nor symbolic play (a nonlinguistic representational measure) covaried with vocabulary competence. Girls consistently outperformed boys on individual language measures, but no differences emerged in any model in the fit for boys and girls. C1 NICHHD, Comparat Ethol Lab, NIH, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, Comparat Ethol Lab, NIH, Bldg 31,Room B2B15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov NR 82 TC 103 Z9 104 U1 15 U2 23 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 JUN PY 1998 VL 69 IS 3 BP 654 EP 671 DI 10.2307/1132196 PG 18 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 100VW UT WOS:000074836900012 PM 9680678 ER PT J AU Lehrnbecher, T Muller-Scholden, J Danhauser-Leistner, I Sorensen, N von Stockhausen, HB AF Lehrnbecher, T Muller-Scholden, J Danhauser-Leistner, I Sorensen, N von Stockhausen, HB TI Perioperative fluid and electrolyte management in children undergoing surgery for craniopharyngioma - A 10-year experience in a single institution SO CHILDS NERVOUS SYSTEM LA English DT Article DE craniopharyngioma; desmopressin; diabetes insipidus; inappropriate secretion of antidiuretic hormone ID DIABETES-INSIPIDUS; WATER METABOLISM; MORBIDITY AB In a retrospective study, the intra- and early postoperative data of 39 children with 46 operations for craniopharyngioma were analyzed. Diabetes insipidus (DI) occurred in 30 out of 32 cases without preoperative evidence of DI. We observed that all children who did not have a pituitary stalk preserved and 5 out of 7 patients with preserved pituitary stalk developed DI within 18 h of surgery. Short-term inappropriate secretion of antidiuretic hormone (SIADH) occurred in 2 children, but was quickly followed by DI. The time of onset of DI and SIADH did not correlate with sex, age, body weight, location of tumor, or duration or extent: of surgery. Parenteral desmopressin was an effective treatment for intra- and postoperative DI. The duration of the clinical effect of desmopressin administration varied in different patients between 4 and 23 h. An approach to the immediate intra- and postoperative management of children with craniopharyngioma is presented. C1 Univ Wurzburg, Dept Pediat, D-97080 Wurzburg, Germany. Univ Wurzburg, Dept Anesthesiol, D-97080 Wurzburg, Germany. Univ Wurzburg, Dept Pediat Neurosurg, D-97080 Wurzburg, Germany. RP Lehrnbecher, T (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 12 TC 32 Z9 38 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0256-7040 J9 CHILD NERV SYST JI Childs Nerv. Syst. PD JUN PY 1998 VL 14 IS 6 BP 276 EP 279 DI 10.1007/s003810050224 PG 4 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA ZZ324 UT WOS:000074718000008 PM 9694340 ER PT J AU Bennett, WP El-Deiry, WS Rush, WL Guinee, DG Freedman, AN Caporaso, NE Welsh, JA Jones, RT Borkowski, A Travis, WD Fleming, MV Trastek, V Pairolero, PC Tazelaar, HD Midthun, D Jett, JR Liotta, LA Harris, CC AF Bennett, WP El-Deiry, WS Rush, WL Guinee, DG Freedman, AN Caporaso, NE Welsh, JA Jones, RT Borkowski, A Travis, WD Fleming, MV Trastek, V Pairolero, PC Tazelaar, HD Midthun, D Jett, JR Liotta, LA Harris, CC TI p21(waf1/cip1) and transforming growth factor beta 1 protein expression correlate with survival in non-small cell lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID KINASE INHIBITOR P21; OVARIAN EPITHELIAL-CELLS; PROGNOSTIC-SIGNIFICANCE; P53 PROTEIN; P53-INDEPENDENT EXPRESSION; BREAST-CARCINOMA; POOR-PROGNOSIS; IMMUNOHISTOCHEMICAL DETECTION; CLINICOPATHOLOGICAL DATA; TUMOR SUPPRESSION AB p2l(waf1/cip1) encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways, Because p21(waf1/cip1), p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate ,vith biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21(waf1/cip1) and TGF-beta 1 and identified four patient groups with distinct survival outcomes, Concordant p2l(waf1/cip1) and TGF-beta 1 expression (i.e., either high p2l(waf1/cip1) and high TGF-beta 1 expression or low p21(waf1/cip1) and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p2l(waf1/cip1) and TGF-beta 1 expression (i.e., either high p2l(waf1/cip1) and low TGF-beta 1 expression or low p21(waf1/cip1) and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21(waf1/cip1) protein expression correlated with high tumor grade (P = 0.014), There is little evidence that p2l(waf1/cip1) protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p2l(waf1/cip1) protein, These findings indicate that p2l(waf1/cip1) immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC. C1 NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Utah, Med Ctr, Salt Lake City, UT 84132 USA. Univ Maryland, Baltimore, MD 21201 USA. Baltimore VA Med Ctr, Baltimore, MD 21201 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Mayo Clin, Rochester, MN 55905 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 2C01,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov NR 79 TC 39 Z9 40 U1 0 U2 0 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 JUN PY 1998 VL 4 IS 6 BP 1499 EP 1506 PG 8 WC Oncology SC Oncology GA ZU654 UT WOS:000074219700018 PM 9626468 ER PT J AU Dries, DL Solomon, AJ Gersh, BJ AF Dries, DL Solomon, AJ Gersh, BJ TI Adjunctive therapy after reperfusion therapy in acute myocardial infarction SO CLINICAL CARDIOLOGY LA English DT Review DE myocardial infarction; thrombolytic therapy; adjunctive therapy; beta blockers; nitrates; angiotensin-converting enzyme inhibitors; magnesium ID LEFT-VENTRICULAR DYSFUNCTION; INTRAVENOUS MAGNESIUM-SULFATE; INTERVENTION-TRIAL LIMIT-2; CONSCIOUS DOGS; BETA-BLOCKADE; SIZE; NITROGLYCERIN; PROPRANOLOL; REDUCTION; EXPANSION AB The current era has witnessed dramatic improvement in the treatment of acute myocardial infarction, due in large part to the more widespread use of thrombolytic therapy aimed at quickly restoring perfusion in the infarct-related artery. This review addresses the role of adjunctive pharmacologic therapy in the thrombolytic era, recognizing that much of the available clinical trial data supporting the role of adjunctive pharmacologic treatment strategies was conducted in patient populations not widely exposed to reperfusion therapy. This review, therefore, explores the data supporting the incremental benefit of therapy with beta blockers, nitrates, angiotensin-converting enzyme inhibitors, or magnesium in addition to thrombolytic therapy. Heparin and aspirin will not be discussed. C1 NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Grp, Rockledge Ctr 2, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Div Cardiol, Washington, DC 20007 USA. RP Dries, DL (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Clin Trials Grp, Rockledge Ctr 2, Room 8149,6701 Rockledge Dr, Bethesda, MD 20892 USA. NR 59 TC 4 Z9 4 U1 0 U2 0 PU CLINICAL CARDIOLOGY PUBL CO PI MAHWAH PA PO BOX 832, MAHWAH, NJ 07430-0832 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD JUN PY 1998 VL 21 IS 6 BP 379 EP 386 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ZT130 UT WOS:000074051500002 PM 9631265 ER PT J AU McNamara, JR Shah, PK Nakajima, K Cupples, LA Wilson, PWF Ordovas, JM Schaefer, EJ AF McNamara, JR Shah, PK Nakajima, K Cupples, LA Wilson, PWF Ordovas, JM Schaefer, EJ TI Remnant lipoprotein cholesterol and triglyceride reference ranges from the Framingham Heart Study SO CLINICAL CHEMISTRY LA English DT Article ID CORONARY-ARTERY DISEASE; LOW-DENSITY-LIPOPROTEIN; COMMERCIAL IMMUNOTURBIDIMETRIC ASSAY; APOLIPOPROTEIN-A-I; RICH LIPOPROTEINS; REFERENCE INTERVALS; BLOOD-PLASMA; RISK FACTOR; MEN; FRACTION AB Remnants of triglyceride-rich lipoproteins of both intestinal and liver origin are considered atherogenic, but they have been difficult to isolate and measure. An assay has been developed that allows the measurement of remnant-like particle cholesterol (RLP-C) and triglyceride (RLP-TG). RLP-C and RLP-TG concentrations were measured in >3000 fasting plasma samples obtained from participants in exam cycle 4 of the Framingham Offspring Study and stored at -80 degrees C. After exclusions, comparisons were made for 2821 samples (1385 women, 1436 men; mean age, 52 years). For women, the mean RLP-C and RLP-TG values were 0.176 +/- 0.058 mmol/L (6.8 +/- 2.3 mg/dL) and 0.204 +/- 0.159 mmol/L (18.1 +/- 14.1 mg/dL), respectively; for men, the mean values were 0.208 +/- 0.096 mmol/L (8.0 +/- 3.7 mg/dL) and 0.301 +/- 0.261 mmol/L (26.7 +/- 23.1 mg/dL), respectively. Women had significantly lower RLP-C and RLP-TG values (P <0.0001) than men; premenopausal women had significantly lower values than postmenopausal women (P <0.0001); and younger subjects (<50 years) had significantly lower values than older individuals (P <0.0001). The 75th percentile values for RLP-C and RLP-TG were 0.186 mmol/L (7.2 mg/dL) and 0.225 mmol/L (19.9 mg/dL), respectively, for women, and 0.225 mmol/L (8.7 mg/dL) and 0.346 mmol/L (30.6 mg/dL) for men. These data provide reference ranges for use in the evaluation of RLP-C and RLP-TG as potential indicators of risk for coronary heart disease. C1 Tufts Univ, USDA, Human Nutr Res Ctr Aging, Lipid Metab Lab, Boston, MA 02111 USA. New England Med Ctr, Lipid Res Lab, Div Endocrinol Diabet Metab & Mol Med, Boston, MA 02111 USA. Otsuka Amer Pharmaceut Inc, Rockville, MD 20850 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA 01701 USA. RP McNamara, JR (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, Lipid Metab Lab, 711 Washington St, Boston, MA 02111 USA. OI Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [N01-HC-38038] NR 48 TC 84 Z9 85 U1 1 U2 1 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 JUN PY 1998 VL 44 IS 6 BP 1224 EP 1232 PN 1 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZR716 UT WOS:000074006600013 PM 9625046 ER PT J AU Cecco, SA Huijgen, HJ Sanders, R Rehak, NN Sanders, GTB Elin, RJ AF Cecco, SA Huijgen, HJ Sanders, R Rehak, NN Sanders, GTB Elin, RJ TI Comparison of two AVL analyzers for ionized magnesium determination. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. Univ Louisville, Pathol & Lab Med, Louisville, KY 40292 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 497 BP A114 EP A114 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700499 ER PT J AU Chesler, R Wang, J Tran, A Costello, R Csako, G AF Chesler, R Wang, J Tran, A Costello, R Csako, G TI Comparison of three "direct" and two indirect low-density lipoprotein-cholesterol (LDL-C) methods in human sera. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 362 BP A83 EP A83 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700364 ER PT J AU Costello, R Tran, A Wang, J Chesler, R Csako, G AF Costello, R Tran, A Wang, J Chesler, R Csako, G TI Effect of various storage conditions on human serum lipids, lipoproteins, and apolipoproteins. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 313 BP A73 EP A73 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700315 ER PT J AU Csako, G Costello, R AF Csako, G Costello, R TI Apolipoprotein(a) [apo(a)] isoform-dependence of serum lipoprotein(a) [Lp(a)] and lipoprotein(a)-cholesterol [Lp(a)-C] concentrations. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 323 BP A75 EP A75 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700325 ER PT J AU DeLeo, JM Remaley, AT AF DeLeo, JM Remaley, AT TI A neural network approach to quality control monitoring of patient laboratory data. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Div Comp Res & Technol, Bethesda, MD 20892 USA. NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 262 BP A60 EP A61 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700264 ER PT J AU Huijgen, HJ Sanders, R Cecco, SA Rehak, NN Sanders, GT Elin, RJ AF Huijgen, HJ Sanders, R Cecco, SA Rehak, NN Sanders, GT Elin, RJ TI Comparison of three commercially available ion-selective electrodes for ionized magnesium determination in serum: a two-center study. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Univ Amsterdam, Acad Med Ctr, Dept Clin Chem, NL-1105 AZ Amsterdam, Netherlands. Dept Clin Pathol, Clin Chem Serv, NIH, Bethesda, MD USA. Univ Louisville, Dept Pathol & Lab Med, Louisville, KY 40292 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 480 BP A111 EP A111 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700482 ER PT J AU Rehak, NN Cecco, SA Csako, G AF Rehak, NN Cecco, SA Csako, G TI Contamination of serum with human saliva causes falsely increased potassium concentration. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 JUN PY 1998 VL 44 SU 6 MA 618 BP A142 EP A142 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700621 ER PT J AU Rehak, NN Cecco, SA Elin, RJ AF Rehak, NN Cecco, SA Elin, RJ TI Concentrations of serum ionized calcium and ionized magnesium in parathyroid diseases. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Louisville, Pathol & Lab Med, Louisville, KY 40292 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 482 BP A111 EP A111 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700484 ER PT J AU Remaley, AT Zweig, MH Sampson, ML Remaley, NA Farsi, BD AF Remaley, AT Zweig, MH Sampson, ML Remaley, NA Farsi, BD TI Comparison of diagnostic test performance by contour cost error plots. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 721A BP A165 EP A166 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700726 ER PT J AU Sampson, ML Hunt, T Ruddel, M Elin, RJ AF Sampson, ML Hunt, T Ruddel, M Elin, RJ TI Comparison between colorimetric and chromatographic methods for the measurement of glutathione. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Lehigh Univ, Bethlehem, PA 18015 USA. Univ Louisville, Louisville, KY 40292 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 729 BP A168 EP A168 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700735 ER PT J AU Stickle, DF Reynolds, MA Quon, MJ Morris, MD AF Stickle, DF Reynolds, MA Quon, MJ Morris, MD TI Dynamic changes in proinsulin/insulin ratio during insulin secretion influence correlation between RIA and IMX measurements of insulin. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Brooke Army Med Ctr, Dept Pathol, Ft Sam Houston, TX 78234 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008; Stickle, Douglas/A-9682-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 628 BP A144 EP A144 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700631 ER PT J AU Thurman, RG Bradford, BU Iimuro, Y Adachi, Y Rivera, C von Frankenberg, M Ikejima, K Kono, H Enomoto, N Arteel, G Zhong, Z Gao, W Lemasters, JJ Raleigh, J Kadiiska, M Stefanovic, B Tsukamoto, H Lin, M Brenner, D Forman, DT Gallucci, RM Luster, M Mason, ML AF Thurman, RG Bradford, BU Iimuro, Y Adachi, Y Rivera, C von Frankenberg, M Ikejima, K Kono, H Enomoto, N Arteel, G Zhong, Z Gao, W Lemasters, JJ Raleigh, J Kadiiska, M Stefanovic, B Tsukamoto, H Lin, M Brenner, D Forman, DT Gallucci, RM Luster, M Mason, ML TI Rat models of alcoholic liver injury and liver transplantation. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Univ N Carolina, Chapel Hill, NC USA. Univ So Calif, Los Angeles, CA 90089 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 JUN PY 1998 VL 44 SU 6 MA 466 BP A107 EP A107 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700468 ER PT J AU Woods, JJ Sampson, M Remaley, AT AF Woods, JJ Sampson, M Remaley, AT TI Threshold-cost plot: Analysis of a risk factor and age adjusted threshold for the primary treatment of hypercholesterolemia. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 319 BP A74 EP A74 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700321 ER PT J AU Woods, JJ Wu, Y Hortin, GL AF Woods, JJ Wu, Y Hortin, GL TI Assessment of telephone reporting of alert values. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 244 BP A56 EP A56 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700247 ER PT J AU Wu, Y Delgado, RM Remaley, AT Hruszkewycz, AM AF Wu, Y Delgado, RM Remaley, AT Hruszkewycz, AM TI Comparison of an ELISA and an electrophoretic telomerase assay. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 NIH, CC, Dept Clin Pathol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 197 BP A45 EP A45 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700200 ER PT J AU Wu, Y Delgado, RM Moon, Y Weil, RJ Vortmeyer, AO Fuller, BG Zhuang, Z Oldfield, EH Remaley, AT AF Wu, Y Delgado, RM Moon, Y Weil, RJ Vortmeyer, AO Fuller, BG Zhuang, Z Oldfield, EH Remaley, AT TI Telomerase detection from microdissected glioma frozen tissues. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 CC Natl Inst Hlth, Dept Clin Pathol, Bethesda, MD USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 1998 VL 44 SU 6 MA 133 BP A32 EP A32 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA ZT249 UT WOS:000074065700135 ER PT J AU Stone, DL Biesecker, LG AF Stone, DL Biesecker, LG TI Identification of microsatellite markers tightly linked to the Gli2 putative zinc finger transcription factor gene SO CLINICAL GENETICS LA English DT Article C1 Natl Ctr Human Genome Res, Lab Genet Dis Res, NIH, Bethesda, MD 20892 USA. RP Stone, DL (reprint author), Natl Ctr Human Genome Res, Lab Genet Dis Res, NIH, 49 Convent Dr,Rm 4B-75, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD JUN PY 1998 VL 53 IS 6 BP 488 EP 489 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 103XC UT WOS:000074982300015 PM 9712541 ER PT J AU Walsh, TJ Hiemenz, JW Seibel, NL Perfect, JR Horwith, G Lee, L Silber, JL DiNubile, MJ Reboli, A Bow, E Lister, J Anaissie, EJ AF Walsh, TJ Hiemenz, JW Seibel, NL Perfect, JR Horwith, G Lee, L Silber, JL DiNubile, MJ Reboli, A Bow, E Lister, J Anaissie, EJ TI Amphotericin B lipid complex for invasive fungal infections: Analysis of safety and efficacy in 556 cases SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; BONE-MARROW TRANSPLANT; APOPHYSOMYCES ELEGANS; ANTIFUNGAL ACTIVITY; RISK-FACTORS; CRYPTOCOCCAL MENINGITIS; ASPERGILLUS-FUMIGATUS; THERAPY; TOXICITY; PHEOHYPHOMYCOSIS AB The safety and antifungal efficacy of amphotericin B lipid complex (ABLC) were evaluated in 556 cases of invasive fungal infection treated through an open-label, single-patient, emergency-use study of patients who were refractory to or intolerant of conventional antifungal therapy, All 556 treatment episodes were evaluable for safety. During the course of ABLC therapy, serum creatinine levels significantly decreased from baseline (P < .02), Among 162 patients with serum creatinine values greater than or equal to 2.5 mg/dL at the start of ABLC therapy (baseline), the mean serum creatinine value decreased significantly from the first week through the sixth week (P less than or equal to .0003), Among the 291 mycologically confirmed cases evaluable for therapeutic response, there was a complete or partial response to ABLC in 167 (57%), including 42% (55) of 130 cases of aspergillosis, 67% (28) of 42 cases of disseminated candidiasis, 71% (17) of 24 cases of zygomycosis, and 82% (9) of 11 cases of fusariosis, Response rates varied according to the pattern of invasive fungal infection, underlying condition, and reason for enrollment (intolerance versus progressive infection), These findings support the use of ABLC in the treatment of invasive fungal infections in patients who are intolerant of or refractory to conventional antifungal therapy. C1 NCI, Infect Dis Sect, Bethesda, MD 20892 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Duke Univ, Med Ctr, Durham, NC USA. Liposome Co, Princeton, NJ USA. Cooper Hosp Univ Med Ctr, Camden, NJ 08103 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Camden, NJ 08103 USA. Hlth Sci Ctr, Winnipeg, MB, Canada. Univ Pittsburgh, Pittsburgh, PA USA. Univ Texas, MD Anderson Cancer Ctr, Houston, TX 77030 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Walsh, TJ (reprint author), NCI, Infect Dis Sect, Bldg 10,Room 13N-240, Bethesda, MD 20892 USA. NR 50 TC 418 Z9 430 U1 1 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN PY 1998 VL 26 IS 6 BP 1383 EP 1396 DI 10.1086/516353 PG 14 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA ZU252 UT WOS:000074177900035 PM 9636868 ER PT J AU Chen, R Hallett, M AF Chen, R Hallett, M TI Focal dystonia and repetitive motion disorders SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID WRITERS CRAMP; RECIPROCAL INHIBITION; BOTULINUM TOXIN; BASAL GANGLIA; HAND CRAMPS; MUSICIANS; MOTOR; POTENTIALS; CORTEX AB It commonly is observed that focal hand dystonias, such as writer's cramp or musician's cramp, are associated with repetitive movements, although definitive proof of a causal relationship is lacking, These focal dystonias are often task specific, with involuntary muscle contractions occurring only when patients perform specific acts such as writing or playing a musical instrument. Physiologic studies show deficiencies in spinal reciprocal inhibition and abnormalities of central sensory processing and motor output that may be related to reduced cortical inhibition. Recent studies in primates support the notion that repetitive motions can induce plasticity changes in the sensory cortex leading to degradation of topographic representations of the hand, and raise the possibility that sensory training may be beneficial. Current treatment options for focal dystonia include botulinum toxin injections, anticholinergics, baclofen, benzodiazepines, and occupational therapy, C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 30 TC 60 Z9 64 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUN PY 1998 IS 351 BP 102 EP 106 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA ZU050 UT WOS:000074156200014 PM 9646753 ER PT J AU Dionne, RA McCullagh, L AF Dionne, RA McCullagh, L TI Enhanced analgesia and suppression of plasma beta-endorphin by the S(+)-isomer of ibuprofen SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID RHEUMATOID-ARTHRITIS; SURGERY AB Background: Peripheral nociceptive barrage after tissue injury results in acute pain and a variety of physiologic responses, including pituitary secretion of beta-endorphin, This study evaluated whether administration of the pharmacologically active S(+)-isomer of ibuprofen suppresses acute pain and plasma beta-endorphin levels in the oral surgery model of acute pain, Methods: Subjects in a single-dose, double-blind, parallel-group study received either 200 mg S(+)-ibuprofen, 400 mg S(+)-ibuprofen, 400 mg racemic ibuprofen, or placebo. Both doses of S(+)-ibuprofen resulted in significantly greater analgesia over the first 60 minutes in comparison to racemic ibuprofen and placebo; the 400 mg dose of S(+)-ibuprofen also produced greater analgesia at 2 and 3 hours. Plasma levels of immunoreactive beta-endorphin decreased over time coincident with the onset of analgesia in all groups but were significantly less than placebo after both doses of S(+)-ibuprofen from 30 to 120 minutes, Conclusions: These findings show that, compared with racemic ibuprofen, administration of the S(+)-isomer of ibuprofen results in faster analgesic onset, greater peak analgesia, similar duration of action, and a low incidence of adverse effects, while suppressing nociceptive activation of the pituitary-adrenal axis. C1 NIDR, Pain & Neurosensory Mechanisms Branch, Dept Nursing, Ctr Clin, Bethesda, MD USA. RP Dionne, RA (reprint author), NIH, 10 Ctr Dr,Room IN-103, Bethesda, MD 20892 USA. NR 19 TC 23 Z9 27 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUN PY 1998 VL 63 IS 6 BP 694 EP 701 DI 10.1016/S0009-9236(98)90094-7 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ZY367 UT WOS:000074613700012 PM 9663185 ER PT J AU Lamb, ME AF Lamb, ME TI Assessing parent-infant interaction during the perinatal period - Some cautions SO CLINICS IN PERINATOLOGY LA English DT Article ID ATTACHMENT AB Pediatricians have recently been urged by professional groups to pay increased attention to parental behavior when serving and discharging newborns. These exhortations are well intended, but they may reflect a misunderstanding of developmental processes and foster a mistaken belief in the ease with which parenting problems can be identified and remedied. This article describes how early experiences affect children's development and then contrasts this view with a popular perspective based on misapplication of the medical model to the conceptualization of behavioral development. C1 NICHHD, Sect Social & Emot Dev, Bethesda, MD 20814 USA. RP Lamb, ME (reprint author), NICHHD, Sect Social & Emot Dev, 9190 Rockville Pike, Bethesda, MD 20814 USA. NR 33 TC 5 Z9 5 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 0095-5108 J9 CLIN PERINATOL JI Clin. Perinatol. PD JUN PY 1998 VL 25 IS 2 BP 461 EP + PG 10 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA ZV991 UT WOS:000074362800014 PM 9647004 ER PT J AU Chene, G Morlat, P Leport, C Hafner, R Dequae, L Charreau, I Aboulker, JP Luft, B Aubertin, J Vilde, JL Salamon, R AF Chene, G Morlat, P Leport, C Hafner, R Dequae, L Charreau, I Aboulker, JP Luft, B Aubertin, J Vilde, JL Salamon, R CA ANRS 005 ACTG 154 Trial Grp TI Intention-to-treat vs. on-treatment analyses of clinical trial data: Experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients SO CONTROLLED CLINICAL TRIALS LA English DT Article DE intention-to-treat; on-treatment analysis; HIV infection ID IMMUNODEFICIENCY-VIRUS INFECTION; TRIMETHOPRIM-SULFAMETHOXAZOLE; MYOCARDIAL-INFARCTION; RANDOMIZED TRIAL; AIDS; ENCEPHALITIS; DESIGN; PNEUMONIA; EVENTS; BIAS AB Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications In the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials. (C) Elsevier Science Inc. 1998. C1 Univ Bordeaux 2, INSERM, U330, Dept Med Informat, F-33076 Bordeaux, France. Hop St Andre, Serv Med Interne, Bordeaux, France. Hop Bichat Claude Bernard, Serv Malad Infect, F-75877 Paris 18, France. NIAID, Div Aids, Bethesda, MD 20892 USA. INSERM, SC10, Villejuif, France. SUNY Stony Brook, Hlth Sci Ctr, Div Infect Dis, Stony Brook, NY 11794 USA. Hop Pellegrin Tripode, Clin Malad Infect, F-33076 Bordeaux, France. RP Chene, G (reprint author), Univ Bordeaux 2, INSERM, U330, Dept Med Informat, 146 Rue Leo Siagnat, F-33076 Bordeaux, France. RI chene, genevieve/H-8665-2014; OI Luft, Benjamin/0000-0001-9008-7004 NR 40 TC 33 Z9 33 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD JUN PY 1998 VL 19 IS 3 BP 233 EP 248 DI 10.1016/S0197-2456(97)00145-1 PG 16 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA ZP514 UT WOS:000073761100001 PM 9620807 ER PT J AU Quinn, TC AF Quinn, TC TI Does Chlamydia pneumoniae cause coronary heart disease? SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review ID CIRCULATING IMMUNE-COMPLEXES; ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; RISK-FACTORS; STRAIN TWAR; ATHEROSCLEROSIS; ASSOCIATION; INFECTION; CYTOMEGALOVIRUS; PATHOGENESIS AB Evidence continues to accumulate to support a role for Chlamydia pneumoniae in the pathogenesis of atherosclerosis, and in particular, coronary heart disease. In an analysis of 18 seroepidemiological studies, individuals with high-titer antibodies to Chlamydia pneumoniae have at least a twofold or larger odds ratio for coronary heart disease compared with seronegative individuals. In addition, viable Chlamydia pneumoniae has been cultured directly from atherosclerotic tissue, and has been demonstrated by polymerase chain reaction, immunocytochemistry, and electron microscopy in nearly 50% of atheromatous lesions, but in only 5% of control samples. Chlamydia pneumoniae has been shown to infect and reproduce in vitro in human smooth muscle cells, coronary artery endothelial cells, and macrophages, and has been shown to induce procoagulant activity and platelet adhesion factors known to contribute to the pathogenesis of atherosclerosis. Furthermore, Chlamydia pneumoniae has been identified in atherosclerotic tissue in two experimental animal models. Finally, two pilot antibiotic trials of post-myocardial infarction patients receiving antibiotics effective against Chlamydia pneumoniae have demonstrated a fivefold reduction in cardiovascular events compared with those patients receiving placebo. Although a causal effect has not been proved, the relationship between Chlamydia pneumoniae and atherosclerosis continues to grow and to stimulate more definitive studies. (C) 1998 Lippincott-Raven Publishers. C1 Johns Hopkins Univ, Sch Med, National Institute Allergy & Infectious Diseases, Div Infect Dis, Baltimore, MD 21205 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, National Institute Allergy & Infectious Diseases, Div Infect Dis, 720 Rutland Ave,Ross 1159, Baltimore, MD 21205 USA. EM tquinn@welchlink.welch.jhu.edu NR 67 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD JUN PY 1998 VL 11 IS 3 BP 301 EP 307 PG 7 WC Infectious Diseases SC Infectious Diseases GA ZQ110 UT WOS:000073822700005 PM 17033395 ER PT J AU Santamarina-Fojo, S Haudenschild, C Amar, M AF Santamarina-Fojo, S Haudenschild, C Amar, M TI The role of hepatic lipase in lipoprotein metabolism and atherosclerosis SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review ID HIGH-DENSITY-LIPOPROTEIN; CHYLOMICRON REMNANT-REMOVAL; RECEPTOR-RELATED PROTEIN; CORONARY-ARTERY DISEASE; TRIGLYCERIDE LIPASE; CHOLESTERYL ESTER; SELECTIVE UPTAKE; POSTHEPARIN PLASMA; RAT-LIVER; TRANSGENIC MICE AB In addition to its traditional role in the hydrolysis of lipoprotein triglycerides and phospholipids, recent studies have implicated hepatic lipase in other aspects of cellular lipid and/or lipoprotein metabolism and atherosclerosis. Hepatic lipase may serve as a ligand that mediates the interaction of lipoproteins to cell surface receptors and/or proteoglycans as well as modulating aortic lesion development in different animal models. Over the past several years significant advances have been made in our understanding of new, alternative mechanisms by which hepatic lipase may modulate lipoprotein metabolism and the development of atherosclerosis in vivo, Curr Opin Lipidol 9:211-219. (C) 1998 Lippincott-Raven Publishers. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, 10 Ctr Dr MSC 1666,Bldg 10,Room 7N115, Bethesda, MD 20892 USA. NR 76 TC 174 Z9 185 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD JUN PY 1998 VL 9 IS 3 BP 211 EP 219 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA ZW377 UT WOS:000074404900005 PM 9645503 ER PT J AU Strey, HH Podgornik, R Rau, DC Parsegian, VA AF Strey, HH Podgornik, R Rau, DC Parsegian, VA TI DNA-DNA interactions SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID CONCENTRATED ISOTROPIC SOLUTIONS; DOUBLE HELICES; HYDRATION FORCES; MULTIMOLECULAR AGGREGATION; MONONUCLEOSOMAL DNA; IN-VIVO; POLYELECTROLYTES; ELECTROPHORESIS; CONDENSATION; ELECTROLYTE AB The forces that govern DNA double helix organization are being finally systematically measured. The non-specific longer-range interactions - such as electrostatic interactions, hydration, and fluctuation forces - that treat DNA as a featureless rod are reasonably well recognized. Recently, specific interactions - such as those controlled by condensing agents or those consequent to helical structure - are beginning to be recognized, quantified and tested. C1 NICHHD, NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. NIDDKD, Off Director, NIH, Bethesda, MD 20892 USA. RP Strey, HH (reprint author), NICHHD, NIH, Lab Phys & Struct Biol, Bldg 12A,Room 2041, Bethesda, MD 20892 USA. EM strey@helix.nih.gov; rudi@helix.nih.gov; donrau@helix.nih.gov; VAP@CU.NIH.GOV RI Strey, Helmut/B-5456-2009; Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 52 TC 110 Z9 111 U1 0 U2 18 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 1998 VL 8 IS 3 BP 309 EP 313 DI 10.1016/S0959-440X(98)80063-8 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZX965 UT WOS:000074573200006 PM 9666326 ER PT J AU Koonin, EV Tatusov, RL Galperin, MY AF Koonin, EV Tatusov, RL Galperin, MY TI Beyond complete genomes: from sequence to structure and function SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID HAEMOPHILUS-INFLUENZAE; ESCHERICHIA-COLI; PROTEINS; EVOLUTION; LIFE AB Computer analysis of complete prokaryotic genomes shows that microbial proteins are in general highly conserved - similar to 70% of them contain ancient conserved regions. This allows us to delineate families of orthologs across a wide phylogenetic range and, in many cases, predict protein functions with considerable precision. Sequence database searches using newly developed, sensitive algorithms result in the unification of such orthologous families into larger superfamilies sharing common sequence motifs. For many of these superfamilies, prediction of the structural fold and specific amino acid residues involved in enzymatic catalysis is possible. Taken together, sequence and structure comparisons provide a powerful methodology that can successfully complement traditional experimental approaches. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 59 TC 112 Z9 118 U1 2 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LB, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD JUN PY 1998 VL 8 IS 3 BP 355 EP 363 DI 10.1016/S0959-440X(98)80070-5 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA ZX965 UT WOS:000074573200013 PM 9666332 ER PT J AU Tessarollo, L AF Tessarollo, L TI Pleiotropic functions of neurotrophins in development SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Trk; neurotrophin; gene targeting; neuronal; non-neuronal ID NERVE GROWTH-FACTOR; FOREBRAIN CHOLINERGIC NEURONS; BASOPHILIC CELL-DIFFERENTIATION; PITUITARY-ADRENOCORTICAL AXIS; LONG-TERM POTENTIATION; PERITONEAL MAST-CELLS; DORSAL-ROOT GANGLION; EAR SENSORY NEURONS; HUMAN LYMPHOCYTES-B; TRKB MESSENGER-RNA AB Neurotrophins are soluble growth factors known mainly for their roles in regulating the development of the mammalian nervous system. Two types of receptors mediate the actions of these polypeptides: the Trk family of tyrosine kinase receptors and the so-called p75 tow-affinity NGF receptor. Neurotrophins and their receptors are highly expressed in the nervous system. Gene targeting approaches in the mouse have uncovered some of their functions in promoting survival and developmental maturation of certain types of neurons of the peripheral and central nervous system, confirming their critical role in neural development. Furthermore, the phenotypes observed in these mutants have demonstrated the specificity of the interactions between neurotrophins and their receptors, These families of genes are also widely expressed in a variety of non-neuronal systems throughout development, including the cardiovascular, endocrine, reproductive and immune systems. Our knowledge of neurotrophin functions in non-neuronal tissues is still fragmented and mostly indirect, Nevertheless, there is increasing evidence that neurotrophins may have broader physiological effects besides regulating neuronal survival and differentiation. Analysis of mice lacking neurotrophins or neurotrophin receptors promises to provide avenues for elucidating these functions. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NCI, Neural Dev Grp, ABL Basic Res Program, FCRDC, Frederick, MD 21702 USA. RP Tessarollo, L (reprint author), NCI, Neural Dev Grp, ABL Basic Res Program, FCRDC, Frederick, MD 21702 USA. EM tessarol@ncifcrf.gov NR 153 TC 129 Z9 132 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD JUN PY 1998 VL 9 IS 2 BP 125 EP 137 DI 10.1016/S1359-6101(98)00003-3 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 157PD UT WOS:000078070100004 PM 9754707 ER PT J AU Bacon, KB Oppenheim, JJ AF Bacon, KB Oppenheim, JJ TI Chemokines in disease models and pathogenesis SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Article DE chemokines; experimental allergic encephalomyelitis leukocyte homing and trafficking; hematopoiesis AB Investigators from a wide variety of disciplines met at the Second National Managed Health Care Congress Meeting on chemokines held in Washington, D.C, on December 14-15, 1997, to discuss the role of chemokines in the pathogenesis of disease states, as well as a number of biological issues. Presentations on the effects of chemokines in animal models were interspersed with talks on fundamental chemokine structure-function relationships, signal transduction, the role of chemokine in cell trafficking, inflammation, immunity and hematopoietic development. Although it was impossible to consider the score of chemokine receptors and the 50 or more chemokines cloned to date, most of the more well established and some of the newer chemokines were discussed, We will first summarize the preconference symposium on the role of chemokines in neurobiology and then review the various issues addressed by the other speakers to provide a more integrated rather than sequential summary of the proceedings. (C) 1998 Elsevier Science Ltd. AII rights reserved. C1 Neurocrine Biosci, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Bacon, KB (reprint author), Neurocrine Biosci, Frederick, MD 21702 USA. NR 0 TC 60 Z9 62 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD JUN PY 1998 VL 9 IS 2 BP 167 EP 173 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 157PD UT WOS:000078070100007 PM 9754710 ER PT J AU Rubinstein, M Dinarello, CA Oppenheim, JJ Hertzog, P AF Rubinstein, M Dinarello, CA Oppenheim, JJ Hertzog, P TI Recent advances in cytokines, cytokine receptors and signal transduction SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Article DE cytokines; chemokines; interferons; receptors; signal transduction; gene disruption AB The Fifth Annual Conference of the International Cytokine Society was held on November 9-13, 1997 at Lake Tahoe, Nevada. This meeting kept up with the tradition of exciting talks and posters, presenting significant advances in our understanding of the cytokine world, As we advance our knowledge, a complex network of interacting cellular communication pathways is revealed. Targeted disruption of genes coding for cytokines, their receptors and their cytoplasmic signaling molecules, became the standard method for a proper assessment of the role of a given cytokine in vivo, Yet, fundamental questions remain unresolved, For instance, it is not yet known how signal specificity is maintained when different cytokine receptors use the same cytoplasmic signaling pathways, The following summary is not comprehensive, rather, it is a collection of representative communications. Many more top quality studies were presented at the meeting and we apologize for not being able to review all of them here, (C) 1998 Elsevier Science Ltd. All rights reserved. C1 Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. Univ Colorado, Hlth Sci Ctr, Div Infect Dis, Denver, CO 80262 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Monash Univ, Inst Reprod & Dev, Clayton, Vic 3168, Australia. RP Rubinstein, M (reprint author), Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. OI Hertzog, Paul/0000-0002-1373-8472 NR 0 TC 17 Z9 18 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD JUN PY 1998 VL 9 IS 2 BP 175 EP 181 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 157PD UT WOS:000078070100008 PM 9754711 ER PT J AU Lu, JN Andrews, J Pauli, D Oliver, B AF Lu, JN Andrews, J Pauli, D Oliver, B TI Drosophila OVO zinc-finger protein regulates ovo and ovarian tumor target promoters SO DEVELOPMENT GENES AND EVOLUTION LA English DT Article DE C2H2 zinc-finger; oogenesis; germline sex determination; transcription factor ID LINE SEX DETERMINATION; RNA-POLYMERASE-II; OTU GENE; MELANOGASTER; LOCUS; DNA; GERMLINE; TRANSCRIPTION; SEQUENCE; CELLS AB The ovo(+) and ovarian tumor(+) genes function in the germline sex determination pathway in Drosophila, but the hierarchical relationship between them is unknown. We found that increased ovo(+) copy number resulted in increased ovarian tumor expression in the female germline and increased ovo expression in the male germline. The ovo locus encodes C2H2 zinc-finger proteins. Bacterially expressed OVO zinc-finger domain bound to multiple sites at or near the ovo and ovarian tumor promoters strongly suggesting that OVO is directly autoregulatory and that ovarian tumor is a direct downstream target of ovo in the germline sex determination hierarchy. Both positive and negative regulation by OVO proteins appears likely, depending on promoter context and on the sex of the fly. Our observation that two strong OVO-binding sites are at the initiator of the TATA-less ovo-B and ovarian tumor promoters raises the possibility that OVO proteins influence the nucleation of transcriptional pre-initiation complexes. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Geneva, Dept Zool & Anim Biol, CH-1204 Geneva, Switzerland. RP Lu, JN (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 39 TC 27 Z9 28 U1 0 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0949-944X J9 DEV GENES EVOL JI Dev. Genes Evol. PD JUN PY 1998 VL 208 IS 4 BP 213 EP 222 DI 10.1007/s004270050175 PG 10 WC Cell Biology; Evolutionary Biology; Developmental Biology SC Cell Biology; Evolutionary Biology; Developmental Biology GA ZZ438 UT WOS:000074729400004 PM 9634487 ER PT J AU Robinson, ML Ohtaka-Maruyama, C Chan, CC Jamieson, S Dickson, C Overbeek, PA Chepelinsky, AB AF Robinson, ML Ohtaka-Maruyama, C Chan, CC Jamieson, S Dickson, C Overbeek, PA Chepelinsky, AB TI Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/Int-2 in transgenic mice SO DEVELOPMENTAL BIOLOGY LA English DT Article ID FIBROBLAST GROWTH-FACTOR; PROTO-ONCOGENE INT-2; MAMMARY-TUMOR VIRUS; FACTOR RECEPTOR; FIBER DIFFERENTIATION; CELL-DIFFERENTIATION; EXTRACELLULAR-MATRIX; FETAL DEVELOPMENT; SUBCELLULAR FATE; ACIDIC FGF AB FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV). Int-2 was later designated FGF-3 based on sequence homology with other members of the fibroblast growth factor (FGF) family. FGF-1 is the prototypical member of the FGF family, and is the only family member which activates all known FGF receptor isoforms. Transgenic mice expressing in the lens a form of FGF-1 engineered to be secreted show premature differentiation of the entire lens epithelium. In contrast, transgenic mice engineered to secrete FGF-P in the lens do not undergo premature differentiation of the lens epithelium (C. M. Stolen et al., 1997, Development 124, 4009-4017). To further assess the roles of FGFs and FGF receptors in lens development, the alpha A-crystallin promoter was used to target expression of FGF-3 to the developing lens of transgenic mice. The expression of FGF-3 in the lens rapidly induced epithelial cells throughout the lens to elongate and to express fiber cell-specific proteins including MIP and beta-crystallins. This premature differentiation of the lens epithelium was followed by the degeneration of the entire lens. Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 nib) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo. Furthermore, transgenic lens cells expressing FGF-3 were able to induce the differentiation of neighboring nontransgenic lens epithelial cells in chimeric mice. Expression of FGF-3 in the lens also resulted in developmental alterations of the eyelids, cornea, and retina, and in the most severely affected transgenic lines, the postnatal appearance of intraocular glandular structures. (C) 1998 Academic Press. C1 Childrens Hosp, Res Fdn, Columbus, OH 43205 USA. Ohio State Univ, Dept Pediat, Columbus, OH 43205 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43205 USA. NEI, NIH, Bethesda, MD 20892 USA. Imperial Canc Res Fund, Viral Carcinogenesis Lab, London WC2A 3PX, England. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. RP Robinson, ML (reprint author), Childrens Hosp, Res Fdn, 700 Childrens Dr, Columbus, OH 43205 USA. RI Ohtaka-Maruyama, chiaki/G-6943-2013 FU NEI NIH HHS [EY-10803, EY-06511, EY-10448] NR 74 TC 68 Z9 69 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 BP 13 EP 31 DI 10.1016/S0012-1606(98)80026-2 PG 19 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900002 PM 9640329 ER PT J AU Rebagliati, MR Toyama, R Fricke, C Haffter, P Dawid, IB AF Rebagliati, MR Toyama, R Fricke, C Haffter, P Dawid, IB TI Cyclops encodes the nodal-related peptide growth factor, Ndr2. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Entwicklungsbiol, D-72076 Tubingen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 38 BP 166 EP 166 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900047 ER PT J AU Mohamed, OA Bustin, M Clarke, HJ AF Mohamed, OA Bustin, M Clarke, HJ TI High-mobility group proteins 14 and 17 are required for normal temporal progression of early mouse embryogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 McGill Univ, Dept Biol, Montreal, PQ, Canada. NCI, Mol Carcinogenesis Lab, NIH, Bethesda, MD USA. RI Bustin, Michael/G-6155-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 64 BP 170 EP 170 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900073 ER PT J AU Cai, T Yu, P Monga, SPS Mishra, B Mishra, L AF Cai, T Yu, P Monga, SPS Mishra, B Mishra, L TI Molecular cloning and chromosomal mapping of elf3, a 200-kD beta-spectrin in mouse liver development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 VAMC, Lab Dev Mol Biol, Washington, DC USA. Temple Univ, Feis Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA. NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 67 BP 171 EP 171 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900076 ER PT J AU Karavanov, A Kodjabachian, L Aoki, T Hikasa, H Taira, M Dawid, I AF Karavanov, A Kodjabachian, L Aoki, T Hikasa, H Taira, M Dawid, I TI Functional knockout of the Spemann organizer specific gene XLIM-1 using a dominant interfering construct SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHD, LMG, NIH, Bethesda, MD USA. RI Aoki, Tazu/F-5051-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 86 BP 174 EP 174 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900095 ER PT J AU Maye, P Becker, S Lock, L Zanders, T Shah, S Grabel, L AF Maye, P Becker, S Lock, L Zanders, T Shah, S Grabel, L TI Analysis of Indian Hedgehog expression during early mouse embryonic development SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Wesleyan Univ, Middletown, CT 06459 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 145 BP 184 EP 184 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900154 ER PT J AU Nguyen, MTT Arnheiter, H AF Nguyen, MTT Arnheiter, H TI Expression of the microphthalmia-associated transcription factor, Mitf, in the developing mouse eye. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 178 BP 189 EP 189 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900187 ER PT J AU Matsuo-Takasaki, M Sato, SM AF Matsuo-Takasaki, M Sato, SM TI The role of XlPOU2 in early neurogenesis. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NIDDK, NIH, Genet & Biochem Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 198 BP 192 EP 192 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900206 ER PT J AU Zhao, Y Sheng, HZ Grinberg, A Lee, EJ Huang, SP Westphal, H AF Zhao, Y Sheng, HZ Grinberg, A Lee, EJ Huang, SP Westphal, H TI Impaired hippocampal development in Lhx5 deficient mice. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 NICHD, NIH, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 211 BP 195 EP 195 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900219 ER PT J AU Campione, M Steinbeisser, H Lowe, L Deissler, K Schweickert, A Langghut, C Kuehn, M Blum, M AF Campione, M Steinbeisser, H Lowe, L Deissler, K Schweickert, A Langghut, C Kuehn, M Blum, M TI The role of the homeobox gene Ptx-2 in specification of left-right body axis and heart morphogenesis in mouse and frog SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Forschungszentrum Karlsruhe, Inst Genet, D-76021 Karlsruhe, Germany. MPI Tubingen, D-72011 Tubingen, Germany. NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RI Campione, Marina/G-9001-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 261 BP 203 EP 203 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900268 ER PT J AU Ding, JX Yan, YT Yang, L Wang, HY Chen, A Wynshaw-Boris, A Shen, MM AF Ding, JX Yan, YT Yang, L Wang, HY Chen, A Wynshaw-Boris, A Shen, MM TI Essential role for Cripto, a member of the EGF-CFC gene family, in murine gastrulation and axial patterning. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol, Piscataway, NJ 08854 USA. Natl Human Genome Res Inst, Lab Genet Dis Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 263 BP 203 EP 203 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900270 ER PT J AU Monga, SPS Cai, T Rashid, A Mishra, B Mishra, L AF Monga, SPS Cai, T Rashid, A Mishra, B Mishra, L TI Molecular analysis of in vitro embryonic liver explant cultures SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 VAMC, GI Mol Bio, Washington, DC USA. Temple Univ, Fels Canc Res & Mol Bio, Philadelphia, PA 19122 USA. JHU, GI Path, Baltimore, MD USA. NHGRI, CGTB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 1998 VL 198 IS 1 MA 300 BP 209 EP 209 PG 1 WC Developmental Biology SC Developmental Biology GA ZV215 UT WOS:000074281900303 ER PT J AU Baier, LJ Wiedrich, C Hanson, RL Bogardus, C AF Baier, LJ Wiedrich, C Hanson, RL Bogardus, C TI Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85 alpha) - Preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women SO DIABETES LA English DT Article C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Baier, LJ (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin 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 8 TC 29 Z9 32 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 1998 VL 47 IS 6 BP 973 EP 975 DI 10.2337/diabetes.47.6.973 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZP494 UT WOS:000073759100019 PM 9604878 ER PT J AU Valle, T Ehnholm, C Tuomilehto, J Blaschak, J Bergman, RN Langefeld, CD Ghosh, S Watanabe, RM Hauser, ER Magnuson, V Eriksson, J Ally, DS Nylund, SJ Hagopian, WA Kohtamaki, K Ross, E Toivanen, L Buchanan, TA Vidgren, G Collins, F Tuomilehto-Wolf, E Boehnke, M AF Valle, T Ehnholm, C Tuomilehto, J Blaschak, J Bergman, RN Langefeld, CD Ghosh, S Watanabe, RM Hauser, ER Magnuson, V Eriksson, J Ally, DS Nylund, SJ Hagopian, WA Kohtamaki, K Ross, E Toivanen, L Buchanan, TA Vidgren, G Collins, F Tuomilehto-Wolf, E Boehnke, M TI Mapping genes for NIDDM - Design of the Finland United States Investigation of NIDDM Genetics (FUSION) study SO DIABETES CARE LA English DT Article ID DEPENDENT DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; GENOME-WIDE SEARCH; INSULIN-RESISTANCE; PIMA-INDIANS; DECARBOXYLASE-ANTIBODIES; SUSCEPTIBILITY GENES; QUANTITATIVE TRAITS; FINNISH POPULATION; HEXOKINASE-II AB OBJECTIVE - To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM. RESEARCH DESIGN AND METHODS - We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM, Detailed description of the study materials and designs of such studies are important, particularly when comparing the findings in these studies and when combining different data sets. RESULTS - Using a careful selection strategy we have ascertained 495 families with confirmed NIDDM in at least two siblings and no history of IDDM among the first-degree relatives. These families were chosen from more than 22,000 NIDDM patients. representative of patients with NIDDM in the Finnish population. In a subset of families, a spouse and offspring were sampled, and they participated in a frequently sampled intravenous glucose tolerance test (FSIGT) analyzed with the Minimal Model. An FSIGT was completed successfully for at least two nondiabetic offspring in 156 families with a confirmed nondiabetic spouse and no history of IDDM in first-degree relatives. CONCLUSIONS - Our work demonstrates the feasibility of collecting a large number of affected sib-pair families with NIDDM to protide data that will enable a whole genome search approach, including linkage analysis. C1 Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Genet Epidemiol & Diabet Unit, SF-00300 Helsinki, Finland. Natl Publ Hlth Inst, Dept Biochem, SF-00300 Helsinki, Finland. Univ So Calif, Dept Physiol & Biophys, Sch Med, Los Angeles, CA 90089 USA. Univ So Calif, Dept Med, Div Endocrinol, Los Angeles, CA 90089 USA. NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Washington, Dept Med, Seattle, WA USA. RP Valle, T (reprint author), Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Genet Epidemiol & Diabet Unit, Mannerheimintie 166, SF-00300 Helsinki, Finland. EM timo.valle@ktl.fi FU NHGRI NIH HHS [R01 HG00376, T32 HG00040]; NIDDK NIH HHS [F32 DK09525] NR 81 TC 76 Z9 77 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 JUN PY 1998 VL 21 IS 6 BP 949 EP 958 DI 10.2337/diacare.21.6.949 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ZN874 UT WOS:000073692200014 PM 9614613 ER PT J AU Filie, AC Abati, A Fetsch, P Azumi, N AF Filie, AC Abati, A Fetsch, P Azumi, N TI Hyaluronate binding probe and CD44 in the differential diagnosis of malignant effusions: Disappointing results in cytology material SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Letter ID MESOTHELIOMA C1 NIH, Cytopathol Sect, Bethesda, MD 20892 USA. RP Filie, AC (reprint author), NIH, Cytopathol Sect, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 18 Z9 18 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD JUN PY 1998 VL 18 IS 6 BP 473 EP 474 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA ZR747 UT WOS:000074009700019 PM 9626526 ER PT J AU Leshner, AI AF Leshner, AI TI Drug addiction research: moving toward the 21st century SO DRUG AND ALCOHOL DEPENDENCE LA English DT Editorial Material C1 NIDA, Rockville, MD 20857 USA. RP Leshner, AI (reprint author), NIDA, 5600 Fishers Lane,Parklawn Bldg, Rockville, MD 20857 USA. NR 3 TC 12 Z9 14 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN-JUL PY 1998 VL 51 IS 1-2 BP 5 EP 7 DI 10.1016/S0376-8716(98)00061-1 PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 103DK UT WOS:000075142600003 PM 9716925 ER PT J AU Gordis, E AF Gordis, E TI The neurobiology of alcohol abuse and alcoholism: Building knowledge, creating hope SO DRUG AND ALCOHOL DEPENDENCE LA English DT Editorial Material C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Gordis, E (reprint author), NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. 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PD JUN-JUL PY 1998 VL 51 IS 1-2 BP 13 EP 22 DI 10.1016/S0376-8716(98)00063-5 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 103DK UT WOS:000075142600005 PM 9716927 ER PT J AU Daly, JW Fredholm, BB AF Daly, JW Fredholm, BB TI Caffeine - an atypical drug of dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article ID ADENOSINE A(2A) RECEPTORS; FOS MESSENGER-RNA; DOPAMINE D-1; LOCOMOTOR-ACTIVITY; DISCRIMINATIVE STIMULUS; ACETYLCHOLINE-RELEASE; BASAL GANGLIA; RAT STRIATUM; NGFI-A; A(1) C1 NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Karolinska Inst, Dept Physiol & Pharmacol, Sect Mol Neuropharmacol, Stockholm, Sweden. RP Daly, JW (reprint author), NIH, Bioorgan Chem Lab, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 144 Z9 145 U1 3 U2 20 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. 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